Evolution and Global Dissemination of Macrolide-Resistant Group A Streptococci

Abstract

Macrolide-resistant group A streptococci (MRGAS) have been recovered from many countries worldwide. However, the strain typing information that is available has been insufficient for estimating the total number of macrolide-resistant clones, their geographic distributions, and their evolutionary relationships. In this study, sequence-based strain typing was used to characterize 212 MRGAS isolates from 34 countries. Evaluation of clonal complexes, emm type, and resistance gene content [erm(A), erm(B), mef(A), and undefined] indicate that macrolide resistance was acquired by GAS organisms via >49 independent genetic events. In contrast to other collections of mostly susceptible GAS, genetic diversification of MRGAS clones has occurred primarily by mutation rather than by recombination. Twenty-two MRGAS clonal complexes were recovered from more than one continent; intercontinental strains represent nearly 80% of the MRGAS isolates under study. The findings suggest that horizontal transfer of macrolide resistance genes to numerous genetic backgrounds and global dissemination of resistant clones and their descendants are both major components of the present-day macrolide resistance problem found within this species.Penicillin and related ␤-lactams are usually the antibiotics of choice for the treatment of infections caused by Streptococcus pyogenes (group A streptococci [GAS]). GAS have remained susceptible to penicillin despite decades of exposure (22). Macrolides are preferred for treatment of GAS infections in patients with ␤-lactam hypersensitivity or chronic, recurrent pharyngitis due to prior treatment failure (26). Clindamycin (a lincosamide) is recommended for patients with life-threatening soft-tissue infections, such as toxic shock syndrome or necrotizing fasciitis, because it halts the exotoxin production that can lead to extensive tissue necrosis, shock, and multiple-organ failure (6).Macrolide-resistant GAS (MRGAS) is an increasingly recognized problem in many parts of the world. Two mechanisms account for most macrolide resistance in GAS. Target site modification by methylases, namely, Erm(A) subclass TR and Erm(B), leads to ribosomal modification and loss of binding by macrolide, lincosamide, and streptogramin B (MLS) antibiotics (29, 51). Macrolide efflux is mediated by MefA (M phenotype), resulting in resistance to 14-and 15-membered, but not 16-membered, ring macrolides (54). The three major resistance genes (R genes) found in GAS, erm(A), erm(B), and mef(A), are associated with mobile genetic elements (3, 18). Mutations in 23S rRNA and the L4 ribosomal protein also seem to confer macrolide resistance in at least some strains (11,33,44).Studies in Japan, Finland, and elsewhere show a strong correlation between national macrolide consumption and resistance in GAS (14,15,17,35,41,50). Between 1998 and 2001, a statistically significant increase in GAS resistant to erythromycin and azithromycin was observed in Spain (2). In Toronto between 1997 and 2001, macrolide resistance in GAS recovered from throat...

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