Rational Use of Antibiotics

Dr Ruzilawati Abu Bakar

Jabatan Farmakologi ext 6126

4th Year Medical Posting

2009/2010

Outline of the lecture

1)Indications for antibacterial therapy – definitive, empiric & prophylaxis

2) Selection of antimicrobial agents

3) Methods of administration of antimicrobials

4) Antibiotics Resistance

5) Classification of antibacterial agents

Indications for antibacterial therapy:

1. Definitive therapy

•This is for proven bacterial infections

•Attempts should be made to confirm the bacterial infection by means of staining of secretions/fluids/exudates, culture & sensitivity, serological tests & other tests

•Based on the reports, a narrow spectrum, least toxic, easy to administer & cheap drug should be prescribed.

2. Empirical therapy• Empirical antibacterial therapy should be restricted to critical cases, when time is inadequate for identification & isolation of the bacteria & reasonably strong doubt of bacterial infection exists:

- septicemic shock/sepsis syndrome

- immunocompromised patients with severe systemic infection

- hectic temperature

- neutropenic patient (reduction in neutrophils)

In such situations, drugs that cover the most probable infective agent/s should be used.

Empiric antibiotic is antibiotic therapy that is begun before a specific pathogen is identified

3. Prophylactic therapy

• Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections.

• In all these situations, only narrow spectrum & specific drugs are used

• The duration of prophylaxis is dictated by the duration of the risk of infection.

• eg.

1. Prevention for persons from non-malarious areas who visit areas endemic for malaria.

2. Treatment prior to certain surgical procedures to prevent infections

Bacteria vs Host

Bacteria Host

Pathogen Vs non pathogen

Virulence

Host defence

antibiotic

Disease

Selection of antimicrobial

agents

Factors should be considered before prescribing antibacterial

agent1.Site of infection

2.Type of infection

3.Severity of infection

4.Isolate & its sensitivity

5.Source of infection

6.Patient factors

7.Drug-related factors

1. Site of infectionInfection above the diaphragm:

•URTI eg pharyngitis, tonsilitis, sinusitis, otitis, epiglottitis etc.

- commonly caused by organism like Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci (rarely Mycoplasma, H. influenzae)

- Can be treated with drugs like penicillins

macrolides

cephalosporins

1. Site of infection…con’tLower respiratory tract infections:

Eg. Bronchitis, pneumonitis, pneumonia, lung abscess etc

-generally caused by the organisms Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci, Staph aureus (rarely Mycoplasma, H. influenzae, Moraxella, Klebsiella) etc.

- can be treated penicillins, cephalosporins, macrolides & tetracylines

1. Site of infection …. con’t

Infection below the diaphragm:

•Eg UTI, intra-abdominal sepsis, pelvic infections etc --- these are caused by the organisms like E. coli, Klebsiella, Proteus, Pseudomonas, Bacteroides etc.

• Quinolones, aminoglycosides, 3rd generation cephalosporins & metronidazole alone or in combination are useful in these infections.

Rule of the thumb

Infections above the diaphragm Cocci & Gram +ve organisms

Infections below the diaphragm Bacilli & Gram -ve organisms

1. Site of infection …. con’t

• There are certain sites where the infection tends to be difficult for treatment :

- meningitis (impenetrable BBB),

- chronic prostatitis (non-fenestrated capillaris),

- intra-ocular infections (non-fenestrated capillaries),

- abscesses (thick wall, acidic pH, hydrolizing enzymes etc.),

- cardiac & intravascular vegetations (poor reach & penetration),

- osteomyelitis (avascular sequestrum) etcIn such cases:- Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugsmay have to be used

2. Type of infection

Infections can be localised/extensive; mild/severe; superficial/deep-seated; acute/sub acute/chronic & extracellular/intracellular.

For extensive, severe, deep-seated, chronic & intracellular infections –

• Higher & more frequent dose

• Longer duration of therapy

• Combinations

• Lipophilic drugs

may have to be used

3. Severity of infections• Bacteremia / sepsis syndrome / septic shock;

• abscess in lung / brain/ liver/ pelvis/ intra-abdominal;

• meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis;

• Severe soft tissue infections / gangrene & hospital acquired infections

For severe infections only IV route - to ensure adequate blood levels. only bacterial drugs - to ensure faster clearance of the infection. dose should be higher & more frequent.

- If the site is unknown, attempt should be made to cover all possible organisms, including drug resistant Staphylococcus, Pseudomonas, & anaerobes.

- A combinations of Penicillins / 3rd generation cephalosporins, aminoglycosides & metronidazole may be used.

4. Isolate & sensitivity• Ideal management of any significant bacterial infection requires culture & sensitivity (C&S) study of the specimen.

• If the situation permits, antibacterials can be started only after the sensitivity report is available.

• Narrow spectrum, least toxic, easy to administer & cheapest of the effective drugs should be chosen.If the patient is responding to the drug that has

already been started, it should not be changed even if the in vitro report says otherwise

5. Source of infection

Community-acquired infections are less likely to be resistant

whereas

Hospital-acquired infections are likely to be resistant & more difficult to treat (eg. Pseudomonas, MRSA etc)

6. Patient factors

• Factors should be considered in choosing the antibacterial agent:

- Age of the patient

- immune status

- pregnancy & lactation

- associated conditions like renal failure, hepatic failure, epilepsy etc.

• In infants, chloramphenicol (can cause grey baby) & sulpha drugs (can cause kernicterus) are contraindicated

• In the elderly, achlorhydria may affect absorption of anticbacterial agents; drug elimination is slower, requiring dose adjustments & ototoxicity of aminoglycosides may be increased.

Patient factors…….con’t

Children

Elderly

- Tetracycline are contraindicated < 8 years because they discolour the teeth- < 18 years ALL fluoroquinolones are contraindicated because they cause arthropathy by damaging the growing cartilage.

• In patients with likelihood of compromised immune status, like extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppresants, patients with cancers/blood dyscrasias, ONLY bactericidal drugs should be used.

Patient factors…….con’t

Patients with compromised immune status

Patient factors…….in pregnancyContraindicated in all trimesters Contraindicated in the last

trimesters

Safe in pregnancy Contraindicated in lactating mothers

• tetracylines

• quinolones

• streptomycin

• clarithromycin

• sulpha drug

• nitrofurantoin

• chloramphenico

l

•penicillins

•cephalosporins

•erythromycin

•isoniazid

•ethambutol

• sulpha drug

• tetracylines

•nitrofurantoin

• quinolones

•metronidazole

Drugs with limited data on safety like aminoglycoside, azithromycin, clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin & pyrazinamide should be used with caution when benefits overweigh the risks

Patient factors…….in patients with renal failure

Absolutely contraindicated Relatively contraindicated

Relatively safe

It is better to avoid combinations of cephalosporins & aminoglycosides in these patients because both classes can cause nephrotoxicity

• tetracycline

•Penicillins

•Macrolides

•Vancomycin

•Metronidazole

•Isoniazid

•Ethambutol

•Rifampicin

•Aminoglycoside

•Cephalosporins

•Fluoroquinolones

•Sulpha drug

Patient factors…….in patients with hepatic

failureNo drugs are absolutely contraindicated.

Relatively contraindicated

Safe

•Chloramphenicol

•Erythromycin estolate

•Fluoroquinolones

•Pyrazinamide

•Rifampicin

•Isoniazid

•Metronidazole

•Penicillins

•Cephalosporins

•Ethambutol

•Aminoglycosides

7. Drug factors

1. Hypersensitivity: If the patient has prior history of hypersensitivity the antibacterial agent should be avoided. It is therefore important to elicit this history in all patients (common with penicillin)

2. Adverse reactions:Certain ADRs warrant discontinuation of therapy & the doctor should adequately educate the patients on these adverse effects.

7. Drug factors

3. Cost:

It should always be remembered that just because as particular drug is expensive, it need not be superior than the cheaper ones.

Eg. Cheaper drug like doxycycline or co-trimoxazole are as effective as the costlier clarithromycin or cephalosporins in the management of lower RTI.

7. Drug factors…….con’t

4. Interactions:Interactions with food & other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy & minimize toxicity.

a) Interactions include enhanced nephrotoxicity or ototoxicity when aminoglycosides are given with loop diuretics, vancomycin or cisplatin.

b) Rifampicin, a strong inducer of hepatic drug-metabolizing enzymes, decreases the effects of digoxin, ketoconazole, oral contraceptives, propranolol, quinidine & warfarin.

c) Erythromycin inhibits the hepatic metabolism of a number of drugs, including phenytoin, terfenadine, theophylline & warfarin.

Methods of administration of antimicrobialsRoute of administration

The route of administration depends on the site, type & severity of the infection & the availability of a suitable drug

- Oral route is the most preferred, easy & cheap, but may not be reliable in all circumstances, esp. in patients with severe infections, non-compliant patients, in the presence of vomiting etc.

Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral administration.

- IM route should generally be restricted for the administration of procaine & benzathine penicillin.

The absorption is not very reliable & it is painful & dislike by the patients.

Route of administration…….con’t

- IV route is the best for the management of severe & deep-seated infections since it ensures adequate serum drug levels.

Procaine penicillin & benzathine penicillin should never be given IV.

•However, some drugs are not available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines)

• Chloramphenicol, the fluoroquinolones & trimethoprim-sulphamethoxazole (TMP-SMZ) are also available orally.

• Antibacterials are also used topically

Dosage

- Dosage depends on patient’s age, weight, associated conditions like pregnancy, renal & hepatic failure & site, type & severity of infection.

- Generally the dose should be higher in cases of severe, deep-seated infections & lower in cases of renal-failure.

- Unnecessary overdosage only adds to the cost & adverse effects.

Frequency of administration

• The drug should be administered 4-5x the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day.

• Frequency can be:-

- increased in cases of severe, deep seated & sequestrated infections

- reduced in cases of renal & hepatic failure.

Duration

• Duration of therapy depends on the site

1)Tonsilitis – 10 days

2) Bronchitis – 5-7 days

3) UTI – single shot to 21 days

4) Lung abscess- 2-4 weeks

5) Tuberculosis – 6-24 months

• Longer courses of therapy are usually required for infections due to fungi or mycobacteria

• Endocarditis & osteomyelitis require longer duration of treatment

Combinations1) For synergistic effect:

eg: combination of 2 bacteriostatic drugs such as

trimethoprim + sulfamethoxazole =

Co-Trimoxazole (bacterim®)

Therapeutic advantage of sulphonamide + trimethoprim

1) Synergistic effects

2) Bactericidal activity

3) Decrease resistance

4) Bigger spectrum of activity

5) Reduced toxicity

2) Treatment of infections with multiple organisms:

Mixed infections in lung abcess, peritonitis, soiled wounds etc naturally require multiple antibiotics for complete clearance of the infection – penicillins (for Gram +ve & certain anaerobes) & aminoglycosides (for Gram –ve); metronidazole for bacteroides.

penicillins + aminoglycosides + metronidazole

Combinations…….con’t

3) To prevent resistance: Use of combination is a well known method of preventing drug resistance. The classic example is the antiTB therapy, Eg isoniazid + ethambutol + rifampicin

4) To overcome resistance: Combination of specific drugs can be useful in overcoming that resistant infections, egPenicillins + -lactamase inhibitors (Co-amoxiclav/augmentin)

Combinations…….con’t

The following combinations are irrational, not useful or even harmful:

1) Bactericidal with bacteriostatic

eg. Penicillins (bactericidal) with tetracyclines ( bacteriostatic)

Bactericidal a/b (kill bacteria) – tend to be used in combination with one another

Bateriostatic a/b (prevent bacteria’s reproduction) – tend to be used on its own

2) Combinations of drugs with similar toxicity

eg. Chloramphenicol & sulpha drug

3) Combining drugs for non-existing “mixed infections”

eg. Tablets of ciprofloxacin + metronidazole/tinidazole

Clinical failure of antimicrobial

therapy

Failure of an antibiotic regimen (1)

1) Drug factors

• incorrect choice,

• poor tissue penetration

• inadequate dose

• pH – low pH reduces effectiveness of aminoglycosides, erythromycin, clindamycin

Inadequate clinical or microbiological response to antimicrobial therapy can result from multiple causes, including;

Failure of an antibiotic regimen (2)

2) Host factors

• poor host defense,

• age

• renal & liver function

• pre-existing dysfunction of other organs

3) Pathogen factors resistance superinfection

Antibiotic Resistance

“Penicillin Era” 1942-1950 available without a prescription1942-1950 available without a prescription Public demand followed by production of throat sprays, Public demand followed by production of throat sprays,

cough lozenges, mouthwashes, soaps and other products cough lozenges, mouthwashes, soaps and other products containing penicillincontaining penicillin

Alexander FlemingAlexander Fleming Warned that excessive use could result in antimicrobial Warned that excessive use could result in antimicrobial

resistanceresistance ““the microbes are educated to resist penicillin and a host the microbes are educated to resist penicillin and a host

of penicillin-fast organisms is bred out which can be of penicillin-fast organisms is bred out which can be passed to other individuals and from them to others until passed to other individuals and from them to others until they reach someone who gets a pneumonia or septicemia they reach someone who gets a pneumonia or septicemia which penicillin cannot savewhich penicillin cannot save.” The New York Times 1945.” The New York Times 1945

Fleming’s words proved to be correct....Fleming’s words proved to be correct....

The Problem of Antibiotic Resistance

Penicillin resistance first identified in Penicillin resistance first identified in 1940’s1940’s

Since then, antibiotic resistance has Since then, antibiotic resistance has developed faster than new drugsdeveloped faster than new drugs

Estimated cost of infections: $4-5 million Estimated cost of infections: $4-5 million per year per year

Antibiotic resistance previously Antibiotic resistance previously concentrated in hospitals, especially ICUsconcentrated in hospitals, especially ICUs

MRSA recently estimated to kill 18,000 MRSA recently estimated to kill 18,000 Americans yearlyAmericans yearly

History

APPEARANCE

DRUG INTRODUCTION OF RESISTANCE

Penicillin 1943 1946

Streptomycin 1945 1959

Tetracycline 1948 1953

Erythromycin 1952 1988

Vancomycin 1956 1988

Methicillin 1960 1961

Ampicillin 1961 1973

Cephalosporins 1964 late 1960’s

Antibiotic ResistanceRelative or complete lack of effect of

antimicrobial against a previously susceptible microbe

• Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth.

What causes the rapid occurrence of widespread resistance?

(1) Incomplete treatment:

- people fail to finish the full course of their medication

- 25% of previously-treated tuberculosis patients relapsed with drug resistant strains; most had failed to complete their initial course

What Factors Promote Antimicrobial Resistance?

(2) Mis-prescription:

- patients demand antibiotics for cold

- widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond

What Factors Promote Antimicrobial Resistance?

(3) Exposure to microbes carrying resistance genes

Inappropriate Antibiotic Use

Prescription not taken correctlyPrescription not taken correctly Antibiotics for viral infectionsAntibiotics for viral infections Antibiotics sold without medical supervisionAntibiotics sold without medical supervision Spread of resistant microbes in hospitals Spread of resistant microbes in hospitals

due to lack of hygienedue to lack of hygiene Lack of quality control in manufacture or outdated Lack of quality control in manufacture or outdated

antimicrobialantimicrobial Use of broad-spectrum agents when a narrow-Use of broad-spectrum agents when a narrow-

spectrum drug would suffice spectrum drug would suffice (eg, use of third-generation cephalosporins for community-(eg, use of third-generation cephalosporins for community-

acquired pneumonia)acquired pneumonia)

• The four main mechanisms by which The four main mechanisms by which microorganisms exhibit resistance to antibiotics microorganisms exhibit resistance to antibiotics are:are:

(1) Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in

some penicillin-resistant bacteria through the production of β-lactamases.

(2) Alteration of target site: e.g. alteration of PBP—the binding target site of

penicillins—in MRSA and other penicillin-resistant bacteria – resulting in decreased binding of the antibiotic to its target.

Mechanisms of Antibiotic Resistance (1)

(3) Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not

require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, they turn to utilizing preformed folic acid.

(4) Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the

drugs across the cell surface.

Mechanisms of Antibiotic Resistance (2)

Resistance: -lactamase Enzymes

•Bacteria produce -lactamase enzymes to hydrolyze the -lactam ring before drugs can reach inner membrane where PG synthesis occurs

•A cell may produce 100,000 - lactamase enzymes, each of which can destroy 1,000 penicillins per second 100 million molecules of drug destroyed per second

• β-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

-lactamases

Enzymes produced by bacteria which Enzymes produced by bacteria which destroy destroy -lactam antibiotics-lactam antibiotics

Many different typesMany different typesPenicillinases, cephalosporinases, Penicillinases, cephalosporinases,

carbapenemasescarbapenemases

Most are plasmid mediatedMost are plasmid mediated

Overcoming -lactam Resistance

slow tohydrolyze

As a response to bacterial resistance to -lactam drugs, there are drugs, such as Augmentin, which are designed to disable the -lactamase enzyme.

Augmentin is made of amoxicillin, a -lactam antibiotic, and clavulanic acid, a -lactamase inhibitor.

The clavulanic acid is designed to overwhelm all -lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the -lactamase enzymes.

Amoxicillin (-lactam antibiotic)

+ clavulanic acid (a -lactamase inhibitor)

= Co-amoxiclav (Augmentin®)

Ampicillin (-lactam antibiotic)

+ sulbactam (a -lactamase inhibitor)

= Unasyn®

Overcoming -lactam Resistance

Resistance in Simpler Terms…

BA

By-pass Altered target

Efflux

ImpermeabilityInactivation

(alteration of metabolic pathway)

(reduced drug accumulation)

(reduced drug accumulation)

Genetic alterations in drug resistance

Acquired antibiotic resistance requires Acquired antibiotic resistance requires the temporary or permanent gain or the temporary or permanent gain or alteration of bacterial genetic alteration of bacterial genetic information.information.

Resistance develops due to the ability of Resistance develops due to the ability of DNA:-DNA:-

1.1. To undergo spontaneous mutationTo undergo spontaneous mutation

2.2. To move from one organism to another To move from one organism to another (DNA/gene transfer)(DNA/gene transfer)

Spontaneous mutation of DNA

Stable and heritable genetic change Not induced by antimicrobial agents Resistance variant will proliferate Eg. The emergence of rifampicin-resistant M.tuberculosis when rifampicin is used as a single antibiotic

DNA/Gene transfer of drug resistant

transduction

conjugation

transformation

DNA Most resistance genes are plasmid mediated Plasmid may enter cells by processes such as conjugation,

transduction (phage mediated) & transformation

Measuring Antimicrobial Sensitivity

Disk DiffusionDisk Diffusion

E- test E- test (antimicrobial (antimicrobial gradient method)gradient method)

Serial dilutionSerial dilution

MIC increase in the case of resistance

(Minimal inhibitory concentration)

- important in diagnostic laboratories to confirm resistance of microorganisms to an antimicrobial agent

Measuring Antimicrobial Sensitivity

Consequences of Antimicrobial Resistance

Infections Infections resistant to resistant to available available antibioticsantibiotics

Increased cost Increased cost of treatmentof treatment

Speed development of new antibioticsTrack resistance data nationwideRestrict antimicrobial useNarrow spectrum Combination in long

term use (TB)Direct observed dosing (TB) Appropriate dose and durationUse more narrow spectrum antibioticsUse more narrow spectrum antibioticsUse antimicrobial cocktailsUse antimicrobial cocktails

Prevention of resistance

Classification of antibacterial

agents

Chemical structureChemical structure

Mechanism of actionMechanism of action

Spectrum of activitySpectrum of activityBroad, extended, narrowBroad, extended, narrow

Types of actionsTypes of actionsBactericidal, bacteriostaticBactericidal, bacteriostatic

Classification of antibacterial agents

Chemical structure

SulfonamidesSulfonamides sulfadiazinessulfadiazines

DiaminopyrimidinesDiaminopyrimidines TrimethoprimTrimethoprim

QuinolonesQuinolones Nalidixic acid, ciprofloxacinNalidixic acid, ciprofloxacin

b-lactam antibioticsb-lactam antibiotics Penicillins, cephalosporins, Penicillins, cephalosporins,

carbapenems, carbapenems, monobactams monobactams

TetracyclinesTetracyclines Tetracycline, doxycyclineTetracycline, doxycycline

Nitrobenzene derivativesNitrobenzene derivatives ChloramphenicolChloramphenicol

AminoglycosidesAminoglycosides Gentamicin Gentamicin

MacrolidesMacrolides ErythromycinErythromycin

Nitrofuran derivativesNitrofuran derivatives NitrofurantoinNitrofurantoin

GlycopeptideGlycopeptide Vancomycin Vancomycin

Nitroimidazoles Nitroimidazoles MetronidazolesMetronidazoles

TermsTerms DefinitionsDefinitionsNarrow-spectrum Narrow-spectrum antibioticsantibiotics

Antibiotics acting only on a single or a Antibiotics acting only on a single or a limited group of microorganismslimited group of microorganisms

Eg.- Eg.- isoniazid active only against active only against mycobacteriamycobacteria

Extended-spectrum Extended-spectrum antibioticsantibiotics

Antibiotics that are effective against Antibiotics that are effective against gram +ve organisms & also against a gram +ve organisms & also against a significant no. of gram -ve organisms.significant no. of gram -ve organisms.

Eg.- Eg.- ampicillin – acts against gram +ve – acts against gram +ve organisms (Listeria monocytogenes) & organisms (Listeria monocytogenes) & some gram -ve organisms (some gram -ve organisms (E. coliE. coli).).

Broad-spectrum Broad-spectrum antibioticsantibiotics

Antibiotics affect a wide variety of Antibiotics affect a wide variety of microbial speciesmicrobial species

Eg.- Eg.- tetracycline active against active against chlamydia, mycoplasma, actinomyces, chlamydia, mycoplasma, actinomyces, anaerobic organisms, gram –ve rods (anaerobic organisms, gram –ve rods (E. E. colicoli))

Spectrum of activity

Spectrum of activity

Summary of antibiotic’s spectrum

Narrow Spectrum

• Aztreonam

• Benzylpenicillin

• Cloxacillin

• Phenoxymethyl-penicillin

• Cephalexin

Broad Spectrum

•Amoxycillin

•Aminoglycoside

•Ciprofloxacin

•Chloramphenicol

•Imipenam

•Tetracycline

•Vancomycin

•Carbenicillin

•3rd generation cephalosporins

Bactericidal vs. bacteriostatic

Bactericidal Bactericidal agents agents

outright kill outright kill bacteria.bacteria.

Bacteriostatic agents inhibit growth but

don’t kill. They rely on body defenses to clear the infection.

Penicillins

Cephalosporins Macrolides

Tetracyclines

Mechanism of actions Mechanism of actionMechanism of action Antibacterial agent Antibacterial agent

Inhibition of cell wall synthesisInhibition of cell wall synthesis PenicillinPenicillin

CephalosporinsCephalosporins

MonobactamsMonobactams

VancomycinVancomycin

Inhibition of DNA gyrase,Inhibition of DNA gyrase,

RNA polymeraseRNA polymerase

QuinolonesQuinolones

RifampicinRifampicin

Inhibition of protein synthesisInhibition of protein synthesis AminoglycosidesAminoglycosides

TetracyclinesTetracyclines

ChloramphenicolChloramphenicol

MacrolidesMacrolides

Inhibition of folic acid metabolismInhibition of folic acid metabolism TrimethoprimTrimethoprim

SulfonamidesSulfonamides

1. Beta-lactam antibiotics1)Penicillin derivatives

2)Cephalosporins

3)Monobactams

4)Carbapenems

1) Penicillin 2) Cephalosporins

-lactam ring in red

A. Cell wall Inhibitors

2. Glycopeptides1)Vancomycin

3. Beta-lactamase inhibitors1)Clavulanic acid

2) Sulbactam

Cell wall inhibitors

1. 1. -lactam -lactam antibiotics antibiotics PenicillinsPenicillinsCephalosporinsCephalosporinsCarbapenemsCarbapenemsMonobactamsMonobactams

2. Glycopeptide2. GlycopeptideVancomycinVancomycinTeicoplaninTeicoplanin

Penicillin core structure. "R" is variable group.

Bacterial cell wall-lactam

antibiotics inhibit

transpeptidases enzymes that

form these crosslinkages

Glycopeptides bind D-alanine and prevent crosslinkage

A schematic of peptidoglycan’s structure. The NAM and NAG sugars are shown as green and blue spheres respectively. The tetrapeptides linked to NAM are cross-linked by a pentaglycine peptide, shown as red lines linking the D-glutamine (L) to the D-alanine (A).

-lactam antibiotics

inhibit transpeptidases enzymes that

form these crosslinkages

Glycopeptides bind D-alanine and prevent crosslinkage

Penicillins - structure

Penicillins - classifications Penicillin G like drugs

Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin) Penicillin V Penicillin V Procaine penicillin G Procaine penicillin G Benzathine penicillin G Benzathine penicillin G

Penicillinase- resistant penicillins (anti staph) Cloxacillin FlucloxacillinCloxacillin Flucloxacillin Methicillin Methicillin

Extended spectrum penicillin Ampicillin-like drugsAmpicillin-like drugs

Ampicillin Ampicillin Amoxicillin Amoxicillin

Broad-spectrum (antipseudomonal) penicillinsBroad-spectrum (antipseudomonal) penicillinsCarbenicillin Carbenicillin Piperacillin Piperacillin

Penicillins - pharmacokinetics

Given parenterally – well distributedCrosses inflamed biological barrierMainly excreted via kidney

Inhibited by probenecid

Penicillins - indication Penicillin GPenicillin G

Gram +ve infectionGram +ve infectionStreptococciStreptococciMeningococciMeningococciPneumococciPneumococciClostridium Clostridium

SyphilisSyphilis

Penicillinase-resistant penicillinsPenicillinase-resistant penicillins Staph infectionStaph infection

ImpetigoImpetigoAbcessAbcess

Extended spectrum penicillinExtended spectrum penicillin Gram +ve & Gram –veGram +ve & Gram –ve

Pneumonia, otitis mediaPneumonia, otitis media

Penicillins – adverse reaction

Relatively non-toxicRelatively non-toxicAllergic reactionAllergic reactionAnaphylaxis Anaphylaxis

- will occur in approximately - will occur in approximately

in 0.01% patientsin 0.01% patients

A rash on the back of a person with anaphylaxis

Cephalosporins

1. 1st generation cephalosporins

2. 2nd generation cephalosporins-best for Gram +ve & -ve-Extended Gram –ve coverage- eg. Cefuroxime, Cefaclor

- best for Gram +ve- eg. Cephalexin, Cephazoline

3. 3rd generation cephalosporins-best for Gram –ve

-antipseudomonas- eg. Ceftazidime, Ceftriaxone, Cefotaxime, Cefoperazone

4. 4th generation cephalosporins-Good coverage for both Gram +ve &

-ve

- antipseudomonal activity

-Eg. Cefipime

Cephalosporins – adverse reactions

Fairly safeFairly safeAllergic reactionAllergic reactionCross reaction with penicillinCross reaction with penicillinSuperinfection Superinfection (an infection following a previous infection, esp. when (an infection following a previous infection, esp. when

caused by microorganisms that have become resistant to caused by microorganisms that have become resistant to the antibiotics used earlier)the antibiotics used earlier)

Carbapenem Examples Examples

ImipenemImipenemMeropenemMeropenem

Wide spectrumWide spectrum Resistant against Resistant against -lactamase-lactamase Good activity against both Gram +ve & -veGood activity against both Gram +ve & -ve Active against pseudomonasActive against pseudomonas Use in resistant organismsUse in resistant organisms

Hospital acquired infectionHospital acquired infection

Monobactam

Example Aztreonam Resistant against -lactamase Antipseudomonal activity Inactive against Gram +ve GIT side effects – diarrhea, nausea &

vomiting IV – poorly absorbed when given via oral

route.

- lactamase inhibitors

Resemble Resemble -lactam molecules-lactam moleculesNo antibacterial activityNo antibacterial activity Inhibits bacterial Inhibits bacterial -lactamase -lactamase Use in combination with penicillins Use in combination with penicillins

Ampicillin–sulbactamAmpicillin–sulbactamPiperacillin-tazobactamPiperacillin-tazobactamAmoxycillin-clavulanate (clavulanic acid)Amoxycillin-clavulanate (clavulanic acid)

Glycopeptides

Vancomycin, teicoplaninVancomycin, teicoplaninActive against Gm +ve esp staphActive against Gm +ve esp staphNot active against Gm –veNot active against Gm –veUse in MRSA infectionUse in MRSA infectionNephrotoxicity, red man syndromeNephrotoxicity, red man syndrome

B. PROTEIN SYNTHESIS INHIBITOR1)

Aminoglycosides

2) Tetracyclines

3) Chloramphenicol

4) Macrolides

5) Fusidic Acid

Aminoglycosides

BactericidalBactericidalFrom various From various StreptomycesStreptomyces species species

StreptomycinStreptomycinNeomycinNeomycinAmikacinAmikacinGentamicinGentamicinTobramycinTobramycinNetilmicinNetilmicin

Aminoglycosides – physical properties

Water soluble (polar)Water soluble (polar)Poorly absorbed from gutPoorly absorbed from gut

Given parenterallyGiven parenterallyLess able to cross biological Less able to cross biological

barrierbarrierMore active at alkaline pHMore active at alkaline pH

Aminoglycosides - MOA Irreversible inhibitor of Irreversible inhibitor of

protein synthesisprotein synthesis

Passive diffusion via porin Passive diffusion via porin channels of outer channels of outer membranemembrane

Actively transport into Actively transport into cytoplasmcytoplasm

Bind to 30S subunit Bind to 30S subunit ribosomeribosome

Interfere with synthesis of Interfere with synthesis of proteinprotein

Use against Gram –ve infectionUsually combined with -lactam

antibioticBetter coverageSynergistic effect

No activity against anaerobe

Aminoglycoside: clinical use

Aminoglycosides - pharmacokinetic

Polar substancePolar substance Given i.m. or i.v.Given i.m. or i.v. Poorly penetrate CSF or eyePoorly penetrate CSF or eye

20% blood level in inflamed meninges20% blood level in inflamed meninges May be given intrathecalMay be given intrathecal

t1/2 = 2-3 hours = 2-3 hours Excreted unchanged by the kidneysExcreted unchanged by the kidneys

Adjust dosage with renal impairmentAdjust dosage with renal impairment Can be calculated based on creatinine Can be calculated based on creatinine

clearanceclearance

Aminoglycosides: PK-PD

Concentration dependent killingConcentration dependent killingRate of killing depend on concentrationRate of killing depend on concentration

Post antibiotic effectPost antibiotic effectAntibacterial activity persist after the Antibacterial activity persist after the

level reduce to below MIClevel reduce to below MICCan be given single daily doseCan be given single daily dose

Same efficacySame efficacyReduce risk of toxicityReduce risk of toxicityconvenienceconvenience

Aminoglycosides: toxicity OtotoxicOtotoxic

Auditory damageAuditory damage Vestibular damageVestibular damage

NephrotoxicNephrotoxic Potentiated by Potentiated by

other nephrotoxic other nephrotoxic drugsdrugs Need to measure Need to measure

level (TDM)level (TDM) Peak and troughPeak and trough

High doseHigh dose Block Block

neuromuscular neuromuscular junctionjunction

Streptomycin

Mainly use in the treatment of TBMainly use in the treatment of TBCombine with other anti TBCombine with other anti TB

Resistance easily developed without Resistance easily developed without combinationcombination

Side effectSide effectFever, rashesFever, rashes Impair vestibular functionImpair vestibular function

Contraindicated in pregnancyContraindicated in pregnancyDeafness in newbornDeafness in newborn

Gentamicin

Active both in Gram +ve & -veActive both in Gram +ve & -veStaphylococci Staphylococci

Resistance rapidly developedResistance rapidly developedPseudomonas, klebsiellaPseudomonas, klebsiella

No activity against streptococci and No activity against streptococci and enterococcienterococciBut can enhance the effect of But can enhance the effect of -lactam -lactam

or vancomycinor vancomycin

Gentamicin – clinical uses

Combine with cell wall inhibitor in Combine with cell wall inhibitor in severe infectionsevere infection

With penicillin G in With penicillin G in Strept viridansStrept viridans endocarditisendocarditis

Should not be used alone for Should not be used alone for pneumoniapneumoniaPoor penetrationPoor penetration

Requires TDM Requires TDM If use more than 5 daysIf use more than 5 daysRenal impairmentRenal impairment

Amikacin

Semi synthetic aminoglycosideSemi synthetic aminoglycosideMore resistant than genta towards More resistant than genta towards

inactivating enzymesinactivating enzymesActive against MDR Active against MDR M. tuberculosisM. tuberculosisUsually use as second line antibioticUsually use as second line antibiotic

Spectinomycin

Structure related to aminoglycoside but lack of amino sugars

Given i.m.Only use as an alternative to

penicillin in gonorrhoea therapyPenicillin sensitivityResistant gonococcal

Rarely nephrotoxic

Macrolides

azithromycin

erythromycin

clarithromycin

Macrolides

MOAMOABind reversibly to Bind reversibly to

the 50S subunit the 50S subunit Inhibit elongation Inhibit elongation

of the proteinof the protein

• Streptomycin obtained from Streptomycin obtained from Streptomyces Streptomyces erythreuserythreus

• Clarythromycin & azithromycin are Clarythromycin & azithromycin are semisyntheticsemisynthetic

Erythromycin- spectrum

Gram +veGram +ve Pneumococci, streptococci, staphPneumococci, streptococci, staph

Atypical organismAtypical organism Mycoplasma, clamydiaMycoplasma, clamydia

MycobacteriaMycobacteria M. kansasiiM. kansasii

Gram –veGram –ve Neiserria sp, Neiserria sp, B pertussis, B pertussis,

CorynebacteriaCorynebacteria Treponema pallidum Treponema pallidum (syphilis)

Erythromycin - pharmacokinetics

Destroyed by stomach acidDestroyed by stomach acidEnteric coated tabletEnteric coated tablet

Food interferes absorptionFood interferes absorption tt1/21/2 = 1.5 hours = 1.5 hoursWell distributed except CSFWell distributed except CSFExcreted in bilesExcreted in biles

Erythromycin- uses

Corynebacterial Corynebacterial infectioninfection DiphteriaDiphteria

Clamydial infectionClamydial infection Community Community

acquired acquired pneumoniapneumonia

PertussisPertussis SyphilisSyphilis

Penicillin allergyPenicillin allergy

Erythromycin- ADR

GITGITNausea, vomiting,diarrhoeaNausea, vomiting,diarrhoea

Liver toxicityLiver toxicityCholestatic jaundiceCholestatic jaundice

Drug interactionDrug interaction Inhibit cytochrome P450Inhibit cytochrome P450

Clarithromycin

Improved acid stabilityImproved acid stabilityBetter absorptionBetter absorptionLonger tLonger t1/21/2

BD dosingBD dosingMetabolised by liverMetabolised by liverMore active against More active against Mycobacterium Mycobacterium

avianavian complex complexMore expensiveMore expensive

Azithromycin

More active againstMore active againstM avianM avian complex complexToxoplasma gondiiToxoplasma gondii

Penetrates well into tissues Penetrates well into tissues Concentration > 10 – 100 times serumConcentration > 10 – 100 times serum

Tissue tTissue t1/21/2 = 2-4 days = 2-4 daysSingle daily doseSingle daily doseShort coursesShort courses

Tetracyclines

Tetracyclines - MOA Bind reversibly to

the 30S subunit Misalignment of

anticodons of the charged tRNAs with the codons of the mRNA.

Failure of protein synthesis

Tetracyclines

Introduced in 1948 (chlortetracycline)Introduced in 1948 (chlortetracycline) BacteriostaticBacteriostatic Coverage Coverage

Gram +ve & -veGram +ve & -ve Atypical bacteriaAtypical bacteria

RickettsiaeRickettsiaeChlamydia Chlamydia mycoplasmamycoplasma

ProtozoaProtozoaAmoebas Amoebas

Tetracyclines – P’kinetics

GI absorption GI absorption tetracycline (60-80%), tetracycline (60-80%), doxycycline (95%), doxycycline (95%), minocycline (100%)minocycline (100%)

Impaired by food (esp with MgImpaired by food (esp with Mg2+2+, , CaCa2+2+))

Ditributed widely except into CSFDitributed widely except into CSF Crosses placentaCrosses placenta Excreted both thru bile and urineExcreted both thru bile and urine TT1/21/2

Short acting (6 hrs)Short acting (6 hrs) Tetracycline Tetracycline

Intermediate (12 hrs)Intermediate (12 hrs) demeclocycline demeclocycline

Long (18 hrs) Long (18 hrs) doxycycline, minocyclinedoxycycline, minocycline

Tetracyclines - uses Drug of choice in atypical bacteria Drug of choice in atypical bacteria

infectioninfection RicketsiaeRicketsiae Used in combination to treat gastric or Used in combination to treat gastric or

duodenal ulcerduodenal ulcer To eradicate To eradicate H. PyloriH. Pylori

CholeraCholera AcneAcne Lyme diseaseLyme disease ((Borelia burgdorferiBorelia burgdorferi))

Tetracyclines - ADR GITGIT

Nausea, vomiting, Nausea, vomiting, diarrhoeadiarrhoea

Damage growing Damage growing bone & teethbone & teeth Due to CaDue to Ca2+ 2+ chelating chelating

propertyproperty Yellow discolourationYellow discolouration Contraindicated in Contraindicated in

children < 8 years children < 8 years oldold

Hepatic injuryHepatic injury Increased during Increased during

pregnancypregnancy NephrotoxicityNephrotoxicity PhotosensitizationPhotosensitization

Severe sunburn ; Severe sunburn ; doxy/demeclocyclindoxy/demeclocyclinee

Chloramphenicol

Binds to 50 S ribosomal Binds to 50 S ribosomal subunitsubunit

Mainly bacteriostaticMainly bacteriostaticBactericidal Bactericidal

H. influenzaH. influenzaN. meningitidisN. meningitidis

Broad spectrum (including Broad spectrum (including rickettsiae)rickettsiae)

Chloramphenicol – P’kinetics

IV (prodrug) or orallyIV (prodrug) or orallyComplete oral absorptionComplete oral absorptionExcretion depends on conversion in Excretion depends on conversion in

liver to glucuronide, then secretion in liver to glucuronide, then secretion in kidneykidney

Slow excretion in liver impairmentSlow excretion in liver impairment

Chloramphenicol - uses

Staph brain abscessTyphusAs an alternative in meningitisConjunctivitis – eye preparation

Chloramphenicol - ADR

Blood dyscrasiasIdiosyncratic aplastic anemia

Gray baby syndromeNeonates if doses not adjusted

D. FOLIC ACID METABOLISM INHIBITOR

1) Trimethoprim

2) Sulfonamides

Sulphonamide - MOA Bacteria cannot Bacteria cannot

transport folate into transport folate into cells cells

Tetrahydrofolate is a Tetrahydrofolate is a DNA precursorDNA precursor

p-aminobenzoic acid p-aminobenzoic acid (PABA) is a precursor (PABA) is a precursor for folate synthesisfor folate synthesis

Sulfonamides are Sulfonamides are structurally similar to structurally similar to PABAPABA

Inhibits synthesis of Inhibits synthesis of dihydropteroate dihydropteroate sythase (DHPS)sythase (DHPS)

DHPS & DHFR absent DHPS & DHFR absent in mammalian cellsin mammalian cells

Sulfonamides - effect

BacteriostaticActive against

Both Gram +ve & -veE. coli, Klebsiella, SalmonellaClamydia Some protozoa –

Pneumocystis cariniiNot active against rickettsiae

Sulfonamides - Pharmacokinetics

Preparation availablePreparation availableTopical Topical OralOral

Well absorbed from gutWell absorbed from gut

Distributed widely including CSFDistributed widely including CSFMetabolized in liver Metabolized in liver Excreted via kidneyExcreted via kidney

Sulfonamides - uses

TopicalTopicalSulfacetamide ophthalmic solutionSulfacetamide ophthalmic solution

ConjunctivitisConjunctivitisTrachomaTrachoma

Silver sulfadiazine (SSD)Silver sulfadiazine (SSD)burns burns

SystemicSystemicUse in combinationUse in combination

Sulfonamides - ADR

Fever Skin rash Exfoliative

dermatitis Steven Johnson

syndrome Crystalluria

Sulfonamides - combination

Sulfadiazine + pyrimethamineSulfadiazine + pyrimethamine Pyrimethamine inhibit protozoan Pyrimethamine inhibit protozoan

DHFRDHFR Synergistic Synergistic Penetrates CSFPenetrates CSF 11stst line for acute toxoplasmosis line for acute toxoplasmosis

Sulfadoxin + pyrimethamine Sulfadoxin + pyrimethamine (Fansidar)(Fansidar) Long actingLong acting Prophylaxis & treatment for Prophylaxis & treatment for

malariamalaria

Trimethoprim + sulfamethoxazole(TMP + SFX = co-trimoxazole)

TMPTMP Inhibit DHFRInhibit DHFR Synergistic when Synergistic when

combined with SFXcombined with SFX Combination is Combination is

bactericidalbactericidal

co-trimoxazole – p’kinetics

TMP:SFX = 1:5Available in IV and oralOral

Well absorbedT1/2 = 10 hrs (both)

Penetrates well into CSF, prostateExcreted in urineUsually given BD dose

co-trimoxazole - uses Infection caused byInfection caused by

ShigellaShigella SalmonelaSalmonela

UTIUTI TreatmentTreatment prophylaxisprophylaxis

Community acquired Community acquired pneumoniapneumonia

PCP pneumonia (PCP pneumonia (P. jiroveciP. jiroveci)) TreatmentTreatment prophylaxisprophylaxis

Co-trimoxazole - ADR

Sulfonamides ADRMegaloblastic anaemiaLeukopeniaGranulocytopenia

C. DNA gyrase / RNA polymerase (Nucleic Acid Synthesis) INHIBITOR

1) Quinolones

Essential structure of all quinolone antibiotics

2) Metronidazole

Fluoroquinolones

Fluoroquinolones

Synthetic fluorinated analogs of Synthetic fluorinated analogs of nalidixic acidnalidixic acid

Inhibit bacterial DNA synthesisInhibit bacterial DNA synthesis Inhibit DNA gyrase & topoisomeraseInhibit DNA gyrase & topoisomeraseExamplesExamples

CiprofloxacinCiprofloxacinNorfloxacinNorfloxacinPerfloxacin Perfloxacin

Required for normal

transcription and

replication

Inhibition of topoisomerase IV

prevents separation of replicated DNA

Fluoroquinolones

Spectrum depend on drugsEarlier fluoroquinolones

(ciprofloxacin)Mainly cover Gram –ve

Later drug (gatifloxacin)Better coverage for Gram +ve

Also useful in Atypical pneumoniaTB, M. avian

Fluoroquinolones - uses

Usually used in multidrug resistant infection

UTIBacterial AGEGonorrhea Eradication of meningococci from

carriers

Fluoroquinolones - ADR

Usually well toleratedGIT upsetAllergic reactionMay damage growing cartilage (rat)

Metronidazole - anaerobes

- It is used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa.

- It is used to treat ameobic dysentry, giardiasis, gangrene, pseudomonas coitis & various abdominal infections, lung abscess & dental sepsis.

Mechanism of actions

- The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.

Metronidazole - anaerobesanaerobes

Side Effects

PK

It is well absorbed after oral or rectal administration

•Nausea & vomiting

•Peripheral neuropathy

•Convulsions, headaches

•Hepatitis

Pathogen Drug (s) of first choice Alternative Drug (s)

Gram +ve cocci PneumococcusPneumococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Erythromycin, CephalosporinErythromycin, Cephalosporin

Streptococcus (common)Streptococcus (common) Penicillin GPenicillin G Erythromycin, CephalosporinErythromycin, Cephalosporin

Staphylococcus Staphylococcus

(penicillase-producing)(penicillase-producing)

AugmentinAugmentin®®, Unasyn, Unasyn®®, Cloxacillin, , Cloxacillin, Methicillin, Nafcillin, TimentinMethicillin, Nafcillin, Timentin®®

CephalosporinCephalosporin

Staphylococcus Staphylococcus

(methicillin resistance)(methicillin resistance)

VancomycinVancomycin TMZ-SMZTMZ-SMZ

EnterococcusEnterococcus Penicillin G plus gentamicinPenicillin G plus gentamicin Vancomycin plus gentamicinVancomycin plus gentamicin

Gram -ve cocci GonococcusGonococcus CetrriaxoneCetrriaxone Penicillin G, Ampicillin, Penicillin G, Ampicillin,

SpectinomycinSpectinomycin

MeningococcusMeningococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Cefotaxime, Cefuroxime, Cefotaxime, Cefuroxime, ChloramphenicolChloramphenicol

Gram -ve rods E.coliE.coli, Proteus, Klebsiella, Proteus, Klebsiella Aminoglycosides, 3Aminoglycosides, 3rdrd generation generation

cephalosporincephalosporinTMZ-SMZ, Fluoroquinolone, TMZ-SMZ, Fluoroquinolone, extended spectrum penicillinextended spectrum penicillin

ShigellaShigella FluoroquinoloneFluoroquinolone TMZ-SMZ, AmpicillinTMZ-SMZ, Ampicillin

Enterobacter, Citrobacter,Enterobacter, Citrobacter,

SerratiaSerratia

Imipenam, FluoroquinoloneImipenam, Fluoroquinolone TMZ-SMZ, extended spectrum TMZ-SMZ, extended spectrum penicillinpenicillin

Hemophilus sppHemophilus spp Cefuroxime or 3Cefuroxime or 3rdrd generation generation cephalosporincephalosporin

TMZ-SMZ, Ampicillin,TMZ-SMZ, Ampicillin,

ChloramphenicolChloramphenicol

Pseudomonas aeruginosa Aminoglycosides plus extended Aminoglycosides plus extended spectrum penicillinspectrum penicillin

Ceftazidime, Aztreonam, ImipenamCeftazidime, Aztreonam, Imipenam

Bacteroides fragillis Metronidazole, ClindamycinMetronidazole, Clindamycin Imipenam, Chloramphenicol, Imipenam, Chloramphenicol, Ampicillin/sulbactamAmpicillin/sulbactam

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