pretomanid

Pretomanid is a nitroimidazole antibiotic used to treat tuberculosis. It was developed for use against Mycobacterium tuberculosis, including certain drug-resistant strains, and is administered as part of combination regimens.

Mechanism of action

Pretomanid is a prodrug activated by the bacterium’s F420-dependent nitroreductases. Once activated, it generates reactive nitrogen species and disrupts cell wall synthesis under aerobic conditions, while under hypoxic conditions it releases nitric oxide that can inhibit bacterial respiration. This dual activity enables killing of both actively replicating and dormant bacilli, supporting efficacy in drug-resistant tuberculosis when used with other agents.

Clinical use and regulatory status

In the United States, pretomanid received FDA approval in 2019 as part of the BPaL regimen, which combines bedaquiline, pretomanid, and linezolid, for adults with highly drug-resistant TB when other treatment options are unsuitable. The drug is used only within the context of such regimens and with appropriate clinical oversight. The World Health Organization and national bodies have evaluated pretomanid for drug-resistant TB, with recommendations varying by programmatic context and available regimens.

Development and clinical evidence

Pretomanid, originally known as PA-824, was developed by TB Alliance. Clinical evidence supporting its use comes from trials evaluating the BPaL regimen in treatment-refractory tuberculosis. The Nix-TB trial, which studied BPaL in XDR-TB, reported favorable outcomes, and subsequent studies explored dosing variations and safety in related populations.

Safety and adverse effects

Common adverse effects include hepatotoxicity, anemia, thrombocytopenia, headache, nausea, and dizziness. When used as part of the BPaL regimen, linezolid-associated toxicities and other combination-related risks may require careful monitoring of liver function, blood counts, and neurologic or hematologic status. Pretomanid is taken orally, with bioavailability improved when taken with food.