By As Prof OPokryshko

Chair of Medical biology Microbiology Virology and Immunology

Antibiotics classificaions and mechanism of action

The main principles of rational antibiotic therapy

of diseases

Lectures schedule

1 History of antibiotics discovery

2 Classification of antibiotics

3 Examination of bacterial susceptibility to antibiotics

4 The main principles of rational antibiotic therapy of diseases

5 Complication of antibioticotherapy

- Diarrheal diseases - 4 billions cases

- Malaria - 500 mln

- acute infection of respiratory tract - 395 mln

- sexual transmitted diseases - 330 mln

- measles - 42 mln

- whooping cough - 40 mln

- tuberculosis ndash 19 bln of infected persons

9 mln of new cases of diseases

- AIDS ndash 50 mln cases 6 mln people died

- SARS hemorrhagic fever

Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)

Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans

He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept

A Fleming

The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming

1940s Penicillin was tested clinically and mass produced

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Lectures schedule

1 History of antibiotics discovery

2 Classification of antibiotics

3 Examination of bacterial susceptibility to antibiotics

4 The main principles of rational antibiotic therapy of diseases

5 Complication of antibioticotherapy

- Diarrheal diseases - 4 billions cases

- Malaria - 500 mln

- acute infection of respiratory tract - 395 mln

- sexual transmitted diseases - 330 mln

- measles - 42 mln

- whooping cough - 40 mln

- tuberculosis ndash 19 bln of infected persons

9 mln of new cases of diseases

- AIDS ndash 50 mln cases 6 mln people died

- SARS hemorrhagic fever

Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)

Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans

He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept

A Fleming

The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming

1940s Penicillin was tested clinically and mass produced

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 65

- Diarrheal diseases - 4 billions cases

- Malaria - 500 mln

- acute infection of respiratory tract - 395 mln

- sexual transmitted diseases - 330 mln

- measles - 42 mln

- whooping cough - 40 mln

- tuberculosis ndash 19 bln of infected persons

9 mln of new cases of diseases

- AIDS ndash 50 mln cases 6 mln people died

- SARS hemorrhagic fever

Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)

Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans

He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept

A Fleming

The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming

1940s Penicillin was tested clinically and mass produced

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)

Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans

He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept

A Fleming

The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming

1940s Penicillin was tested clinically and mass produced

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
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• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
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• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

A Fleming

The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming

1940s Penicillin was tested clinically and mass produced

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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• Slide 65

He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus

Figure 15

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
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• Slide 65

In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples

S Waksman

In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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In 1939 Florey and colleagues at Oxford University again isolated penicillin

G Florey E Chainy

AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them

Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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• Slide 65

The term ldquoantibioticsrdquo proposed in 1942 S Waksman

It means anti ndash against bios - life

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
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• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Microbial antagonism is the basis of modern use of antibiotics

L Pasteur

Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Peculiarities of antibiotics

- high level of biological activity

- high election specificity

Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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Activity of antibiotics is evaluated in International Unit

Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Classification of antibiotics according to their origin

11 Antibiotics from fungiAntibiotics from fungi

Penicillins (Penicillium notatum Pchryzogenum)

Cephalosporins (Cephalosporium salmosynnematum)

Griseofulvinum (P griseofulvum P patulum P nigricans)

Fusidin (Fusidium coccineum)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)

Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)

Chloramphenicol (S venezuelae)

Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)

2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces

Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)

Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)

Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)

Carbapenem (S olivaceus)

Thienamycin (S cattleya)

33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
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• Slide 3
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33 Antibiotics from bacteriaAntibiotics from bacteria

Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)

Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)

other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 64
• Slide 65

4 Antibiotics from plants4 Antibiotics from plants

Chorellin (Chlorella vulgaris)

Arenarin (Helichrysum arenarium)

Gordecin (barley)

Chinin (cinchona tree)

Alicin (garlic Allium sativum)

Raphanin (radish Raphanus sativum)

Phaseolin (haricot bean Phaseolus vulgaris)

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
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• Slide 65

55 Antibiotics from animal tissuesAntibiotics from animal tissues

interferons (spleen macrophages tissue cells)

lysozyme (most body fluid salive eggs)

erythrin (red cells liver)

ecmolin (fish)

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
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• Slide 22
• Slide 23
• Slide 24
• Slide 25
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• Slide 27
• Slide 28
• Slide 29
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• Slide 31
• Slide 32
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• Slide 38
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• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
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• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action

1 Antibacterial

А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes

Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones

2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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2 Antifungal (amphotericin)

3 Antiviral (amantadin vidarabin)

4 Antiprotozoal (emethin chinin)

5 Antineoplastic (bleomycin mitomycin C actinomycines)

Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action

Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
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Spectrum of ActivityRelates to the number of microbes that are

susceptible to the action of the drugndashNarrow (limited number) Broad (wide)

bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-

positive and gram-negative microbes (Broad)

Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms

BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate

BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate

Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action

Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Mechanism of Action1 Inhibition of Cell Wall Synthesis

2 Disruption of Cell Membrane

3 Inhibition of Protein Synthesis

4 Interference with Metabolic

Processes

NBBactericidalBacteriostatic

Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
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Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis

Most bacteria possess a cell wall to protect from osmotic pressures

Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being

susceptible to external influencesndash Cell ruptures Microbe death

Eg Penicillinsm cephalosporins vancomycin and bacitracin

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 61
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• Slide 63
• Slide 64
• Slide 65

Disruption of the microbial cell Disruption of the microbial cell membranemembrane

Essentially affect cell membrane transportation in and out

Increases permeability of membranendash External influences have greater effectndash Microbe death

Eg Polymyxin Colistin

Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Inhibition of Protein SynthesisInhibition of Protein Synthesis

Proteins vital for growth and repairAct either at

ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic

acidsbull DNA replication RNA synthesis = TRANSCRIPTION

Eg Tetracyclines aminoglycosides and macrolides (erythromycin)

Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity

Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Interference with metabolic Interference with metabolic processesprocesses

bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it

microbes can not produce the proteins for growth

ndash Exploits microbes need to create their own folic acid whilst we get it in our diets

bull Eg Sulphonamides Trimethoprim

Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics

Serial dilutions

- in a liquid medium

- in a solid medium

Disc diffusion method

Rapid methods

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Demands to nutrient media

1 to be standard and provide optimal conditions for microbial growth

2do not have inhibitors of bacterial growth and a lot of stimulators

3do not have substances which inhibit antibiotic activity

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
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• Slide 64
• Slide 65

Disc diffusion methodDisc diffusion method

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Serial dilution in liquid mediumSerial dilution in liquid medium

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 51
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• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Serial dilution in solid mediumSerial dilution in solid medium

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
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• Slide 33
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• Slide 35
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• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Minimal Inhibitory Concentration (MIC)

10487091048709Lowest concentration of antibiotic that prevents visible growth

bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic

bull 1048709Accurate but time-consuming

bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method

Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Minimal Bactericidal Concentration (MBC)

10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold

bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media

bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies

ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
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• Slide 59
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• Slide 61
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• Slide 63
• Slide 64
• Slide 65

Rapid methodsRapid methods

examination of changes of microbial enzymes activity under the influence of antibiotics

examination of color of redox-indicators

cytological evaluation of morphological changes

automatic

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
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• Slide 63
• Slide 64
• Slide 65

Automatic metod of examination of bacterial susceptibility

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

1 Selective toxicity - destroys or inhibits microbe without affecting host cells

2 Broad spectrum - effective against a wide variety of organisms

3 Non-mutagenic - does not induce development of resistant strains

4 Soluble in body fluids - distributed through body (in bloodstream)

Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Criteria that determines the effectiveness of

antimicrobial agents used in the treatment

of infectious diseases

5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels

6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause

adverse reactions in host8 Should not disturb hostrsquos normal flora

(organisms normally living in body) causing secondary (super) infections produced by opportunists

General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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General principles

1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics

All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse

2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential

3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days

4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult

5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
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5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity

Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

• Slide 1
• Slide 2
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Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes

1 Wrong diagnosis (a viral infection does not respond to antibiotics)

2 Wrong choice of antibiotic

3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)

4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)

FailureFailure of antibiotic therapy

5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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5 Superinfection by resistant bacteria

6 Accumulation of pus necessitating surgical drainage (buttock abscess)

7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication

8 Drug fever

Failure of antibiotic therapyFailure of antibiotic therapy

І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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І Allergic reactions

ІІ Toxic effects on normal tissues

ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)

Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

І Allergic reactions

- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)

- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)

ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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ІІ Toxic reactions

- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)

- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)

Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy

ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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ІІІ ІІІ DysbacteriosisDysbacteriosis

- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)

- non-dangerous for life (local candidiases)

Secondary action of antibioticsSecondary action of antibiotics

Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Natural resistance

Acquired resistanse

primary

secondary

Types of resistanceTypes of resistance

Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Mechanisms of ResistanceMechanisms of Resistance

Development of resistant strains ndash spontaneous mutations DNA transfer

a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so

bypass metabolic step inhibited by AMA (L-forms - no cell wall)

c Over produce target molecules increase in quantity overcomes action of AMA

d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction

R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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R-Plasmids

Resistance transfer factors or RTFs

Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Transposons

Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages

Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance

Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community

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