Rationalism of antibiotic therapy copy

Dr.T.V.Rao MD 1

Rationalism In Antibiotic Therapy

Dr.T.V.Rao MD

Fleming and Penicillin

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• 50 penicillin's• 71 cephalosporins• 12 tetracycline's• 8 aminoglycosides• 1 monobactam• 5 Carbapenems

• 9 macrolides• 2 streptogramins• 3 dihydrofolate

reductase inhibitors

• 1 oxazolidinone• 5.5 quinolones

Antibiotic brands

1920 1930 1940 1950 1960 1970 1980 1990 2000

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

The development

of anti-infectives …

Development of anti-microbials

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1962 and 2000, no major classes of antibiotics were introduced

Fischbach MA and Walsh CT Science 2009

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Antibiotics• Biology and Society

About 50% of the antibiotics produced today are used in the livestock industry.

What impact does this have on the treatment of human diseases?

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ANTIMICROBIAL RESISTANCE:The role of animal feed antibiotic additives

• 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

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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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How are antibiotics overused or misused?

• Seven out of ten Americans receive antibiotics when they seek treatment for a common cold! Only one-third of patients use antibiotics the way doctors tell them.

• .This allows bacteria to become resistant by not killing them completely.

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Antibiotic PrescribingChildren are real Concern

• Antibiotics were prescribed in 68% of acute respiratory tract visits – and of those, 80% were unnecessary according to CDC guidelines

• Children are of particular concern because they have the highest rates of antibiotic use.

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We too Contribute for Creating Drug Resistance

• Every time a person takes antibiotics, sensitive bacteria are killed, but resistant microbes may be left to grow and multiply. Repeated and improper uses of antibiotics are primary causes of the increase in drug-resistant bacteria.

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The consequences of antibiotic resistance

• Increased morbidity & mortality– “best-guess” therapy may fail with the patient’s

condition deteriorating before susceptibility results are available

– no antibiotics left to treat certain infections

• Greater health care costs– more investigations– more expensive, toxic antimicrobials required– expensive barrier nursing, isolation, procedures, etc.

• Therapy priced out of the reach of some third-world countries

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Costs Associated withIncreased Bacterial

Resistance• ↑Treatment failures• ↑Morbidity and mortality• ↑Risk of hospitalization• ↑Length of hospital stays• ↑Need for expensive and broad

spectrum antibiotics

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Social factors fuelling resistance

• Poverty encourages the development of resistance through under use of drugs– Patients unable to afford the full course of the medicines – Sub-standard & counterfeit drugs lack potency

• In wealthy countries, resistance is emerging for the opposite reason – the overuse of drugs. – Unnecessary demands for drugs by patients are often eagerly met

by health services and stimulated by pharmaceutical promotion– Overuse of antimicrobials in food production is also contributing

to increased drug resistance. Currently, 50% of all antibiotic production is used in animal husbandry and aquiculture

• Globalization, increased travel and trade ensure that resistant strains quickly travel elsewhere. So does excessive promotion.

Classification of Pencillins• Natural Benzyl penicillin Phenoxymethyl penicillin Penicillin v Semi synthetic and pencillase resistant 1 Methicillin 2 Nafcillin 3 Cloxacillin 4 Oxacillin 5 Floxacillin

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• Contain macro cyclic lactone ring Erythromycin. Is popularly used drug

• Other drugs Roxithromycin,Azithromycin

• Inhibits the protein synthesis.

• Used as alternative to pencillin allergy patients.

Macrolides,Azalides,Ketolides

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• Like penicillin acts similar

• Products of the molds of genus Cephalosporium except cefoxilin

• Divided into 4 generation of Cephalosporins depending on the spectrum of activity.

Cephalosporins

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Major generations of Cephalosporins

• Cephalosporins are divided into 3 generations:• 1st generation: Cephalexin, cefadroxil,

cephradine • 2nd generation: Cefuroxime, cofactor • 3rd generation: cefotaxime, Ceftazidime,

cefepime - these give the best CNS penetration • 4th generation Cephalosporins are already

available

• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first Cephalosporins were designated first generation while later, more extended spectrum Cephalosporins were classified as second generation Cephalosporins.

Different Generations of Cephalosporins

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5th Generation Cephalosporins

• Ceftaroline is a new intravenous (IV) cephalosporin that was FDA-approved October 2010. It is labelled for the treatment of adults with infections caused by susceptible bacteria, specifically skin and skin structure infections (SSSIs) caused by methicillin-sensitive

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5th Generation Cephalosporins

• Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, or Klebsiella oxytoca; and community acquired pneumonia (CAP) caused by Streptococcus pneumoniae (with or without concurrent bacteraemia), MSSA, E coli, Haemophilus influenza, K.pneumoniae, or K oxytoca

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Ceftaroline is effective …

• Ceftaroline is a fifth generation cephalosporin with excellent activity against GPCs including MRSA & DRSP Affinity for all PBPs including PBP 2’ and PBP 2X Not ESBL stable, Not active against Non fermenters

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Advantages with Newer generations

• Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram-positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity

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Other Beta-lactams include• Other beta-lactams include:• Aztreonam: a monocytic beta-

lactam, with an antibacterial spectrum which is active only against Gram negative aerobes, including Pseudomonas aeruginosa, Neisseria meningitides and N. gonorrhoea.

• Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram-positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity

Advantages with Newer generations

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How are Carbapenems Used?

Uses by Clinical Syndrome• Bacterial meningitis• Hospital-associated

sinusitis• Sepsis of unknown origin• Hospital-associated

pneumonia

Use by Clinical Isolate Acinetobacter spp. Pseudomonas aeruginosa Alcaligenes spp. Enterobacteriaceae

Mogenella spp. Serratia spp. Enterobacter spp. Citrobacter spp. ESBL or AmpC + E. coli

and Klebsiella spp.

Reference: Sanford Guide

Spectrum of ActivityDrug

Strep spp. &MSSA

Entero-bacteriaeae

Non-fermentors

Anaerobes

Imipenem + + + +

Meropenem + + + +

Ertapenem + + Limited activity +

Doripenem + + + +

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Emerging Carbapenem Resistance in Gram-Negative Bacilli

• Significantly limits treatment options for life-threatening infections

• No new drugs for gram-negative bacilli • Emerging resistance mechanisms,

carbapenemases are mobile, • Detection of carbapenemases and

implementation of infection control practices are necessary to limit spread

• Imipenem: a carbapenem with a broader spectrum of activity against Gram positive and negative aerobes and anaerobes. Needs to be given with cilastatin to prevent inactivation by the kidney.

Other drugs

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• Quinolones are the first wholly synthetic antimicrobials. The commonly used Quinolones.

• Act on the DNA gyrase which prevents DNA polymerase from proceeding at the replication fork and consequently stopping synthesis.

Quinolones

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Activity of New Fluoroquinolones Against MRSA, VRE and PRSP

MRSA VRE PRSP QTc change

Levofloxacin +/- +/- ++ 4.6 msc

Gatifloxacin +/- +/- ++++ 2.9 msc

Moxifloxacin +/- +/- ++++ 6 msc

Gemifloxacin +/- +/- ++++ 5 msc

Ciprofloxacin +/--- +/--- +/--- ?

• Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds

• Eg Streptomycin, • Act at the level of Ribosome's

and inhibits protein synthesis• Other Aminoglycosides –

Gentamycin, neomycins,paromomycins,tobramycins Kanamycins and

spectinomycins

Aminoglycosides

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• Broad spectrum antibiotic produced by Streptomyces species

• 1. Oxytetracycle, chlortetracycle and tetracycline

• Tetracyclnes are bacteriostatic drugs inhibits rapidly multiplying organisms

• Resistance develops slowly and attributed to alterations in cell membrane permeability to enzymatic inactivation of the drug

Tetracycline's

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• Lincomycins Clindamycin

resembles Macrolides in biting site and antimicrobial activity.

Streptogramins Quinpristin /

dalfopristin useful in gram

positive bacteria

Other Antimicrobial agents

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• Major anaerobes – Anaerobic cocci, clostridia and Bactericides are susceptible to Benzyl pencillin

• Bact.fragilis as well as many other anaerobes are treatable with Erythromycin,Lincomycin, tetracycline and Chloramphenicol

• Clindamycin is effective against many strains of Bacteroides

Antibiotics in Anaerobes

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• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.

• But also useful in treating parasitic infections

Trichomonas, Amoebiasis and other protozoan infections.

Metronidazole in Anaerobic Infections

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• In spite discovery of several antibiotics several microorganisms attained resistance.

• The major factor contributing to persistence of infectious disease has been the tremendous capacity of microorganisms for circumventing the action of inhibitory drugs.

• The drug resistance continues to be a threat for usefulness of the chemotherapeutic agents.

Drug Resistance

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

< Use of broad spectrum antibiotics when not indicated

< Inappropriate choice of empiric antibiotics

Inappropriate Antibiotic Use

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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

Multi Drug resistant pathogens

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Extended-Spectrum β-Lactamases

• β-lactamases capable of conferring bacterial resistance to

– the penicillins– first-, second-, and third-generation

cephalosporins– aztreonam – (but not the cephamycins or carbapenems)

• These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and SHV-1)

– differ from their progenitors by as few as one AA

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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

Antibiotic Resistance Threat to Humans and Animals

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Carbapenemases• Ability to hydrolyze penicillins, cephalosporins,

monobactams, and carbapenems• Resilient against inhibition by all commercially viable ß-

lactamase inhibitors– Subgroup 2df: OXA (23 and 48) carbapenemases– Subgroup 2f : serine carbapenemases from molecular class

A: GES and KPC – Subgroup 3b contains a smaller group of MBLs that

preferentially hydrolyze carbapenems• IMP and VIM enzymes that have appeared globally, most

frequently in non-fermentative bacteria but also in Enterobacteriaceae

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• KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumonia

• Substrate hydrolysis spectrum includes

cephalosporins and carbapenems

K. pneumonia carbapenemases)

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Consequences of Antibiotic drug Resistance

• People infected with drug-resistant organisms are more likely to have longer and more expensive hospital stays, and may be more likely to die as a result of the infection. They require treatment with second- or third-choice drugs that may be less effective, more toxic, and more expensive. This means that patients with an antimicrobial-resistant infection may suffer more and pay more for treatment. (Issues with Insurance)

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Emerging Trends in Antibiotic Resistance

• Reports of methicillin-resistant Staphylococcus aureus (MRSA)—a potentially dangerous type of staph bacteria that is resistant to certain antibiotics and may cause skin and other infections—in persons with no links to healthcare systems have been observed with increasing frequency in the United States and elsewhere around the globe.

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Gram negative bacteria a great threat

• Multi-drug resistant Klebsiella species and Escherichia coli have been isolated in hospitals throughout the United States.

• It is a Universal phenomenon

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Fungi too becoming resistant

• Antimicrobial resistance is emerging among some fungi, particularly those fungi that cause infections in transplant patients with weakened immune systems.

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Resistance in Virus• Antimicrobial

resistance has also been noted with some of the drugs used to treat human immunodeficiency virus (HIV) infections and influenza.

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Parasites too are Problematic• The development of

antimicrobial resistance to the drugs used to treat malaria infections has been a continuing problem in many parts of the world for decades. Antimicrobial resistance has developed to a variety of other parasites that cause infection.

•

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Identification of The Etiological Agent

Laboratory diagnosis Interpretation of the report What is isolated is not necessarily the

pathogen Was the specimen properly collected ? Is it a contaminant or colonizer ? Sensitivity reports are at best a guide

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• The role of combination antimicrobial therapy for the prevention of resistance is limited to those situations in which there is

A high organism load A high frequency of

mutational resistance during therapy.

• Classic examples are tuberculosis or HIV infection.

Limitations of combination of antibiotics

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Problems With Improper Use of Antibiotics

• They don’t 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

• Development of resistance: the antibiotic won’t work when you really DO need it for a bacterial infection

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WHO global strategy on reducing the antibiotic resistance

• The WHO Global Strategy for Containment of Antimicrobial Resistance identifies the establishment and support of microbiology laboratories as a fundamental priority in guiding and assessing intervention efforts.

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Importance of local antibiotic Resistance data

Resistance patterns vary From country to country From hospital to hospital in the same country From unit to unit in the same hospital

Regional/Country data useful only for looking at trends NOT guide empirical therapy

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Streamlining or De-Escalation of Therapy

–On the basis of culture and sensitivity reports we can more effectively target the causative pathogens, by elimination of redundant combination therapy

–Resulting in decreased Ab exposure and substantial cost savings

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• Training and educating health care professionals on the appropriate use of antibiotics must include appropriate selection, dosing, route, and duration of antibiotic therapy. To ensure that training and education is working, there should be extensive collaboration between the antibiotic stewardship and hospital infection prevention and control teams.

Continuous Medical Education a Must ..

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Antibiotic Pressure and Resistance in Bacteria What factors promote their development and

spread ?

< Alteration of normal flora

< Practices contributing to misuse of antibiotics

< Settings that foster drug resistance

< Failure to follow infection control principles

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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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Hospital < Intensive care units

< Oncology units

< Dialysis units

< Rehab units

< Transplant units

< Burn units

Settings that Foster Drug Resistance

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Implementation of WHONET CAN HELP TO MONITOR RESISTANCE

• Legacy computer systems, quality improvement teams, and strategies for optimizing antibiotic use have the potential to stabilize resistance and reduce costs by encouraging heterogeneous prescribing patterns and use of local susceptibility patterns to inform empiric treatment.

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Drugs Under DevelopmentPRSP, MRSA,VISA,VRE

• Lipopetides (Daptomycin: narrow therapeutic index)

• Glycyclines• Glycopeptides (Vancomycin analogues)• Fluoroquinolones • Macrolides/Ketolides• Evernimicin (trials on hold)

Physicians Can Impact

O th e r clin ician s

Patients

Optimize patient evaluation Adopt judicious antibioticprescribing practicesImmunize patients

Optimize consultations with other cliniciansUse infection control measuresEducate others about judicious use of antibiotics

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• Treatment should be limited to bacterial infections, using antibiotics directed against the causative agent, given in optimal dosage, interval and length of treatment, with steps taken to ensure maximum patient compliance with the treatment regimen and only when the benefit of treatment outweighs the individual and global risks

A good clinical practice saves antibiotics

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• Training and educating health care professionals on the appropriate use of antibiotics must include appropriate selection, dosing, route, and duration of antibiotic therapy. To ensure that training and education is working, there should be extensive collaboration between the antibiotic stewardship and hospital infection prevention and control teams

Continuous Medical Education a Must ..

Are we overusing Antibiotics

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Good hand washing practices still reduces antibiotic resistance and spread

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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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Antibiotics save LivesSave Antibiotics from Misuse

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• Programme Created by Dr.T.V.Rao MD for Medical and

Paramedical Professionals in the Developing World

• Email• doctortvrao@gmail.com