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Cited by 420Urinary Tract Infections ManagementAntibiotic Resistance in BacteriaAntibiotics Pharmacokinetics and Efficacy

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

Portsmouth, Simon, van Veenhuyzen, David, Echols, Roger, Machida, Mitsuaki, Ferreira, Juan Camilo Arjona, Ariyasu, Mari, Tenke, Peter, Nagata, Tsutae Den·2018·The Lancet Infectious Diseases
DOI 10.1016/s1473-3099(18)30554-1
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Abstract

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 as Pseudomonas 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 with ClinicalTrials.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 × 10 5 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.

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  • One of the most recent and promising achievements is the development and therapeutic application of Trojan-horse antibiotics that exploit the microbial quest for iron by delivering a siderophore-antibiotic conjugate directly into bacterial cells.

    “One of the most recent and promising achievements is the development and therapeutic application of Trojan-horse antibiotics that exploit the microbial quest for iron as they deliver a siderophoreantibiotic conjugate directly into bacterial cells (Portsmouth et al., 2018).”

    From Iron in infection and immunity (2020) · cites this paper as Portsmouth et al., 2018

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Authors
Portsmouth, S., van Veenhuyzen, D., Echols, R., Machida, M., Ferreira, J. C. A., Ariyasu, M., Tenke, P., & Nagata, T. D.
Affiliations
  • Shionogi (United States) (US)
  • Shionogi (Japan) (JP)
Corresponding author
Portsmouth, Simon
ORCID
Venue
The Lancet Infectious Diseases
Publisher
Elsevier BV
Published
2018-12
Volume
18
Issue
12
Pages
1319-1328
ISSN
1473-3099 (ISSN-L)
DOI
10.1016/s1473-3099(18)30554-1
OpenAlex
W2898144230
Cited by
420
References
23
Citations by year
2026: 38 · 2025: 43 · 2024: 53 · 2023: 63 · 2022: 57 · 2021: 60 · 2020: 56 · 2019: 44 · 2018: 5
FWCI
32.18
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Infectious Diseases (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cell Science Research Foundation
  • Shionogi
Topics
  • Health Sciences › Medicine › Epidemiology › Urinary Tract Infections Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
cefiderocol, imipenem/cilastatin, complicated urinary tract infection, pyelonephritis, carbapenem resistance, Gram-negative uropathogens, multidrug resistance, siderophore cephalosporin, non-inferiority, test of cure, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, antibiotic resistance
MeSH terms
Cilastatin, Imipenem Drug Combination, Cefiderocol, Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents, Cephalosporins, Double-Blind Method, Female, Gram-Negative Bacteria, Humans, Infusions, Intravenous, Male, Middle Aged, Protease Inhibitors, Urinary Tract Infections, Urine, Colony Count, Microbial, Treatment Outcome, Gram-Negative Bacterial Infections, Young Adult, Drug-Related Side Effects and Adverse Reactions

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