In a nationwide study in Germany covering 13 clinical microbiology laboratories, a total of 307 Streptococcus pyogenes (mainly pharyngitis) and 333 Streptococcus pneumoniae (respiratory tract infections) strains were collected from outpatients less than 16 years of age. The MICs of penicillin G, amoxicillin, cefotaxime, erythromycin A, clindamycin, levofloxacin, and telithromycin were determined by the microdilution method. In S. pyogenes isolates, resistance rates were as follows: penicillin, 0%; erythromycin A, 13.7%; and levofloxacin, 0%. Telithromycin showed good activity against S. pyogenes isolates (MIC 90 ؍ 0.25 g/ml; MIC range, 0.016 to 16 g/ml). Three strains were found to be telithromycin-resistant (MIC > 4 g/ml). Erythromycin-resistant strains were characterized for the underlying resistance genotype, with 40.5% having the efflux type mef(A), 38.1% having the erm(A), and 9.5% having the erm(B) genotypes. emm typing of macrolide-resistant S. pyogenes isolates showed emm types 4 (45.2%), 77 (26.2%), and 12 (11.9%) to be predominant. In S. pneumoniae, resistance rates were as follows: penicillin intermediate, 7.5%; penicillin resistant, 0%; erythromycin A, 17.4%; and levofloxacin, 0%. Telithromycin was highly active against pneumococcal isolates (MIC 90 < 0.016 g/ml; range, 0.016 to 0.5 g/ml). The overall resistance profile of streptococcal respiratory tract isolates is still favorable, but macrolide resistance is of growing concern in Germany.Streptococcus pyogenes is responsible for the majority of cases of pharyngitis in children and adolescents and can also cause severe life-threatening diseases, such as necrotizing fasciitis and toxic shock syndrome (6). Streptococcus pneumoniae continues to be a significant cause of morbidity and mortality in humans and is responsible for respiratory tract infections and otitis media (15).Macrolide resistance in S. pneumoniae is usually caused by the presence of the erm(B) or mefE [renamed mef(A)] resistance determinants. The erm(B) protein encodes a 23S rRNA methylase, and most pneumococcal strains that harbor the gene are resistant to 14-, 15-, and 16-membered-ring macrolides, lincosamides, and streptogramin B (MLS B phenotype). The mef(A) protein encodes an efflux pump that leads to resistance to only 14-and 15-membered-ring macrolides (24). Other mechanisms of macrolide resistance have only been described in a few clinical isolates of S. pneumoniae, and changes were clustered in a highly conserved sequence of L4 and in the nucleotide residues of domain V of 23S rRNA, which have a key role in macrolide binding (5,7,26).Macrolide resistance has also been increasingly detected in S. pyogenes in Europe and other parts of the world and is mediated by erm(A), mef(A) and, less commonly, by erm(B) mechanisms.Telithromycin (HMR 3647) is the first of a novel family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections.The ketolides are a new addition to the MLS group of antimicrobials. Ketolides ar...