Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model.
Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model.
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DOI：
10.3389/fphar.2022.874176
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发表时间：
2022
影响因子：
5.6
通讯作者：
Unemo, Magnus
中科院分区：
文献类型：
--
作者：
Jacobsson, Susanne;Golparian, Daniel;Oxelbark, Joakim;Franceschi, Francois;Brown, David;Louie, Arnold;Drusano, George;Unemo, Magnus
关键词：
有效治疗单纯性淋病的新型抗菌药物至关重要，而一流的口服螺嘧啶三酮 DNA 促旋酶 B 抑制剂佐利氟达星 (zoliflodacin) 似乎很有前景。使用我们新开发的中空纤维感染模型（HFIM），检查了佐利氟达星的药效学。临床对佐利氟达星敏感的淋病奈瑟菌菌株 SE600/18（含有 GyrB S467N 氨基酸取代；MIC = 0.25 mg/L）和 SE600/18-D429N（在 HFIM 实验中选择的具有第二个 GyrB 取代 D429N 的佐利氟达星抗性突变体；佐利氟达星 MIC = 2 mg/L），进行了检查。针对 SE600/18 进行了剂量范围实验，模拟 0.5、1、2、3 和 4 g 佐利氟达星单次口服剂量方案。对于 SE600/18-D429N，进行了剂量范围实验，模拟佐利氟达星单次口服 2、3、4 和 6 g 剂量，以及按每 12 小时给药 4、6 和 8 g 剂量的佐利氟达星口服剂量分次实验。两种菌株在未经处理的 HFIM 生长对照臂中均生长良好，并且大部分以 1010–1011 CFU/ml 的速度维持生长 7 天。 Zoliflodacin 3 和 4 g 单剂量口服方案成功根除 SE600/18，并且在 7 天的实验中没有恢复生长。然而，单次口服 0.5、1 和 2 g 剂量未能根除 SE600/18，并且使用所有这些剂量选择了具有 GyrB D429N 取代的唑利氟达星耐药群体。任何检查的治疗方案均未根除唑利氟达星耐药性 SE600/18-D429N 突变体。然而，与佐利氟达星敏感的 SE600/18 亲本菌株相比，这种体外选择的佐利氟达星抗性突变体的适应性要差得多。总之，具有 GyrB S467N 取代的罕见临床淋球菌菌株容易产生佐利氟达星耐药性，可能需要使用佐利氟达星 ≥3 g 治疗。未来的发展可能需要考虑纳入诊断方法，旨在在人群水平上识别耐药菌株或易产生耐药性的菌株，并加强监测（表型和遗传学），也可能在患者水平上指导治疗。
Novel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible N. gonorrhoeae strain, SE600/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.25 mg/L), and SE600/18-D429N (zoliflodacin-resistant mutant with a second GyrB substitution, D429N, selected in the HFIM experiments; zoliflodacin MIC = 2 mg/L), were examined. Dose-range experiments, simulating zoliflodacin single oral dose regimens of 0.5, 1, 2, 3, and 4 g, were performed for SE600/18. For SE600/18-D429N, dose-range experiments, simulating zoliflodacin single oral 2, 3, 4, and 6 g doses, and zoliflodacin oral dose-fractionation experiments with 4, 6, and 8 g administered as q12 h were performed. Both strains grew well in the untreated HFIM growth control arms and mostly maintained growth at 1010–1011 CFU/ml for 7 days. Zoliflodacin 3 and 4 g single dose oral regimens successfully eradicated SE600/18 and no growth was recovered during the 7-days experiments. However, the single oral 0.5, 1, and 2 g doses failed to eradicate SE600/18, and zoliflodacin-resistant populations with a GyrB D429N substitution were selected with all these doses. The zoliflodacin-resistant SE600/18-D429N mutant was not eradicated with any examined treatment regimen. However, this in vitro-selected zoliflodacin-resistant mutant was substantially less fit compared to the zoliflodacin-susceptible SE600/18 parent strain. In conclusion, the rare clinical gonococcal strains with GyrB S467N substitution are predisposed to develop zoliflodacin resistance and may require treatment with zoliflodacin ≥3 g. Future development may need to consider the inclusion of diagnostics directed at identifying strains resistant or predisposed to resistance development at a population level and to strengthen surveillance (phenotypically and genetically), and possibly also at the patient level to guide treatment.
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