Effectiveness of Rifampin, Rifabutin, and Rifapentine for Preventive Therapy of Tuberculosis in Mice

Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin. Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid-or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single-and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid-or moxifloxacincontaining therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg). In the treatment of drug-susceptible pulmonary tuberculosis (TB), daily administration of a standardized 6-mo regimen including rifampin (R), isoniazid (H), and pyrazinamide (Z; collectively, RHZ) is highly effective in achieving cure (1). But, because supervision of daily treatment imposes a substantial burden on both patients and treatment programs (2, 3), intermittent regimens with predominantly twice-or thrice-weekly drug administration are recommended for supervised therapy (4, 5). Although at least one randomized clinical trial has shown that daily and thrice-weekly RHZ-based regimens have similar efficacy, more recent observational studies suggest intermittent therapy is not as effective as daily therapy, particularly in patients at high risk for relapse (6-8). 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).The rifamycins are the key drugs in modern short-course therapy. Rifapentine (P) is a rifamycin with a lower minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis and a much longer serum half-life compared with R (10). While P is approved for twice-weekly administration at a dose of 10 mg/kg during the initial phase of therapy (11), several influential clinical trials have focused attention on the use of once-weekly administration of P in combination with H during the continuation phase. In Tuberculosis Trials Consortium Study 22, once-weekly PH was less effective than twice-weekly RH, and was associated with rifamycin-resistant relapse among HIVinfected patients (12...

Section: Treatment Efficacy In Studysupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Rosenthal

Williams²,

Tyagi³

et al. 2006

“…Rifamycins have durable sterilizing activity against Mycobacterium tuberculosis, and the currently recommended 10 mg/kg dosage of rifampin, the most commonly used rifamycin, is at the low end of the dose-response curve (2)(3)(4)(5)(6)(7)(8)(9). Historically, selection of this rifampin dose seems to have been influenced by cost in the setting of incomplete dose-finding studies (10).…”

mentioning

confidence: 99%

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

Dorman

Savic

Goldberg

et al. 2015

Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. Measurements and Main Results:A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

“…Previously, it was shown that when INH was concomitantly given with RIF and PZA the AUC 0→∞ for RIF was significantly reduced by 39% when compared with treatment with RIF and PZA (25). As might be predicted by the substantial difference in the time to peak serum level (Tmax) between INH (0.24 h) and RPT (10.7 h), no difference was observed in the AUC 0→∞ when RPT was administered alone (179.5 g · h/ml) or in combination with INH-MXF (177.6 g · h/ml) (23,26).…”

Section: Discussionmentioning

confidence: 99%

Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

Rosenthal

Williams

Tyagi

et al. 2005

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 ...