Intravenous plazomicin was non-inferior to meropenem for the treatment of complicated urinary tract infections (UTIs), including acute pyelonephritis, a randomized trial found.
Composite cure was achieved in 88.0% of patients in the plazomicin group compared to 91.4% of those in the meropenem group (difference -3.4, 95% CI -10.0 to 3.1) on day 5, reported Florian M.E. Wagenlehner, MD, of Justus Liebig University in Geisen, Germany, and colleagues.
At the test-of-cure visit, occurring 15 to 19 days after therapy initiation, composite cure was achieved in 81.7% of the plazomicin group versus 70.1% of the meropenem group (difference 11.6, 95% CI 2.7-20.3), the authors wrote in the New England Journal of Medicine.
The trial met the non-inferiority margin of 15 percentage points for both primary endpoints, they noted.
Multidrug resistance is a global concern for complicated UTIs, with the authors commenting that patients with multidrug-resistant UTIs are three times as likely to receive inappropriate empirical antibiotic therapy, and are associated with longer hospital stays, higher hospital costs, and have a higher risk of septic shock and death.
Carbapenems are now being used to treat complicated UTIs, but the authors said that with emerging carbapenem resistance, "alternative treatment options are needed."
Plazomicin is described as an aminoglycoside engineered in part to maintain "activity in the presence of most mechanisms that lead to resistance in Enterobacteriaceae," they noted.
Researchers conducted the Evaluating Plazomicin in cUTI (EPIC) trial, a multi-center phase III trial to show non-inferiority of plazomicin to meropenem. Participants were adults ages ≥18 with a creatinine clearance of >30 ml per minute, pyuria, and clinical symptoms of a complicated UTI or acute pyelonephritis requiring ≥4 days of intravenous antibiotics.
Patients were randomized to receive intravenous plazomicin (15 mg/kg of body weight once daily) or meropenem (1 g every 8 hours), with oral step-down therapy after ≥4 days of intravenous therapy, the authors said.
Overall, 604 patients were included in the safety and modified intention-to-treat populations and 388 were included in the microbiologic modified intention-to-treat population. Participants were a mean age of about 59, and a little under three-quarters had impaired renal function. About 60% had complicated UTIs, and about 40% had acute pyelonephritis, and mean duration of intravenous therapy was 5.5 days in each group. The most common uropathogen was Escherichia coli, followed by Klebsiella pneumoniae.
Along with achieving its two primary efficacy endpoints, the authors noted that a higher portion of patients in the plazomicin group had microbiologic eradication at the test-of-cure visit compared to the meropenem group. They also noted lower incidence of microbiologic recurrence and clinical relapse in the plazomicin group at late follow-up.
"[This] suggests that the greater microbiologic eradication with plazomicin has additional clinical benefit for patients with complicated UTIs, including acute pyelonephritis," the authors wrote.
Examining safety, the most frequent adverse events in the plazomicin group were diarrhea, hypertension, headache, nausea, vomiting, and hypotension. The authors also noted that 7.0% of patients in the plazomicin group and 4.0% of patients in the meropenem group had increases in serum creatinine level of ≥0.5 mg per dL above baseline. The authors said a total of six patients per group discontinued treatment due to adverse events, and there was one death in the plazomicin group that was unrelated to the trial drug.
In an accompanying editorial, Edward Cox, MD, MPH, of the FDA in Silver Spring, Maryland, and colleagues, described the results of this study as "central in evaluating the efficacy and safety profile of plazomicin for the treatment of complicated UTIs." However, they pointed to a second study in the NEJM Correspondence section that was stopped early due to "major challenges with enrollment."
Cox and colleagues discussed the challenges of studying new antibacterial drugs, particularly having a "sustainable enterprise" to help support these types of drugs in the future.
"Those who have followed this field will recognize that scientific challenges and economic strain are not the exception but represent the typical scenario that is faced when a new antibacterial drug is developed," the editorialists wrote.
They noted important progress in initiatives to encourage antibacterial drug development, including passage of the GAIN (Generating Antibiotic Incentives Now) legislation.
Study limitations include the fact that patients from countries outside Europe, and patients of non-white race, were underrepresented in the study.
The study was supported by Achaogen and the Biomedical Advanced Research and Development Authority, and the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response.
Wagenlehner disclosed support from AstraZeneca, Bionorica, Enteris BioPharma, Helperby Therapeutics, Janssen, Leo Pharma, MerLion, MSD, OM Pharma/Vifor Pharma, Pfizer, RosenPharma, Shionogi, VenatoRx, GSK, and Deutsches Zentrum für Infektionsforschung (DZIF) (Giessen-Marburg-Langen site). Co-authors disclosed support from BARDA, Achaogen, Contrafect, Theravance, Spero Therapeutics, Tetraphase, Cepheid, Merck, Abbott, Gilead Sciences, Genentech, AtoxBio, and Paratek.
Cox disclosed no relevant relationships with industry. One co-author disclosed support from the Ragon Institute, the NIH National Institute of Allergy and Infectious Diseases, and the Gates Foundation; serving as an NEJM deputy editor; serving as chair of the FDA AntiMicrobial Drug Advisory Committee (AMDAC); and being involved in HIV vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Military HIV Research Program (MHRP), the Gates Foundation, and the Ragon Institute.
Plazomicin Tx Non-Inferior to Meropenem for Complicated
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Plazomicin, a next-generation aminoglycoside with in vitro activity against MDR Enterobacteriaceae, demonstrated non-inferior efficacy to meropenem for treatment of cUTI, including AP, and significantly higher microbiological eradication rates at the test-of-cure (TOC) visit in the epic study (Cloutier DJ,. FDA Approves Drug for Complicated UTIs. In the trial, plazomicin demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiologic eradication) in the microbiological modified intent-to-treat population at day 5 and test-of-cure (TOC) visit. Plazomicin Gets Priority Review for Complicated UTI, Bloodstream study Quantifies Dental, Jaw Risks With Denosumab Infections. Plazomicin was developed to treat serious bacterial infections due to multi-drug resistant (MDR) Enterobacteriaceae. A Phase 3 trial (epic) which included 609 patients with cUTI and acute pyelonephritis found plazomicin to be non-inferior to meropenem.Reply
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