Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection

Abstract

The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the 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 <i>Mycobacterium bovis</i> rBCG30, BALB/c mice were challenged by aerosol infection with <i>M. tuberculosis</i> H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), 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 mg/kg (B_2.67), 5.33 mg/kg (B_5.33), or 8 mg/kg (B₈) to deliver the same total amount of 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 <i>M. tuberculosis</i> lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of B_LAI-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 that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.