For the treatment of complicated urinary tract infection (UTI) in people with multidrug-resistant gram-negative infections, treatment with cefiderocol may be noninferior to imipenem‑cilastatin treatment, according to a study recently published in Lancet Infectious Diseases.

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An increasing number of gram-negative pathogens has been categorized as extensively drug-resistant, with susceptibility to 2 or fewer antibiotic classes, because of the worldwide spread of carbapenemases and their frequent co-occurrence with other β-lactam resistance mechanisms. Carbapenem-resistant, gram-negative infections are often acquired in hospital or are associated with high mortality. These infections represent the highest priority for addressing global antibiotic resistance, as the availability of effective therapies, including carbapenem-resistant Enterobacteriaceae and nonfermenting bacteria, is an unmet medical need. However, cefiderocol is the first siderophore antibiotic to reach late-stage development that has broad activity against Enterobacteriaceae and nonfermenting bacteria, including carbapenem-resistant strains. Therefore, this phase 2, multicenter, double-blind, parallel‑group noninferiority trial assessed the efficacy and safety of cefiderocol vs imipenem-cilastin for the treatment of complicated UTI in patients at risk for multidrug‑resistant gram-negative infections (ClinicalTrials.gov identifier: NCT02321800).

Between 2015 and 2016, 371 patients with a clinical diagnosis of complicated UTI with or without pyelonephritis or those with acute uncomplicated pyelonephritis were included in the intention-to-treat population and randomly assigned (2:1) to receive either 1 hour of intravenous infusions of 2 g cefiderocol (n=252) or 1 g (each) of imipenem-cilastin (n=119) 3 times/day every 8 hours for 7 to 14 days. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (7 days after treatment cessation), which was used to establish noninferiority of cefiderocol vs imipenem-cilastatin.

Results showed that intravenous infusion of 2 g cefiderocol 3 times/day was noninferior compared with 1 g (each) imipenem-cilastatin for the treatment of complicated UTI in people with multidrug-resistant gram-negative infections. Post hoc analysis showed that cefiderocol was superior to imipenem-cilastatin. At test of cure, the primary efficacy endpoint was achieved by 73% in patients in the cefiderocol group and 55% of patients in the imipenem-cilastatin group. Cefiderocol was well tolerated; adverse events occurred in 51% of patients in the imipenem-cilastatin group and 41% of patients in the cefiderocol group, with gastrointestinal disorders being the most common adverse events for both treatment groups.

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Overall, the study authors concluded that, “This study represents the first clinical trial done to obtain marketing approval for cefiderocol in the [United States] as part of the streamlined development process of the [US Food and Drug Administration] for antibiotics meeting a high unmet medical need.”

Disclosure: This study was funded by Shionogi & Co Ltd, Shionogi Inc.

Reference

Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomized, double‑blind, non-inferiority trial [published online October 25, 2018]. Lancet Infect Dis. doi: 10.1016/S1473‑3099(18)3055401