TURNING INTERMITTENT REGIMENS INTO DAILY REGIMENS USING BLISTER-PACKS - AN EXPLORATION IN MURINE TUBERCULOSIS

Setting: Blisterpacks might be used to present low cost intermittent regimens while maintaining an easily remembered daily frequency of opening blisters, by alternating blisters containing 2 of the drugs of a 4-drug regimen with blisters containing the remaining 2 drugs. Objective: The efficacy of the alternating regimens was examined in murine tuberculosis. Design: 2 weeks after infection with Mycobacterium tuberculosis H37Rv, groups of mice were treated with rifampicin (R) 15 mg/kg, isoniazid (H) 25 mg/kg, pyrazinamide (Z) 300 mg/kg, ethambutol (E) 100 mg/kg three times weekly (RHZE3); RH/ZE, an alternating regimen of RH on days 1, 3 and 5 of the week and ZE on days 2, 4 and 6, RZ/HE or RE/HZ. Results: Spleen and lung bacillary counts at 7 and 12 weeks indicated large differences in the efficacy of the regimens: RZ/HE > RE/HZ > RHZE, > RH/ZE. Serum assays showed that Rifampicin (RMP) levels were much lower after HRZE and slightly lower after RZ, RE and RH than after R alone, whereas levels were similar when R was given before the remaining drugs; also, the absorption of Z was slightly increased by R. A second experiment used the same 4 regimens but gave R before other drugs. The organ colony forming units counts at 6 and 12 weeks were then similar. A third experiment examined continuation phase regimens of R3, R2, R2H-2 and R2H-6 given after daily RHZ treatment for 4 weeks. It found R2H-2 only slightly superior to R2H-6 and R, much better than R2. Conclusion: 1. Alternating initial phase regimens were as effective as conventional intermittent regimens. 2. R3H-6 might be an optimal continuation phase regimen for blisterpacks.