Sulopenem Etzadroxil and Probenecid (Orlynvah)
December 15, 2024
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has approved a combination of sulopenem and probenecid for the treatment of uncomplicated urinary tract infections (uUTIs). Sulopenem is an oral broad-spectrum thiopenem β-lactam antibiotic (similar to ertapenem) formulated as a prodrug (sulopenem etzadroxil). Probenecid is an inhibitor of organic anion transporter 3 (OAT3), reducing renal tubular clearance and increasing plasma concentrations of sulopenem. The combination received Fast Track Breakthrough designation and was given an accelerated priority review.1 It is distributed by Iterum Therapeutics as Orlynvah.
Indications
Sulopenem/probenecid is indicated for the treatment of uUTIs caused by designated microorganisms Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women who have limited or no alternative oral antibacterial treatment options.2
Dosage
The recommended dose is one tablet orally twice daily for five days, preferably with food.2 Sulopenem/probenecid is available as 500 mg sulopenem etzadroxil and 500 mg of probenecid tablets.
Potential Advantages
Sulopenem demonstrated in vitro activity against multidrug-resistant, gram-negative pathogens, including extended-spectrum β-lactamases and AmpC-producing Enterobacterales.3 It is effective against uropathogens resistant to ciprofloxacin and trimethoprim-sulfamethoxazole.3,4
Potential Disadvantages
Sulopenem is not indicated for the treatment of complicated urinary tract infection, complicated intra-abdominal infections, or as step-down treatment after an intravenous antibacterial for these infections.2 Efficacies in these clinical settings have not been demonstrated. Probenecid also can cause exacerbation of gout. Appropriate therapy for gout should be instituted when prescribing sulopenem/probenecid to patient with a known history of gout.2 The most frequent adverse reaction is diarrhea (10%) compared to 4% for amoxicillin/clavulanate and 3% for ciprofloxacin.2 In a comparative trial, diarrhea occurred more frequently with sulopenem vs. ciprofloxacin (12.4% vs. 2.5%).4 Potential drug-drug interactions may occur with probenecid, an inhibitor of organic anion transporters 1 and 3. Probenecid is contraindicated in patients with known blood dyscrasias and known uric acid kidney stones or concomitantly with ketorolac tromethamine.2
Comments
The efficacy of sulopenem/probenecid was evaluated in two Phase III, randomized, double-blind, active controlled trials. One compared sulopenem/probenecid to amoxicillin/clavulanate and the other to ciprofloxacin in adult women with uUTIs and with no structural abnormalities of their urinary tract.2,4 In the first trial, adult women with uUTIs were randomized to sulopenem/probenecid or amoxicillin 875 mg/clavulanate 125 mg. Both were taken twice daily for five days. Composite response (combined microbiological response and clinical cure) was evaluated at a test of cure visit (12 days after randomization). Data were stratified into two subpopulations — amoxicillin/clavulanate-susceptible and nonsusceptible baseline uropathogens. Composite responses for the two subpopulations were 61.7% and 52.4% for sulopenem/probenecid vs. 55% and 68% for amoxicillin/clavulanate, respectively.
For the second trial, which compared sulopenem/probenecid to ciprofloxacin using the same subpopulation stratification, response rates were 60.4% and 48.1% vs. 71.8% and 32.9%, respectively. Against nonsusceptible microorganisms, sulopenem was superior to ciprofloxacin, but against susceptible microorganisms, sulopenem was not noninferior to ciprofloxacin, driven by a higher rate of asymptomatic bacteriuria in those who received sulopenem.4
Clinical Implications
UTI is very common, with 50% to 60% of women having at least one UTI in their lifetime.5 Causative uropathogens are from the order Enterobacterales from the gastrointestinal tract. These include E. coli, K. pneumoniae, and P. mirabilis. There are numerous treatment options, including nitrofurantoin, trimethoprim/sulfamethoxazole, oral beta-lactams (e.g., amoxicillin/clavulanate), fluoroquinolones (e.g., ciprofloxacin), fosfomycin, and pivmecillinam.5,6 However, the emergence of extended-spectrum beta-lactamases (ESBL-E)-producing Enterobacterales has limited the utility of some of these agents. The Centers for Disease Control and Prevention has defined these as one of the seven key antimicrobial-resistant pathogens.7
The Infectious Diseases Society of America recommends nitrofurantoin and trimethoprim/sulfamethoxazole as preferred options for uncomplicated cystitis caused by ESBL-E.8 A single intravenous dose of an aminoglycoside or fosfomycin (for E. coli only) also are options. While sulopenem seems to have impressive in vitro activity against multidrug-resistant Enterobacterales, the two clinical trials suggest sulopenem to be numerically less effective against nonsusceptable microorganisms compared to amoxicillin/clavulanate but superior to ciprofloxacin-nonsusceptible microorganisms. The current FDA-approved indication is for use when there are limited or no alternative oral options. The cost for sulopenen/probenecid was not available at the time of this review.
References
- U.S. Food and Drug Administration. FDA approves new treatment for uncomplicated urinary tract infections in adult women who have limited or no alternative oral antibiotic treatment options. Published Oct. 24, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-uncomplicated-urinary-tract-infections-adult-women-who-have-limited-or-no
- Iterum Therapeutics Orlynvah prescribing information. Revised October 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213972s000lbl.pdf
- Karlowsky JA, Adam HJ, Baxter MR, et al. In vitro activity of sulopenem, an oral penem, against urinary isolates of Escherichia coli. Antimicrob Agents Chemother 2018;63:e01832-18.
- Dunne MW, Aronin SI, Das AF, et al. Sulopenem for the treatment of complicated urinary tract infections including pyelonephritis: A Phase 3, randomized trial. CID 2023;76:66-77.
- Al Lawati H, Blair BM, Larnard J. Urinary tract infections: Core curriculum 2024. Am J Kidney Dis 2023;83:90-100.
- Bono MJ, Leslie SW, Reygaert WC. Uncomplicated urinary tract infections. StatPearls [Internet]. Updated Nov. 13, 2023. https://www.ncbi.nlm.nih.gov/books/NBK470195/
- Centers for Disease Control and Prevention. Antimicrobial resistance threats in the United States, 2021-2022. Published July 16, 2024. https://www.cdc.gov/antimicrobial-resistance/data-research/threats/update-2022.html
- Tamma PD, Heil EL, Justo JA, et al. IDSA 2024 guidance on the treatment of antimicrobial resistant gram-negative infections. Infectious Diseases Society of America. Published July 12, 2024. https://www.idsociety.org/practice-guideline/amr-guidance/#Section1:Extended-spectrum%CE%B2-lactamase-ProducingEnterobacterales
The U.S. Food and Drug Administration has approved a combination of sulopenem and probenecid for the treatment of uncomplicated urinary tract infections.
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