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Background Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. Methods Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). Results Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum β-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, −6.1%; 95% confidence interval, −12.0 to −.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. Conclusions Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. Clinical Trial Registration NCT03357614.

Background Rezafungin is a next-generation, once-weekly echinocandin in development for treatment of candidemia and invasive candidiasis (IC), and for prevention of invasive fungal diseases caused by Candida, Aspergillus, and Pneumocystis in allogeneic blood and marrow transplant recipients (Fig 1). ReSTORE (NCT03667690) is a global, double-blind, double-dummy, 1:1 randomized, controlled, Phase 3 non-inferiority trial that evaluated the efficacy and safety of rezafungin once weekly (QWk) versus caspofungin once daily (QD) in patients with candidemia and/or IC. This analysis of the completed ReSTORE trial was conducted to evaluate outcomes by baseline pathogen and susceptibility. Methods In ReSTORE, adults (≥18 y) with systemic signs and mycological confirmation of candidemia and/or IC received either rezafungin QWk (400 mg Week 1, then 200 mg QWk) or caspofungin QD for ≥14 days (up to 4 weeks) with optional oral fluconazole step-down in the caspofungin arm. The primary endpoints were global cure at day (D) 14 (per Data Review Committee confirmation of investigator-assessed clinical cure [and radiological cure for IC) + mycological eradication]) and all-cause mortality (ACM) at D30 (Fig 2). Secondary endpoints included mycological eradication at D14. For this analysis, D14 global cure and mycological eradication by treatment group were analyzed by Candida species and in vitro susceptibility at baseline (CLSI broth microdilution MIC values; M27 Ed4) (Fig 3). Results A total of 204 Candida isolates were recovered in 187 patients across both treatment groups. Of the 204 isolates, C. albicans was the most common species, followed by C. glabrata, C. tropicalis, and C. parapsilosis; 61% of all baseline isolates were non-albicans Candida (Fig 3). The rates of D14 global cure and mycological eradication by pathogen are shown in Tables 1 and 2. Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either rezafungin or caspofungin (Table 3). Conclusion Rezafungin was efficacious across multiple Candida species in the Phase 3 ReSTORE trial that demonstrated non-inferiority of rezafungin to caspofungin. There was no clear correlation between increased MIC values and clinical outcomes. Disclosures George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Alex Soriano, MD, MSD, Pfizer, Shionogi, Angelini, Menarini, Gilead: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Bart-Jan Kullberg, MD, FRCP, FIDSA, Cidara: Independent Data Review Committee Jeffrey B. Locke, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.