High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection

The use of isoniazid (INH) for the treatment of INH-resistant Mycobacterium tuberculosis infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susce ptible M, tuberculosis Erdman (ATCC 35801), and whether high-dose WH (100 m g/kg of body weight) was more effective than standard-dose INH (25 mg/kg) f or therapy of tuberculosis infections caused by INH-resistant mutants of M, tuberculosis Erdman, Six-week-old CD-I mice were infected with approximate ly 10(7) viable mycobacteria, Early control groups of infected but untreate d mice were euthanized by CO2 inhalation 1 week later when treatment was in itiated. INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week fo r 4 weeks, Late control groups of untreated mice and treated mice were sacr ificed 2 days after the last dose of drug, Spleens and right lungs were rem oved aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates. In the next study, INH at 100 mg/kg was com pared to INH at 25 mg/kg against an isogenic mutant of M, tuberculosis Erdm an (INH MIG, 2 mu g/ml) and the parent strain. This mutant was found to hav e a mutation in the KatG protein (Phe to Leu at position 183), In the first study, there was no dose response with increasing doses of INH. In the sec ond study, there was no significant difference between the reduction of via ble cell counts for mice treated with INH at 100 mg/kg and that for mice tr eated with INH at 25 mg/kg (parent or INH-resistant mutant), These prelimin ary results suggest that INH may be useful in combination therapy of M, tub erculosis infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 mu g/ml) and that higher doses of INH are unlikely to be more eff icacious than the standard 300-mg/day dose.