Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen

Abstract

e Strategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin-isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824 -moxifloxacin-pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ϳ2 log 10 bacilli of wild-type Mycobacterium tuberculosis H37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two-drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid-and rifamycin-sparing regimen suitable for treatment of both drug-sensitive TB and MDR-TB. The increasing global burden of drug-resistant tuberculosis (TB) underscores the need for new drugs but also for shorter, better-tolerated regimens to reduce treatment durations from the current 18 to 24 months for multidrug-resistant TB (MDR-TB) (1, 2). Shorter regimens are expected to improve adherence to treatment, thereby reducing transmission and the emergence of new drug resistance, as well as facilitating coadministration with antiretroviral regimens and curbing costs. As a result of continuing efforts to evaluate novel drug combinations with treatmentshortening potential, several new drugs have been shown to contribute to reducing the time required to achieve a relapse-free state in animal models (3-6).A paradigm shift from "drug development" to "regimen development," wherein the regimen, not an individual drug, is the unit of development, seems a more feasible approach to deliver sufficiently novel combinations more rapidly (1). The novel regimen PaMZ, comprising PA-824 (Pa), moxifloxacin (M), and pyrazinamide (Z), a combination containing neither rifampin (R) nor isoniazid (H), was found to have a sterilizing activity superior to that of the current first-line regimen, RHZ, in mice (3, 7). In addition, studies in the mouse model have revealed synergism between the agents in the novel combination (3, 7). Recently, a phase II clinical study confirmed the potent initial activ...

In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

“…A comparison of the efficacy of delamanid, Pa, and TBA-354 against TB in other mouse models, in addition to other preclinical species and with other infecting M. tuberculosis strains will be important to corroborate our findings. These types of evaluations have begun for Pa, providing a baseline for the comparison of TBA-354 and delamanid (13,31). It will also be of interest to assess the contribution of TBA-354 to the bactericidal and sterilizing efficacy of drug combinations.…”

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

“…All treatment groups were given daily (7 days/week) rifampicin 50 mg/kg in a 40% sucrose (w/v)/20%pumpkin puree (w/v) solution containing 50 mg/kg vitamin C and 1% Lactobacillus acidophilus and Lactobacillus bulgaricus (Lactinex, BD) as described (41). Each day, rifampicin dosing preceded PAE or PZA dosing by at least 30 min.…”

Assessment of Clofazimine Activity in a Second-Line Regimen for Tuberculosis in Mice

“…Oral drugs were given together in a single dose of 0.2 ml in water, with the exception of clofazimine, which was given separately in 0.2 ml of 0.05% agar suspension. Dosages (described in Table 1) were chosen to produce area under the (serum) concentration curve values in mice estimated to be close to those obtained with currently recommended human dosages (12)(13)(14)(15)(16).…”