Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis: A Multicenter, Randomized, Double-Blind, Phase 2 Study [PublishAheadOfPrint]

Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a next-generation aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae. We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to intravenous plazomicin (10 or 15 mg/kg) or intravenous levofloxacin (750 mg) once daily for 5 days. Co-primary efficacy endpoints were microbiological eradication at test-of-cure (TOC; 5-12 days after last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the plazomicin 10 mg/kg, 15 mg/kg, and levofloxacin groups, respectively, microbiological eradication rates (n/N [95% CI]) were 50.0% (6/12 [21.1-78.9]), 60.8% (31/51 [46.1-74.2]), and 58.6% (17/29 [38.9-76.5]) in the MITT population and 85.7% (6/7 [42.1-99.6]), 88.6% (31/35 [73.3-96.8]), and 81.0% (17/21 [58.1-94.6]) in the ME population. In the MITT population, 66.7% (34.9-90.1), 70.6% (56.2-82.5), and 65.5% (45.7-82.1) of patients were assessed as clinically cured by the investigator at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of patients. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success rates and an overall safety profile supportive of further clinical development. (ClinicalTrials.gov registration: NCT01096849.)

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