Allen Vanessa G, Seah Christine, Martin Irene, Melano Roberto G
Public Health Ontario Laboratories, Toronto, Ontario, Canada.
Antimicrob Agents Chemother. 2014 May;58(5):2528-34. doi: 10.1128/AAC.02608-13. Epub 2014 Feb 10.
Azithromycin (AZM) is routinely recommended as a component of dual therapy for gonorrhea in combination with third-generation cephalosporins (3GC). In this study, we examined the prevalence of AZM-resistant (AZM(r)) Neisseria gonorrhoeae from July 2010 to February 2013, assessed the rate of concurrent cephalosporin resistance under the current treatment recommendations, and analyzed the clonal distribution of AZM(r) isolates in Ontario, Canada. Nineteen AZM(r) clinical isolates (one per patient; MIC, ≥2 μg/ml) were included in the study. Susceptibility profiles of these isolates to 11 antibiotics, molecular typing, characterization of macrolide resistance mechanisms, and penicillin-binding protein 2 (PBP2) patterns were determined for all the isolates. Two groups were defined based on AZM(r) level; group A isolates displayed high-level resistance (MIC, ≥2,048 μg/ml) due to mutations (A2143G) in the four copies of the 23S rRNA rrl gene, and group B isolates had moderate resistance to AZM (MICs, 2 to 8 μg/ml, C2599T mutation in the rrl gene), with a subgroup belonging to sequence type 3158 (ST3158) (n = 8), which also showed reduced susceptibility to 3GC (MICs, 0.12 to 0.25 μg/ml, PBP2 pattern XXXIV). This AZM(r) phenotype was not observed in previous provincial surveillance in 2008 (the ST3158 clone was found, with AZM MICs of 0.25 to 0.5 μg/ml associated with mtrR mutations). We hypothesized that the AZM mutant prevention concentration (MPC) in the ST3158 subpopulation we found in 2008 was higher than the MPC in wild-type isolates (AZM MIC, ≤0.031 μg/ml), increasing the chances of additional selection of AZM(r) mutations. Full AZM resistance is now emerging in this clone together with reduced susceptibility to 3GC, threatening the future efficacy of these antibiotics as therapeutic options for treatment of gonorrhea.
阿奇霉素（AZM）常被推荐作为淋病双联疗法的组成部分，与第三代头孢菌素（3GC）联合使用。在本研究中，我们调查了2010年7月至2013年2月期间阿奇霉素耐药（AZM(r)）淋病奈瑟菌的流行情况，评估了在当前治疗建议下头孢菌素耐药率，并分析了加拿大安大略省AZM(r)分离株的克隆分布。19株AZM(r)临床分离株（每位患者1株；MIC≥2μg/ml）纳入研究。测定了这些分离株对11种抗生素的药敏谱、分子分型、大环内酯类耐药机制特征以及青霉素结合蛋白2（PBP2）模式。根据AZM(r)水平定义了两组；A组分离株由于23S rRNA rrl基因的四个拷贝发生突变（A2143G）而表现出高水平耐药（MIC≥2048μg/ml），B组分离株对AZM有中度耐药（MIC为2至8μg/ml，rrl基因中的C2599T突变），其中一个亚组属于序列型3158（ST3158）（n = 8），该亚组对3GC也表现出敏感性降低（MIC为0.12至0.25μg/ml，PBP2模式XXXIV）。在2008年的省级监测中未观察到这种AZM(r)表型（发现了ST3158克隆，其AZM MIC为0.25至0.5μg/ml，与mtrR突变相关）。我们推测，我们在2008年发现的ST3158亚群中的阿奇霉素突变预防浓度（MPC）高于野生型分离株中的MPC（AZM MIC≤0.031μg/ml），增加了额外选择AZM(r)突变的机会。现在该克隆中正在出现完全的阿奇霉素耐药，同时对3GC的敏感性降低，这威胁到这些抗生素作为淋病治疗选择的未来疗效。
