Chen, Aiyi

Olsen, Landon

Vu, Thanh-Liem

Yang, Daniel J

English

eCommons at Roseman University

Complicated Urinary Tract Infection (cUTI)• NCT03357614 Trial (Dunne et al, 2023).5• Multicenter, randomized, comparative, double-blind trial , multicentered, multinational non-inferiority trial.Study DesignSubjects• Hospitalized adults with pyuria, bacteriuria, and signs and symptoms; average age 58 years, 60% females, 5% from the U.S.• 90% with CrCl > 30 ml/min, pyelonephritis 58%, cUTI42%; bacteremia 10%Pathogen Isolates• 77% E coli, 11% K. pneumoniae• 26% ESBL- positive• 38% FQ-nonsusceptible• 35% TMP-SMX-nonsusceptible• 21% ESBL-positive/FQ-nonsusceptible• 15% ESBL-positive/ FQ-nonsuscpetible/ TMP/SMX-nonsuscpetibleSulopenem for the Treatment of Complicated and Uncomplicated Bacterial Urinary Tract Infection (UTI)Aiyi Ivy Chen, Thanh-Liem Vu, Daniel J Yang, Landon Olsen, PharmD Candidates, and H Stephen Lee, PharmD, MSc, BSc (Honors)College of Pharmacy, Roseman University of Health Sciences, South Jordan, UTUrinary Tract Infections (UTIs)• E. Coli and K. pneumoniae are the leading causes of UTIs, and the increased use of antibiotics has conferred increasing drug resistance1, such as extended spectrum beta-lactamase (ESBL), fluoroquinolone (FQ), and trimethoprim-sulfamethoxazole (TMP-SMX) resistance.• UTIs may be classified as complicated due to a variety of factors like treatment failure, pregnancy, renal failure, diabetes, immunosuppression, or symptoms of UTI lasting > 7 days. 2ESBLs and the Need for an Oral Carbapenem• E. coli and K. pneumoniae have extended spectrum β-lactamase (ESBL) that confers their multidrug resistance• Incidences of ESBL in uropathogens are on the rise.3• Current recommended therapy for ESBL-producing isolates includes carbapenems, fluoroquinolones and ceftolozane/tazobactam.• Carbapenems are especially effective against ESBLs, but they are currently FDA-approved only as IV formulation.• An oral carbapenem would, therefore, be an excellent addition for UTI therapy for individuals with ESBL-positive uropathogens.Sulopenem• A novel carbapenem (beta lactam) that is given by oral or intravenous routes.• Sulopenem etzadroxil is a oral prodrug that is metabolized to the active form sulopenem.• Oral bioavailability = ~25% (without probenecid or food); With probenecid- ↑AUC by 63% and ↑bioavailability by 60%; in fed state- ↑AUC by 24%.4• Serum half-life = ~1 hour; VD = ~22 L.4Common Therapeutic Options ESBL Complicated UncomplicatedAbsence (Negative)• 3rd Generation cephalosporins                  (e.g. ceftriaxone)• Fluoroquinolones            (e.g. ciprofloxacin, levofloxacin)• TMP/SMX• Fosfomycin• Nitrofurantoin• Ciprofloxacin, LevofloxacinPresence (Positive)Carbapenem (e.g. ertapenem)FluoroquinolonesUncomplicated Urinary Tract Infection• SURE-1 Trial (Dunne et al, 2020).6• NCT03354598 Trial (Dunne et al, 2023).7• Multicenter, randomized, prospective, double-blind, double dummy trial, multicentered, multinational non-inferiority trialStudy DesignSubjects• Women aged ≥ 18 years with pyruira, bacteriuria, and signs and symptoms of uUTI; average age 55 years, 90% Caucasian, 55% from the U.S.• 70% with CrCl > 90 mL/minPathogen Isolates• 86% E. coli, 11% K. pneumoniae• 14% ESBL- positive• 32% TMP-SMX-nonsusceptible,• 18% nitrofurantoin-nonsusceptible• 28% ciprofloxacin-nonsusceptibleDiscussion/Conclusion• The overall responses of sulopenem in the cUTI trial did not demonstrate noninferiority to ertapenem, and the uUTI trial demonstrated sulopenem was noninferiority to ciprofloxacin.• Sulopenem appeared to be safe and tolerated.• FDA required additional clinical studies to demonstrate further activity in the quinolone-resistant patient population in cUTI trials, and with additional agents for uUTI trials.• The FDA approval and commercial availability of sulopenem remains to be determined, similar to oral tebipenem. 8Phase 3 Clinical Trials ReviewIV sulopenem1000 mg dailyIV Sulopenem 1000 mg dailyORPO Sulopenem Etzadroxil 500 mg with Probenecid 500 mg BIDIV ertapenem 1000 mg dailyIV Ertapenem 1000 mg once dailyORPO ciprofloxacin 500 mg BID0rPO amoxicillin–clavulanate 875-125 mg BIDEndpoints7-10 days≥ 5 daysvsUp to 14 daysBacteremiaSulopenem etzadroxil500mg/probenecid 500mg bilayer tablet BID Ciprofloxacin 250mg BIDVS5 days3 daysNon-Inferiority Margin 10%NON-INFERIORTreatment Difference0%MARGIN 10%-10%Primary ClinicalMicrobiologicACCEPTABLEPrimary endpoint -6.1% (-12.1% to -0.1%)Microbiologic endpoint -6.8% (-12.5% to -1.1%)Clinical endpoint 1.0% (-5.3% to 3.1%)Non-Inferiority Margin 10%Adverse Events (AEs)Complicated UTI5 Uncomplicated UTI7Treatment GroupsSulopenem ErtapenemSulopenemEtzadroxil / ProbenecidCiprofloxacinAny AEs 15.1% 16.4% 25.0% 14.0%Treatment-Related AEs6.0% 9.2% 24.8% 13.9%Most Common Treatment-Related Adverse EventDiarrhea 2.7% 3.0% 12.4% 2.5%Nausea - - 3.8% 3.6%Headache 3.0% 2.3% 2.2% 2.2%Vomiting - - 1.6% 1.3%Dizziness - - 1.1% 0.6%Resistance in Complicated Urinary Tract Infections5Sulopenem Ertapenem Difference. 95% CIESBL-positive79/110(71.8%)85/125(68.0%)3.8% (-7.9% to 15.5%)ESBL-positive, Quinolone-resistant64/92(69.6%)64/99(64.6%)4.9% (-8.5% to 18.1%)Quinolone resistant112/162(69.1%)116/179(64.8%)4.3% (-5.6% to 14.3%)TMP-SMX resistant106/154(68.8%)111/161(68.9%)-0.1% (-10.3% to 10.1%)ESBL-positive, quinolone-resistant, TMP-SMX resistant43/59(72.9%)47/75(62.7%)10.2% (-5.5% to 26.0%)Combined clinical and microbiologic response at Test of Cure (TOC)Treatment GroupsSulopenemEtzadroxil / ProbenecidCiprofloxacinDifference(95% CI)Quinolone nonsusceptiblepopulation (mMITT-R)92/147 (62.6%)50/139 (36.0%)26.6%(15.1% to 37.4%)Quinolone susceptible population (mMITT-S)247/370 (66.8%)326/415 (78.6%)-11.8%(-18.0% to -5.6%)Combined (mMITT)339/517 (65.6%)376/554 (67.9%)-2.3%(-7.9% to 3.3%)References 1. Zumla A. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Lancet Infect Dis. 2010;10(5):303-304. doi:10.1016/S1473-3099(10)70089-X    2. Sabih A, Leslie SW. Complicated Urinary Tract Infections. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 28, 2022 3. Aboumarzouk OM. Extended spectrum beta-lactamase urinary tract infections. Urol Ann. 2014;6(2):114-115.    4. Zhanel GG, Pozdirca M, Golden AR, et al. Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria. Drugs. 2022;82(5):533-557. doi:10.1007/s40265-022-01688-1 5. Dunne MW, Aronin SI, Das AF, et al. Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial. Clin Infect Dis. 2023;76(1):78-88. doi:10.1093/cid/ciac704 6. Dunne MW, Das AF, Zelasky Met al. LB-1. Efficacy and Safety of Oral Sulopenem Etzadroxil/Probenecid Versus Oral Ciprofloxacin in the Treatment of Uncomplicated Urinary Tract Infections (uUTI) in Adult Women: Results from the SURE-1 Trial, Open Forum Infectious Diseases, Volume 7, Issue Supplement_1, October 2020, Page S844, https://doi.org/10.1093/ofid/ofaa515.1898 7. Dunne MW, Aronin SI, Das AF, et al. Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial. Clin Infect Dis. 2023;76(1):66-77. doi:10.1093/cid/ciac738    8. Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. NEJM. 2022;386(14):1327-1338. doi:10.1056/nejmoa2105462 Endpoints

Sulopenem for the Treatment of Complicated and Uncomplicated Bacterial Urinary Tract Infection (UTI)

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Sulopenem for the Treatment of Complicated and Uncomplicated Bacterial Urinary Tract Infection (UTI)

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