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

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

  • 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

  • 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

  • Pneumonia

    • Vent associated

  • Bacteremia/fungemia

    • Line associated

  • MDR Urinary tract infections

    • Catheter associated

  • Prolonged hospital stay

  • Excessive costs


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

  • Producers = PHARMA

  • Pushers = physicians

  • Victims = all of us

  • Drugs = antimicrobials

  • Root Causes = ignorance of microbiology, epidemiology, pharmacology

  • DRUGS OF FEAR


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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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?

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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.


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

  • 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?

  • Patient unable to take enteral meds/food

  • Patient unable to absorb enterally

    • Short bowel syndrome

    • Malabsorption

    • Vascular collapse

    • Ileus


“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

  • 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?

  • 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?

  • Increases antibiotic resistance

  • Exposes patient to more toxicity

  • Increases cost

  • May actually increase the risk of some infections


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?

  • 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

  • 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

  • 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?

  • 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

  • “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

  • “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

  • 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

  • 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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