Turning intermittent regimens into daily regimens using blister-packs. An exploration in murine tuberculosis.
METHODS
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.


METHODS
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 > RHZE3 > 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, R2H2 and R2H6 given after daily RHZ treatment for 4 weeks. It found R2H2 only slightly superior to R2H6 and R3 much better than R2.


CONCLUSIONS
1. Alternating initial phase regimens were as effective as conventional intermittent regimens. 2. R3H6 might be an optimal continuation phase regimen for blisterpacks.
Guy
A
A
Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, London.
Dickinson
J M
JM
Mitchison
D A
DA
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004349:Drug Packaging; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage; D007538:Isoniazid / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D011718:Pyrazinamide / Q000008:administration & dosage / Q000097:blood; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin