Abstract | Importance: Objective: Design, Setting, and Participants: A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Interventions: Eligible patients were randomized to receive either cefepime, 2 g/ enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/ tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). Main Outcomes and Measures: The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Results: Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/ enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/ enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/ enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Conclusions and Relevance: Trial Registration: ClinicalTrials.gov Identifier: NCT03687255.
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Authors | Keith S Kaye, Adam Belley, Philip Barth, Omar Lahlou, Philipp Knechtle, Paola Motta, Patrick Velicitat |
Journal | JAMA
(JAMA)
Vol. 328
Issue 13
Pg. 1304-1314
(10 04 2022)
ISSN: 1538-3598 [Electronic] United States |
PMID | 36194218
(Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial)
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Chemical References |
- Anti-Bacterial Agents
- Drug Combinations
- beta-Lactamase Inhibitors
- Piperacillin, Tazobactam Drug Combination
- Cefepime
- enmetazobactam
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Topics |
- Acute Disease
- Anti-Bacterial Agents
(administration & dosage, adverse effects, therapeutic use)
- Cefepime
(administration & dosage, adverse effects, therapeutic use)
- Double-Blind Method
- Drug Combinations
- Female
- Gram-Negative Bacterial Infections
(drug therapy)
- Humans
- Infusions, Intravenous
- Male
- Middle Aged
- Piperacillin, Tazobactam Drug Combination
(administration & dosage, adverse effects, therapeutic use)
- Pyelonephritis
(drug therapy, microbiology)
- Urinary Tract Infections
(complications, drug therapy, microbiology)
- beta-Lactamase Inhibitors
(administration & dosage, adverse effects, therapeutic use)
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