Dr.T.V.Rao MD

ANTIBIOTICS USE, MISUSE, CONSEQUENCES

WHAT IS A ANTIBIOTIC• Antibiotic (from the Ancient Greek: ντί – ἀ

anti, "against", and βίος – bios, "life") is a substance or compound that kills bacteria or inhibits its growth. Antibiotics belong to the broader group of antimicrobial compounds, used to treat infections caused by microorganisms, including fungi and protozoa .

• The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life

EARLY DEFINITION OF ANTIBIOTIC

BEGINNING OF ANTIBIOTICS WITH DISCOVERY OF PENICILLIN

• The discovery of penicillin has been attributed to Scottish scientist Alexander Fleming in 1928 and the development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey

FLEMING AND PENICILLIN

• Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism

• Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms

ANTIBIOTIC/ANTIMICROBIAL AGENT

• The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life

EARLY DEFINITION OF ANTIBIOTIC

SELMAN WAKSMAN The term "antibiotic"

was coined by Selman Waksman in 1942 to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution

DISCOVERY OF PENICILLIN AWARDED NOBEL PRIZE

Brief History of Antibiotics• 1928- Penicillin discovered by Fleming

• 1932- Sulfonamide antimicrobial activity discovered {Erlich}•

• 1943- Drug companies begin mass production of penicillin

• 1948- Cephalosporins precursor sent to Oxford for synthesis

• 1952- Erythromycin derived from Streptomyces erythreus

• 1956- Vancomycin introduced for penicillin resistant staphylococcus

• 1962- Quinolone antibiotics first discovered

• 1970s- Linezolid discovered but not pursued

• 1980s- Fluorinated Quinolones introduced, making then clinically useful

• 2000- Linezolid introduced into clinical practice

Antibiotic natural source first description as anti-infective drug

discoverer

sulfanilamide (prontosil 1932

1941

G.Domagk

penicillin Penicillium notatum A.Fleming, Florey, Chain

streptomycin Streptomyces griseus 1944 S.A.Waksman

cephalosporin Cephalosporium acremonium 1945 G.Brotzu

bacitracin Bacillus subtilis 1945

B.A.Johnson

chloramphenicol Streptomyces venezuellae 1947 I.Ehrlich

polymyxin Bacillus polymyxa 1947 C.G.Ainsworth

chlortetracyclin Streptomyces aureofaciens 1948 B.M.Duggar

neomycin Streptomyces fradiae 1949

S.A.Waksman

oxytetracyclin Streptomyces rimosus 1950 A.C.Finlay

1920 1930 1940 1950 1960 1970 1980 1990 2000

ertapenem

tigecyclin daptomicin linezolid

telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil

The development of anti-infectives …

Development of anti-microbials

• Bacteriostatic - Antimicrobial agents that reversibly inhibit growth of bacteria are called as bacteriostatic (Tetracycline's, Chloramphenicol )

• Bactericidal – Those with an irreversible lethal action on bacteria are known as bactericidal ( Penicillin, Isoniazid )

DEFINITION

• Antimicrobial agents – that are produced synthetically but have action similar to that of antibiotics and are defined as chemotherapeutic agents

• Eg Sulphonamides, Quinolones.

CHEMOTHERAPEUTIC AGENTS

IDEAL ANTIBIOTIC Toxic to microbes, and not to humans Bactericidal rater than bacteriostatic Effective against broad range of bacteria Should not be allergic and hypersensitive

reactions Should be active in plasma, and other body

fluids Desired levels should be reached rapidly and

maintained for adequate period of time. Should not give drug resistance, long shelf life, Cheaper

• Drugs differ on their capabilities to act at different sites on bacteria.

• Some drugs have more than one site of action

HOW DRUGS ACT

RESISTANCE AND SUSCEPTIBILITY

• Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation.

• The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient.

•Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose.

•Resistant - MIC is not exceeded by normally attainable levels

MAJOR MECHANISMS OF ANTIMICROBIAL DRUGS

• 1 Inhibition of cell wall synthesis• 2 Inhibition of cell membrane function• 3 Inhibition of protein synthesis ( inhibition of

translation and transcription of genetic material)

• 4 Inhibition of nucleic acid synthesis.

Inhibition of cell wall synthesis Target: block peptidoglycan (murein) synthesis

Peptidoglycan Polysaccharide (repeating disaccharides of N-

acetyl glucosamine and N-acetylmuramic acid) + cross-linked pentapeptide

Pentapeptide with terminal D-alanyl-D-alanine unit required for cross-linking

Peptide cross-link formed between the free amine of the amino acid in the 3rd position of the peptide & the D-alanine in the 4th position of another chain

Inhibition of cell wall synthesis A. -lactam antibiotics

inhibit transpeptidation reaction (3rd stage) to block peptidoglycan synthesis involves loss of a D-alanine from the pentapeptide

Steps:a. binding of drug to PBPsb. activation of autolytic enzymes (murein

hydrolases) in the cell wallc. degradation of peptidoglycand. lysis of bacterial cell

Inhibition of cell wall synthesis A.-lactam antibiotics

Penicillin binding proteins (PBPs) enzymes responsible for:

a. cross-linking (transpeptidase)b. elongation (carboxypeptidase)c. autolysis

Inhibition of cell wall synthesis A. -lactam antibiotics

Lysis of bacterial cello Isotonic environment cell swelling

rupture of bacterial cello Hypertonic environment – microbes

change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane swell and rupture if placed in isotonic environment

PENICILLINS AND CEPHALOSPORINS

Pencillin and cephalosporins act inhibiting Trans peptidases, the enzyme catalyses the final linking step in synthesis of peptidoglycan.

Due to this reason Pencillin in bactericidal for grwoing bacteria since new peptidoglycan is synthesized at that stage only.

In nongrwoing cells pencillin is inactive An intact beta – lactum is essential for

antibacterial activity of pencillins

CLASSIFICATION OF PENCILLINS• Natural Benzyl penicillin

Phenoxymethyl penicillin Penicillin v

Semi synthetic and pencillase resistant

1 Methicillin 2 Nafcillin 3 Cloxacillin 4 Oxacillin 5 Floxacillin

PENICILLINASE (B LACTAMASE)

Figure 20.8

• Penicilinase-resistant penicillins

• Carbapenem: very broad spectrum

• Monobactams: Gram negative

• Extended-spectrum penicillins

• Penicillins + -lactamase inhibitors

SEMI SYNTHETIC PENICILLINS

OTHER INHIBITORS OF CELL WALL SYNTHESIS

• Cephalosporins• 2nd, 3rd, and 4th

generations more effective against gram-negatives

Figure 20.9

EXTENDED SPECTRUM PENCILLINS

Aminopencillins - Ampicillin, Amoxycillin Carboxypencillins – Carbencillin, Ticarcillin Ureidopencillin - PiperacillinResistance to penicillin is due to pencillinase commonly

called as ßlactamaseThe enzyme opens Betalactum ring hydrolytically and thus

converts the antibiotic to inactive pencillonic acid.

• Clavulinic acid which is a product of Strept.clavuligerus

• Acts against the Staphylococcal beta ßlactamase.

• And plasmid mediated Betalactamase of Gram negative bacteria.

• Salbactum – this is a semisyntetic sulfone derivative with weak antibacterial activity

INHIBITORS TO BETALACTAMASE

• Like penicillin acts similar

• Products of the molds of genus Cephalosporium except cefoxilin

• Divided into 4 generation of Cephalosporins depending on the spectrum of activity.

CEPHALOSPORINS

• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first Cephalosporins were designated first generation while later, more extended spectrum Cephalosporins were classified as second generation Cephalosporins.

DIFFERENT GENERATIONS OF CEPHALOSPORINS

Cephalosporins are divided into 3 generations:

1st generation: Cephelexin, cefadroxil, cephradine

2nd generation: Cefuroxime, cefaclor

3rd generation: cefotaxime, Ceftazidime, cefixime - these give the best CNS penetration

4th and 5th generation Cephalosporins are already available

MAJOR GENERATIONS OF CEPHALOSPORINS

• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first cephalosporins were designated first generation while later, more extended spectrum cephalosporins were classified as second generation cephalosporins.

BASIS OF GENERATIONS IN CEPHALOSPORINS

• Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram-positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity

ADVANTAGES WITH NEWER GENERATIONS

• Imipenem: a carbapenem with a broader spectrum of activity against Gram positive and negative aerobes and anaerobes. Needs to be given with cilastatin to prevent inactivation by the kidney.

OTHER DRUGS

• Quinolones are the first wholly synthetic antimicrobials. The commonly used Quinolones.

• Act on the DNA gyrase which prevents DNA polymerase from proceeding at the replication fork and consequently stopping synthesis.

QUINOLONES

• Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds

• Eg Streptomycin,

• Act at the level of Ribosome's and inhibits protein synthesis

• Other Aminoglycosides –

Gentamycin, neomycins,paromomycins,tobramycins Kanamycins and spectinomycins

AMINOGLYCOSIDES

• Broad spectrum antibiotic produced by Streptomyces species

• 1. Oxytetracycle, chlortetracycle and tetracycline

• Tetracyclnes are bacteriostatic drugs inhibits rapidly multiplying organisms

• Resistance develops slowly and attributed to alterations in cell membrane permeability to enzymatic inactivation of the drug

TETRACYCLINE'S

• Chloramphenicol is bacteriostatic drug

• Can produce bone marrow depression

• Chloramphenicol interferes with protein synthesis.

CHORAMPHENICOL

• Contain macro cyclic lactone ring Erythromycin. Is popularly used drug

• Other drugs Roxithromycin,Azithromycin

• Inhibits the protein synthesis.

• Used as alternative to pencillin allergy patients.

MACROLIDES,AZALIDES,KETOLIDES

• Lincomycins

Clindamycin resembles Macrolides in biting site and antimicrobial activity.

Streptogramins

Quinpristin / dalfopristin

useful in gram positive bacteria

OTHER ANTIMICROBIAL AGENTS

• Major anaerobes – Anaerobic cocci, clostridia and Bactericides are susceptible to Benzyl pencillin

• Bact.fragilis as well as many other anaerobes are treatable with Erythromycin,Lincomycin, tetracycline and Chloramphenicol

• Clindamycin is effective against many strains of Bacteroides

ANTIBIOTICS IN ANAEROBES

• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.

• But also useful in treating parasitic infections

Trichomonas, Amoebiasis and other protozoan infections.

METRONIDAZOLE IN ANAEROBIC INFECTIONS

• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.

• But also useful in treating parasitic infections

Trichomonas, Amoebiasis and other protozoan infections.

METRONIDAZOLE IN ANAEROBIC INFECTIONS

• Other beta-lactams include:

• Aztreonam: a monocytic beta-lactam, with an antibacterial spectrum which is active only against Gram negative aerobes, including Pseudomonas aeruginosa, Neisseria meningitidis and N. gonorrhoea.

OTHER BETA-LACTAMS INCLUDE

Emergence of Antibiotic-Resistant Bacteria

Cohen; Science 1992;257:1050

Gram-negative rods

Enterococcus sp.

N. gonorrhoeae

H. influenzae

M. catarrhalis

S. pneumoniae

1950 1960 1970 1980 1990

S aureus

Penicillin

Ampicillin

3rd gen Cephalosporins

Quinolones

ANTIBIOTIC RESISTANCE Antibiotic resistance is the ability of a micro organism

to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves naturally via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange.

ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIAWHAT IS IT ?

• ”Selection pressure of antibiotics has led to the emergence of antibiotic-resistant bacteria.”

• Antibiotics can effect bacteria unrelated to the targeted infectious agent; these may be “normal” flora, leading to the emergence of resistant mutants inhabiting the same environment.

Baquero et al., International Report 1996;23:819

• All antibiotics do NOT kill bacteria in the same way.

• Various classes of antibiotics work on different aspects of bacterial replication.

ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA

HOW DOES IT OCCUR?

RESISTANCE AND SUSCEPTIBILITY• Determined by in vitro activity, pharmacologic

characteristics, and clinical evaluation.• The minimal inhibitory concentration (MIC) can be

comfortably exceeded by doses tolerated by the patient.• Susceptible - implies their MIC is at a concentration

attainable in the blood or other body fluid at the recommended dose.

• Resistant - MIC is not exceeded by normally attainable levels

• In spite discovery of several antibiotics several microorganisms attained resistance.

• The major factor contributing to persistence of infectious disease has been the tremendous capacity of microorganisms for circumventing the action of inhibitory drugs.

• The drug resistance continues to be a threat for usefulness of the chemotherapeutic agents.

DRUG RESISTANCE

RESISTANCE

ORIGIN OF DRUG RESISTANCENON-GENETIC

1. Metabolically inactive organisms may be phenotypically resistant to drugs – M. tuberculosis

2. Loss of specific target structure for a drug for several generations

3. Organism infects host at sites where antimicrobials are excluded or are not active – aminoglycosides (e.g. Gentamicin) vs. Salmonella enteric fevers (intracellular)

Folic acid synthesis

ß-lactams & Glycopeptide (Vancomycin)

50 50 5030 30 30

DNA

mRNA

Ribosomes

PABA

DHFA

THFA

Cell wall synthesis

DNA gyrase Quinolones

Protein synthesis inhibition

Protein synthesis inhibitionTetracycline's

Protein synthesis mistranslation

Macrolides & Lincomycins

Cohen. Science 1992; 257:1064

DNA-directed RNA polymeraseRifampin

Aminoglycosides

Sulfonamides

Trimethoprim

• The resistant strains arise either by mutation and selection or by genetic exchange in which sensitive organisms receive the genetic material ( part of DNA) from the resistant organisms and the part of DNA carries with it the information of mode of inducing resistance against one or multiple antimicrobial agents.

ORIGIN OF DRUG RESISTANT STRAINS

< Inappropriate specimen selection and collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Practices Contributing to Misuse of Antibiotics

< Use of antibiotics with no clinical indication (eg, for viral infections)

< Use of broad spectrum antibiotics when not indicated

< Inappropriate choice of empiric antibiotics

Inappropriate Antibiotic Use

< Inappropriate dose - ineffective concentration of antibiotics at site of infection

< Inappropriate route - ineffective concentration of antibiotics at site of infection

< Inappropriate duration

Inappropriate Drug Regimen

ANTIBIOTIC RESISTANCE Antibiotic resistance is a specific type of drug

resistance when a microorganism has the ability of withstanding the effects of antibiotics. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by conjugation, transduction, or transformation.

PLASMIDS • Plasmid seem to be ubiquitous in bacteria, May encode genetic

information for properties

1 Resistance to Antibiotics

2 Bacteriocins production

3 Enterotoxin production

4 Enhanced pathogen city

5 Reduced Sensitivity to

mutagens

6 Degrade complex organic molecules

RESISTANCE TRANSFER FACTORRTF

Plasmids – helps to spread multiple drug resistance Discovered in 1959 Japan Infections caused due to Shigella spread resistance to

following Antibiotics Sulphonamides Streptomycin Choramphenicol, Tetracycline

RTF Shigella + E.coli

excreted in the stool resistant to several drugs in vivo and vitro

Plasmid mediated –transmitted by Conjugation

Episomes spread the resistance

TRANSPOSONS AND R FACTOR

R forms may have evolved as a collection of Transposons

Each carrying Genes that confers resistance to one or several Antibiotics

Seen in Plasmids, Microorganisms AnimalsLaboratory Manipulations are called as Genetic

Engineering

• If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes use to explicitly encompass organisms other than bacteria

MULTI DRUG RESISTANT PATHOGENS

• Resistance arises due to Biochemical changes

Increased synthesis of drug antagonist

Decreased permeability to drug

Increased destruction of inhibitor

BIOCHEMICAL MECHANISMS OF DRUG RESISTANCE

Mutation • Usually one drug• Low degree of resistance• Increasing dose can

benefit• Prevented by

combination of drugs• Low virulence of bacteria

Transferable• Multiple drugs• High degree of resistance• Increasing dose do not

benefit• Can not be prevented by

combination of drugs• High virulence of bacteria

DIFFERENTIATION OF MUTATION AND TRANSFERABLE DRUG RESISTANCE

PLASMID MEDIATED DRUG RESISTANCE

Sulphonamides --- Reduce permeability

Erythromycin ---- Modification of ribosome's

Tetracyclnes ----- Reduced permeability

Chloramphenicol ---- Acetylation of drug

Streptomycin ----- Adenylation of drug

Pencillin ----- Hydrolysis of lactum ring

• Many antibiotic resistance genes reside on plasmids facilitating their transfer. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes used to explicitly encompass organisms other than bacteria

ANTIBIOTICS RESISTANCE AND PLASMIDS

• Antibiotic resistance has become a serious problem in both developed and underdeveloped nations. By 1984 half of those with active tuberculosis in the United States had a strain that resisted at least one antibiotic. In certain settings, such as hospitals and some childcare location

ANTIBIOTIC RESISTANCE THREAT TO HUMANS AND ANIMALS

BETWEEN 1962 AND 2000, NO MAJOR CLASSES OF ANTIBIOTICS WERE INTRODUCED

Fischbach MA and Walsh CT Science 2009

EXTENDED-SPECTRUM Β-LACTAMASES• β-lactamases capable of conferring bacterial resistance to

• the penicillins

• first-, second-, and third-generation cephalosporins

• aztreonam

• (but not the cephamycins or carbapenems)• These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and

SHV-1)

• differ from their progenitors by as few as one AA

CARBAPENEMASES• Ability to hydrolyze penicillins, cephalosporins, monobactams,

and carbapenems• Resilient against inhibition by all commercially viable ß-

lactamase inhibitors• Subgroup 2df: OXA (23 and 48) carbapenemases• Subgroup 2f : serine carbapenemases from molecular class A:

GES and KPC • Subgroup 3b contains a smaller group of MBLs that

preferentially hydrolyze carbapenems• IMP and VIM enzymes that have appeared globally, most frequently in

non-fermentative bacteria but also in Enterobacteriaceae

• KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K.

pneumonia• Substrate hydrolysis

spectrum includes

cephalosporins and carbapenems

K. PNEUMONIA CARBAPENEMASES)

Nordmann P et al. LID 2009

K.PNEUMONIAE CARBAPENEMASE-PRODUCING BACTERIA

Antibiotic resistance

“Antibiotic resistance continues to plague antimicrobial

chemotherapy of infectious diseases” Keith. Poole. J Antimicrob Chemother 2005; 56: 20-51

“Evolution of bacteria towards resistance… …is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable”

Patrice Courvalin. Emerg Infect Dis 2005; 11: 1507-6

“Antibiotic resistance has resulted in a continuous need for

new therapeutic alternatives” Carl Erik Nord. Clin Microbiol Infect 2004;10 (Supp

4)

“There is a need to re-invigorate antimicrobial development, which has been downgraded by major pharmaceutical houses”

David Livermore. Lancet Infect Dis 2005; 5:450-59

< Inappropriate specimen selection and collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Practices Contributing to Misuse of Antibiotics

< Use of antibiotics with no clinical indication (eg, for viral infections)

< Use of broad spectrum antibiotics when not indicated

< Inappropriate choice of empiric antibiotics

Inappropriate Antibiotic Use

• Optimize patient evaluation

• Adopt judicious antibiotic

• prescribing practices

• Immunize patients

PHYSICIANS CAN IMPACT PATIENTS

• Optimize consultations with other clinicians

• Use infection control measures

• Educate others about judicious use of antibiotics

PHYSICIANS CAN IMPACT OTHER CLINICIANS

ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA: CONCLUSIONS

• Bacteria evolve resistance to antibiotics in response to environmental pressure exerted by the use of antibiotics.

• Many of these bacteria are significant pathogens.

• Our responsibility to our community is to use antibiotics prudently, for appropriate indications.

ARE WE OVERUSING ANTIBIOTICS

DEDICATED HANDWASHING HAS MANY SOLUTIONS TO PREVENT SPREAD OF DRUG RESISTANT STRAINS

• Programme created by Dr.T.V.Rao MD for Medical Professionals in the

Developing World • Email

• doctortvrao@gmail.com