Augmentin ES Clinical Microbiology Review

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Augmentin ES Clinical Microbiology Review

• Sousan S. Altaie, Ph.D.
• Clinical Microbiology Reviewer
• Division of Anti-Infective Drug Products

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Overview

• Introduction
• Provisional Breakpoints
• In Vitro Antimicrobial Activity
• Pharmacokinetic and Pharmacodynamic Studies
• Efficacy Studies in Animal Models of Infection
• Final Breakpoints
• Efficacy Studies in Humans

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Introduction

• Pending Applications for Determination of
  Susceptibility Breakpoints
• Augmentin 71 (45/6.4 mg/kg/day)
• Sponsor proposed amox/clav susceptible
  breakpoint, lt 2.0 mg/mL
• Augmentin ES 141 (90/6.4 mg/kg/day)
• Sponsor proposed amox/clav susceptible
  breakpoint, lt 4.0 mg/mL

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Provisional BreakpointsIn Vitro Antimicrobial
Activity
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In Vitro Antimicrobial Activity

• Data generated from
• Alexander Project (AP) 1997 1998
• International Surveillance Study (ISS) 1997-1998
• Clinical Microbiology Institute (CMI) 1999
• Consultants in Anti-Infectives Surveillance and
  Testing (CAST) 1999

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In Vitro Antimicrobial Activity
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In Vitro Antimicrobial Activity
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In Vitro Antimicrobial Activity
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Provisional BreakpointsPharmacokinetic and
Pharmacodynamic Studies
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Pharmacokinetic Pharmacodynamic Studies In
Animals

• Relationship between therapeutic efficacy and
  TgtMIC
• Neutropenic Murine Thigh Model
• Efficacy observed if TgtMIC was at least 30 of
  the dosing interval
• Neutropenic Murine Pneumonia Model
• Bacterial counts decreased if TgtMIC exceeded 40
  of the dosing interval

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Pharmacokinetic Pharmacodynamic Studies In
Humans

• Study 25000/382
• Conclusion from extrapolated data
• TgtMIC approximately 41 (4.9 h/12 h) of a dosing
  interval when an amoxicillin MIC of 4.0 mg/mL is
  used in the calculation
• TgtMIC approximately 51 (6.1 h/12 h) of a dosing
  interval when an amoxicillin MIC of 2.0 mg/mL is
  used in the calculation

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Pharmacokinetic Pharmacodynamic Studies In
Humans

• Study 25000/446
• Conclusion from extrapolated data
• TgtMIC approximately 38 (4.7 h/12 h) of a dosing
  interval when an amoxicillin MIC of 4.0 mg/mL is
  used in the calculation
• TgtMIC approximately 50 (6.0 h/12 h) of a dosing
  interval when an amoxicillin MIC of 2.0 mg/mL is
  used in the calculation

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Provisional BreakpointsEfficacy Studies in
Animal Models of Infection
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Efficacy Studies in Animal Models of infection

• Rat experimental RTI caused by S. pneumoniae
• Treated with Augmentin 71 or 141
• Counted numbers of viable bacteria per lung

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Final BreakpointsEfficacy Studies in Humans
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Efficacy Study In AOM

• Study 25000/536
• Open-label, Augmentin ES (141) for 10 days
• Tympanocentesis at baseline, on-therapy, and some
  at the time of clinical failure
• 521 patients, 157 S. pneumoniae, 41 PRSP, 9 with
  amox/clav MICs of gt 4.0 mg/mL

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Amox/Clav Breakpoint Discussions

• Important Note
• Clinical success rate for isolates with MICs lt
  1.0 mg/mL is 79
• Clinical success rate for isolates with MICs gt2.0
  mg/mL is 53
• Clinical success rate for isolates with MICs gt4.0
  mg/mL is 38

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Amox/Clav Breakpoint Discussions

• The amox/clav MIC frequency distribution
  histograms for S. pneumoniae indicate a bimodal
  distribution separated at the current FDA
  approved susceptible breakpoint of 0.5 mg/mL
• PSSP and PISP isolates which have amox/clav MICs
  of lt 1.0 mg/mL
• PRSP isolates which have amox/clav MICs of gt 4.0
  mg/mL
• These two populations should be examined
  separately when setting breakpoints

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Issue For Discussion

• Considering the bimodal distribution of S.
  pneumoniae and the clinical failure rates for
  patients with isolates having amox/clav MICs gt
  2.0 mg/mL what would be the most informative
  susceptibility breakpoint for S. pneumoniae
  against amox/clav?
• lt 1.0, lt 2.0, or lt 4.0 mg/mL