期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 62, 期 12, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01221-18
关键词
Neisseria gonorrhoeae; microbiology; urogenital gonorrhea
资金
- GSK
- Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development [HHSO100201300011C]
- GlaxoSmithKline (Collegeville, PA, USA)
We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae 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 N. gonorrhoeae. Against 69 baseline urogenital isolates, gepotidacin MICs ranged from <= 0.06 to 1 mu g/ml (MIC90 = 0.5 mu g/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of >= 48 and decreased to 63% (5/8) for fAUC/MICs of <= 25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 mu g/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 in vitro FoR to gepotidacin was low (10(-9) to 10(-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, fAUC/MICs of >= 48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs >= 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted.
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