To identify alternative regimens for preventive therapy of tuberculosis, the pharmacokinetics and antimicrobial activities of rifampin (RMP), rifabutin (RBT), and rifapentine (RPT) were compared in BCG-vaccinated and M. tuberculosis-infected immunocompetent mice. RPT showed the highest serum peak level (Cmax) and the longest half-life (t1/2), whereas RBT displayed the lowest Cmax and the shortest t1/2. On weight-to-weight basis, both RPT and RBT were more bactericidal than RMP. The activity of RMP was significantly reduced when the frequency of administration was reduced from six to three times weekly, whereas significant bactericidal activity was still observed in mice treated with RPT, 10 mg/kg up to once fortnightly, or RBT, 10 mg/kg twice weekly. Because the bactericidal activity of RBT, 10 mg/kg six times/wk for 6 wk, or RPT, 10 mg/kg two times/wk for 12 wk, was comparable to that of RMP, 10 mg/kg six times/wk for 12 wk in mice, the two regimens are appropriate for clinical trials of preventive therapy of tuberculosis.
The aminoglycoside, aminosidine exhibited ED50S of between 1 and 5 microM against the amastigotes of Leishmania major and Leishmania tropica in mouse peritoneal macrophages whereas other strains causing New World cutaneous leishmaniasis such as Leishmania braziliensis were more refractory. Aminosidine was also active against all but one of the Leishmania donovani strains tested and when combined with sodium stibogluconate, the drug showed marked potentiation against the amastigotes of L. donovani in vitro and an additive effect in experimentally infected BALB/c mice.
The efficacy and safety of rifabutin (RBT) and rifampicin (RMP) were compared in 298 patients with newly diagnosed pulmonary tuberculosis. In the initial 8-wk phase, all patients received isoniazid 400 mg/d, ethambutol 1200 mg/d, and pyrazinamide 2 g/d and were randomly allocated to receive either RMP 600 mg/d or RBT 300 mg/d. In the 16-wk continuation phase, patients received intermittent treatment (twice weekly) with isoniazid 600 mg/d, ethambutol 2400 mg/d and either RMP 600 mg/d or RBT 300 mg/d. Two hundred twenty-five (RMP = 118; RBT = 107) patients completed the 24-wk treatment period (evaluable patient population). Bacteriologic conversion rates in the RMP and RBT groups were 87.7 versus 92.0% at Week 8, 99.1 versus 99.0% at Week 12, 93.5 versus 93.8% at Week 24, and 89.8 versus 95.3% at the last valid observation. The mean time to first bacteriologic conversion was 14.1 wk in the RMP group and 14.3 wk in the RBT group. None of these differences was significant. Adverse events were reported by four patients (five events) in the RMP group and six patients (six events) in the RBT group. Those events thought to be associated with RMP were increased SGOT and leucopenia and, with RBT, increased SGOT and thrombocytopenia. Two hundred four patients entered the follow-up phase, and, of these, 95 (RMP = 49; RBT = 46) completed the scheduled 24-mo period. The overall rate of relapse was 3.8% (4/106) for the RMP group and 5.1% (5/98) for the RBT group. These differences were not significant. All relapsed patients, except for two who could not be traced, were successfully retreated. We conclude that the efficacy and tolerability of RBT is equivalent to that of RMP in the treatment of newly diagnosed uncomplicated tuberculosis, and that RBT can be effectively administered in a part-daily, part-intermittent dosage schedule.
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