WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Centre for Genomic Pathogen Surveillance, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK.
J Antimicrob Chemother. 2021 Apr 13;76(5):1221-1228. doi: 10.1093/jac/dkab024.
Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used.
MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates.
Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin.
The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.
治疗淋病需要新型抗生素。首个类别的螺吡喃并嘧啶酮唑利福霉素具有很大的应用前景，目前正在进行国际 3 期随机对照临床试验（RCT），以评估其治疗单纯性淋病的疗效。我们评估了 1209 例连续分离自 2018 年 25 个欧盟/欧洲经济区（EEA）国家的淋病奈瑟菌临床分离株的目标（GyrB）和其他潜在唑利福霉素耐药决定因素的体外活性和遗传保守性，并比较了唑利福霉素与目前使用的治疗性抗生素的活性。
采用琼脂稀释法测定唑利福霉素的 MIC，采用 MIC 梯度条试验或琼脂稀释法测定其他抗生素的 MIC。96.1%的分离株可获得基因组序列。
唑利福霉素的模式 MIC、MIC50、MIC90 和 MIC 范围分别为 0.125、0.125、0.125 和 ≤0.004-0.5mg/L。对环丙沙星、阿奇霉素、头孢克肟和头孢曲松的耐药率分别为 49.9%、6.7%、1.6%和 0.2%。唑利福霉素与其他测试的抗生素之间没有交叉耐药性。GyrB 高度保守，未发现唑利福霉素 gyrB 耐药突变。氟喹诺酮靶标 GyrA 或 ParC 耐药突变或导致 MtrCDE 外排泵过度表达的突变并未显著影响唑利福霉素的 MIC。
2018 年，欧盟/EEA 淋病奈瑟菌分离株对唑利福霉素的体外敏感性较高，唑利福霉素的靶标 GyrB 也保持保守。本研究支持进一步开发唑利福霉素。然而，关于特别是治疗咽部淋病、药代动力学/药效学和耐药性选择（包括抑制）的额外唑利福霉素数据将是有价值的。
