FDA approves new oral antibiotic to treat uncomplicated UTIs

The Food and Drug Administration (FDA) recently approved a new oral antibiotic named Orlynvah to treat uncomplicated urinary tract infections (UTIs) in women. The drug treats lower urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis that affect otherwise healthy individuals (1).

This antibiotic, from Iterum Therapeutics, is the first oral penem antibiotic approved in the United States. Penem antibiotics are a class of synthetic antibiotics with broad spectrum antibacterial activity. This approval marks one of the first new oral antibiotics to treat uncomplicated UTIs in more than 20 years in the United States. In fact, the FDA approved nitrofurantoin, the leading product to treat uncomplicated UTIs, in 1953.

“The antibiotic development world was slowing down. But since 2015, there’s definitely been stimulus and increased activity in terms of bringing more antibiotics to market,” said Keith Kaye, an infectious disease physician scientist at Rutgers University. Developing antibiotics is tricky for companies, said Florian Wagenlehner, a urologist at Justus-Liebig University Giessen, because the return on investment is low in antibiotic development; it’s important to prevent antibiotic overuse that can lead to further antibiotic resistance.

Orlynvah is a combination of the prodrug sulopenem etzadroxil and probenecid. When metabolized, sulopenem becomes activated and interferes with how bacteria build their cell walls, which ultimately causes bacteria to die (2). The addition of probenecid, a renal tubular transport inhibitor, inhibits the clearance of sulopenem from the body and extends its half-life in plasma (3).

Iterum Therapeutics began working on sulopenem after it acquired the license to the compound from Pfizer in 2015. Pfizer had discovered sulopenem in the 1980s but abandoned the drug after Phase 1 and 2 clinical trials to favor the development of other drugs. In 2021, Iterum Therapeutics filed a New Drug Application after they completed a Phase 3 clinical trial comparing Orlynvah to ciprofloxacin, an antibiotic currently used to treat uncomplicated UTIs (3). While the trial showed that Orlynvah was superior in treating fluoroquinolone-resistant infections when compared to ciprofloxacin, it was inferior to ciprofloxacin for infections that were ciprofloxacin-sensitive. Thus, the FDA requested another clinical trial using a different drug as a comparison point. This additional trial found that Orlynvah compared to amoxicillin/clavulanic acid (Augmentin) — another antibiotic used to treat UTIs — was statistically superior in Augmentin-susceptible infections.

Orlynvah’s approval could pave the way towards its use in other indications. “This kind of drug [could also apply to] other entities of UTI — for example, pyelonephritis, uncomplicated pyelonephritis, kidney infection — where we really lack oral antibiotics,” said Wagenlehner.

This kind of drug [could also apply to] other entities of UTI — for example, pyelonephritis, uncomplicated pyelonephritis, kidney infection — where we really lack oral antibiotics.
- Florian Wagenlehner, Justus-Liebig University Giessen

The Orlynvah approval comes at a time when antibiotic-resistant organisms are becoming more prevalent. “Two of the types of pathogens that we’re seeing with increasing frequency, not only in hospital and healthcare settings, but also in the community, are quinolone-resistant organisms … and ESBL-producing E. coli,” said Kaye. Extended-spectrum beta-lactamase (ESBL)-producing E. coli generate enzymes that break down beta-lactam antibiotics commonly used to treat bacterial infections. Orlynvah is effective against both ESBL-producing E. coli and quinolone-resistant organisms.

Kaye added that there has been a dearth of oral antibiotics that are effective against these and multidrug-resistant bacteria. Prior to its approval, patients whose UTIs required penem antibiotic treatment had to receive the drug intravenously in the hospital. With the availability of an oral penem, patients can leave the hospital quicker or avoid hospitalization altogether if they have a multidrug-resistant infection. While this mode of administration will make many uncomplicated UTIs easier to treat, Kaye cautioned, “whenever there is a drug that is pretty well tolerated and can be given orally anywhere in the inpatient or outpatient setting, I think there is concern about overuse and subsequent development of resistance.”

Wagenlehner agreed and added that its use “should be restricted to cases where there are patients with high resistances, or maybe patients that cannot tolerate other antibiotics, [like] first-line recommended antibiotics. … It is certainly for a niche patient group.”

As the first oral penem approved in the United States, Orlynvah makes UTI treatment more accessible for patients and may open doors for its use in treating other bacterial infections.

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