Abstract
Background
Existing oral antibiotics for treatment of uUTI are not reliably effective due to rising antimicrobial resistant uropathogens. Sulopenem is a broad-spectrum IV/oral penem being developed for treatment of multidrug resistant infections. We conducted a pivotal Phase 3 randomized, double-blind, double-dummy, active controlled trial to evaluate the safety and efficacy of sulopenem/probenecid (SUL) vs amoxicillin/clavulanate (AMC) for treatment of uUTI.
Methods
Adult women with uUTI were randomized to SUL or AMC, both bid for 5 days. The primary objective was to establish noninferiority of SUL to AMC in the mMITT population (patients with ≥105 CFU/mL Enterobacterales in baseline urine culture). The primary endpoint was overall success (combined clinical and microbiologic success) at the Test of Cure (TOC) visit. Using a pre-specified procedure to control for multiplicity, mMITT patients with baseline pathogens susceptible to AMC (mMITTS) were tested for noninferiority/superiority and those with nonsusceptible pathogens (mMITTR) were tested for superiority.
Results
Of 2222 women randomized, 990 (44.6%) had ≥105 CFU/mL Enterobacterales in baseline urine cultures and were in the mMITT population (Table 1). Of these, 922 had pathogens susceptible to AMC (mMITTS). The sample size in the mMITTR population (N=67) was lower than anticipated and not sufficiently powered to draw any conclusions.
Treatment emergent adverse events (TEAE) occurred more frequently in SUL treated patients (all, 18.9% vs 12.3%; related, 14.0% vs 7.7%) with the most frequent TEAEs being diarrhea, nausea and headache. Premature discontinuation from study drug due to TEAEs was low in both treatment groups (≤1%). No serious adverse events were reported in the SUL group, while 5 (0.5%) occurred in the AMC group.
Conclusion
Sulopenem/probenecid was non-inferior to AMC for the treatment of adult women with uUTI in the mMITT population. In the mMITTS population, SUL demonstrated non-inferiority and based on an ad hoc analysis, demonstrated superiority to AMC. SUL was well tolerated with a safety profile consistent with other β-lactams and has the potential to fill the substantial unmet medical need for an empiric oral antibiotic option for outpatients with uUTI in this era of rising antimicrobial resistance.
Disclosures
Sailaja Puttagunta, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Steven I. Aronin, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Jayanti Gupta, PhD, Iterum Therapeutics: Advisor/Consultant Anita F. Das, PhD, Cidara: Advisor/Consultant|Contrafect: Advisor/Consultant|Iterum Therapeutics: Advisor/Consultant|Paratek: Advisor/Consultant|Utility therapeutics: Advisor/Consultant Kalpana Gupta, MD, Iterum Therapeutics: Advisor/Consultant Michael W. Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds (Public Company)