We evaluated microbiological correlates of 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 µg/mL (MIC90 = 0.5 µg/mL). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs ≥48 and decreased to 63% (5/8) for fAUC/MICs ≤25. All 3 isolates from microbiological failures were ciprofloxacin-resistant, had a baseline gepotidacin MIC of 1 µg/mL, and carried a pre-existing ParC D86N mutation, a critical residue for gepotidacin binding. At test-of-cure, resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with an additional GyrA A92T mutation, 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, in vitro FoR to gepotidacin was low (10–9 to 10–10); resistant mutants had the same A92T mutation as the 2 emergence of resistance isolates. Five participants with isolates with a ParC D86N mutation were successes. In summary, fAUC/MICs ≥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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