Pharmacodynamic Analysis and Clinical Trial of Amoxicillin Sprinkle Administered Once Daily for 7 Days Compared to Penicillin V Potassium Administered Four Times Daily for 10 Days in the Treatment of Tonsillopharyngitis Due to Streptococcus pyogenes in Children

Abstract

An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC 90 of 0.06 g/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, ؊12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of >85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, ؊11.6% to ؊0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC 90 more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between longer treatment courses and maximal bacterial eradication rates reported in the literature, an alternative composite PK/PD target taking into consideration the duration of therapy, or total T >MIC, was considered and provides an alternative explanation for the observed failure rate of amoxicillin sprinkle.

Guideline for the management of acute sore throat

“…No significant differences in clinical cure rate were found in both trials. Another RCT compared the efficacy of amoxicillin and penicillin in children with acute streptococcal tonsillopharyngitis [110]. The clinical cure rates for amoxicillin and penicillin were 86% and 92%, respectively, confirming that amoxicillin could be an alternative regimen for the treatment of streptococcal tonsillopharyngitis in children.…”

“…Pichichero [110] To compare the amoxicillin sprinkle administered daily for 7 days with penicillin VK four times a day for 10 days in children with tonsillopharyngitis secondary to Streptococcus pyogenes…”

Relative bioequivalence of amoxicillin dissolved in breast milk

“…In the previous study,8 infants were fed about 120 mL of milk or formula immediately after ingesting amoxicillin in suspension. Therefore, we cannot rule out a possibility that a larger milk volume (per body weight) changes absorption profiles of the drug through influences on gastrointestinal motility and function, although relatively recent evidence suggests otherwise 12. Second, although highly speculative, the formulation which Ginsburg et al 8 used, may have a pharmaceutical property different from those currently in use.…”

Modern Diagnostics and Treatment of Acute Streptococcal Pharyngitis and Tonsillitis in Children and Adults

“…However, that review received rather critical response in most publications. It did not include several broad studies, which obtained different results; many of the included studies gave unclear randomization criteria of patients, singular studies were double blind; acute rheumatic fever development was not seen as an efficacy criterion [43,44]. At the same time, a range of authors demonstrated lesser efficacy of short antibiotic acute GABHS pharyngitis therapy courses in terms of clinical symptoms and bacteriological results [45].…”