antibiotic use and misuse 2

8/3/2019 Antibiotic Use and Misuse 2

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Dr.T.V.Rao MD

ANTIBIOTICSUSE, MISUSE,consequences

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What is a Antibiotic Antibiotic (from the AncientGreek: anti , "against", and

bios , "life") is a substanceor compound that kills bacteriaor inhibits its growth. Antibiotics

belong to the broader group of antimicrobial compounds, usedto treat infections caused bymicroorganisms, including fungiand rotozoa .Dr.T.V.Rao MD 22


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The word antibiotic camefrom the word antibiosis aterm coined in 1889 by LouisPasteur's pupil Paul Vuilleminwhich means a process by

which life could be used todestroy life

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Third level Fourth level

Fifth level

Early definition of Antibiotic

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Beginning of Antibiotics

with Discovery of Penicillin The discovery of penicillin has beenattributed to Scottish

scientist AlexanderFleming in 1928 andthe development of penicillin for use as a

medicine is attributedto the AustralianNobel LaureateHoward Walter Florey



Fifth level

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Fleming and Penicillin

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Antibiotic: Chemicalproduced by amicroorganism that kills orinhibits the growth of another microorganismAntimicrobial agent:Chemical that kills orinhibits the growth of microorganisms



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Antibiotic/Antimicrobial agent

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The word antibiotic camefrom the word antibiosis aterm coined in 1889 by LouisPasteur's pupil Paul Vuilleminwhich means a process by

which life could be used todestroy life



Fifth level

Early definition of Antibiotic

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Selman WaksmanClick to edit Master text stylesSecond level


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The term "antibiotic" wascoined by SelmanWaksman in 1942 todescribe any substanceproduced by a

microorganism that isantagonistic to the growthof other microorganisms inhigh dilution

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Discovery of Penicillin

Awarded Nobel Prize

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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 practiceDr.T.V.Rao MD 1010


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Antibiotic natural sourcefirst descriptionas anti-infectivedrug

discovere r sulfanilamide(prontosil 1932

1941

G.Domagk

penicillin Penicilliumnotatum

A.Fleming,Florey, Ch

streptomycin Streptomycesgriseus

1944 S.A.Waksm

cephalosporin Cephalosporium

acremonium1945 G.Brotzu

bacitracin

Bacillus subtilis 1945 B.A.Johns

chloramphenicolStreptomycesvenezuellae

1947 I.Ehrlich

polymyxi

n

Bacillus

polymyxa 1947

C.G.Ainsw

chlortetracyclin

Streptomycesaureofaciens

1948B.M.Dugga

neomycin Streptomyces fradiae 1949

S.A.Waksn

oxytetracyclin Streptomyces rimosus 1950 A.C.FinlaDr.T.V.Rao MD 1111


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ertapenem tigecyclin

daptomicinlinezolid

telithromicinquinup./dalfop.cefepime

ciprofloxacinaztreonamnorfloxacin

imipenemcefotaxime

clavulanic ac.cefuroximegentamicin

cefalotinanalidxico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycinpencillin G

prontosil

The development of anti-infectives

Development of anti-microbials

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Bacteriostatic -Antimicrobialagents that

reversibly inhibitgrowth of bacteriaare called asbacteriostatic

(Tetracycline's,Chloramphenicol )

Bactericidal Those with anirreversible lethal

Definition

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Ideal Ant ibiot ic Toxic to microbes, and not to humansBactericidal rater than bacteriostaticEffective against broad range of bacteriaShould not be allergic and hypersensitive reactionsShould be active in plasma, and other body fluidsDesired levels should be reached rapidly andmaintained for adequate period of time.Should not give drug resistance, long shelf life,Cheaper

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Drugs differ on theircapabilities to act atdifferent sites onbacteria.Some drugs havemore than one siteof action



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How Drugs Act

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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 bythe patient.

Susceptible - implies their MIC is at aconcentration attainable in the blood or other

body fluid at the recommended dose. Resistant - MIC is not exceeded by normally

attainable lev els

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Major mechanisms of antimicrobial drugs

1 Inhibition of cell wall synthesis

2 Inhibition of cell membranefunction3 Inhibition of protein synthesis

( inhibition of translation andtranscription of genetic material)4 Inhibition of nucleic acidsynthesis.Dr.T.V.Rao MD 1818


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

Peptidoglycan Polysaccharide (repeating disaccharides of N-

acetyl glucosamine and N-acetylmuramicacid) + 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 positionof the peptide & the D-alanine in the 4thposition of another chain

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Inhibition of cell wall synthesis

A. -lactam antibiotics inhibit transpeptidation reaction (3rd stage)

to block peptidoglycan synthesisinvolves loss of a D-alanine from the

pentapeptide Steps:

a. binding of drug to PBPs

b. activation of autolytic enzymes( murein hydrolases ) in the cell wall

c. degradation of peptidoglycan

d. lysis of bacterial cell

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A. -lactam antibiotics

Penicillin binding proteins (PBPs) enzymes responsible for:

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

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A. -lactam antibiotics

Lysis of bacterial cello.Isotonic environment cell swelling

rupture of bacterial cello.Hypertonic environment microbes

change to protoplasts (gram +) orspheroplasts (gram -) covered by cellmembrane swell and rupture if placed in isotonic environmentDr.T.V.Rao MD 2222


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Penicillins andCephalosporins

Pencillin and cephalosporins act inhibiting Transpeptidases, the enzyme catalyses the final linkingstep in synthesis of peptidoglycan.Due to this reason Pencillin in bactericidal for

grwoing bacteria since new peptidoglycan issynthesized at that stage only.In nongrwoing cells pencillin is inactiveAn intact beta lactum is essential for antibacterialactivity of pencillins

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Classification of Pencillins

Natural

Benzyl penicillin

Phenoxymethyl penicillin Penicillin v

Semi synthetic and pencillase resistant 1 Methicillin

2 Nafcillin

3 Cloxacillin4 Oxacillin5 Floxacillin

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Penicillinase ( Lactamase)

Figure 20.8Dr.T.V.Rao MD 2525


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Penicilinase-resistantpenicillins

Carbapenem: verybroadspectrum

Monobactams:Gramnegative

Extended-spectrumpenicillins

Semi syntheticPenicillins

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Other Inhibitors of Cell

Wall SynthesisCephalosporins2nd, 3rd, and4th

generationsmoreeffectivea ainst ram- Figure 20.9Dr.T.V.Rao MD 2727


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Extended spectrumpencillins

Aminopencillins - Ampicillin, AmoxycillinCarboxypencillins Carbencillin, Ticarcillin

Ureidopencillin - PiperacillinResistance to penicillin is due to pencillinasecommonly called as lactamase

The enzyme opens Betalactum ringhydrolytically and thus converts theantibiotic to inactive pencillonic acid.

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Clavulinic acid which is aproduct of Strept.clavuligerus

Acts against theStaphylococcal betalactamase.

And plasmid mediatedBetalactamase of Gramnegative bacteria.

Salbactum this is asemisyntetic sulfonederivative with weakantibacterial activity

Inhibitors to Betalactamase

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Like penicillin acts similar

Products of the molds of genus Cephalosporiumexcept cefoxilin

Divided into 4 generationof Cephalosporinsdepending on thespectrum of activity.

Cephalosporins

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Cephalosporins are groupedinto "generations" based ontheir spectrum of antimicrobialactivity. The firstCephalosporins weredesignated first generationwhile later, more extendedspectrum Cephalosporins wereclassified as secondgeneration Cephalosporin s.

Different Genera t ions ofCephalospor ins

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Cephalosporins are divided into3 generations:1st generation : Cephelexin,cefadroxil, cephradine2nd generation : Cefuroxime,cefaclor3rd generation : cefotaxime,Ceftazidime, cefixime - thesegive the best CNS penetration4th and 5th generationCephalosporins are alreadyavail able

Major generations of Cephalosporins

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Cephalosporins are groupedinto "generations" based ontheir spectrum of antimicrobialactivity. The firstcephalosporins weredesignated first generationwhile later, more extendedspectrum cephalosporins wereclassified as secondgeneration cephalosporins.

Basis of generations inCephalosporins

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Each newer generation of cephalosporins has significantlygreater gram-negativeantimicrobial properties than thepreceding generation, in mostcases with decreased activity

against gram-positiveorganisms. Fourth generationcephalosporins, however, havetrue broad spectrum activity

Advantages with Newergenerations

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Imipenem : acarbapenem with abroader spectrum of activity against Grampositive and negativeaerobes andanaerobes. Needs tobe given with

cilastatin to preventinactivation by thekidney.

Other drugs

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Quinolones are the firstwholly syntheticantimicrobials. Thecommonly usedQuinolones.

Act on the DNA gyrasewhich prevents DNApolymerase fromproceeding at the

replication fork andconsequently stoppingsynthesis.

Quinolones

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Aminoglycosides are groupof antibiotics in which aminosugars liked by glycosidebonds

Eg Streptomycin,

Act at the level of Ribosome'sand inhibits protein synthesis

Other Aminoglycosides

Gentamycin,neomycins,paromomycins,tobramycins Kanamycins andspectinomycins

Aminoglycosides

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Broad spectrum antibiotic producedby Streptomyces species

1. Oxytetracycle, chlortetracycleand tetracycline

Tetracyclnes are bacteriostaticdrugs inhibits rapidly multiplyingorganisms

Resistance develops slowly andattributed to alterations in cellmembrane permeability toenzymatic inactivation of the drug

Tetracycline's

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Chloramphenicol isbacteriostatic drugCan produce bonemarrow depressionChloramphenicolinterferes with proteinsynthesis.

Choramphenicol

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Contain macro cycliclactone ring Erythromycin.Is popularly used drug

Other drugsRoxithromycin,Azithromycin

Inhibits the proteinsynthesis.

Used as alternative topencillin allergy patients.

Macrolides,Azalides,Ketolides

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LincomycinsClindamycin resembles

Macrolides in biting siteand antimicrobial activity.

StreptograminsQuinpristin / dalfopristin

useful in gram positivebacteria

Other Antimicrobial agents

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Major anaerobes Anaerobic cocci, clostridiaand Bactericides aresusceptible to Benzylpencillin

Bact.fragilis as well asmany other anaerobes aretreatable withErythromycin,Lincomycin,tetracycline andChloramphenicol

Clindamycin is effectiveagainst many strains of Bacteroides

Antibiotics in Anaerobes

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Since the discovery of Metronidazole in 1973since then it wasidentified as leading

agent anaerobes.But also useful intreating parasiticinfections

Trichomonas,Amoebiasis and otherprotozoan infections.

Metronidazole in AnaerobicInfections

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Since the discovery of Metronidazole in 1973since then it wasidentified as leading

agent anaerobes.But also useful intreating parasiticinfections

Trichomonas,Amoebiasis and otherprotozoan infections.

Metronidazole in AnaerobicInfections

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Other beta-lactams include:

Aztreonam : a monocyticbeta-lactam, with anantibacterial spectrum whichis active only against Gram

negative aerobes, includingPseudomonas aeruginosa ,Neisseria meningitidis and N.gonorrhoea .

Other Beta-lactams include

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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 genCephalosporins

Quinolones

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Antibiotic resistance

Antibiotic resistance is the ability of a micro organism towithstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves naturally vianatural selection acting upon random mutation, but it canalso be engineered by applying an evolutionary stress on a

population. Once such a gene is generated, bacteria canthen transfer the genetic information in a horizontal fashion(between individuals) by plasmid exchange.

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Antibiotic Pressure and Resistance inBacteria

What is it ?

Selection pressure of antibiotics hasled to the emergence of antibiotic-resistant bacteria.

Antibiotics can effect bacteria unrelated tothe targeted infectious agent; these may benormal flora, leading to the emergence of resistant mutants inhabiting the sameenvironment.

Baquero et al., International Report 1996;23:Dr.T.V.Rao MD 5151

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All antibioticsdo NOT killbacteria in thesame way.Various classes

of antibioticswork ondifferent

aspects of

Antibiotic Pressure and Resistance inBacteria

How does it occur?

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Resistance andSusceptibility

Determined by in vitro activity,pharmacologic characteristics, and clinicalevaluation.

The minimal inhibitory concentration (MIC)can be comfortably exceeded by dosestolerated by the patient.Susceptible - implies their MIC is at a

concentration attainable in the blood orother body fluid at the recommendeddose.Resistant - MIC is not exceeded by

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In spite discovery of severalantibiotics severalmicroorganisms attainedresistance.

The major factor contributing topersistence of infectious diseasehas been the tremendouscapacity of microorganisms forcircumventing the action of inhibitory drugs.

The drug resistance continues tobe a threat for usefulness of thechemotherapeutic agents.

Drug Resistance

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RESISTANCE

ORIGIN OF DRUG RESISTANCENON-GENETIC

1. Metabolically inactive organisms may bephenotypically resistant to drugs M.

tuberculosis2. Loss of specific target structure for a drug

for several generations3. Organism infects host at sites where

antimicrobials are excluded or are notactive aminoglycosides (e.g.Gentamicin) vs. Salmonella entericfevers (intracellular)

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Folic acidsynthesis

-lactams &Glycopeptide(Vancomycin)

50 50 5030 30 30

DNA

mRNA

Ribosomes

PABA

DHFA

THFA

Cell wall synthesis

DNA gyrase

Quinolones

Proteinsynthesisinhibition

ProteinsynthesisinhibitionTetracycline's

Protein synthesismistranslation

Macrolides &Lincomycins

Cohen. Science 1992; 257:1064

DNA-directedRNA polymeraseRifampin

Aminoglycosides

Sulfonamides

Trimethoprim

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The resistant strains arise eitherby mutation and selection or bygenetic exchange in whichsensitive organisms receive thegenetic material ( part of DNA)from the resistant organisms

and the part of DNA carries withit the information of mode of inducing resistance against oneor multiple antimicrobial agents.

Origin of Drug Resistant Strains

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< Inappropriate specimen selection and

collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibilitytests

Practices Contributing toMisuse of Antibiotics

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< Use of antibiotics withno clinical indication(eg, for viral infections)

antibiotic use and misuse 2

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