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

2. 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

3. 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

4. Provisional Breakpoints In Vitro Antimicrobial Activity

5. In Vitro Antimicrobial Activity
Data generated from:
Alexander Project (AP) 1997 – 1998
International Surveillance Study (ISS)
Clinical Microbiology Institute (CMI) 1999
Consultants in Anti-Infectives Surveillance and Testing (CAST) 1999

8. In Vitro Antimicrobial Activity

9. In Vitro Antimicrobial Activity

10. In Vitro Antimicrobial Activity

11. Provisional Breakpoints Pharmacokinetic and Pharmacodynamic Studies

12. 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

13. 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

14. 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

15. Provisional Breakpoints Efficacy Studies in Animal Models of Infection

16. 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

18. Final Breakpoints Efficacy Studies in Humans

19. 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

23. 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%

24. 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

26. 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