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To determine whether treatment failures occurred more commonly with azithromycin than with β-lactam antibiotics in children who developed invasive pneumococcal disease within 30 days of receiving prior antimicrobial therapy.Retrospective review of medical records of children evaluated at Texas Children’s Hospital between 1996 and 2002 who had received antimicrobials (azithromycin or a β-lactam antibiotic) and developed invasive pneumococcal disease within 30 days. Treatment failure was defined as invasive pneumococcal infection that occurred while taking antimicrobials or within 3 days of stopping azithromycin treatment or 1 day of stopping β-lactam treatment. Penicillin and azithromycin susceptibilities were determined and categorized according to National Committee for Clinical Laboratory Standards guidelines.We identified 21 and 33 children with similar demographic features who had developed invasive pneumococcal disease within 1 month of receiving azithromycin or a β-lactam antibiotic, respectively. Eleven (52%) children in the azithromycin group and 11 (33%) in the β-lactam group met the definition for treatment failures (P = 0.34). Eight treatment failures while receiving azithromycin were caused by pneumococci with the macrolide-resistant (M) phenotype, 2 with the macrolide-, lincosamide- and streptogramin B-resistant (MLSB) phenotype and 1 by a macrolide-susceptible organism. In the β-lactam group 7 had a penicillin-resistant isolate, 3 had an intermediately susceptible isolate and 1 had a susceptible isolate.Our study suggests that treatment failures among patients who developed invasive disease within 30 days of receiving an antimicrobial occur as frequently in patients who receive β-lactam antibiotics as in those who receive azithromycin. Furthermore macrolide resistant organisms are not more likely to be recovered after a macrolide treatment failure than a penicillin-nonsusceptible isolate being recovered after a β-lactam treatment failure (P = 1.0).