Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models

Abstract

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen.

Mycobacterium tuberculosis DprE1 inhibitor OPC-167832 is active against Mycobacterium abscessus in vitro

“…2). Absence of antagonism with clarithromycin, amikacin (Sigma-Aldrich), cefoxitin (MedChem Express) or imipenem (Cayman Chemical) (Table 3), together with the clean drug-drug interaction profile of OPC-167832 as required under multi-drug TB therapy (25, 37, 38), suggest that dihydrocarbostyril analogs are compatible with the current standard of care for M. abscessus lung disease.…”

Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments

“…Table 1 summarizes treatment duration that results in 95% cure ( T 95 ) values and the relapse rank order. In experiment 2, the rank order of treatment-shortening activity based on microbiologic relapse was as follows: bedaquiline, moxifloxacin, pyrazinamide, rifabutin (BMZRb) (fastest) > bedaquiline, moxifloxacin, pyrazinamide (BMZ) > rifapentine, moxifloxacin, pyrazinamide (PMZ) > isoniazid, rifampin, pyrazinamide, ethambutol (HRZE) (slowest) ( 11 ). In experiment 3, the rank order of treatment-shortening activity based on microbiologic relapse was as follows: bedaquiline, pretomanid, moxifloxacin, pyrazinamide (BPaMZ) (fastest) > bedaquiline, pretomanid, linezolid (BPaL) > pretomanid, moxifloxacin, pyrazinamide (PaMZ) > HRZE (slowest) ( 10 ).…”

“…Experiments 2 and 3 evaluated combination regimens to determine whether changes in PD markers during the first weeks of treatment distinguish between regimens and indicate regimen treatment-shortening activity. Efficacy outcomes from experiments 2 and 3 are reported elsewhere ( 10 , 11 ).…”

“…Full details of murine protocols are included in the supplemental material and in other publications ( 10 , 11 ). Briefly, all three experiments employed female pathogen-free BALB/c mice infected by the same high-dose aerosol (HDA) procedure in a Glas-Col inhalation exposure system ( 21 , 22 ) and treated mice 5 of 7 days a week via oral gavage.…”

“…Experiments 2 and 3 used the standard conventional relapsing mouse model described in the supplemental material ( 1 , 10 , 11 ). In experiment 2, treatment began on day 14 postinfection with the following: isoniazid, rifampin, pyrazinamide, ethambutol (HRZE); rifapentine, moxifloxacin, pyrazinamide (PMZ); bedaquiline, moxifloxacin, pyrazinamide (BMZ); or bedaquiline, moxifloxacin, pyrazinamide, rifabutin (BMZRb).…”