Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 10⁶ CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 10⁸ CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.

中文翻译：

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淋病奈瑟氏球菌中空纤维体外感染模型中吉博达霉素暴露与治疗耐药性扩增的预防之间的关系。

耐多药性淋病奈瑟菌已经对全球健康构成威胁。使用7天的中空纤维体外感染模型检查了吉博达霉素暴露与预防耐药性淋病奈瑟氏球菌在治疗中扩增之间的关系。研究设计包括非活性（未经治疗和环丙沙星）和活性（头孢曲松）控制方案。在体外系统中模拟了单次口服0.5 g环丙沙星剂量，单次肌肉内0.25 g头孢曲松剂量和单次或两次（相隔8至12小时）口服gepotidacin剂量范围为0.75至12 g的研究药物浓度-时间曲线。模型中接种的初始细菌负荷为10 ⁶CFU /毫升。攻击分离物（淋病奈瑟氏球菌GSK＃8）的gepotidacin，环丙沙星和头孢曲松肉汤MIC值分别为0.5、2和0.002 mg / L。收集样品，以求出细菌总数和耐药菌总数以及药物浓度。未经处理的对照达到的细菌密度大于10 ⁸24小时内的CFU / ml，在7天的研究期内保持一致。在整个研究期间，环丙沙星方案模型系统中的细菌密度与生长控制相符，而头孢曲松方案在第1天结束时对模型系统进行了灭菌。对于gepotidacin，观察到了完全的剂量反应关系。尽管在0.75g，1.5g和3g单剂量方案中观察到失败，但所有总剂量至少为4.5g的gepotidacin单剂量或分剂量方案均阻止了耐药性扩增并对模型系统进行了灭菌。这些数据可用于为治疗淋病感染的患者提供Gepotidacin剂量选择支持。