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Abstract：
The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is seriously threatening the treatment and control of gonorrhea globally. Novel treatment options are essential, coupled with appropriate methods to pharmacodynamically examine the efficacy and resistance emergence of these novel drugs. Herein, we used our dynamic in vitro hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against N. gonorrhoeae. Dose-range and dose-fractionation experiments with N. gonorrhoeae reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2 mg/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. The dose-range experiments, simulating a single oral dose of lefamulin based on human plasma concentrations, indicated that ≥1.2 g, ≥2.8 g, and ≥9.6 g of lefamulin were required to eradicate WHO F, X, and V, respectively. Dose-fractionation experiments, based on human lefamulin plasma concentrations, showed that WHO X was eradicated with ≥2.8 g per day when administered as q12 h (1.4 g twice a day) and with ≥3.6 g per day when administered as q8 h (1.2 g thrice a day), both for 7 days. However, when simulating the treatment with 5-10 times higher concentrations of free lefamulin in relevant gonorrhea tissues (based on urogenital tissues in a rat model), 600 mg every 12 h for 5 days (approved oral treatment for community-acquired bacterial pneumonia) eradicated all strains, and no lefamulin resistance emerged in the successful treatment arms. In many arms failing single or multiple dose treatments for WHO X, lefamulin-resistant mutants (MIC = 2 mg/l), containing an A132V amino acid substitution in ribosomal protein L3, were selected. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs).
摘要：
淋病奈瑟菌耐药性的出现和蔓延严重威胁着全球淋病的治疗和控制。新的治疗方案至关重要，加上适当的药效学方法来检查这些新药的疗效和耐药性的出现。在这里，我们使用我们的动态体外中空纤维感染模型（HFIM）来评估未结合蛋白的lefamulin，一种半合成的截短侧耳素,对抗淋病奈瑟菌.淋病奈瑟菌参考菌株的剂量范围和剂量分级实验：WHOF（对所有相关抗菌药物敏感），WHOX（广泛耐药，包括头孢曲松耐药)，和WHOV（高度耐药的阿奇霉素，和最高淋球菌MIC的lefamulin（2mg/l）报告），在治疗期间进行检查lefamulin淋球菌的杀伤和耐药性发展。剂量范围实验,模拟基于人血浆浓度的单一口服剂量的lefamulin，表示≥1.2g，≥2.8g,根除WHOF，需要≥9.6glefamulin，X,V,分别。剂量分级实验，根据人类lefamulin血浆浓度，显示WHOX在q12h给药时每天≥2.8g（每天两次1.4g），在q8h给药时每天≥3.6g（每天三次1.2g），都是7天。然而,当模拟在相关淋病组织中使用5-10倍高浓度的游离lefamulin治疗时（基于大鼠模型中的泌尿生殖组织），600毫克每12小时5天（批准口服治疗社区获得性细菌性肺炎）根除所有菌株，在成功的治疗组中没有出现lefamulin抗性。在许多未能通过WHOX的单剂量或多剂量治疗的武器中，耐lefamulin突变体（MIC=2mg/l），选择在核糖体蛋白L3中含有A132V氨基酸取代。然而，这些耐利福蛋白的突变体表现出受损的生物特性。总之,有必要进行一项临床研究,以阐明lefamulin作为单纯性淋病(以及其他几种细菌性性传播感染)治疗方案的临床潜力.
