Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy

Background: The management of pulmonary disease caused by opportunist mycobacteria is bedevilled by a lack of randomized trials to provide an evidence-base for treatment. Rifampicin (R) and ethambutol (E) are the mainstay of treatment but the roles of macrolides and quinolones are not clear. Aims: This trial was designed to compare clarithromycin (Clari) and ciprofloxacin (Cipro) as third drugs added to two years of rifampicin and ethambutol as treatment for pulmonary disease caused by M.avium-intracellulare (MAC), M.malmoense and M.xenopi. There was also an optional comparison of immunotherapy with M.vaccae with no immunotherapy. Methods: Patients with pulmonary disease caused by these organisms were recruited to the trial once two positive cultures were confirmed. A factorial design permitted comparisons of clarithromycin and ciprofloxacin as well as immunotherapy/no immunotherapy. Information on clinical and bacteriological progress was obtained annually during the two years of treatment and for three years thereafter. If the patient was not improving at 1 year, the regimen was supplemented by the addition of the drug which he/she had not received in the original allocation of treatment. Results: Three hundred and seventy-one patients (186 REClari, 185 RECipro) were entered by 191 physicians, 170 with MAC, 167 with M.malmoense and 34 with M.xenopi. Optional immunotherapy randomization was chosen by 170 patients of whom 84 received M.vaccae. No significant differences in outcomes were found between M.vaccae-treated patients and those who had not been randomised to M.vaccae. These patients were combined with the remaining 201 for purposes of comparison of REClari with RECipro. All cause mortality was high for both groups (44% REClari, 43% RECipro). In patients with MAC the all-cause death rates were higher with REClari ( 48% ) than with RECipro (29 %), whereas for M.malmoense (42% vs 56% ) and M.xenopi (29% vs 47%) the rates were higher with RECipro (p=0.006). Most strikingly, only 3% died because of their mycobacterial disease (REClari = RECipro). At the end of treatment 4% of REClari and 10% of RECipro patients still had positive cultures. Among those with negative cultures at end of treatment 6% of REClari and 4% of RECipro patients relapsed. At 5 years 30% of REClari patients were known to have completed treatment as allocated and to be alive and cured, compared with 21% of the RECipro group (p=0.04), but this difference was principally due to those with M.malmoense (REClari 38%, RECipro 20%). Patients with MAC or M.xenopi were more likely to have poor outcome (death due to mycobacterial disease, failure of treatment or relapse) than those with M.malmoense (p=0.004), there being no difference between REClari and RECipro in this respect. Overall, 20% in each group were unable to tolerate the regimen allocated, Cipro being associated with a trend towards more unwanted effects (16%) than Clari (9%), p=0.05. Conclusion: Considering all three species together, there were no differences in outcome between the REClari and RECipro groups. Immunotherapy did not improve outcome. Mortality rates were high but only a small proportion died because of their mycobacterial disease. For M.malmoense and M.xenopi REClari appeared preferable to RECipro, whereas for MAC the opposite was true. Patients with MAC or M.xenopi had worse outcomes than those with M.malmoense, but there was no significant difference between REClari and RECipro. Comparison with other studies suggest that these triple-drug regimens, whilst having much the same beneficial effects as RE alone, resulted in twice as many unwanted effects and are consequently likely to reduce concordance. New therapies, optimised management of co-morbid conditions and a more holistic approach must be explored in the hope of improving outcome. Clinical trials.gov reg no: NCT 00367913