GlaxoSmithKline, Upper Providence, Pennsylvania, USA
GlaxoSmithKline, Upper Providence, Pennsylvania, USA.
Antimicrob Agents Chemother. 2018 Nov 26;62(12). doi: 10.1128/AAC.01221-18. Print 2018 Dec.
We evaluated microbiological correlates for the successful treatment of isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (AUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at AUC/MICs of ≥48 and decreased to 63% (5/8) for AUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the FoR to gepotidacin was low (10 to 10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, AUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (AUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).
我们评估了 gepotidacin（一种新型三氮杂萘并乙内酰脲类抗菌药物）治疗 2 期研究中分离株成功治疗的微生物学相关性，用于治疗单纯性泌尿生殖系统淋病。对选定的分离株进行培养、药敏试验、基因特征分析和耐药频率（FoR）检测。微生物学成功定义为培养证实消除基线泌尿生殖系统 69 株分离株，gepotidacin MIC 范围为≤0.06 至 1µg/ml（MIC=0.5µg/ml）。对于 gepotidacin，游离药物浓度-时间曲线下面积与 MIC 的比值（AUC/MIC）与治疗成功相关。AUC/MIC≥48 时成功率为 100%（61/61），AUC/MIC≤25 时成功率降至 63%（5/8）。3 例微生物学失败的分离株均对环丙沙星耐药，基线 gepotidacin MIC 为 1µg/ml，携带预先存在的 ParC D86N 突变，这是 gepotidacin 结合的关键残基。在治愈试验分析中，2 例分离株（MIC 增加≥32 倍）出现对 gepotidacin 的耐药性，这些分离株还携带 GyrA A92T 突变，也与 gepotidacin 结合有关。治愈试验分离株与相应基线分离株的序列类型相同。对于 5 株携带 ParC D86N 突变的选定基线分离株，对 gepotidacin 的 FoR 较低（10 至 10）；耐药突变株与其中 2 株出现耐药性的分离株具有相同的 A92T 突变。携带 ParC D86N 突变的 5 名参与者的分离株治疗成功。总之，AUC/MIC≥48 预测微生物学成功率为 100%，包括 3 株携带 ParC D86N 突变（AUC/MIC≥97）。药代动力学/药效学测定可能有助于评估淋病的新疗法；需要进一步研究 gepotidacin。（本研究已在 ClinicalTrials.gov 注册，标识符为 NCT02294682。）
