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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

Dr.T.V.Rao MD


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Beginning of Antibiotics with Discovery of Pencillin

  • 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


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Discovery of Pencillin Awarded Nobel Prize

Dr.T.V.Rao MD


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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

Dr.T.V.Rao MD


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Chemotherapeutic Agents

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

  • Eg Sulphonamides, Quinolones.

Dr.T.V.Rao MD


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Definition

  • 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 )

Dr.T.V.Rao MD


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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

Development of anti-infectives

The development

of anti-infectives …

Dr.T.V.Rao MD


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Uses of Antimicrobial Agents

  • 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.

Dr.T.V.Rao MD


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ANTIBIOTICS

  • Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism

Dr.T.V.Rao MD


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ANTIBIOTICS – Sources

  • Natural

    • Fungi – penicillin, griseofulvin

    • Bacteria – Bacillus sp. (polymixin, bacitracin) ; Actinomycetes (tetracycline, chloramphenicol, streptomycin)

  • Synthetic

Dr.T.V.Rao MD


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ANTIMICROBIAL AGENT

  • Ideal Qualities:

  • kill or inhibit the growth of pathogens

  • cause no damage to the host

  • cause no allergic reaction to the host

  • stable when stored in solid or liquid form

  • remain in specific tissues in the body long enough to be effective

  • kill the pathogens before they mutate and become resistant to it

Dr.T.V.Rao MD


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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.

–β-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 metabolism

Dr.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 ?

Dr.T.V.Rao MD


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Is an antibiotic necessary ?

  • 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

Dr.T.V.Rao MD


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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 infections as good as parenteral

Dr.T.V.Rao MD


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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

Dr.T.V.Rao MD


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Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Antimicrobial-ResistantPathogen

Prevent

Infection

PreventTransmission

Infection

Antimicrobial Resistance

Effective

Diagnosis

& Treatment

Optimize Use

Antimicrobial Use

Antimicrobial Resistance:Key Prevention Strategies

Susceptible Pathogen

Pathogen

Dr.T.V.Rao MD


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Emerging Resistance Settings

  • 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.

Dr.T.V.Rao MD


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Irrational Use of Third Generation Cephalosporins Settings

  • 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 third-generation Cephalosporins, generate resistant strains.

Dr.T.V.Rao MD


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Origin of Drug Resistant Strains Settings

  • 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.

Dr.T.V.Rao MD


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RESISTANCE Settings

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:

    • Mutational – chromosomal

    • Genetic exchange – transformation, transduction, conjugation

Dr.T.V.Rao MD


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Self Medication Settings

  • 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-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

Dr.T.V.Rao MD


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Historical aspects Settings

  • 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

Dr.T.V.Rao MD


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Evolution of b-Lactamase Settings

Plasmid-Mediated TEM and SHV Enzymes

Third-Generation

Cephalosporins

Ampicillin

1980s

1965

1970s

1987

2000

1983

1963

TEM-1

Reported in

28 Gram-

Negative

Species

TEM-1

E coli

S paratyphi

ESBL

in

United

States

>120 ESBLs

Worldwide

ESBL in

Europe

Dr.T.V.Rao MD


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Resistance to Antibiotics Settings

•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 (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 difficult for the antibiotic to get into the cell

5.Actively remove the antibiotic from the cell

Dr.T.V.Rao MD


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Plasmids Settings

  • 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

    T.V.Rao MD

Dr.T.V.Rao MD


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Resistance Transfer Factor SettingsRTF

  • 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

Dr.T.V.Rao MD


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RTF Settings

  • Shigella + E.coli excreted in the stool resistant to several drugs in vivo and vitro

  • Plasmid mediated –transmitted by Conjugation

  • Episomes spread the resistance

Dr.T.V.Rao MD


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Transposons and R factor Settings

  • 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

Dr.T.V.Rao MD


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Plasmid Mediated Drug resistance Settings

Sulphonamides --- Reduce permeability

Erythromycin ---- Modification of ribosome's

Tetracyclnes ----- Reduced permeability

Chloramphenicol ---- Acetylation of drug

Streptomycin ----- Adenylation of drug

Pencillin ----- Hydrolysis of lactum ring

Dr.T.V.Rao MD


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RESISTANCE Settings

ACQUIRED RESISTANCE – EXAMPLES:

  • Resistance (R) plasmids

    • Transmitted by conjugation

  • mecA gene

    • Codes for a PBP with low affinity for -lactam antibiotics

    • Methicillin-resistant S. aureus

Dr.T.V.Rao MD


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RESISTANCE Settings

ORIGIN OF DRUG RESISTANCE

NON-GENETIC

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

  • Loss of specific target structure for a drug for several generations

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

Dr.T.V.Rao MD


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RESISTANCE Settings

GENETIC

  • 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

      b. transport system in the membrane that controls drug uptake

Dr.T.V.Rao MD


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RESISTANCE Settings

GENETIC

  • 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

Dr.T.V.Rao MD


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Practices Contributing to Settings

Misuse of Antibiotics

  • Inappropriate specimen selection and collection

  • Inappropriate clinical tests

  • Failure to use stains/smears

  • Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD


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RESISTANCE Settings

LIMITATION OF DRUG RESISTANCE

Maintain sufficiently high levels of the drug in the tissues  inhibit original population and first-step mutants.

Simultaneous administration of two drugs that do not give cross-resistance  delay emergence of mutants resistant to the drug (e.g. INH + Rifampicin)

Limit the use of a valuable drug  avoid exposure of the organism to the drug

Dr.T.V.Rao MD


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What Is Antimicrobial Stewardship? Settings

• A cominationof infection control and antimicrobial 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

Dellit TH, et al. Clin Infect Dis. 2007;44:159-177.

Dr.T.V.Rao MD


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IDSA Guidelines – Definition of Settings

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

Dr.T.V.Rao MD


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The Primary Goal of Settings

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

Dr.T.V.Rao MD


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The Primary Goal of Settings

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

Dr.T.V.Rao MD


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Practices Contributing to Settings

Misuse of Antibiotics

  • Inappropriate specimen selection and collection

  • Inappropriate clinical tests

  • Failure to use stains/smears

  • Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD


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Inappropriate Antibiotic Use Settings

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

  • Use of broad spectrum antibiotics when not indicated

  • Inappropriate choice of empiric antibiotics

Dr.T.V.Rao MD


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Inappropriate Drug Regimen Settings

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

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

  • Inappropriate duration

Dr.T.V.Rao MD


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Multi Drug resistant pathogens Settings

  • 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

Dr.T.V.Rao MD


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Antibiotic Resistance SettingsThreat 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

Dr.T.V.Rao MD


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Dr.T.V.Rao MD Settings


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Between 1962 and 2000, no major classes of antibiotics were introduced

Fischbach MA and Walsh CT Science 2009

Dr.T.V.Rao MD


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Physicians Can Impact introduced

Other clinicians

Patients

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

Dr.T.V.Rao MD


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Antibiotic Pressure and Resistance in Bacteria: introducedConclusions

  • 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.

Dr.T.V.Rao MD


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Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Prevent Transmission

Use Antimicrobials Wisely

Diagnose & Treat Effectively

Prevent Infections

12 Break the chain

11 Isolate the pathogen

10 Stop treatment when cured

9 Know when to say “no” to vanco

8 Treat infection, not colonization

7 Treat infection, not contamination

6 Use local data

5 Practice antimicrobial control

4 Access the experts

3 Target the pathogen

2 Get the catheters out

1 Vaccinate

12 Steps to Prevent Antimicrobial Resistance

Dr.T.V.Rao MD


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Conclusions Settings

  • 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

Dr.T.V.Rao MD


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Are we overusing Antibiotics Settings

Dr.T.V.Rao MD


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Choose the Appropriate Antibiotic Settings

Think before prescribing Are we using Right drug for the Right bug ?

Dr.T.V.Rao MD


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The e-programme created by Dr.T.V.Rao MD for teaching the Medical Graduates in the Developing world.

Email

doctortvrao@gmail.com

Dr.T.V.Rao MD


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