Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection [Experimental Therapeutics]

The potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (B_LAI-160); and test regimens of daily bedaquiline at 2.67 (B_2.67), 5.33 (B_5.33), or 8 (B₈) mg/kg to deliver the same total bedaquiline as one, two, or three doses of B_LAI-160, respectively. All drugs were administered orally, except for B_LAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of B_LA-160 resulted in decreases of 2.9, 3.2, and 3.5 log₁₀ CFU/lung, respectively by week 12. Daily oral dosing with B_2.67, B_5.33, and B₈ decreased lung CFU counts by 1.6, 2.8, and 4.1 log₁₀, respectively. One dose of B_LAI-160 exhibited activity for at least 12 weeks. The sustained activity of B_LAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

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