In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae
In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae
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DOI：
10.1093/jac/dkz376
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发表时间：
2019-12-01
影响因子：
5.2
通讯作者：
Unemo, Magnus
中科院分区：
文献类型：
--
作者：
Foerster, Sunniva;Drusano, George;Unemo, Magnus
目的：淋病奈瑟菌对所有淋病治疗性抗菌素的耐药性已经出现。新型治疗性抗菌剂势在必行，而一流的螺嘧啶三酮唑氟西林似乎很有希望。唑氟达星可用于双重抗菌药物治疗，以防止耐药性的出现和/或传播。研究了唑氟菌素单用和联用6种淋病治疗性抗菌药物对淋病奈瑟菌的体外活性和耐药性选择。方法：检测国际淋球菌参考菌株WHO F （WT）和不同AMR谱菌株WHO O、WHO V和WHO X。采用棋盘法、时间杀伤曲线分析和耐药性选择研究，评价唑氟达星单独使用或与头孢曲松、头孢克肟、大观霉素、庆大霉素、四环素、头孢霉素或西他沙星联合使用。结果：唑氟达星单独或与所有6种抗菌剂联合使用对所有检测菌株均有快速生长抑制作用。时间杀伤曲线分析表明，四环素或奇霉素与唑氟哌啶联用可显著降低唑氟哌啶的体外杀伤率。当作为单一药物评估时，选择的唑氟哌啶耐药突变的频率较低，并且在所有抗菌药物组合中进一步降低。所有耐药突变体均含有GyrB突变D429N、K450T或K450N，导致唑氟西林mic为0.5-4mg/L。结论：唑氟达星单独使用或与性传播感染治疗性抗菌药物联合使用可迅速杀死淋球菌，且很少出现耐药性。唑氟达星作为淋病口服单药治疗和双抗微生物治疗的一部分仍有希望，具有低耐药性出现的可能性。计划于2019年进行一项评估唑氟达星治疗无并发症淋病疗效和安全性的III期试验。
Objectives: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.Methods: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies.Results: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4mg/L.Conclusions: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.