Potent twice-weekly rifapentine-containing regimens in murine tuberculosis

被引:70
作者
Rosenthal, Ian M.
Williams, Kathy
Tyagi, Sandeep
Peloquin, Charles A.
Vernon, Andrew A.
Bishai, William R.
Grosset, Jacques H.
Nuermberger, Eric L.
机构
[1] Johns Hopkins Univ, Sch Med, Dept Med, Ctr TB Res, Baltimore, MD USA
[2] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA
[3] Univ Colorado, Infect Dis Pharmacokinet Lab, Natl Jewish Med & Res Ctr, Denver, CO USA
[4] Univ Colorado, Dept Pharm, Denver, CO USA
[5] Univ Colorado, Dept Med, Denver, CO USA
[6] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA
关键词
moxifloxacin; rifampin; rifapentine; tuberculosis; treatment;
D O I
10.1164/rccm.200602-280OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
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 moxifloxacin-containing 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). Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
引用
收藏
页码:94 / 101
页数:8
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