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Rationalism of
Antibiotic TherapyConsequences of Misuse
Dr.T.V.Rao MD
Dr.T.V.Rao MD
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ANTIMICROBIAL AGENT
Any chemical or drug used
to treat an infectious disease,either by inhibiting or killing
the pathogens in vivo
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Discovery of Pencillin
Awarded Nobel Prize
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Selman Waksman
The term "antibiotic"was coined by Selman Waksman in 1942 to
describe anysubstance producedby a microorganism that is antagonistic to
the growth of othermicroorganisms in high dilution
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Chemotherapeutic Agents
Antimicrobial agents
that are produced
synthetically but have
action similar to that of antibiotics and are
def ined as
chemotherapeutic
agents
Eg Sulphonamides,
Q uinolones.
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Def inition
Bacteriostatic - Antimicrobial agents that
reversibly inhibit growth of bacteria are called
as bacteriostic ( Tetracyclnes, Chloramphenicol )
Bactericidal Those with an irreversible lethal
action on bacteria are known as bactericidal (
Pencillin, Isoniazid )
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1920 1930 1940 1950 1960 1970 1980 1990 2000
ertapenemtigecyclin
dapto
micinlinezolidtelithromicin
quinup./dalfop.cef epime
ciprof loxacinaztreonam
norf loxacinimipenem
cefotaximeclavulanic ac.
cef uroximegentamicin
cefalotinanalidí xico ac.
ampicillinmethicilin
vancomicinrifampin
chlortetracyclin
streptomycinpencillin G
prontosil
The development
of anti-infectives
Development of anti-infectives
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ANTIBIOTICS
Substances derivedfrom amicroorganism or
producedsynthetically, thatdestroys or limitsthe growth of a
living organism
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ANTIBIOTICS ± Sources
1. Natural
a.Fungi ± penicillin, griseofulvin
b.Bacteria ± Bac illus sp.(polymixin, bacitracin) ;
Act inomy cetes (tetracycline,chloramphenicol,streptomycin)
2. Synthetic Dr.T.V.Rao MD
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ANTIMICROBIAL AGENT
Ideal Qualities:
1. kill or inhibit the growth of pathogens
2. cause no damage to the host
3. cause no allergic reaction to the host
4. stable when stored in solid or liquid form
5. remain in specific tissues in the body long enoughto be effective
6. kill the pathogens before they mutate and becomeresistant to it
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Basic Classes of Antibiotics
Although a large number of antibiotics exist, they fall into only a few classes with
an even more limited number of targets.
-lactams (penicillins) cell wall biosynthesis
Glycopeptides (vancomycin) cell wall biosynthesis
Aminoglycosides (gentamycin) protein synthesis
Macrolides (erythromycin) protein synthesis
Quinolones (ciprofloxacin) nucleic acid synthesis
Sulfonamides (sulfamethoxazole) folic acid metabolismDr.T.V.Rao MD
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Prescribing an antibiotic
Is an antibiotic necessary ?
What is the most appropriate
antibiotic ?
What dose, frequency, route and
duration ? Is the treatment effective ?
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Is an antibiotic necessary ?
Useful only for the treatment of bacterialinfections
Not all fevers are due to infection
Not all infections are due to bacteria
There is no evidence that antibioticswill prevent secondary bacterial
infection in patients with viralinfection
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Choice of regimen
Oral vs parenteral
Traditional view
serious = parenteral
previous lack of broad spectrum oral antibiotics with reliable bioavailability
Improved oral agents
higher and more persistent serum and tissue levels
for certain inf ections as good as parenteral
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Advantages of oral treatment
Eliminates risks of complications associated
with intravascular lines
Shorter duration of hospital stay
Savings in nursing time
Savings in overall costs
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Antimicrobial Resistance: Antimicrobial Resistance:
Key Prevention StrategiesKey Prevention Strategies
Optimize Use
Prevent Transmission
Prevent Infection
Effective Diagnosis & Treatment
Pathogen Antimicrobial-Resistant Pathogen
AntimicrobialResistance
AntimicrobialUse
Infection
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Susceptible Pathogen
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Emerging Resistance
Antibiotic resistance is aconsequence of evolution via natural selection. The antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to
reproduce. They will then pass this trait to theiroff spring, which will be af ully resistant generation.
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Irrational Use of Third Generation
Cephalosporins Several studies have demonstrated that patterns of antibiotic usage greatly aff ect the number of resistant organisms which develop.Overuse of broad-spectrum antibiotics, such
as second- and third-generation Cephalosporins, generate resistant strains.
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Origin of Drug Resistant Strains
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.
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RESISTANCE
ACQUISITION OF BACTERIAL RESISTANCE
ACQUIRED RESISTANCE
Species develop ability to resist anantimicrobial drug to which it is as awhole naturally susceptible
Two mechanisms:
1. Mutational ± chromosomal
2. Genetic exchange ±transformation, transduction,
conjugationDr.T.V.Rao MD
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Self Medication
The greatest possibility of evil in self-medication is
the use of too small doses so that instead of
clearing up infection, the microbes are educated to
resist penicillin and a host of penicillin-fastorganisms is bread out which can be passed to
other individuals and from them to other until they
reach someone who gets a septicemia or a
pneumonia which penicillin cannot save.
. Sir AlexanderFlemming
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Historical aspects
1980s ESBL producing GN bacteria
1990 Vancomycin resistant Enterococci
emerged2000 VISA (intermediate level resistance)
2002-VRSA (high level resistance)
2002- Linezolid resistant enterococci andStaphylococci reported
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Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-Generation
Cephalosporins
1963
1965
TEM-1
E coli
S paratyphi
1970s
TEM-1
Reported in
28 Gram-
Negative
Species
1980s1983
ESBL
in
United
States
1987
ESBL in
Europe
2000
>120 ESBLs
Worldwide
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Resistance to Antibiotics
Bacteria (and viruses) are very resourcef ul creatures and they have developed resistanmechanisms to essentially every antibiotic that has been developed.
Moreover, increased use of antibiotics results in increased resistance (the paradox of
antibiotics).
The basic resistance mechanisms are quite simple:
1.Modify the antibiotic
2.Modify the target of the antibiotic
3.Destroy the antibiotic
4.Make it more diff icult for the antibiotic to get into the cell
5.Actively remove the antibiotic from the cellDr.T.V.Rao MD
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P lasmids
Plasmid seem to be ubiquitous in bacteria, Mayencode genetic information for properties
1 Resistance to Antibiotics
2 Bacteriocins production3 Enterotoxin production4 Enhanced pathogen city5 Reduced Sensitivity to
mutagens6 Degrade complex organic molecules
T.V.Rao MD
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Resistance Transfer Factor
RTF
Plasmids helps to spread multiple drug resistance
Discovered in 1959 Japan
Inf ections caused due to Shigella spread resistance to
following Antibiotics
Sulphonamides
Streptomycin
Choramphenicol,
Tetracycline
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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
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Transposons and R factor
R forms may have evolved as a collection of Transposons
Each carrying Genes that conf ers resistance to one orseveral Antibiotics
Seen in Plasmids,
Microorganisms
Animals
Laboratory Manipulations are called as Genetic Engineering
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Plasmid Mediated Drug
resistanceSulphonamides --- Reduce permeability
Erythromycin ---- Modif ication of ribosome's
Tetracyclnes ----- Reduced permeabilityChloramphenicol ---- Acetylation of drug
Streptomycin ----- Adenylation of drug
Pencillin ----- Hydrolysis of lactum ring
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RESISTANCE
ACQUIRED RESISTANCE ± EXAMPLES:
1. R esistance (R ) plasmids
Transmitted by conjugation
2. mecA gene
Codes for a PBP with low affinityfor F-lactam antibiotics
Methicillin-resistant S. aureus
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RESISTANCE
ORIGIN OF DRUG RESISTANCE
NON-GENETIC
1. Metabolically inactive organisms maybe phenotypically resistant to drugs
± M. tuberculosis
2. Loss of specific target structure for adrug for several generations
3. Organism infects host at sites whereantimicrobials are excluded or arenot active ± aminoglycosides (e.g. Gentamicin) vs. Salmonella entericfevers (intracellular)
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RESISTANCE
GENETIC
1. Chromosomal
Occurs at a frequency of 10-12 to 10-7
20 to spontaneous mutation in a locusthat controls susceptibility to a givendrug due to mutation in gene that
codes for either:
a. drug target
b. transport system in the membranethat controls drug uptake
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RESISTANCE
GENETIC
2. Extrachromosomal
a. Plasmid-mediated
Occurs in many different species, esp. gram
(-) rods Mediate resistance to multiple drugs
Can replicate independently of bacterialchromosome many copies
Can be transferred not only to cells of thesame species but also to other species andgenera
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< 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
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RESISTANCE
LIMITATION OF DRUG RESISTANCE
1. Maintain sufficiently high levels of thedrug in the tissues inhibit original
population and first-step mutants.
2. Simultaneous administration of twodrugs that do not give cross-resistance
delay emergence of mutants resistant tothe drug (e.g. INH + R ifampicin)
3. Limit the use of a valuable drug avoidexposure of the organism to the drug
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What Is Antimicrobial Stewardship?
A comination of inf ection control and antimicrobial management
Mandatory inf ection control compliance
Selection of antimicrobials from each class of drugs that does
the least collateral damage
Collateral damage issues include MRSA
ESBLs
C difficile
Stable derepression
MBLs and other carbapenemases
VRE
Appropriate de-escalation when culture results are available
Dellit TH, et al. C lin Infect Dis. 2007;44:159-177.
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IDSA Guidelines Def inition of
Antimicrobial Stewardship
Antimicrobial stewardship is an activity that
promotes
The appropriate selection of antimicrobials
The appropriate dosing of antimicrobials
The appropriate route and duration of
antimicrobial therapy
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The Primary Goal of
Antimicrobial Stewardship The primary goal of antimicrobial stewardship is to
Optimize clinical outcomes while minimizing unintended
consequences of antimicrobial use
Unintended consequences include the following
Toxicity
The selection of pathogenic organisms, such as C difficile
The emergence of resistant pathogens
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The Primary Goal of
Antimicrobial Stewardship The primary goal of antimicrobial stewardship is to
Optimize clinical outcomes while minimizing unintended
consequences of antimicrobial use
Unintended consequences include the following
Toxicity
The selection of pathogenic organisms, such as C difficile
The emergence of resistant pathogens
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< 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
Dr.T.V.Rao MD
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Inappropriate dose - ineff ective concentration of antibiotics at site of
inf ection
Inappropriate route - ineff ective concentration of antibiotics at site of
inf ection
Inappropriate duration
Inappropriate Drug Regimen
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Multi Drug resistant pathogens
If a bacterium carries several
resistance genes, it is called
multiresistant or, informally, asuperbug. The term antimicrobial
resistance is sometimes use to
explicitly encompass organisms otherthan bacteria
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Antibiotic Resistance
Threat to Humans and Animals
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
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Between 1962 and 2000, no major classes of
antibiotics were introduced
Fischbach MA and Walsh CT Science 2009
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Physicians Can Impact
Other clinicians
Patients
Optimize patient evaluationAdopt judicious antibiotic
prescribing practicesImmunize patients
Optimize consultations withother cliniciansUse infection control measuresEducate others about judicioususe of antibiotics
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Antibiotic Pressure and Resistance in Bacteria:
C onclusions
Bacteria evolve resistance to antibiotics in
response to environmental pressure exerted
by the use of antibiotics.
Many of these bacteria are signif icant
pathogens.
Our responsibility to our community is to use
antibiotics prudently, for appropriate
indications.
Dr.T.V.Rao MD
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12 Steps to Prevent AntimicrobialResistance
12 Break the chain11 Isolate the pathogen
10 Stop treatment when cured9 Know when to say no to vanco
8 Treat inf ection, not colonization7 Treat inf ection, not contamination
6 Use local data5 Practice antimicrobial control
4 Access the experts3 Target the pathogen
2 Get the catheters out1 Vaccinate
Prevent Transmission
Use Antimicrobials Wisely
Diagnose & Treat Effectively
Prevent Inf ections
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
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Conclusions
Antibiotic resistance is a major problem
world-wide
Resistance is inevitable with use
No new class of antibiotic introduced over
the last two decades
Appropriate use is the only way of prolonging the useful life of an antibiotic
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Are we ov erusing Antibiotics
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Choose the Appropriate
Antibiotic
Think before
prescribingAre we using
Right drug
for the Rightbug ?
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