#Cefiderocol versus #imipenem-cilastatin for the #treatment of complicated #UTIs caused by Gram-negative #uropathogens: a phase 2, randomised, double-blind, non-inferiority trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial

Simon Portsmouth, MD,  David van Veenhuyzen, MBChB, Roger Echols, MD, Mitsuaki Machida, MS, Juan Camilo Arjona Ferreira, MD, Mari Ariyasu, BPharm, Prof Peter Tenke, MD, Tsutae Den Nagata, MD

Published: October 25, 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30554-1

 

Summary

Background

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such asPseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections.

Methods

We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7–14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 10 5 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered withClinicalTrials.gov, number NCT02321800.

Findings

Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 105 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23–28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group).

Interpretation

Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing.

Funding

Shionogi & Co Ltd, Shionogi Inc.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Imipenem-Cilastatin; Cefiderocol.

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Published by

gimi69

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.

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