First randomised trial of treatments for pulmonary disease caused by M avium intracellulare, M malmoense, and M xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol

Background-The treatment of pulmonary disease caused by opportunist mycobac teria is controversial. It is uncertain whether in vitro sensitivity testin g predicts clinical response in the way it does for Mycobacterium tuberculo sis. The literature suggests that the combination of rifampicin (R) and eth ambutol (E) is important whereas isoniazid (H) may not be, but to date ther e have been no published reports of randomised controlled trials in the tre atment of these conditions. The British Thoracic Society has conducted the first such trial, a randomised study of two regimens in HIV negative patien ts with pulmonary disease caused by IM avium intracellulare (MAC), M malmoe nse, and M xenopi. Methods-When two positive cultures were confirmed by the Mycobacterium Refe rence Laboratories for England, Wales and Scotland, the coordinating physic ian invited the patient's physician to enrol the patient. Patients were als o recruited from Scandinavia. Randomisation to 2 years of treatment with RE or REH was performed from lists held in the coordinator's office. Clinical , bacteriological, and radiological progress was monitored at set intervals up to 5 years. Results-From October 1987 to December 1992, 141 physicians entered 223 pati ents (106 with M malmoense, 75 with MAC, 42 with M xenopi). At entry the RE and REH groups were comparable over a range of demographic and clinical fe atures. For each species there was no significant difference between RE and REH in the number of deaths, but when the three species were combined ther e were fewer deaths from the mycobacterial disease with RE (1% v 8%, p=0.01 8, odds ratio 0.10, exact 95% CI 0.00 to 0.76). For M malmoense the failure of treatment/relapse rates did not differ appreciably between the regimens , but for MAC there were fewer failures of treatment/relapses with REH (16% v 41%, p=0.033) With M xenopi there was a non-significant trend in the sam e direction (5% v 18%, p=0.41) and when all three species were combined the re was a significant difference in favour of REH (11% v 22%, p=0.033). Ther e was no correlation between failure of treatment/relapse and in vitro resi stance. M xenopi was associated with the greatest mortality (57% at 5 years ), A IAC was the most difficult to eradicate, and M malmoense had the most favourable outlook (42% known to be alive and cured at 5 years). Conclusions-The results of susceptibility tests performed by the modal resi stance method do not correlate with the patient's response to chemotherapy. RE and REH are tolerated better than previous regimens containing second o r third line antimycobacterial drugs. Treatment of M malmoense with RE for 2 years is preferable to REH. The addition of H reduces the failure of trea tment/relapse rates for MAC and has a tendency to do so also for M xenopi, but there is a suggestion that REH is associated with higher death rates ov erall. Better regimens are required.