The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dosage should be reduced, typically by half. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 600 mg/d. Rifabutin may accumulate in severe renal impairment, and the dose should be reduced by half if creatinine clearance is less than 30 mL/min. Rifabutin is associated with similar rates of hepatotoxicity or rash compared to rifampin; it can also cause leukopenia, thrombocytopenia, and optic neuritis.
Rifapentine is another analog of rifampin. It is active against both M tuberculosis and MAC. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile; however, when rifapentine is administered intermittently, induction of metabolism of other medications is less pronounced compared to rifampin. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly, has been used for treatment of tuberculosis caused by rifampinsusceptible strains during the continuation phase (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative); however, this regimen has decreased efficacy compared with the standard rifampin-based regimen. Revised guidelines for treatment of drug-susceptible tuberculosis published in 2016 recommend against it. In particular, its use should be avoided in patients at higher risk of failure, including those with positive cultures at the end of the intensive treatment phase and those with evidence of cavitation on chest radiographs. Rifapentine should not be used to treat active tuberculosis in patients with HIV infection because of an unacceptably high relapse rate with rifampin-resistant organisms. Rifapentine in combination with isoniazid, typically both dosed at 900 mg once weekly for 3 months (12 doses each in total), is an effective short course treatment for latent tuberculosis infection.
Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M tuberculosis to be approved since 1971. Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in mycobacteria, has in vitro activity against both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of tuberculosis. Cross-resistance has been reported between bedaquiline and clofazimine, likely via upregulation of the multisubstrate efflux pump, MmpL5.
Peak plasma concentration and plasma exposure to bedaquiline increase approximately twofold when administered with high-fat food. Bedaquiline is highly protein-bound (>99%), is metabolized chiefly through the cytochrome P450 system, and is excreted primarily via the feces. The mean terminal half-life of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. CYP3A4 is the major isoenzyme involved in the metabolism of bedaquiline, and potent inhibitors or inducers of this enzyme cause clinically significant drug interactions.