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Animal model studies have demonstrated the failure of penicillin to cure Streptococcus pyogenes myositis and have suggested that clindamycin is a more effective treatment.To determine the most effective antibiotic treatment for invasive S. pyogenes infection in humans.We conducted a retrospective review of the outcomes of all inpatients from 1983 to 1997 treated for invasive S. pyogenes infection at Children's Hospital.Fifty-six children were included, 37 with initially superficial disease and 19 with deep or multiple tissue infections.Lack of progression of disease (or improvement) after at least 24 h of treatment.The median number of antibiotic exposures was 3 per patient (range 1 to 6) with clindamycin predominating in 39 of 45 courses of protein synthesis-inhibiting antibiotics and beta-lactams predominating amongst the cell wall-inhibiting antibiotics in 123 of 126 of the remainder. Clindamycin was often used in combination with a beta-lactam antibiotic. Overall there was a 68% failure rate of cell wall-inhibiting antibiotics when used alone. Patients with deep infection were more likely to have a favorable outcome if initial treatment included a protein synthesis-inhibiting antibiotic as compared with exclusive treatment with cell wall-inhibiting antibiotics (83% vs. 14%, P = 0.006) with a similar trend in those with superficial disease (83% vs. 48%, P = 0.07). For those children initially treated with cell wall-inhibiting antibiotics alone, surgical drainage or debridement increased the probability of favorable outcome in patients with superficial disease (100% vs. 41%, P = 0.04) with a similar trend in a smaller number of deep infections (100% vs. 0%, P = 0.14).This retrospective study suggests that clindamycin in combination with a beta-lactam antibiotic (with surgery if indicated) might be the most effective treatment for invasive S. pyogenes infection.