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Rao MD
Dr.T.V.Rao MD
Virus Common cold Diarrhea (99%) Acute Bronchitis Influenza (flu) Measles Chicken Pox AIDS Rabies Hepatitis
Bacteria Urine infections Strep Throat Boils/abscesses Gangrene Some pneumonia Ear infections (half) Sinus infections (< half) Bubonic Plague Tuberculosis
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Bacteria
are the cause of the vast majority of deaths due to infection in the United States: sepsis, meningitis, pneumonia Most viral infections get better all by themselves in 1-3 weeks; no medications are required: colds, flu, stomach virus
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Development
They dont help the patient at all Expense: 75% of outpatient antibiotics are used for respiratory infections Patient expectations: why no better? Side effects: diarrhea, rash, allergy antibiotic wont work when you really DO need it for a bacterial infection
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of resistance: the
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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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
Dr.T.V.Rao MD
Dr.T.V.Rao MD
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
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Antimicrobial agents that are produced synthetically but have action similar to that of antibiotics and are defined as chemotherapeuti c agents
Eg Sulphonamides, Quinolones.
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Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism
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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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Development of anti-infectives
ertapenem tigecyclin daptomicin The development linezolid of anti-infectives telithromicin
quinup./dalfop.
1920 prontosil
pencillin G
cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin
1930
1940
1950
1960
1970
1980
1990
2000
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Dr.T.V.Rao MD
Antimicrobial agents are widely employed to cure bacterial diseases Definition of Antibiotic Antibiotics are substances that are derived from a various species of microorganisms and are capable of inhibiting the growth of other microorganism even in small concentrations.
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ANTIBIOTICS Sources
Natural
a.Fungi penicillin, griseofulvin
1.
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
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
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Is
an antibiotic necessary ? What is the most appropriate antibiotic ? What dose, frequency, route and duration ? Is the treatment effective ?
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Useful only for the treatment of bacterial infections Not all fevers are due to infection Not all infections are due to bacteria
There is no evidence that antibiotics will prevent secondary bacterial infection in patients with viral infection
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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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Decreased entry
Mechanisms of Resistance
Enzymatic degradation
Bypass pathway
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Antimicrobial Resistance:
Antimicrobial Resistance
Optimize Use
Infection
Effective Diagnosis & Treatment
Antimicrobial Use
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Antibiotic resistance is a consequence 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 their offspring, which will be a fully resistant generation.
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48% of all antibiotics by weight is added to animal feeds to promote growth. Results in low, sub therapeutic levels which are thought to promote resistance. Farm families who own chickens feed tetracycline have an increased incidence of tetracycline resistant fecal flora Chickens at Spanish supermarkets have >90% of cultured campylobacter resistant to quinolones 39% of enterococci in the fecal flora of pigs from the Netherlands is resistant to vancomycin vs 0% in Sweden. (Sweden bans antibiotic Dr.T.V.Rao MD additives in animal feed)
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Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and thirdgeneration Cephalosporins, generate resistant strains.
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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 an antimicrobial drug to which it is as a whole naturally susceptible Two mechanisms: 1. Mutational chromosomal 2. Genetic exchange transformation, transduction, conjugation
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The greatest possibility of evil in selfmedication 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-fast organisms 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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1980s ESBL producing GN bacteria 1990 Vancomycin resistant Enterococci emerged 2000 VISA (intermediate level resistance) 2002-VRSA (high level resistance) 2002- Linezolid resistant enterococci and Staphylococci reported
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Plasmid-Mediated TEM and SHV Enzymes ThirdGeneration Cephalosporins 1965 1970s 1980s
Evolution of b-Lactamase
Ampicillin
1983
1987
2000
TEM-1
Resistance to Antibiotics
Bacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed.
Moreover, increased use of antibiotics results in increased resistance (th paradox of antibiotics). The basic resistance mechanisms are quite simple: 1.Modify the antibiotic
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
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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
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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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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 Animals Laboratory Manipulations are called as Genetic Engineering
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Sulphonamides --- Reduce permeability Erythromycin ---- Modification of ribosome's Tetracyclnes ----- Reduced permeability Chloramphenicol ---- Acetylation of drug Streptomycin ----- Adenylation of drug Pencillin ----- Hydrolysis of lactum ring
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Therapeutic
failures and relapse Facilitates spread in the hospital under antibiotic pressure Need to use more costly and toxic agents The emergence of untreatable pathogens
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RESISTANCE
ACQUIRED RESISTANCE EXAMPLES:
2. mecA gene
Codes for a PBP with low affinity for -lactam antibiotics Methicillin-resistant S. aureus
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RESISTANCE
ORIGIN OF DRUG RESISTANCE NON-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)
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RESISTANCE
GENETIC
1. Chromosomal Occurs at a frequency of 10-12 to 10-7 20 to spontaneous mutation in a locus that controls susceptibility to a given drug due to mutation in gene that codes for either: a. drug target
RESISTANCE
GENETIC 2. Extrachromosomal a. Plasmid-mediated
Occurs in many different species, esp. gram (-) rods Mediate resistance to multiple drugs Can replicate independently of bacterial chromosome many copies
Can be transferred not only to cells of the same species but also to other species and genera
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100 90 80 70 60 50 40 30 20 10 1975
MRSA = methicillin-resistant Staphylococcus aureus VRE = vancomycin-resistant enterococci GISA = glycopeptide-intermediate S aureus VRSA = vancomycin-resistant S aureus MRSA1
VRE2 GISA3
1980 1985 1990
VRSA4
2002
Year
1995
1996
2000
1Smith
TL et al. N Engl J Med. 1999;340:493-501. 2Martone WJ. Infect Control Hosp Epidemiol. 1998;19:539-545. 3Hiramatsu K et al. J Antimicrob Chemother. 1997;40:135-136. 4CDC. MMWR Morb Mortal Wkly Rep. 2002;51:565-567.
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RESISTANCE
LIMITATION OF DRUG RESISTANCE
1. Maintain sufficiently high levels of the drug in the tissues inhibit original population and first-step mutants. 2. Simultaneous administration of two drugs that do not give cross-resistance delay emergence of mutants resistant to the drug (e.g. INH + Rifampicin)
3. Limit the use of a valuable drug avoid exposure of the organism to the drug
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management Mandatory infection 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 Dr.T.V.Rao MD
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The appropriate selection of antimicrobials The appropriate dosing of antimicrobials The appropriate route and duration of antimicrobial therapy
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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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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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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
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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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Patients
Other clinicians
Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients
Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics
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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.
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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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Surveillance
Prevention and Control Research Product Development
Health Care Financing Administration Department of Agriculture Agency for Health Care Research and Department of Quality Defense
Environmental Protection Agency Department of Veterans Affairs Health Resources and Services Administration Dr.T.V.Rao MD
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Think before prescribing Are we using Right drug for the Right bug ?
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Created
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