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Background Per FDA Guidance, the primary efficacy endpoint for trials evaluating antimicrobials for treatment of uncomplicated urinary tract infection (uUTI) and complicated urinary tract infection (cUTI) is a combined clinical/microbiologic outcome response. Overall success requires both resolution of UTI symptoms and demonstration that the causative uropathogen is reduced to < 103 CFU/mL at a fixed time point after randomization, regardless of whether the patient is symptomatic. In clinical practice, it is not standard of care to routinely screen for or treat asymptomatic bacteriuria (ASB), nor to obtain ‘proof of cure’ cultures. In the clinical trial setting, the impact of post-treatment asymptomatic bladder recolonization on the rates of microbiologic response, re-infection, or emergence of resistance is unknown. Methods Study IT001-301 and -302 are double blind, double-dummy, Phase 3 randomized trials comparing sulopenem to comparator for patients with pyuria, bacteriuria, and clinical signs/symptoms of uUTI and cUTI, respectively. In Study 301, 1671 ambulatory female adults with uUTI were randomized to oral sulopenem bid x 5d or oral ciprofloxacin bid x 3d. In Study 302, 1395 hospitalized adults with cUTI were randomized to sulopenem IV once daily x 5d followed by oral sulopenem bid or ertapenem IV once daily x 5d followed by either oral ciprofloxacin or amoxicillin-clavulanate bid, depending on baseline uropathogen susceptibility. The primary endpoint was overall (clinical + microbiologic) response in micro-MITT population at TOC visit (D12 in uUTI study and D21 in cUTI study). Results Figure 1 Conclusion Different classes of antibiotics appear to have a differential effect on the frequency of post-treatment ASB with quinolones having a lower rate relative to beta-lactams. The presence of ASB a week or more after completing UTI therapy was not associated with a higher rate of clinical relapse for UTI patients; treatment with ciprofloxacin was associated with the selection of resistant pathogens in the post-treatment flora. Inclusion of ASB in the primary endpoint for studies of UTI should be reconsidered as it implies that a post-treatment culture should be obtained to document resolution of infection, a practice inconsistent with available treatment recommendations. Disclosures Steven I. Aronin, MD, Iterum Therapeutics: Stocks/Bonds Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Sailaja Puttagunta, MD, Iterum Therapeutics: Stocks/Bonds. |
