Introduction

Combining beta (β)-lactams with novel β-lactamase inhibitors can improve therapeutic benefit against extended-spectrum β-lactam–resistant pathogens. Cefepime/enmetazobactam combination could be a potential empirical therapy for these resistant gram-negative infections.

Aim

To evaluate whether the treatment efficacy of cefepime 2 g/enmetazobactam 0.5 g was noninferior to piperacillin 4 g/tazobactam 0.5 g and to evaluate adverse events in patients with complicated urinary tract infections (UTI) or pyelonephritis

Patient Profile

• 1041 patients with complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens
• Patients in the primary analysis set included those who received at least one dose of study drug and had a gram-negative baseline pathogen in urine at >10⁵ colony forming units (CFU)/mL or the same pathogen present in both blood and urine cultures that was not resistant to either treatment

Method

Study Design

• ALLIUM study: phase 3, randomized, double-blind, active-controlled, multicentre, noninferiority clinical trial
• Patients received either cefepime/enmetazobactam or piperacillin/tazobactam by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline)
• Clinical outcomes were assessed at day 3 of treatment, end of treatment, day 14, day 21 and at time of early termination

Endpoints

• Proportion of patients in the primary analysis set who achieved a composite outcome of complete resolution of the baseline signs and symptoms present at screening (clinical cure) and reduction of qualifying baseline pathogen to <10³ CFU/mL in urine (microbiological eradication) at day 14

Results

Efficacy

• Cefepime/enmetazobactam was noninferior to piperacillin/tazobactam in achieving the primary composite outcome (79.1% versus 58.9% patients; difference, 21.2%, Figure 1)
• It also met the criterion for superiority as compared with piperacillin/tazobactam 
• Cefepime/enmetazobactam therapy achieved significant microbiological eradication versus piperacillin/tazobactam at day 14 (82.9% vs 64.9%; treatment difference, 19.0%) and day 21; however, the clinical cure rate was similar between the two groups
• The composite outcome was significantly higher with cefepime/enmetazobactam vs. piperacillin/tazobactam at day 14 in patients with an extended-spectrum β-lactamase–producing baseline pathogen (73.7% vs. 51.5%; treatment difference, 30.2%), in patients not excluded from the study (78.6% vs. 58.7%, treatment difference, 20.7%) and among patients who received at least 1 dose of drug (59.1% vs. 43.4%; treatment difference, 15.6%)
• Microbiological recurrence was lower with cefepime/enmetazobactam than piperacillin/tazobactam at day 14 (11.3% vs. 29.4%) in the primary analysis set
• Among patients in the primary analysis set but excluding those with a piperacillin/tazobactam minimum inhibitory concentration >16 μg/mL &/or an Enterobacterales pathogen with an extended-spectrum β-lactamase genotype, cefepime/enmetazobactam was significantly better than piperacillin/tazobactam (80.9% vs 60.7%; difference, 20.2%)

Figure 1: Effect of cefepime/enmetazobactam and piperacillin/tazobactam on the primary composite outcome

Safety 

• Treatment-emergent adverse events (TEAE) occurred in 50% patients in cefepime/enmetazobactam and 44% in piperacillin/tazobactam groups; TE serious AE were seen in 4.3% and 3.7%, respectively
• Most of the TEAE were mild to moderate in severity (89.9% vs. 88.6%, respectively); common TEAE observed were elevations of liver function parameters like alanine aminotransferase (11.4% vs 11.6%), aspartate aminotransferase (9.1% vs 8.9%), and blood bilirubin (5.8% vs 3.9%)
• Rates of drug-related TEAE were 19.8% and 14.5%, respectively; drug-related TE serious AE were experienced in 0.2% vs. 0.6% cases
• AE related therapy discontinuation was seen in 1.7% in cefepime/enmetazobactam vs. 0.8% in piperacillin/tazobactam; study drug discontinuations due to drug-related TEAE were seen in 1.0% on vs. 0.4%, resp.
• No deaths were drug related

Conclusion

• 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
• Cefepime/enmetazobactam may be an appropriate empirical therapy for suspected gram-negative complicated UTI

JAMA 2022; 328(13): 1304-1314