Antibiotic resistance� What�s dosing got to do with it?

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Antibiotic resistance� What�s dosing got to do with it? Powered By Docstoc
					        Antibiotic resistance—
        What’s dosing got to do
                with it?
Crit Care Med 2008
Jason A. Roberts, B Pharm (Hons); Peter Kruger, MBBS, FJFICM; David L.
Paterson, MBBS, FRACP, PhD; Jeffrey Lipman, MBBCh, FJFICM, MD

                                                       Ri 高姿芸
 Bacteria continue to out-perform clinician by
  developing increasing levels of resistance
 Protecting the efficacy of existing antibiotic
  armamentarium is essential.
 Increasing rate of antibiotic resistance

 inappropriate antibiotic dosing

 poor infection control
                             Crit Care Med 2008
   Objective: link antibiotic dosing and the
    development of antibiotic resistance for
    different antibiotic classes apply
    pharmacodynamic principles to assist clinical
    practice for suppressing the emergence of
   Data Sources: PubMed, EMBASE, and the
    Cochrane Controlled Trial Register.
   Study Selection: antibiotic doses and exposure
    to the formation of antibiotic resistance “antibiotic” or
    “antibacterial,” “resistance” or “susceptibility,” and “dosing” or “exposure.”
   Some conceptions:
    Mutant Prevention Concentration ; Mutant Selection Window
    Antibiotic Pharmacodynamics
   Antibiotics : fluoroquinolone, aminoglycoside, B-lactam,
    carbapenem, glycopeptide
   Combination Antibiotic Therapy
   Effect of Bacterial Factors
   Cross Resistance
   Patient Factors?
        Resistance Development can
          Depend on the Level of
            Antibiotic Exposure
   1976, Stamey and Bragonje: correlated antibiotic
    underdosing with resistance formation.
   100 strains of Enterobacteriaceae in vitro
   Resistance to nalidixic acid increased w/ lower
    underdosage probably cause resistance
             Mutant Prevention
 Prevent emergence of all single step mutations
  in a population of at least 1010 bacterial cells
 Determining optimal dosing regiment

   Specific target concentrations  minimize
  the formation of resistant mutants
 With increasing antibiotic concentrations, colony numbers exhibited a
 sharp drop (first-step resistant mutants), followed by a plateau and then a
 Second sharp drop in colony numbers.
The mutant prevention concentration requires at least a second-step
mutation for bacterial survival
   MPCs for individual antibiotics: important step
    in developing dosing guidelines
           Mutant Selection Window
   antibiotic concentrations between MIC and
    MPC—resistant mutants may be selected

- been defined for many of the fluoroquinolones and some B-lactams
against various organisms. clinical relevance is still not clear
       Resistance Depends on the
        Antibiotic Administered
 Some antibiotics are associated with higher rates
  of resistance
 Ex: fluoroquinolones

 moxifloxacin superior to ciprofloxacin

  - in vitro ; Stenotrophomonas maltophilia model
  - delaying the selection of resistant mutants
         Antibiotic Pharmacodynamics

rate and extent of an antibiotic’s activity depend on:
-drug concentrations at the site of infection,
-bacterial load
-phase of bacterial growth
-MIC of the pathogen
   fluoroquinolone,
   aminoglycoside,
   B-lactam,
   carbapenem,
   glycopeptide
   Largely concentration-dependent (some time-
    dependent )
   a high Cmax:MIC ratio
         (e.g.,up to 10 for ciprofloxacin and lomefloxacin)
# assists bacterial killing
# minimizing the development of resistant mutants
 AUC0–24/MIC: >125GNO
 Reduce the development of resistance
 Eg: Gumbo et al.:AUC0–24/MIC of 53 :
  moxifloxacin for complete suppression of
  Mycobacterium tuberculosis
   Recommended dose of fluoroquinolones
    may be inappropriately low
   Reevaluation of existing dosing regimens
    are appropriate
   dosing attains high Cmax:MIC is

   Concentration- dependent
     Cmax:MIC >10: recommended for optimal
     - Suboptimal dosing : may lead to adaptive
   Improved Cmax:MIC reduce
    thispostantibiotic effect
   Bacterial mutability can occur with
    subtherapeutic aminoglycoside exposure
   Maximize Cmax:MIC & inherent postantibiotic
    effect to reduced toxicityonce daily dosing

   Time-dependent: T > MIC
   Maximal killing :
   antibiotic concentration maintained at 4–5 MIC
   minimum standard: time above MIC
   - about 50% of dosing interval for penicillins
    - 60%–70% for cephalosporins
    - 40% for carbapenems
   Fantin et al. experimental Pseudomonas
    aeruginosa aortic endocarditis in rabbits
   cefpirome and ceftazidime
   antibiotic concentration fall below MIC for
    >50% the dosing interval
    bacterial resistance to B-lactams may
   how B-lactam exposures may prevent
    resistance? No accurately define
   concentrations greater than 4 MIC for
    extended intervals
    more frequent dosing or even
       extended- or continuous-infusion.

   a reduced percentage of T > MIC
    compared with other B-lactams
   serious P. aeruginosa infections:risk of
    resistance development
   Eg: imipenem 1-g Q8h 50% of P.
    aeruginosa strains developed resistance
   Hoe to prevent??
   in vitro hollow-fiber infection model:
    Cmin:MIC > 6.2 could suppress
   Maintain carbapenem : 4–6 MIC
   Extended infusions may be beneficial
   Eg: extended infusion doripenem
    V.S.conventional infusion imipenem
    Only 18% V.S. 50% resistance of P.

 time-dependent ; Cmax:MIC ??
 AUC0–24:MIC : clinical efficacy

 Resistance: total exposure.

 higher dosing (up to 40 mg/kg): may be
  important for reducing resistance development
 Dosage adjustments:

 assist achieve target concentrations (15–25
    Combination Antibiotic Therapy

 Theoretically, avoiding resistance development
 AUC0–24/MIC: additive or even synergistic

 reach target exposure & avoiding excess total
  time in mutant selection window
 reduce the chance of resistance

 Early in the infection course : inoculum of
  infecting organisms is highest.
    Effect of Bacterial Factors—
Species,Subpopulation, Fitness, Load
    Antibiotic treatment on the development of
     resistance in normal commensal flora.
    Bacteria Speciesl:P. aeruginosa
     resistance to moxifloxacin more readily
     than S. pneumoniae
 Subpopulations: opportunities increase
 Bacterial fitness

 Bacterial load
P. aeruginosa:
  bacterial population increase 10X
 dose requirements increase 2–6 X
   Maximum    tolerated antibiotic doses
          Cross Resistance

 Exposure to an antibiotic can induce
  resistance to antibiotics with different
  modes of action
 in vitro model by Fung-Tomc et al.

 exposure of MRSA to subinhibitory levels
  of ciprofloxacin low-level resistance to
  tetracycline, imipenem, fusidic acid, and
           Patient Factors?

 altered pharmacokinetic
 organ dysfunction and various disease
 Further research: optimal dosing in
  specific patient populations and disease
  states for minimize resistance
 Highest tolerated dose

   Achieving specific pharmacodynamic
    targets for antibiotic exposure can help
    reduce the development of resistance
   Research has defined pharmacodynamic
    parameters for different antibiotic classes
    particularly fluoroquinolones, and different
    bacterial species that are reported to
    correlate with clinical efficacy and reduce
    the formation of antibiotic resistance.
 optimize our use of available antibiotics
 antibiotic dosing: the most resistant
  subpopulation in the bacterial population
 to prevent the emergence of resistant

 antibiotic selection and dosing strategies
  are designed to consider limiting
  antimicrobial resistance
 by highest tolerated dose of antibiotic
          Take Home Message
   Inappropriately low antibiotic dosing may
    be contributing to the increasing rate of
    antibiotic resistance
   Antibiotic dosing must aim to address not
    only the bacteria isolated, but also the
    most resistant subpopulation in the colony,
    to prevent the advent of further resistant
   Mutant Prevention Concentration
   Maximizing antibiotic exposure (highest
    tolerated dose )
Thank You for Your
             KEY WORDS
   Antibiotic resistance
   Mutant Prevention Concentration
   Fluoroquinolone,
   Aminoglycoside
   B-lactam,
   Glycopeptide
   Highest tolerated dose

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