The war on drugs the mythology of antibiotics
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The War on Drugs: The Mythology of Antibiotics. Edward L. Goodman, MD, FACP, FIDSA, FSHEA May 9, 2005. An Epidemic of Drastic Proportions: demographics. Affects people of all ages Disproportionately involves the very young and very old Involves the more affluent and well insured

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The War on Drugs: The Mythology of Antibiotics

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The war on drugs the mythology of antibiotics

The War on Drugs:The Mythology of Antibiotics

Edward L. Goodman, MD, FACP, FIDSA, FSHEA

May 9, 2005


An epidemic of drastic proportions demographics

An Epidemic of Drastic Proportions: demographics

  • Affects people of all ages

    • Disproportionately involves the very young and very old

    • Involves the more affluent and well insured

  • Costs in the billions

    • Producers reap huge profits

    • Pushers are among elite

    • Users are not addicted

      • Sometimes still demand a drug fix


Effects of the epidemic

Effects of the Epidemic

  • Direct toxicity of the drugs

    • Diarrhea from most

    • Deafness from a few

    • Renal failure from quite a few

    • Skin rash from all

    • Secondary infections from all

    • IV phlebitis from all


Indirect effects secondary infections

Indirect Effects: Secondary Infections

  • Pneumonia

    • Vent associated

  • Bacteremia/fungemia

    • Line associated

  • MDR Urinary tract infections

    • Catheter associated

  • Prolonged hospital stay

  • Excessive costs


Description of pushers

Description of “Pushers”

  • Well educated

  • Well intentioned

  • Extremely Defensive

    • Fearful of lawyers

    • Use that as an excuse

  • Forgetful

    • Forgotten lessons of graduate school

  • Addicted to the culture of cultures


The truth

The Truth

  • Producers = PHARMA

  • Pushers = physicians

  • Victims = all of us

  • Drugs = antimicrobials

  • Root Causes = ignorance of microbiology, epidemiology, pharmacology

  • DRUGS OF FEAR


More of the truth

More of the Truth

  • Antibiotic use (appropriate or not) leads to microbial resistance

  • Resistance results in increased morbidity, mortality, and cost of healthcare

  • Antibiotics are used as “drugs of fear”

  • (Kunin et al. Annals 1973;79:555)

  • Appropriate antimicrobial stewardship will prevent or slow the emergence of resistance among organisms (Clinical Infectious Diseases 1997; 25:584-99.)


Antibiotic misuse

Antibiotic Misuse

  • Published surveys reveal that:

    • 25 - 33% of hospitalized patients receive antibiotics (Arch Intern Med 1997;157:1689-1694)

    • At PHD during 1999, 2000 and 2001, 50-60% of patients received antibiotics

    • 22 - 65% of antibiotic use in hospitalized patients is inappropriate (Infection Control 1985;6:226-230)


Consequences of misuse of antibiotics

Consequences of Misuse of Antibiotics

  • Contagious RESISTANCE

    • Nothing comparable for overuse of procedures, surgery, other drugs

  • Morbidity - drug toxicity

  • Mortality - MDR bacteria harder to treat

  • Cost


Appropriate use of antibiotics

Appropriate Use of Antibiotics

  • Need 8-10 lectures

  • Many useful reference sources

    • Sanford Guide (hard copy or electronic)

    • Epocrates (epocrates.com)

    • Hopkins abx-guide (hopkins-abx.guide.org)

    • ID Society – practice guidelines (idsociety.org)


Inappropriate use of antibiotics

Inappropriate Use of Antibiotics

  • Asymptomatic UTI in non pregnant patients

  • “Acute sinusitis” before trial of 7-10 days of symptomatic treatment (NEJM 8/26/04)

  • Respiratory cultures when there is no clinical evidence of pneumonia

  • Positive catheter tip cultures when no bacteremia

  • Coagulase negative staph in single blood cultures

  • FUO with no clinical site of infection

  • Prophylaxis for surgery beyond 24 hours


More inappropriate uses

More Inappropriate Uses

  • Aseptic meningitis when already pretreated

    • Consider observe 6-8 hours, then retap

  • Abnormal CXR when no clinical symptoms for pneumonia

  • Swabs of open wounds growing potential pathogens

  • THE LIST COULD GO ON FOREVER!


Antibiotic myths

Antibiotic Myths

  • More is better

  • IV is better than oral

  • Longer duration is better

  • Multiple drugs are better

  • Vancomcyin: a whole mythology of its own

  • Miscellaneous


Is more better

Is More Better?

  • What does “more” (higher doses) accomplish?

    • Higher serum levels, and thus

    • Higher tissue levels

  • But when are higher levels needed?

    • Privileged sanctuary where drugs penetrate poorly

      • CSF/vitreous

      • Heart valve vegetations

      • Implants/prostheses/biofilms

    • Defenseless host


Pharmacodynamics

Pharmacodynamics

  • MIC=lowest concentration to inhibit growth

  • MBC=the lowest concentration to kill

  • Peak=highest serum level after a dose

  • AUC=area under the concentration time curve

  • PAE=persistent suppression of growth following exposure to antimicrobial


Parameters of antibacterial efficacy

Parameters of antibacterial efficacy

  • Time above MIC - beta lactams, macrolides, clindamycin, glycopeptides

  • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin

  • Peak/MIC - aminoglycosides, fluoroquinolones


Time over mic associated with better killing

Time over MIC associated with better killing

  • Should exceed MIC for at least 50% of dose interval for beta lactams and vancomycin

  • Higher doses may allow longer time over MIC

  • For most beta lactams, optimal time over MIC can be achieved by continuous infusion (except unstable drugs such as imipenem, ampicillin)


Higher serum tissue levels are associated with faster killing

Higher serum/tissue levels are associated with faster killing

  • Aminoglycosides

    • Peak/MIC ratio of >10-12 optimal

    • Achieved by “Once Daily Dosing”

    • PAE helps

  • Fluoroquinolones

    • 10-12 ratio achieved for enteric GNR

      • PAE helps

    • not achieved forPseudomonas

    • Not always for Streptococcus pneumoniae


Auc mic auic

AUC/MIC = AUIC

  • For Streptococcus pneumoniae, FQ should have AUIC >= 30

  • For gram negative rods where Peak/MIC ratio of 10-12 not possible, then AUIC should >= 125.


The war on drugs the mythology of antibiotics

AUC

MIC90

Pharmacodynamic Parameters of Fluoroquinolones

Cmax (peak)

  • For optimal antimicrobial effect:– Cmax/MIC should be > 8-10or

  • – AUC/MIC should be > 125 for GNR, >30 for GPC

Antibiotic

serum concentration

AUC

MIC

Time above MIC

Time (h)


More is better continued

“More is Better” continued

  • Since beta lactams don’t kill any better at higher concentrations

    • Why give them IV?

    • Why increase dose?

    • Just give often enough

  • Confounding factor

    • Higher dose gives higher serum levels which may exceed MIC for longer time


When is iv better than enteral

When is IV better than enteral?

  • Patient unable to take enteral meds/food

  • Patient unable to absorb enterally

    • Short bowel syndrome

    • Malabsorption

    • Vascular collapse

    • Ileus


Completely bioavailable iv and enteral essentially identical give enterally if possible

“Completely” BioavailableIV and enteral essentially identicalGIVE ENTERALLY IF POSSIBLE

  • Respiratory quinolones (90-98%)

  • Fluconazole (90%)

  • Trimethoprim sulfa (85%)

  • Metronidazole (90%)

  • Doxycycline/minocycline (93/95%)

  • Clindamycin (90%)

  • Linezolid (100%)


Well absorbed no iv formulation to compare

Well Absorbed No IV formulation to compare

  • Cephalexin (90%)

  • Amoxycillin (75%)

  • Dicloxacillin (50%)

  • Clarithromycin (50%)

  • Since none of these are concentration dependent, enteral therapy should suffice if levels >MIC for >50% dosing interval

    • Easily achieved for these agents


Is longer duration better

Is Longer Duration Better?

  • In every study comparing two lengths of therapy, shorter is as good

    • Two weeks Pen & Gent for viridans strept SBE = 4 weeks of Pen alone

    • Two weeks of PO Cipro and Rif for right sided OSSA endocarditis = 4 weeks of IV Nafcillin

    • Five days of Levaquin 750 for CAP = 10 days of 500 daily (CID 10/03)

    • Eight days Rx for HAP (non Pseudomonas) = 14 days (ATS/IDSA 1/05)

    • Three days of T/S or FQ for cystitis = 10 days


Is longer worse

Is Longer Worse?

  • Increases antibiotic resistance

  • Exposes patient to more toxicity

  • Increases cost

  • May actually increase the risk of some infections


When are multiple antibiotics indicated

When are Multiple Antibiotics Indicated?

  • Empiric therapy when organism(s) not known

  • For mixed infections when one drug won’t cover

  • For synergy

  • To retard or prevent the development of resistance


When is synergy needed

When is Synergy Needed?

  • If it allows reduction in dosage of toxic components of a combination

    • Flucytosince with AMB can shorten the course and lower the dose of AMB for Crypto meningitis (non HIV patients)

    • No other good example


Synergy needed

Synergy Needed

  • When monotherapy is not bactericidal

    • Enterococcal endocarditis

      • Neither penicillin nor aminoglycoside are ‘cidal by themselves

      • When combined ‘cidal activity produced

    • Other enterococcal infections do not need ‘cidal therapy including bacteremia unassociated with IE


When is cidal therapy needed

When is Cidal Therapy Needed

  • Bacterial Endocarditis

  • Bacterial Meningitis

  • Maybe neutropenic or immunocompetent host

  • Maybe osteomyelitis

  • Not for almost all other bacterial infections


When are multiple drugs needed to prevent retard development of resistance

When are Multiple Drugs Needed to Prevent/Retard Development of Resistance?

  • HIV therapy

  • Chemotherapy of active TB

  • ? Severe P. aeruginosa bacteremia/ pneumonia

    • No real data that dual Rx prevents emergent beta lactam resistance

    • Instead it provides a second drug in case beta lactam resistance emerges


Vancomycin myths

Vancomycin Myths

  • “Ultimate drug for gram positive”

    • Clearly inferior to Nafcillin for sensitive staph

    • Slowly bactericidal

    • High failure rate in MRSA infections

    • Will likely be supplanted by Daptomycin/Linezolid

  • “Vancomycin is a toxic drug”

    • No clear evidence of renal or oto-toxicity in monoRx

    • When combined with aminoglycoside, 30-40% risk of toxicity


More vanco myths

More Vanco Myths

  • “Must do serum levels” (predicted on prior myth)

    • Non concentration dependent

      • So peaks unnecessary except for meningitis

    • No correlation with efficacy/toxicity ever demonstrated in literature

    • Cannot measure true peaks

      • Long alpha phase

      • Must do log decay curve

  • Troughs may allow less frequent dosing


More myths

More Myths

  • Keflex is still a appropriate for outpatient SSI, respiratory infections

    • >50% of staph aureus are MRSA

    • Poor activity vs. pen resist pneumococcus, Hemophilus

  • Fluoroquinolones are superior for UTI, sinusitis, bronchitis, pneumonia

    • Not unless resistant organisms


The solution

The Solution

  • Vaccinate against preventable infections

  • Reduction in promiscuous cultures

    • Lead to unnecessary Rx

  • Antimicrobial stewardship

    • Restriction of drugs by

      • Payors

      • Antimicrobial Management Programs

  • EDUCATION

  • Computerized Physician Order Entry


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