ABSTRACT

Mycoplasma genitalium has developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is only 75% effective. Gepotidacin, a novel triazaacenaphthylene topoisomerase II inhibitor, blocks bacterial DNA replication. We determined the in vitro activity of gepotidacin alone and in combination with doxycycline against a diverse collection of Mycoplasma genitalium isolates (n = 54).

Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined by a Vero-cell culture method. Macrolide resistance was present in 31 (57%) isolates, fluoroquinolone resistance in 18 (33%) isolates, and 17 (31%) had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard analysis for two macrolide- and two dual-resistant isolates.

Gepotidacin was active against all 54 M. genitalium isolates with median and modal MICs of 0.125 mg/L and MIC₉₀ of 0.25 mg/L (range ≤0.016–0.5 mg/L). No difference in gepotidacin MIC between macrolide-resistant and -susceptible isolates (p = 0.24) or between fluoroquinolone-, dual-resistant and -susceptible isolates (p = 0.2) was demonstrated. Gepotidacin MBCs were available for 44 M. genitalium isolates with median MIC of 0.064 mg/L and median MBC of 0.125 mg/L. All isolates had ≤4-fold difference between MIC and MBC, suggesting bactericidal effect for gepotidacin. Checkerboard analysis indicated synergistic effect for gepotidacin in combination with doxycycline [fractional inhibitory concentration index (ΣFICI) of 0.5] for two isolates and additive/indifference (ΣFICI at 0.62 and 0.75) for two isolates.

Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of gepotidacin resistance.

摘要

生殖支原体对一线阿奇霉素和二线莫西沙星产生了耐药性。三线菌素只有75％有效。新型的三氮杂ac烯拓扑异构酶II抑制剂Gepotidacin可以阻止细菌DNA复制。我们确定了单独和与多西环素合用的吉博达霉素对多种多样的生殖器支原体分离株的体外活性（n  = 54）。

最小抑制浓度（MIC）和最小杀菌浓度（MBC）通过Vero细胞培养方法确定。31株（57％）菌株中存在大环内酯类耐药，18株（33％）菌株中对氟喹诺酮类耐药，17株（31％）具有双重耐药性。通过对两个大环内酯类和两个双重耐药菌株的棋盘格分析，对gepotidacin和强力霉素进行了协同测试。

吉普达星对所有54. M.生殖器分离物均具有活性，中位和模态MIC均为0.125 mg / L，MIC ₉₀为0.25 mg / L（范围≤0.016-0.5mg / L）。在大环内酯耐药和易感菌株之间（p  = 0.24）或对氟喹诺酮，双重耐药和易感菌株（p  = 0.2）之间的吉博达霉素MIC无差异。Gepotidacin MBC可用于44 M生殖器分离株的MIC中位数为0.064 mg / L，MBC中位数为0.125 mg / L。所有分离株的MIC和MBC差异均≤4倍，表明其对gepotidacin具有杀菌作用。棋盘格分析表明，吉博达霉素与多西环素联合使用具有协同作用[分数抑制浓度指数（ΣFICI）为0.5]对于两种分离株，加/差（ΣFICI在0.62和0.75）对于两种分离株。

吉波达星值得在生殖器支原体的临床治疗试验中进行进一步评估。应对多西环素联合治疗进行临床研究，以评估其对gepotidacin耐药性发生和/或扩散的作用和潜在保护作用。