Seasonality of Antibiotic Resistance and Correlation with Antibiotic Use
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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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
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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
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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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Inhibition of cell wall synthesis
A. -lactam antibiotics
Penicillin binding proteins (PBPs) enzymes responsible for:
a. cross-linking (transpeptidase)b. elongation (carboxypeptidase)c. autolysis
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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 +) 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
normally attainable levelsDr.T.V.Rao MD 5353
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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)