GAITHERSBURG, Md. - A new formulation of amoxicillin-clavulanate may prove an effective drug against acute otitis media (AOM), according to members of a Food and Drug Administration (FDA) advisory committee. The proposed wording for the labeling was the subject of discussion at the committee meeting.
The FDA's Anti-Infective Drugs Advisory Committee met at the end of January to review safety and efficacy data of high-dose amoxicillin-clavulanate (90/6.4 mg/kg/day, Augmentin ES, GlaxoSmithKline) for treatment of AOM caused by penicillin-resistant Streptococcus pneumoniae. The committee members' decision not to recommend it for approval was based largely on the wording of the label for PRSPAOM with penicillin minimum inhibitory concentrations (MIC) >2. Committee members noted that the formulation works well, but they hesitated to recommend approval for all PRSP.
Still, high-dose amoxicillin-clavulanate is expected to benefit many difficult-to-treat cases of AOM once it wins approval.
"There is no other oral formulation antibiotic presently available to pediatricians that is effective against penicillin-resistant S. pneumoniae and ß-lactamase-positive Haemophilus influenzae," said George H. McCracken, MD, professor of pediatrics at the University of Texas Southwest Medical Center in Dallas. "Of the 16 orally administered antibiotics with an indication for treatment of AOM, only the 90 mg/kg amoxicillin-clavulanate formulation is effective against the two most frequent resistant pathogens causing disease in high-risk infants and children. For years, many of us have recommended that amoxicillin be poured into amoxicillin-clavulanate (Augmentin, GlaxoSmithKline) to get to a formulation of about 80 mg/kg or 90 mg/kg."
Committee members also noted the formulation's potential benefits, but added that it should be used with caution.
"We think this compound used at 90 mg/kg works for pneumococci with amoxicillin MIC=2," said Barth Reller, MD, chairman of the committee and director of clinical microbiology at Duke University Medical Center in Durham, N.C. "In fact, those isolates are often going to have penicillin MICs=2."
However, "it's the `or more' that I think the committee is uncomfortable with. This compound in this formulation at the higher dose is a useful addition and would be efficacious in strains that heretofore many would have considered as not being susceptible to penicillin. And it works for most of those strains as long as there's delineation somehow in the labeling that this does not mean you can forget about penicillin resistance when you use this compound."
"My anxiety is saying that this is good for resistant organisms and having physicians believe that it will work for all organisms including those with an MIC of 16 or 32," said P. Joan Chesney, MD, professor of pediatrics at the University of Tennessee College of Medicine in Memphis, Tenn. "I'm comfortable using this as empiric therapy, because the vast majority of pneumococci have MICs of <2 mg/ml for amoxicillin. I'm comfortable with even an MIC=4."
Study data presented to the committee showed high-dose amoxicillin-clavulanate to be effective against PRSP with amoxicillin MICs=2 and MIC=4 in young children with AOM.
Researchers studied the effects of the formulation in 521 children with AOM between the ages of 3 months and 50 months, with a mean age of 19 months. Children were excluded if they had received systemic antibiotics within three days of study enrollment but not for recurrent or recent AOM.
Researchers performed tympanocentesis on the initial visit and after four to six days of therapy. Children who continued to improve were scheduled for an end-of-therapy visit between days 12 and 15 and a final test-of-cure visit at days 25 to 28. Children were evaluated within 24 hours if their symptoms worsened or did not improve. Baseline tympanocentesis isolated at least one baseline pathogen in 363 children. S. pneumoniae was isolated in 159 children, including 41 with PRSP (penicillin MIC >2). These 41 constituted the PRSP Intent To Treat (ITT) population. The 34 children with PRSP who could be assessed for bacterial eradication constituted the PRSP Per Protocol (PP) population.
Twenty children failed therapy. Nine were assessed after day 18, and 11 were assessed before day 17.
GlaxoSmithKline argued that treatment success should be measured by bacterial eradication while on treatment (days four to six) and by clinical response at the end of treatment (days 12-15). Tympanocentesis on days four to six showed that S. pneumoniae was eradicated in 98% of all 125 children with any pneumococcal strain who could be assessed for bacterial eradication; 93% of the PRSP ITT group and 94% of the PRSP PP group.
Clinical success at the end of treatment was reported for 89% of children with any pneumococcal strain, 28 of 34 (82%; 95% CI=65%-93%) in the PRSP PP group and 29 of 41 (71%; CI-54%-84%) in the PRSP ITT group. These results suggest the true clinical success rate in patients with PRSP AOM might be as low as 54%.
The FDA analysis differed from that presented by GlaxoSmithKline in that it defined success as clinical response at the test-of-cure visit and included four additional failures. According to the FDA analysis, clinical response at the test-of-cure visit was 41.2% (CI=25%-59%) in the PRSP PP group and 36.6% (CI=22%-53%) in the PRSP ITT group, while bacteriological response was 94% at the on-therapy visit but only 53% at the test-of-cure visit.
Researchers noted that end-of-therapy success rates differed from test-of-cure rates. However, they said it was difficult to determine whether this was due to treatment failure, relapse or new infection.
MIC played an important role as well. In the PRSP per protocol group, high-dose amoxicillin eradicated S. pneumoniae in 12 of 14 children (86%) with a penicillin MIC=4 and all 19 (100%) with a penicillin MIC=2.
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