Research findings published in The New England Journal of Medicine found once-daily plazomicin was noninferior to meropenem for treating complicated urinary tract infections (UTIs) and acute pyelonephritis caused by Enterobacteriaceae.

In this noninferiority trial, 609 individuals with complicated UTIs, including acute pyelonephritis, were randomly assigned in a 1:1 ratio to receive intravenous (IV) plazomicin (15 mg/kg of body weight once daily) or meropenem (1 g every 8 hours) with optional oral step-down therapy after at least 4 days of IV treatment, for a total of 7 to 10 days of therapy (ClinicalTrials.gov NCT02486627). Of the patients enrolled in the study, 604 were included in the safety and modified intention-to treat population and 388 were included in the microbiologic modified intention-to-treat population. The most common cause for exclusion from the latter population was the absence of a qualifying baseline uropathogen.

Plazomicin was noninferior to meropem with respect to the primary efficacy end point of composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15-19 days after initiation of therapy) in the microbiologic modified intention-to-treat population. Composite cure at day 5 was observed in 88% of the 191 patients who received plazomicin and 91.4% of the 197 patients who received meropem (difference, –3.4%; 95% CI, –10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% and 70.1% of the plazomicin and meropem groups, respectively (difference, 11.6%; 95% CI, 2.7 to 20.3). Also, a higher percentage of patients in the plazomicin group were found to have microbiologic eradication, including eradication of Enterobacteriaceae resistant to aminoglycoside antibiotics, compared with patients in the meropenem group (78.8% vs 68.6%) at the test-of-cure visit. A similar result was demonstrated for eradication of Enterobacteriaceae that produce extended-spectrum β-lactamases (82.4% vs 75.0%, plazomicin and meropenem groups, respectively). The results also showed that compared with patients in the meropenem group, fewer patients in the plazomicin group had microbiologic recurrence (3.7% vs 8.1%) or clinical relapse (1.6% vs 7.1%) at late follow-up, 24 to 32 days after therapy commenced.

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While the study investigators believe the underrepresentation in the trial of patients from outside of Europe and of non-white race likely did not affect the results, they noted that this presents a limitation to the study, similar to previous research on UTIs.  The study investigators reported that it is unlikely that the pharmacokinetics of either drug is affected by race and “the analysis in the microbiologic modified intention-to-treat population excluded patients with pathogens resistant to the trial drugs, so geographic differences in resistance rates also would not have affected the results.”

Increases in multi-drug resistance in gram-negative uropathogens means new treatments will be required in the near future. The study investigators purport that plazomicin may be one such option as, “these findings support the use of once-daily plazomicin in adult patients with complicated UTIs or acute pyelonephritis, including infections caused by extended spectrum β-lactamase–producing Enterobacteriaceae and Enterobacteriaceae that are not susceptible to other aminoglycosides.”

Disclosure

This study was sponsored and funded in part by Achaogen Inc.

Reference

Wagenlehner FM, Cloutier DJ, Komirenko AS, et al. Once-daily plazomicin for complicated urinary tract infections. New Engl J Med. 2019;380:729-740.