Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial

New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, op...

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Bibliographic Details
Published in:The Lancet infectious diseases 2021-02, Vol.21 (2), p.226-240
Main Authors: Bassetti, Matteo, Echols, Roger, Matsunaga, Yuko, Ariyasu, Mari, Doi, Yohei, Ferrer, Ricard, Lodise, Thomas P, Naas, Thierry, Niki, Yoshihito, Paterson, David L, Portsmouth, Simon, Torre-Cisneros, Julian, Toyoizumi, Kiichiro, Wunderink, Richard G, Nagata, Tsutae D
Format: Article
Language:English
Subjects:
Adult
Adverse events
Aged
Aged, 80 and over
Anti-Bacterial Agents - therapeutic use
Antibiotics
Bacteremia - drug therapy
Bacteremia - microbiology
Bacteria
Carbapenems
Carbapenems - pharmacology
Cefiderocol
Cephalosporins
Cephalosporins - therapeutic use
Drug Resistance, Bacterial
Fatalities
FDA approval
Female
Gram-negative bacteria
Gram-Negative Bacterial Infections - drug therapy
Health aspects
Health services
Hospitals
Humans
Infections
Infectious diseases
Intravenous administration
Intravenous infusion
Klebsiella
Male
Middle Aged
Mortality
Nosocomial infection
Pathogens
Patients
Pharmacokinetics
Pneumonia
Pneumonia, Bacterial - drug therapy
Pneumonia, Bacterial - microbiology
Polymyxins
Pseudomonas aeruginosa
Randomization
Safety
Sepsis
Sepsis - drug therapy
Sepsis - microbiology
Therapy
Urinary tract
Urinary tract diseases
Urinary tract infections
Urinary Tract Infections - drug therapy
Urinary Tract Infections - microbiology
Urogenital system
Ventilators
Young Adult
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Summary:New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination thera
ISSN:1473-3099
1474-4457
DOI:10.1016/S1473-3099(20)30796-9