Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis

Abstract

Rationale: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens.

Methods: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy.

Results: After 2 mo of treatment, lung colony-forming unit counts were 1 log(10) lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen.

Conclusions: These results suggest that the efficacy of the once-weekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.

Figure 1.

Change in log₁₀ lung colony-forming unit (CFU) counts after 2 mo of treatment with standard daily therapy (rifampin–isoniazid–pyrazinamide) or the intermittent Denver regimen. * Significant difference when compared with the Denver regimen (p < 0.0001).

Figure 2.

Proportion of mice with culture-positive lungs 3 mo after completing treatment with 4, 5, and 6 mo of the Denver regimen (rifampin plus isoniazid, 2/7) or once-weekly (1/7) rifapentine-based continuation regimens. Mice were considered to be culture positive if one or more colony-forming units was detected when the entire organ was plated. * One of five lung homogenates harbored rifamycin-resistant mutants. Significant differences compared with the Denver regimen (rifampin plus isoniazid, 2/7) are shown as ^†p = 0.04, ^‡p = 0.016. RH = rifampin plus isoniazid; MHP = moxifloxacin plus isoniazid plus rifapentine; HP = isoniazid plus rifapentine; P = rifapentine; MP = moxifloxacin plus rifapentine.