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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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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
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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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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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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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