An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the minimum inhibitory concentration (T >MIC; based on the literature reported MIC90 of 0.06microg/mL for S. pyogenes) was shown to be achievable in a phase 1 study of 23 children with a once daily (QD) pulsatile-release, multiparticulate formulation of amoxicillin sprinkle. The daily T>MIC achieved by the QD amoxicillin sprinkle formulation was comparable to four times daily (QID) penicillin VK suspension. An investigator-blind, randomized, parallel-group, multicenter study was then undertaken involving 579 children age 6 months to 12 years old with acute streptococcal tonsillopharyngitis. Children were randomized 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 penicillin VK 10 mg/kg QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, bacteriological eradication at the test-of-cure for the amoxicillin sprinkle was 65.3% (132/202) and for penicillin VK was 68.0% (132/194) (95% confidence interval: -12.0%, 6.6%). Thus, neither antibiotic regimen met the minimum criterion standard of >/=85% eradication ordinarily required by the US FDA for first line treatment of tonsillopharyngitis due to S. pyogenes. Subgroup analyses across demographic characteristics, 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%, -0.4%). A post hoc PD analysis suggested that a requirement for 60% daily T>MIC90 more accurately predicted the observed high failure rates for bacteriologic eradication with the studied amoxicillin sprinkle and penicillin VK suspension. Based on literature reported association between longer treatment courses and maximal bacterial eradication rates, an alternative composite PK/PD target taking into consideration duration of therapy, total T>MIC, was considered and provides an alternative explanation for the observed failure rate of amoxicillin sprinkle.