Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial

Abstract

Importance: Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections.

Objective: To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis.

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: Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis.

Trial registration: ClinicalTrials.gov Identifier: NCT03687255.

Figure 1.. Patient Disposition and Analysis Populations

Analysis populations referenced in this study are described in the Methods section. Other study populations are defined in eTable 1 in Supplement 3. ^aThe inclusion and exclusion criteria are listed in the eBox in Supplement 3. ^bIntravenous drug administration was not feasible in this patient and therefore the patient was not able to comply with the protocol. ^cA patient could discontinue treatment but remain in the study, discontinue treatment but discontinue study at a later date, or discontinue treatment and discontinue study at the same time. ^dThree patients refused continuation of study treatment; 1 patient did not have clinical improvement; 1 patient was deemed resistant to cefepime; 1 patient had an estimated glomerular filtration rate drop below 30 mL/min/1.73 m² on day 2; 1 patient did not receive last dose on day 7 by error; in 1 patient treatment could not be continued due to lack of investigational product; and 1 patient discharged themself early. ^eNine patients did not return to site for assessment but were contacted and 1 with whom contact was lost. ^fTwo patients refused continuation of study treatment and 1 patient had a negative confirmation result of urine culture. ^gFour patients did not return to site for assessment but were contacted and 1 patient had a negative confirmation result of urine culture. ^hIncludes 10 patients who had a baseline culture that was considered contaminated and 16 patients with a baseline gram-positive pathogen only.

Figure 2.. Subgroup Analyses in the Primary Analysis Set

Treatment differences in the proportions of patients between the 2 treatment groups at day 14 were determined by the stratified Newcombe 2-sided 95% CIs. Treatment differences were not evaluated due to too low numbers for the Black race subgroup. eGFR indicates estimated glomerular filtration rate; ESBL, extended-spectrum β-lactamase; and UTI, urinary tract infection. ^aThe “other” category indicates race was not identified.