Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Jan 6;76(1):66-77.
doi: 10.1093/cid/ciac738.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial

Michael W Dunne  1 , Steven I Aronin  1 , Anita F Das  2 , Karthik Akinapelli  1 , Michael T Zelasky  1 , Sailaja Puttagunta  1 , Helen W Boucher  3
Affiliations
Clinical Trial

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial

Michael W Dunne et al. Clin Infect Dis. .

Erratum in

Abstract

Background: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs.

Methods: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively.

Results: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%).

Conclusions: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin.

Clinical trial registration: NCT03354598.

Keywords: sulopenem; uncomplicated urinary tract infection.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. M. W. D., S. I. A., S. P., K. A., and M. T. Z. report being employees of Iterum Therapeutics during the conduct of the study and owning stock in Iterum Therapeutics. A. F. D. reports receiving consulting fees from Iterum Therapeutics, ContraFect, UTILITY, MicuRX, and Paratek, including serving on a data and safety monitoring board for Paratek. H. W. B. reports consulting fees and serving as associate editor of Antimicrobial Agents and Chemotherapy and editor of Infectious Diseases Clinics of North America and Sanford Guide. M. W. D. reports patents pending from Iterum Therapeutics and serving on the Iterum Therapeutics Board of Directors. S. P. reports consulting fees and being an employee and stockholder of Iterum Therapeutics, the sponsor for this study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Analysis population disposition. Abbreviations: ITT, intent-to-treat; MITT, modified intent-to-treat; microMITT, microbiologic modified intent-to-treat with a qualifying baseline urine isolate; microMITT-R, microbiologic modified intent-to-treat with a qualifying baseline urine isolate nonsusceptible to ciprofloxacin; microMITT-S, microbiologic modified intent-to-treat with a qualifying baseline urine isolate susceptible to ciprofloxacin.
Figure 2.
Figure 2.
Kaplan–Meier analysis of the time to resolution of symptoms in days since first treatment for patients treated with either sulopenem or ciprofloxacin. A, mMITT-R, microbiologic modified intent-to-treat with a qualifying baseline urine isolate nonsusceptible to ciprofloxacin. B, mMITT-S, microbiologic modified intent-to-treat with a qualifying baseline urine isolate susceptible to ciprofloxacin. C, mMITT, microbiologic modified intent-to-treat with a qualifying baseline urine isolate. Patients who received rescue antibiotic therapy prior to resolution are censored at day 29. Abbreviation: uUTI, uncomplicated urinary tract infection.
Figure 3.
Figure 3.
The proportion of patients with asymptomatic bacteriuria at the test-of-cure visit by the MIC to ciprofloxacin of that patient's baseline isolate, treated with either sulopenem or ciprofloxacin. The AUC0–24 for ciprofloxacin is calculated based on the US Ciprofloxacin Prescribing Information [12] and the AUC0–24/MIC is provided as per reference [21]. The red box indicates urine isolates with an MIC at the projected AUC/MIC threshold for tissue levels of ciprofloxacin. Abbreviations: AUC, area under the curve; MIC, minimum inhibitory concentration; SEM , standard error of the mean.
Figure 4.
Figure 4.
Organisms at screening and baseline include any uropathogen isolated in the urine culture, regardless of colony count. N above columns indicates number of organisms.
Figure 5.
Figure 5.
Organisms at screening and baseline include any uropathogen isolated in the urine culture, regardless of colony count. N above columns indicates number of organisms. Abbreviations: mMITT, microbiologic modified intent-to-treat with a qualifying baseline urine isolate; mMITT-R, microbiologic modified intent-to-treat with a qualifying baseline urine isolate nonsusceptible to ciprofloxacin; mMITT-S, microbiologic modified intent-to-treat with a qualifying baseline urine isolate susceptible to ciprofloxacin.
See this image and copyright information in PMC

References

    1. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011; 52:e103–20. - PubMed
    1. Fihn SD. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003; 349:259–66. - PubMed
    1. Talan DA, Takhar SS, Krishnadasan A, et al. Emergence of extended-spectrum β-lactamase urinary tract infections among hospitalized emergency department patients in the United States. Ann Emerg Med 2021; 77:32–43. - PubMed
    1. Critchley IA, Cotroneo N, Pucci MJ, Mendes R. The burden of antimicrobial resistance among urinary tract isolates of Escherichia coli in the United States in 2017. PLoS One 2019; 14:e0220265. - PMC - PubMed
    1. Dunne MW, Puttagunta S, Aronin SI, Brossette S, Murray J, Gupta V. Impact of empirical antibiotic therapy on outcomes of outpatient urinary tract infection due to nonsusceptible Enterobacterales. Microbiol Spectrum 2022; 10:e02359–21. - PMC - PubMed

Publication types

Associated data