Authorities have suggested restriction of azithromycin use as a principal strategy to contain the spread of azithromycin-nonsusceptible Streptococcus pneumoniae (ANSP). In 83 children persistently colonized by pneumococcus during and after treatment of acute otitis media, 17 acquired a new strain, 9 of which were less susceptible to azithromycin than the original isolate. New appearance of ANSP was documented after both beta-lactam and azithromycin exposure. ANSP is likely to disseminate even with significant reduction of azithromycin use unless other antibiotic use is decreased as well.