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 highrisk 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 onceweekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen. Conclusions: These results suggest that the efficacy of the onceweekly 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. Keywords: antibiotics; intermittent therapy; mouse; treatment Effective control of tuberculosis (TB), especially in the setting of the HIV pandemic, requires the use of long and cumbersome chemotherapeutic regimens (1). Despite implementation of the World Health Organization directly observed therapy shortcourse strategy, nonadherence remains a serious threat to effective control of TB (2). Effective regimens employing drugs that could be administered once weekly (1 of 7 d) would be expected to facilitate supervised therapy by reducing the number of doses requiring supervision (3), leading to improved completion rates and raising prospects for expansion of DOTS coverage throughout the developing world.Rifapentine (RPT), a long-lasting rifamycin, is currently recommended for use at a dose of 10 mg/kg in combination with isoniazid (INH) during once-weekly continuation phase therapy (4). However, treatment restrictions limit the use of INH-RPT to non-highrisk patients (HIV seronegative with noncavitary TB) and are based on higher rates of treatment failure or relapse with rifamycinmonoresistant bacilli in high-risk patients (3, 5). Moreover, once-weekly INH-RPT has been shown to be less active than three times-or twice-weekly (3 of 7 or 2 of ...

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

“…Recent experience in the murine model of TB supports the latter observations. Daily administration of the 6-mo RHZ-based regimen is significantly more effective than the same regimen administered according to a predominantly twice-weekly schedule (9).…”

“…This led us to hypothesize that using P twice weekly rather than once weekly would significantly increase the rifamycin exposure and result in activity similar to that of standard daily therapy. Prior experience in the murine model suggested that the substitution of moxifloxacin (M) for H would lead to additional gains in activity (9,20,21).In the current series of studies, the bactericidal and sterilizing activities of modified twice-weekly regimens were compared with those of standard daily therapy in the murine model of TB. In Study 1, we used the predominantly twice-weekly RHZ-based regimen as the foundation to assess the effect of three modifications: substitution of M for H, substitution of P for R during the intermittent phase of therapy, and increasing the dose of P from 10 to 15 and 20 mg/kg.…”

“…Once-weekly continuation phase regimens based on a 15-mg/kg dose of P are at least as active as twice-weekly RH, but are not as active as daily RH (9). This led us to hypothesize that using P twice weekly rather than once weekly would significantly increase the rifamycin exposure and result in activity similar to that of standard daily therapy.…”

“…This led us to hypothesize that using P twice weekly rather than once weekly would significantly increase the rifamycin exposure and result in activity similar to that of standard daily therapy. Prior experience in the murine model suggested that the substitution of moxifloxacin (M) for H would lead to additional gains in activity (9,20,21).…”

Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model

“…The drug dosages (in mg/kg) were as follows: INH (25 daily or 75 weekly), RPT (15), PZA (150), EMB (100), MXF (100), ETH (50), and PA-824 (100), as previously published (24,26,37). For RPT, 15 mg/kg in mice is equipotent to 15 mg/kg (900 mg) in humans (38).…”