In this article an infectious diseases pharmacist discusses five interesting things to know about sulopenem (Orlynvah).
Authored by: Tina Zheng, Pharm.D., BCIDP
Article Posted 15 January 2025
Sulopenem etzadroxil and probenecid (Orlynvah) was recently approved in October 2024 for the treatment of uncomplicated urinary tract infections (uUTI) caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis. It is the first oral beta-lactam on the market with in vitro activity against extended-spectrum beta-lactamases (ESBL) and cephalosporinases. At first glance, it seems to be a promising oral option to expand our toolbox for the treatment of uUTI caused by resistant Gram negative bacteria.
So what are the importance nuances about sulopenem? There are many of course. In this article I will go into five interesting things about sulopenem.
Note that referencing sulopenem in this article sometimes refers to it as a single drug and other times refer to the combination of sulopenem with probenicid.
1. Sulopenem is in a new beta-lactam class
Despite its name, sulopenem is not quite part of the carbapenem class, as one might assume from the “- penem” suffix. Instead, sulopenem belongs to a newly designated class of beta-lactams called penems. Specifically, it is a thiopenem, characterized by a sulfur atom in the five-membered ring adjacent to the beta-lactam ring, in contrast to the carbon ring found in carbapenems.
Pharmacy students may groan at the prospect of memorizing yet another beta-lactam class. However, despite structural differences, sulopenem’s spectrum of activity closely resembles that of ertapenem. It demonstrates in vitro activity against MSSA, Streptococcus spp., anaerobes, and Enterobacterales, including strains producing extended-spectrum beta-lactamases (ESBL). However, sulopenem does not cover Pseudomonas aeruginosa, Enterococcus faecalis, or carbapenemase producers such as KPC, OXA-48, and NDM.
2. Sulopenem has an oral formulation
Sulopenem etzadroxil is a prodrug that is converted into its active form, sulopenem, by intestinal esterases. Its oral bioavailability is 40% when taken without food and increases to 64% when consumed with a high-fat meal. A high-fat meal is defined as containing 800–1,000 calories, with 400–500 calories derived from fat.
The package insert for sulopenem recommends taking it with food to maximize bioavailability. However, given that the general daily calorie intake is around 2,000 calories, and sulopenem is taken twice daily, adhering to the dietary specifications needed to optimize its absorption may be challenging for most patients.
3. Unlike most beta-lactams, sulopenem requires no renal dose adjustment
Sulopenem is administered at a dose of 500 mg/500 mg twice daily. Renal dose adjustments are not required for patients with a creatinine clearance (CrCl) above 15 mL/min. However, sulopenem is not recommended for patients with a CrCl below 15 mL/min or those on hemodialysis due to a lack of pharmacokinetic data in these populations. The absence of renal dose adjustments may be attributed to sulopenem dual excretion pathways, with elimination occurring through both feces and urine.
Given that many beta-lactams do require renal dose adjustments, you can add this one to your short study list of ones that do not need it.
In case you are wondering, the FDA label does not list any hepatic dose adjustments.
4. Sulopenem has the addition and removal of drug interactions
Sulopenem is coformulated with probenecid, a combination that impacts its pharmacokinetics. Sulopenem is a substrate of OAT3 (organic anion transporter 3), while probenecid is an inhibitor of both OAT1 and OAT3. By inhibiting OAT3, probenecid reduces the renal clearance of sulopenem, enhancing its bioavailability. However, this coformulation introduces potential drug interactions. For example, ketorolac and ketoprofen, which are also OAT1 and OAT3 substrates, should not be used concomitantly with sulopenem.
A notable drug interaction common to carbapenems—but not observed with sulopenem—is with valproic acid (VPA). Although the exact mechanism of the carbapenem-VPA interaction is unclear, it is thought to involve inhibition of VPA’s enterohepatic recirculation. Accidentally reducing the concentration of VPA (an anticonvulsant) in the body can be quite serious, because it can illicit seizures.
Interestingly, the inclusion of probenecid in sulopenem mitigates it from interacting with VPA. While sulopenem alone reduces VPA exposure by 25%, coadministration with probenecid decreases VPA exposure by only 8%.
5. Sulopenem is a new option for difficult to treat organisms that cause a uncomplicated UTI – but not for other indications
Sulopenem is currently approved for treating uncomplicated urinary tract infections (uUTIs) in adult women, but it is not indicated for complicated UTIs (cUTIs) or complicated intra-abdominal infections (cIAIs). This approval is based on data from the REASSURE (REnewed ASsessment of Sulopenem in uUTI caused by Resistant Enterobacterales) and SURE1 (Sulopenem for Resistant Enterobacteriaceae) trials.
In the REASSURE trial, sulopenem was compared to amoxicillin/clavulanate (875/125 mg twice daily for 5 days). The study demonstrated non-inferiority in amoxicillin/clavulanate- susceptible isolates, with overall response rates of 61.7% for sulopenem and 55% for amoxicillin/clavulanate.
The SURE1 trial compared sulopenem to ciprofloxacin (250 mg twice daily for 3 days). Sulopenem showed superior efficacy in ciprofloxacin-resistant isolates, with overall response rates of 48.1% versus 32.9%. However, in ciprofloxacin-susceptible isolates, sulopenem did not demonstrate non-inferiority, primarily due to a lower microbiological response (60.4% for sulopenem vs. 80.4% for ciprofloxacin).
While sulopenem performs well in uUTIs, its results were less favorable in trials for more complicated infections.
In the SURE2 trial, which evaluated sulopenem for cUTIs, the drug was compared to ertapenem with an oral step-down regimen. Sulopenem did not meet the non-inferiority criteria, with an overall response difference of -6.1% (95% CI, -12 to -0.1), primarily due to a weaker microbiological response.
Similarly, the SURE3 trial assessed sulopenem for cIAIs and found it did not achieve non- inferiority compared to standard therapies, with an overall response difference of -6% (95% CI, -12.2 to 0.2).
Closing Comments
It is exciting to have a new oral antibiotic that might help patients avoid the need for intravenous catheters. As this product comes to market it will be important for pharmacists to maintain an awareness of what was discussed here, to help steward it’s safe and appropriate use.
Disclosure: The views and opinions in this article are that of the author and may not represent the policy or position of any past, current, or potential future employer.
REFERENCES
- Al-Quteimat O, et al. Valproate Interaction With Carbapenems: Review and Recommendations. Hosp Pharm. 2020 Jun;55(3):181-187.
- Dunne MW, et al. A phase 3 randomized trial of sulopenem vs. ertapenem in patients with complicated intra-abdominal infections. Clin Microbiol Infect. 2024 Nov 2:S1198-743X(24)00507- X.
- Dunne MW, et al. Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial. Clin Infect Dis. 2023 Jan 6;76(1):78-88.
- Dunne MW, et al. Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial. Clin Infect Dis. 2023 Jan 6;76(1):66-77. Erratum in: Clin Infect Dis. 2023 Sep 18;77(6):937.
- Orlynvah [package insert]. Chicago, IL: Iterum Therapeutics; 2024.
- Zhanel GG, et al. Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria. Drugs. 2022 Apr;82(5):533-557.
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