The War on Drugs: The Mythology of Antibiotics

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The War on DrugsThe Mythology of Antibiotics

• Edward L. Goodman, MD, FACP, FIDSA, FSHEA
• May 9, 2005

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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

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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

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Indirect Effects Secondary Infections

• Pneumonia
• Vent associated
• Bacteremia/fungemia
• Line associated
• MDR Urinary tract infections
• Catheter associated
• Prolonged hospital stay
• Excessive costs

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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

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The Truth

• Producers PHARMA
• Pushers physicians
• Victims all of us
• Drugs antimicrobials
• Root Causes ignorance of microbiology,
  epidemiology, pharmacology
• DRUGS OF FEAR

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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 197379555)
• Appropriate antimicrobial stewardship will
  prevent or slow the emergence of resistance among
  organisms (Clinical Infectious Diseases 1997
  25584-99.)

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Antibiotic Misuse

• Published surveys reveal that
• 25 - 33 of hospitalized patients receive
  antibiotics (Arch Intern Med 19971571689-1694)
  
• 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
  19856226-230)

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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

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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)

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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

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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!

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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

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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

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Pharmacodynamics

• MIClowest concentration to inhibit growth
• MBCthe lowest concentration to kill
• Peakhighest serum level after a dose
• AUCarea under the concentration time curve
• PAEpersistent suppression of growth following
  exposure to antimicrobial

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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

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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)

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Higher serum/tissue levels are associated with
faster killing

• Aminoglycosides
• Peak/MIC ratio of gt10-12 optimal
• Achieved by Once Daily Dosing
• PAE helps
• Fluoroquinolones
• 10-12 ratio achieved for enteric GNR
• PAE helps
• not achieved for Pseudomonas
• Not always for Streptococcus pneumoniae

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AUC/MIC AUIC

• For Streptococcus pneumoniae, FQ should have AUIC
  gt 30
• For gram negative rods where Peak/MIC ratio of
  10-12 not possible, then AUIC should gt 125.

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Pharmacodynamic Parameters of Fluoroquinolones
Cmax (peak)

• For optimal antimicrobial effect Cmax/MIC
  should be gt 8-10or
• AUC/MIC should be gt 125 for GNR, gt30 for GPC

Antibiotic serum concentration
AUC
MIC
Time above MIC
Time (h)
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Parameters of Killing

• Concentration dependent pharmacodynamics
• Quinolones
• Aminoglycosides
• Telithromycin
• Non concentration dependent
• All the others
• Various parameters of efficacy

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Concentration Dependent

• Need peak level/MIC of 10-12
• Easily achieved with most enteric pathogens with
  FQ
• Less easily achieved for FQ with Pseudomonas
• Easily achieved with once daily aminoglycoside
• Cant push levels much higher
• Narrow therapeutic index

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Non Concentration DependentTime Dependent
Killing

• Beta lactams, glycopeptides, macrolides and most
  others
• Parameters of efficacy
• Time above MIC 50 of dose interval
• Unless significant post antibiotic effect (PAE)
• AUC/MIC above a certain threshold

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More is Better continued

• Since beta lactams dont 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

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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

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Completely BioavailableIV and enteral
essentially identical GIVE ENTERALLY IF POSSIBLE

• Respiratory quinolones (90-98)
• Fluconazole (90)
• Trimethoprim sulfa (85)
• Metronidazole (90)
• Doxycycline/minocycline (93/95)
• Clindamycin (90)
• Linezolid (100)

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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 gtMIC
  for gt50 dosing interval
• Easily achieved for these agents

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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

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Is Longer Worse?

• Increases antibiotic resistance
• Exposes patient to more toxicity
• Increases cost
• May actually increase the risk of some infections

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When are Multiple Antibiotics Indicated?

• Empiric therapy when organism(s) not known
• For mixed infections when one drug wont cover
• For synergy
• To retard or prevent the development of resistance

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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

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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

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When is Cidal Therapy Needed

• Bacterial Endocarditis
• Bacterial Meningitis
• Maybe neutropenic or immunocompetent host
• Maybe osteomyelitis
• Not for almost all other bacterial infections

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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

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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

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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

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More Myths

• Keflex is still a appropriate for outpatient SSI,
  respiratory infections
• gt50 of staph aureus are MRSA
• Poor activity vs. pen resist pneumococcus,
  Hemophilus
• Fluoroquinolones are superior for UTI,
  sinusitis, bronchitis, pneumonia
• Not unless resistant organisms

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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