Background: The mainstays of treatment for pulmonary disease caused by opportunist mycobacteria are rifampicin (R) and ethambutol (E). The role of macrolides, quinolones and immunotherapy with Mycobacterium vaccae is not clear. A trial was undertaken to compare clarithromycin (Clari) and ciprofloxacin (Cipro) as third drugs added after 2 years of treatment with R and E for pulmonary disease caused by M avium-intracellulare (MAC), M malmoense and M xenopi (REClari and RECipro). An optional comparison of immunotherapy with M vaccae vs no immunotherapy was also performed.Methods: Progress was monitored annually during the 2 years of treatment and for 3 years thereafter. If the patient was not improving at 1 year the regimen was supplemented by the addition of the drug not received in the original allocation of treatment.Results: 371 patients (186 REClari, 185 RECipro) entered the study (170 MAC, 167 M malmoense, 34 M xenopi). All-cause mortality was high for both groups (44% REClari, 43% RECipro); for MAC it was higher with REClari than with RECipro (48% vs 29%) but for M malmoense (42% vs 56%) and M xenopi (29% vs 47%) it was higher with RECipro (p= 0.006). 3% died from 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 the end of treatment, 6% of the REClari group and 4% of the RECipro group had relapsed. At 5 years 30% of the REClari group 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 a poor outcome than those with M malmoense (p= 0.004), with no difference between REClari and RECipro. Overall, 20% in each group were unable to tolerate the regimen allocated, Cipro being associated with more unwanted effects than Clari (16% vs 9%, p= 0.05). No significant differences in outcomes were found between M vaccae-treated patients and those not treated with M vaccae immunotherapy.Conclusion: Considering all three species together, there were no differences in outcome between the REClari and RECipro groups. Immunotherapy did not improve outcome. New therapies, optimised management of comorbid conditions and a more holistic approach must be explored in the hope of improving outcome.

The literature concerning the management of pulmonary disease caused by Mycobacterium malmoense consists of retrospective reports on small series of patients. A recent multicentre trial conducted by the British Thoracic Society provided an opportunity to prospectively document the clinical features and response to treatment of this relatively rare but challenging disease in a substantial number of patients. When two positive cultures were confirmed by the Mycobacterium Reference Units for England, Wales, Scotland or Scandinavia, the coordinating physician invited the patient's physician to enrol the patient, who was then treated on a random basis with either rifampicin plus ethambutol or rifampicin, ethambutol and isoniazid for 2 yrs. Clinical, bacteriological and radiological progress were monitored at set intervals for 5 yrs. In over 5 yrs a total of 106 patients were recruited to the study. The mean age was 58 yrs, range 24–89 yrs. A total of 58% were male and just over half previously or at the time of the study had other lung diseases. Sputum was positive on direct smear in 58%. Cavitation was seen on the chest radiographs of 74%, the majority having cavities of ≥2 cm in diameter. Less than half of the patients showed bilateral disease, 26% having involvement of more than three lung zones. Disease was confined to the upper zone(s) in 30%. Other lung diseases were evident in 52%. Although clinical response was judged satisfactory at most reviews (90%), one in three patients died within 5 yrs and <5% were thought to have died primarily because of M. malmoense. There were three failures of treatment and eight relapses after the end of treatment. There was no correlation between failure of treatment/relapse and in vitro resistance. A total of 63 (59%) of patients were alive at 5 yrs, of whom 44 (42% of the total entry) were known to be cured. Pulmonary disease caused by Mycobacterium malmoense is a serious condition that is associated with high morbidity and mortality. The results of standard susceptibility tests do not correlate with the bacteriological response of the disease to chemotherapy. Rifampicin and ethambutol, with or without isoniazid, cured only 42% of patients but were better tolerated than previously described, more complex regimens of equal or lesser efficacy. There is a need for more effective regimens that will reduce mortality and failure of treatment/relapse rates, but, in addition, attention should be directed at improving management of comorbid conditions and improving the general health of the patient.

SETTING AND OBJECTIVE: Previous reports on small numbers highlighted the need for a prospective study of the clinical features and response to treatment of pulmonary disease caused by Mycobacterium avium-intracellulare (MAC).DESIGN AND METHODS: Patients with two positive cultures were randomised to 2 years of rifampicin and ethambutol or of rifampicin, ethambutol and isoniazid. Clinical, bacteriological and radiological progress was monitored for 5 years.RESULTS: Seventy-five patients entered the study. They had a mean age of 64 years (range 29-87) and the sexes were balanced. Approximately two-thirds had previous/co-existing lung disease(s). Sputum was positive on direct smear ill 56%, and cavitation was observed in 61%, most having at least one large cavity. just under half had bilateral disease and one-third extensive disease. Disease was confined to upper zone(s) in 25%. Twenty-seven (36%) died within 5 years, three because of MAC disease. There were 11 treatment failures and 10 relapses, with no correlation between those and in vitro resistance. Forty-five (60%) were alive at 5 years, of whom 23 were confirmed cured.CONCLUSION: Pulmonary disease caused by MAC is associated with high morbidity and mortality. Standard susceptibility tests do not correlate with the response of the disease to chemotherapy. Rifampicin and ethanibutol, with or without isoniazid, cured 31%, a result comparable with or better than that found previously with more toxic regimens, but mortality (36%) remains high. More effective regimens are needed, and management of coexisting illnesses and general health needs to be to maximised.

Background-The treatment of pulmonary disease caused by opportunist mycobacteria is controversial. It is uncertain whether in vitro sensitivity testing predicts clinical response in the way it does for Mycobacterium tuberculosis. The literature suggests that the combination of rifampicin (R) and ethambutol (E) is important whereas isoniazid (H) may not be, but to date there have been no published reports of randomised controlled trials in the treatment of these conditions. The British Thoracic Society has conducted the first such trial, a randomised study of two regimens in HIV negative patients with pulmonary disease caused by IM avium intracellulare (MAC), M malmoense, and M xenopi.Methods-When two positive cultures were confirmed by the Mycobacterium Reference Laboratories for England, Wales and Scotland, the coordinating physician invited the patient's physician to enrol the patient. Patients were also 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 patients (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 features. For each species there was no significant difference between RE and REH in the number of deaths, but when the three species were combined there were fewer deaths from the mycobacterial disease with RE (1% v 8%, p=0.018, 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 same direction (5% v 18%, p=0.41) and when all three species were combined there was a significant difference in favour of REH (11% v 22%, p=0.033). There was no correlation between failure of treatment/relapse and in vitro resistance. 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 resistance method do not correlate with the patient's response to chemotherapy. RE and REH are tolerated better than previous regimens containing second or 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 treatment/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 overall. Better regimens are required.

Background - Pulmonary disease caused by Myocobacterium kansasii is reported in approximately 50 new patients in Britain annually. Rifampicin and ethambutol are effective in vitro but the optimal duration of treatment, and whether isoniazid should also be given, are uncertain. The British Thoracic Society has conducted a prospective, multicentre study of the treatment of this condition with rifampicin and ethambutol given for nine months. Methods - One hundred and seventy three patients with two or more positive cultures and radiological evidence of disease were recruited via the Mycobacterium Reference Unit (PHLS) in Cardiff from 113 physicians in England, Scotland, and Wales. Rifampicin and ethambutol were given for nine months, other antituberculosis drugs being discontinued once the culture was identified as M kansasii. Patients were reviewed, sputum cultured, and chest radiographs performed before, during, and at regular intervals for 51 months after chemotherapy. Results - The mean (SD) age was 55.5 (11.7) years, 73% were men, and 50% had other lung problems. Cavitation was seen in 88%, bilateral shadowing in 48%, and three or more lung zones were affected in 46%. All cultures were sensitive to rifampicin and ethambutol but resistant to isoniazid and pyrazinamide. One patient who took chemotherapy irregularly still had positive cultures at seven and eight months. Fifteen patients developed positive cultures after the end of chemotherapy; factors which might account for the relapse were identified in eight. Reinfection rather than relapse was suspected in three of the 15. Radiographic improvement stabilised within three years in 80%. Conclusions - M kansasii pulmonary infection responds well to nine months of treatment with rifampicin and ethambutol but patients who contract this disease have a high mortality rate from other causes. Isoniazid does not appear to be a necessary part of the regimen.

Forty seven patients (82% male) with pulmonary infection caused by Mycobacterium xenopi have been reviewed. Pre-existing lung disease was present in 35 (75%). In 21 patients the disease was characterised by a subacute illness developing over a period of two to four months, while in another 20 patients there was a longer history of chronic respiratory problems often associated with slowly progressive changes evident from chest radiographs. Response to treatment was poor and unpredictable, and was not related to the results of in vitro sensitivity tests, pre-existing lung disease, or mode of onset of symptoms. Eleven patients (23%) were cured with chemotherapy. The best drug regimen appeared to be rifampicin and isoniazid combined with either streptomycin or ethambutol. Another 12 (26%) showed favourable responses to drug treatment initially, but eventually relapsed. Four patients had progressive disease while receiving prolonged courses of chemotherapy. Resection was performed in five patients with resultant cure in four. Since the prognosis with drug treatment alone is so unpredictable it is suggested that resection might be part of first line treatment, and that it should usually be performed if patients fail to respond to initial chemotherapy or if they relapse.

Une observation rare: fibrose pulmonaire nodulaire, chez un agriculteur de 71 ans, due a une exposition non industrielle a de la poussiere riche en silice, provenant du sol du Pakistan

Thirty-five patients (88% male) with pulmonary infection caused by Mycobacterium kansasii have been reviewed. Sixty-six per cent had pre-existing lung disease, chronic bronchitis and emphysema accounting for half of the disorders. Unilateral lesions were present in 69% of patients whose chest radiographs were reviewed and 90% had cavitating disease. The development of unilateral or bilateral disease appeared to be independent of any delay in starting treatment. Five patients died while receiving treatment, but none of these deaths was due to M kansasii infection. The remaining 30 patients were successfully treated with drug regimens, all of which included rifampicin and 86% of which included ethambutol. There was 100% sputum conversion, with no relapses after a mean follow-up period of five-and-a-half years. Rifampicin and ethambutol given for a mean period of 15 months appeared to be a non-toxic, effective combination.

Sixty-four patients with pulmonary infection caused by mycobacteria of the M avium-intracellulare complex have been reviewed. Patients who were asymptomatic on presentation often had a benign course but some developed progressive disease. Symptomatic patients who were not treated usually deteriorated. Various treatment regimens were used. Successful treatment was achieved in the majority of patients using a combination of isoniazid, rifampicin, and either ethambutol or streptomycin given for 24 months. Other forms of treatment given including multiple drug regimens were not as effective.