February 2001
GAITHERSBURG, Md. - New drug application data was presented to the Food and Drug Administration (FDA) on amoxicillin/clavulanate 90/6.4 mg/kg/day (Augmentin ES, GlaxoSmithKline) for the treatment of pediatric patients with acute otitis media (AOM) due to penicillin-resistance Streptococcus pneumoniae (PRSP).
The FDA's Anti-Infective Drugs Advisory Committee recommended the use of Augmentin ES as empiric therapy in a selected high-risk population. This population was defined as children who have already had one or more episodes of AOM, children who may have underlying risk factors such as cleft lip or palate, children attending day care and who come from large families.
However, proposed wording on the label kept the committee from recommending approval of the extra strength version of Augmentin for its proposed indication since data showed the drug has good activity against pneumococcal resistance with a minimum inhibitory concentration (MIC) of 2; but proposed wording for the labeling was open-ended, implying the drug is effective against higher MICs of 4, 8, 16 or beyond.
What the FDA committee largely struggled with was the question of whether study data presented support the use of amoxicillin/clavulanate 90/6.4 mg/kg/day for MICs of 2 and above.
"The data are substantial and solid for the therapy of pneumococci with MICs to amoxicillin up to and including 2 µg/ml, but beyond that the numbers fall off," said Barth Reller, MD,director of clinical microbiology, Duke University Medical Center in Durham, N.C.
According to Reller, clinical data on pharmacokinetics and pharmacodynamics made a "pretty impressive validation of efficacy at 2 µg/ml." But he noted that with 4 µg/ml or 8 µg/ml, the data presented did not have a sufficient number of cases to indicate efficacy based on the confidence intervals.
Manufacturer study data showed a success rate of 82%, or 28 of 34 penicillin-resistant patients who took the drug. The low end of the confidence interval showed a 65% success rate. Data also showed a 71% success rate, or 29 of 41 patients, in the intent-to-treat group, with a low-end confidence interval of 54%.
There were 521 patients in the study who received at least one dose of therapy. Of those, 359 had a baseline pathogen; 157 had an isolate of S. pneumoniae at baseline. Of the 157, 41 had PRSP.
The mean age of study patients was approximately 18 months, approximately 60% were male and 60% were white.
The FDA interpreted the manufacturer's study data and classified four patients as clinical failures instead of clinical successes as listed by the manufacturer. Hence numbers differed slightly in their assessment.
According to Memodikoe Makhene, MD, FDA, who presented the FDA assessment, the confidence interval in the PRSP population ranged from 25% to 60%, and the numbers in the intent-to-treat group were slightly lower.
Since the indication sought was not just for PRSP, but for all AOM pathogens, FDA data showed 68% of patients with Haemophilus influenzae had favorable response at test for cure and 56% did for Moraxella catarrhalis.
Editor's note: Please see the March issue of Infectious Diseases in Children for a more thorough look at the study data and current breakpoints for amoxicillin/clavulanate.
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