Augmentin® ES Clinical Microbiology Review

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Presentation transcript:

Augmentin® ES Clinical Microbiology Review Sousan S. Altaie, Ph.D. Clinical Microbiology Reviewer Division of Anti-Infective Drug Products

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

Introduction Pending Applications for Determination of Susceptibility Breakpoints Augmentin® 7:1 (45/6.4 mg/kg/day) Sponsor proposed amox/clav susceptible breakpoint, < 2.0 mg/mL Augmentin® ES 14:1 (90/6.4 mg/kg/day) Sponsor proposed amox/clav susceptible breakpoint, < 4.0 mg/mL

Provisional Breakpoints In Vitro Antimicrobial Activity

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

In Vitro Antimicrobial Activity

In Vitro Antimicrobial Activity

In Vitro Antimicrobial Activity

Provisional Breakpoints Pharmacokinetic and Pharmacodynamic Studies

Pharmacokinetic & Pharmacodynamic Studies In Animals Relationship between therapeutic efficacy and T>MIC Neutropenic Murine Thigh Model Efficacy observed if T>MIC was at least 30% of the dosing interval Neutropenic Murine Pneumonia Model Bacterial counts decreased if T>MIC exceeded 40% of the dosing interval

Pharmacokinetic & Pharmacodynamic Studies In Humans Study 25000/382 Conclusion from extrapolated data T>MIC 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 T>MIC 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

Pharmacokinetic & Pharmacodynamic Studies In Humans Study 25000/446 Conclusion from extrapolated data T>MIC 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 T>MIC 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

Provisional Breakpoints Efficacy Studies in Animal Models of Infection

Efficacy Studies in Animal Models of infection Rat experimental RTI caused by S. pneumoniae Treated with Augmentin 7:1 or 14:1 Counted numbers of viable bacteria per lung

Final Breakpoints Efficacy Studies in Humans

Efficacy Study In AOM Study 25000/536 Open-label, Augmentin ES (14:1) 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 > 4.0 mg/mL

Amox/Clav Breakpoint Discussions Important Note Clinical success rate for isolates with MICs < 1.0 mg/mL is ~ 79% Clinical success rate for isolates with MICs >2.0 mg/mL is ~ 53% Clinical success rate for isolates with MICs >4.0 mg/mL is ~ 38%

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 < 1.0 mg/mL PRSP isolates which have amox/clav MICs of > 4.0 mg/mL These two populations should be examined separately when setting breakpoints

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