ACUTE uUTI — The most common cause of acute uUTI (cystitis or lower UTI in otherwise healthy non-pregnant women) is E. coli; other common pathogens include K. pneumoniae, P. mirabilis, and Staphylococcus saprophyticus. Infections caused by drug-resistant E. coli, including extended-spectrum beta-lactamase (ESBL)-producing strains, have been increasing worldwide.1

STANDARD TREATMENT — Preferred drugs for first-line empiric treatment of uUTIs in nonpregnant women include trimethoprim/sulfamethoxazole, nitrofurantoin, fosfomycin, and pivmecillinam.2-4 Amoxicillin/clavulanate, cefpodoxime, and cefadroxil are second-line options. The fluoroquinolones ciprofloxacin and levofloxacin are alternatives for patients who cannot take a beta-lactam antibacterial drug. Increasing resistance of common uropathogens to all of these drugs is a concern.

SPECTRUM OF ACTIVITY — Sulopenem, the active metabolite of sulopenem etzadroxil, inhibits bacterial cell wall synthesis. It has bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, including multidrug-resistant Enterobacterales that produce extended-spectrum beta-lactamases (ESBLs) or AmpC-type beta-lactamases. Sulopenem is not active against Pseudomonas aeruginosa.

Coadministration of probenecid, which does not have antimicrobial activity, blocks organic anion transporter 3 (OAT 3)-mediated renal clearance of sulopenem, increasing its serum concentrations.5

CLINICAL STUDIES — FDA approval of sulopenem etzadroxil/probenecid was based on the results of two double-blind trials (REASSURE and SURE 1) in women with uUTIs.

In REASSURE, 2222 women were randomized to receive sulopenem etzadroxil/probenecid or amoxicillin/clavulanate twice daily for 5 days. The sulopenem combination was noninferior to amoxicillin/clavulanate for the composite rate of clinical cure and microbiologic response at the test-of-cure visit (day 12) in women with amoxicillin/clavulanatesusceptible isolates (61.7% vs 55.0%) and in those with amoxicillin/clavulanate-nonsusceptible isolates (52.4% vs 68.0%).6

In SURE 1, 1660 women were randomized to receive sulopenem etzadroxil/probenecid twice daily for 5 days or ciprofloxacin twice daily for 3 days. The combination was noninferior to ciprofloxacin for the composite rate of clinical cure and microbiologic response at the test-of-cure visit (day 12) in women with ciprofloxacin-susceptible isolates (66.8% vs 78.6%); it was superior to ciprofloxacin in those with ciprofloxacin-resistant isolates (62.6% vs 36.0%).7

Complicated UTI – In a randomized trial, 1392 hospitalized adults with complicated UTIs (not an FDA-approved indication) received 5 days of IV treatment with either sulopenem or ertapenem, followed by oral sulopenem etzadroxil/probenecid in those who received sulopenem initially or ciprofloxacin or amoxicillin/clavulanate in those who received ertapenem initially. On day 21, the composite rate of clinical and microbiologic response in the sulopenem group was not noninferior to that in the ertapenem group (67.8% vs 73.9%).8

ADVERSE EFFECTS — In clinical trials, the most common adverse effects (frequency ≥2%) of Orlynvah were diarrhea, nausea, vomiting, vulvovaginal mycotic infection, and headache. Hypersensitivity reactions, Clostridioides difficile-associated diarrhea, and exacerbations of gout can occur.

DRUG INTERACTIONS — Probenecid inhibits OAT1/3 and may increase serum concentrations of drugs that are dependent on OAT1/3 for elimination, such as the NSAIDs ketorolac and ketoprofen. Use of Orlynvah with ketorolac is contraindicated and use with ketoprofen is not recommended. Sulopenem is a substrate of OAT3; use of other drugs that inhibit OAT3 may increase serum concentrations of sulopenem and the risk of adverse effects.

PREGNANCY AND LACTATION ― In animal studies, administration of sulopenem etzadroxil during pregnancy was associated with fetal malformations. No data are available on the presence of sulopenem in human milk or its effects on the breastfed infant or milk production. Sulopenem has been detected in rat milk. Probenecid has been detected in human milk.

DOSAGE, ADMINISTRATION, AND COST — Orlynvah tablets contain 500 mg of sulopenem etzadroxil and 500 mg of probenecid. The recommended dosage is one tablet taken twice daily with food for 5 days. Dosage adjustments are not required for renal dysfunction, but the combination should not be used in patients with a creatinine clearance <15 mL/min or in those on hemodialysis. Orlynvah is contraindicated for use in patients with blood dyscrasias, uric acid kidney stones, or a history of hypersensitivity to any beta-lactam antibacterial drug.

Orlynvah is only available through specialty pharmacy distribution. A 5-day course of the drug costs $2975.9

CONCLUSION — Orlynvah, an oral fixed-dose combination of the new thiopenem antibacterial sulopenem etzadroxil and the renal tubular transport inhibitor probenecid, was at least as effective as ciprofloxacin or amoxicillin/clavulanate in women with uncomplicated urinary tract infections (uUTIs). Because of concerns about development of resistance and its high cost, Orlynvah should be reserved for women who cannot be treated with a preferred first-line antibacterial drug.

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