Antibiotic resistance

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Antibiotic resistanceWhats 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 ???

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Introduction

• 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

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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
  resistance.
• 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.

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Outline

• 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?

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Resistance Development canDepend on the Level
ofAntibiotic Exposure

• 1976, Stamey and Bragonje correlated antibiotic
  underdosing with resistance formation.
• 100 strains of Enterobacteriaceae in vitro
• Resistance to nalidixic acid increased w/ lower
  concentrations
• ? underdosage probably cause resistance

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Mutant PreventionConcentration

• 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

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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
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• MPCs for individual antibiotics important step
  in developing dosing guidelines

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Mutant Selection Window

• antibiotic concentrations between MIC and
  MPCresistant mutants may be selected

- been defined for many of the fluoroquinolones
and some B-lactams against various organisms.
clinical relevance is still not clear
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Resistance Depends on theAntibiotic 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

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Antibiotic Pharmacodynamics

• rate and extent of an antibiotics activity
  depend on
• -drug concentrations at the site of infection,
• bacterial load
• phase of bacterial growth
• MIC of the pathogen

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• fluoroquinolone,
• aminoglycoside,
• B-lactam,
• carbapenem,
• glycopeptide

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Fluoroquinolones

• Largely concentration-dependent (some
  time-dependent )
• a high CmaxMIC ratio
• (e.g.,up to 10 for ciprofloxacin
  and lomefloxacin)
• assists bacterial killing
• minimizing the development of resistant
  mutants
• AUC024/MIC gt125?GNO
• Reduce the development of resistance
• Eg Gumbo et al.AUC024/MIC of 53
• moxifloxacin for complete suppression of
  Mycobacterium tuberculosis

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• Recommended dose of fluoroquinolones may be
  inappropriately low
• Reevaluation of existing dosing regimens are
  appropriate
• ?dosing attains high CmaxMIC is suggested

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Aminoglycosides

• Concentration- dependent
• CmaxMIC gt10 recommended for optimal efficacy
• - Suboptimal dosing may lead to adaptive
  resistance
• Improved CmaxMIC? reduce this?postantibiotic
  effect
• Bacterial mutability can occur with
  subtherapeutic aminoglycoside exposure
• Maximize CmaxMIC inherent postantibiotic
  effect to reduced toxicity?once daily dosing

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B-Lactams

• Time-dependent T gt MIC
• Maximal killing
• antibiotic concentration maintained at 45 MIC
• minimum standard time above MIC
• - about 50 of dosing interval for penicillins
• - 6070 for cephalosporins
• - 40 for carbapenems

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• Fantin et al. experimental Pseudomonas aeruginosa
  aortic endocarditis in rabbits
• cefpirome and ceftazidime
• antibiotic concentration fall below MIC for gt50
  the dosing interval
• ? bacterial resistance to B-lactams may develop

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• 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.

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Carbapenems

• a reduced percentage of T gt MIC compared with
  other B-lactams
• serious P. aeruginosa infectionsrisk of
  resistance development
• Eg imipenem 1-g Q8h? 50 of P. aeruginosa
  strains developed resistance
• Hoe to prevent??
• in vitro hollow-fiber infection model
• CminMIC gt 6.2 could suppress

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• Maintain carbapenem 46 MIC
• Extended infusions may be beneficial
• Eg extended infusion doripenem V.S.conventional
  infusion imipenem
• ? Only 18 V.S. 50 resistance of P. aeruginosa,

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Glycopeptides

• time-dependent CmaxMIC ??
• AUC024MIC 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 (1525
  mg/L).

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Combination Antibiotic Therapy

• Theoretically, avoiding resistance development
• AUC024/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.

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Effect of Bacterial FactorsSpecies,Subpopulation
, Fitness, Load

• Antibiotic treatment on the development of
  resistance in normal commensal flora.
• Bacteria SpecieslP. aeruginosa resistance to
  moxifloxacin more readily than S. pneumoniae

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• Subpopulations opportunities increase
• Bacterial fitness
• Bacterial load
• P. aeruginosa
• bacterial population increase 10X
• ? dose requirements increase 26 X
• ?Maximum tolerated antibiotic doses

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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
  gentamicin.

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Patient Factors?

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

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CONCLUSIONS

• 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.

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• 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

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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 infections
• Mutant Prevention Concentration
• Maximizing antibiotic exposure (highest tolerated
  dose )

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Thank You for Your Attention
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KEY WORDS

• Antibiotic resistance
• Mutant Prevention Concentration
• Fluoroquinolone,
• Aminoglycoside
• B-lactam,
• Glycopeptide
• Highest tolerated dose