• Wagenlehner Florian M E FME From the Justus Liebig University, Giessen, Germany (F.M.E.W.); Achaogen, South San Francisco (D.J.C., A.S.K., D.S.C., K.M.K., T.R.K., L.E.C.,, Daniel J Cloutier, Allison S Komirenko, Deborah S Cebrik, Kevin M Krause, Tiffany R Keepers, Lynn E Connolly, Loren G Miller, Ian Friedland, Jamie P Dwyer, and EPIC Study Group.
• From the Justus Liebig University, Giessen, Germany (F.M.E.W.); Achaogen, South San Francisco (D.J.C., A.S.K., D.S.C., K.M.K., T.R.K., L.E.C., I.F.), the David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles (L.G.M.), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (L.G.M.) - all in California; and Vanderbilt University Medical Center, Nashville (J.P.D.).
• N. Engl. J. Med. 2019 Feb 21; 380 (8): 729-740.

BackgroundThe increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae.MethodsWe randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population.ResultsPlazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, -3.4 percentage points; 95% confidence interval [CI], -10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum β-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 μmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group.ConclusionsOnce-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).Copyright © 2019 Massachusetts Medical Society.

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