Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis?

Abstract

Rationale: Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens.

Objectives: We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily.

Methods: Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure.

Measurements and main results: After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.

Conclusions: These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.

Figures

Figure 1.

Lung log10 colony-forming unit (CFU) counts at treatment initiation (Day 0 [D0; black bars]) and after (a) 4 weeks, (b) 8 weeks, (c) 10 weeks, and (d) 12 weeks in Mycobacterium tuberculosis–infected mice. Data are presented as means and SD (n = 5 mice per time point). H = isoniazid; M = moxifloxacin; ND = not determined; P = rifapentine; R = rifampin; Z = pyrazinamide. *One of five mice harbored 1 cfu/lung; **three of five mice harbored 1 cfu/lung.