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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® 7:1 (45/6.4 mg/kg/day)

• Sponsor proposed amox/clav susceptible breakpoint, < 2.0 g/mL

– Augmentin® ES 14:1 (90/6.4 mg/kg/day) • Sponsor proposed amox/clav susceptible breakpoint,

< 4.0 g/mL

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Provisional Breakpoints

In 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

Penicillin-Susceptible S. pneumoniae

Study Namox/clav

MIC90

amox/clav% Susc. @

< 2.0 g /mL

amox/clav% Susc. @

< 4.0 g /mL

AP- 1997 82 0.03 100 100

CAST 354 < 0.25 100 100

AP-1998 787 0.03 100 100

ISS 186 0.03 100 100

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In Vitro Antimicrobial ActivityPenicillin-Intermediate S. pneumoniae

Study Namox/clav

MIC90

amox/clav% Susc. @

< 2.0 g /mL

amox/clav% Susc. @

< 4.0 g /mL

AP- 1997 19 1 100 100

CAST 87 1 100 100

AP-1998 217 1 100 100

ISS 65 1 100 100

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In Vitro Antimicrobial ActivityPenicillin-Resistant S. pneumoniae

Study Namox/clav

MIC90

amox/clav% Susc. @< 2 g /mL

amox/clav% Susc. @< 4 g /mL

AP- 1997 23 4 65.2 95.7

CAST 111 4 80.2 92.8

AP-1998 452 8 64.6 79.9

ISS 96 8 79.2 86.5

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Provisional Breakpoints

Pharmacokinetic and Pharmacodynamic Studies

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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

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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 g/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 g/mL is used in the calculation

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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 g/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 g/mL is used in the calculation

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Provisional Breakpoints

Efficacy 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 7:1 or 14:1

• Counted numbers of viable bacteria per lung

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Log10 CFU/lungsStrains of

S.pneumoniae

AmoxMIC

g/mL

Control Augmentin7:1

Augmentin14:1

N1387 2 7.0+0.3 4.4+0.9* 2.6+0.9**

14319 4 6.8+0.6 6.3+0.5 4.3+0.8**

41010 4 7.1+0.5 6.1+0.6* 3.9+0.8**

RS1 8 6.0+0.6 6.1+0.7 5.9+0.7

* Significantly different from control (p<0.01)** Significantly different from control & amx/cla 45/6.4,

p<0.01

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Final Breakpoints

Efficacy Studies in Humans

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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 g/mL

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Augmentin ESITT Bacteriological Population

Success n/N (%)

S. pneumoniae alone or mixedamox/clav MIC (g/mL)

0.0160.030.060.120.250.51.02.04.08.0

2/276/8011/12

5/512/13

2/23/3

27/293/35/6

--(95)(92)

--(92)

----

(93)----

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Augmentin ESPP Bacteriological Population

Success n/N (%)

S. pneumoniae alone or mixedamox/clav MIC (g/mL)

0.0160.030.060.120.250.51.02.04.08.0

2/262/628/84/4

10/102/23/3

22/233/33/4

--(100)

----

(100)----

(96)----

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Augmentin ESPP Clinical Response at TOC

Success n/N (%)

S. pneumoniae alone or mixedamox/clav MIC (g/mL)

0.0160.030.060.120.250.51.02.04.08.0

1/158/738/114/57/92/21/2

14/242/31/5

--(80)(73)

--(78)

----

(58)----

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Amox/Clav Breakpoint Discussions

• Important Note– Clinical success rate for isolates with MICs

< 1.0 g/mL is ~ 79% – Clinical success rate for isolates with MICs

>2.0 g/mL is ~ 53% – Clinical success rate for isolates with MICs

>4.0 g/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 g/mL – PSSP and PISP isolates which have amox/clav MICs

of < 1.0 g/mL – PRSP isolates which have amox/clav MICs of > 4.0

g/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 > 2.0 g/mL what would be the most informative susceptibility breakpoint for S. pneumoniae against amox/clav?

< 1.0, < 2.0, or < 4.0 g/mL