The Microbiological and Clinical Effects of Combined Therapy according to Guidelines on the Treatment of Pulmonary Mycobacterium avium Complex Disease in Japan – Including a Follow-Up StudyKobashi Y. · Matsushima T.
Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan
Background: The difficulty of treatment for pulmonary Mycobacterium avium complex (MAC) in Japan. Objectives: To investigate the clinical and microbiological effects of treatment according to the guidelines proposed by the American Thoracic Society and the Japanese Society for Tuberculosis and prospective follow-up studies after the completion of treatment of patients with pulmonary MAC disease. Methods: Analysis of the microbiological effects with regard to sputum conversion rate and the sputum relapsing rate and the clinical effects with regard to clinical symptoms and radiological findings for patients with pulmonary MAC disease treated with a regimen consisting of rifampicin, ethambutol, streptomycin, and clarithromycin over 24 months and follow-up over 12 months. Results: Sixty-five patients with pulmonary MAC disease were enrolled in this trial. In 39 patients, negative sputum conversion was observed within 6 months after the initiation of this regimen, 16 relapsed, and 20 experienced clinical worsening within 1 year after the completion of treatment. Although retreatment with the same regimen or a regimen including new quinolones was carried out for these patients, we could not achieve negative sputum conversion and/or clinical improvement. Conclusions: We believe that the dose of clarithromycin for pulmonary MAC disease may be increased and recommend surgery for patients with a localized lesion at early-stage MAC disease to prevent a high rate of relapse.
Copyright © 2006 S. Karger AG, Basel
Pulmonary Mycobacterium avium complex (MAC) disease is the most common nontuberculous mycobacterial infection in Japan, and is increasing in incidence .
Regarding the treatment for pulmonary MAC disease, the American Thoracic Society (ATS) recommended a four-drug regimen including clarithromycin (CAM) or azithromycin (AZM), rifampicin (RFP) or rifabutin (RBT), ethambutol (EB), and an initial aminoglycoside (streptomycin, SM, or kanamycin) in 1997 . The Japanese Society for Tuberculosis (JST) also recommended a four-drug regimen including CAM, RFP, EB, and an initial aminoglycoside in 1998 . Since 1998, we have prospectively performed combined therapy according to the guidelines of the ATS and JST. Because prospective studies that substantiate the clinical efficacy of the regimen according to both guidelines and follow-up studies after the completion of treatment have been few, we report our results on the clinical effects and a follow-up study.
Patients and Methods
Seventy-three human immunodeficiency virus (HIV)-negative patients in whom pulmonary MAC disease was diagnosed at the Kawasaki Medical School and 13 hospitals belonging to the Research Committee of Mycobacterium in the Chugoku and Shikoku areas between April 1998 and March 2004 were included in this study. They satisfied the diagnostic criteria of nontuberculous mycobacterial infection set up by the ATS . Another inclusion criterion was availability for the interval of treatment over 24 months or follow-up over 12 months. Finally, after excluding 8 patients who could not complete treatment over 24 months or follow-up over 12 months, the remaining 65 patients were included and the following clinical features were examined: age, gender, underlying diseases, microbiological findings, radiological findings, dose and duration of RFP, EB, SM, CAM, clinical efficacy and adverse reactions. A follow-up study was also carried out after the completion of treatment. Patients were required to have negative serologic findings for HIV type 1 and type 2 or absence of obvious risk factors for this disease. Informed consent was obtained from each patient at study entry under protocols approved by the Ethical Committee of the Kawasaki Medical School.
A four-drug regimen consisting of RFP 450 mg/day, EB 400 mg/day, CAM 400 mg/day (weight <50 kg) or 600 mg/day (weight ≥50 kg; however, CAM >600 mg/day has not yet been approved for clinical use by the Ministry of Health and Welfare in Japan), given orally every day, and SM 1 g given intramuscularly three times a week for the initial 2–3 months was used as a standard regimen. The overall treatment period was at least 24 months except for those patients who showed severe adverse reactions. Patients were advised to consult an otolaryngologist and an ophthalmologist initially and as needed thereafter. A visual acuity test, perimetry, and a red-green color discrimination test were performed routinely to check EB toxicity at least every 2 months.
Routine expectorated sputum was submitted for examination on 3 consecutive days at study entry. The sputum was examined by Ziehl-Neelsen staining. Specimens submitted for culture were digested and decontaminated by the sodium hydroxide method, and the samples were inoculated onto slants of 3% Ogawa egg medium (Japan BCG, Tokyo, Japan) and identified and differentiated by growth characteristics and conventional biochemical tests. Mycobacterium avium and Mycobacterium intracellulare were identified by the Amplicor polymerase chain reaction assay (Roche Diagnostic Systems, Branchburg, N.J., USA).
Computed tomography was performed initially in all patients to evaluate lesions including cavities and bronchiectasis, and underlying pulmonary conditions. Chest roentgenograms were taken initially and at least every 2 months thereafter. Extension of the lesions was evaluated on the basis of both chest roentgenograms and CT findings.
Sputum conversion was defined as three consecutive negative sputum cultures within 6 months, with the time of conversion defined as the date of the first negative culture. If the patient could not expectorate sputum (12 months), it was considered that sputum culture had converted to negative. The sputum relapse rate was defined as two consecutive positive cultures after sputum conversion.
Clinical efficacy was evaluated on the basis of clinical improvement including clinical symptoms [those which were considered comparatively characteristic for active pulmonary MAC disease, such as continuous cough, weight loss (≥5 kg during 3 months), hemoptysis or hemosputum and fever] and radiological findings as well as the opinions of several attending respiratory specialists. Clinical improvement was defined as follows; ‘improving’ if abnormal shadows due to pulmonary MAC disease had decreased within half of the lesion before treatment and improvement of any clinical symptoms was found; namely, a decrease in continuous cough, normalization of weight loss or body temperature, or diminishment of hemoptysis or hemosputum, ‘unchanging’ if abnormal shadows had decreased over half of the lesion or were almost the same before treatment and clinical symptoms were unchanged, and ‘worsening’ if abnormal shadows had increased compared with the lesion before treatment and any clinical symptoms had increased.
The MAC isolates obtained at entry were stored in an 85% 7H9 medium:15% glycerol at –80°C. Minimal inhibitory concentrations (MICs) to CAM were determined by broth microdilutions in Middlebrook 7H9 broth (pH corrected to 7.4) or a Muller-Hinton broth supplement with 5% oleic acid, albumin and dextrose, as previously described [4, 5]. Isolates were interpreted as CAM-susceptible if they had MICs of 8 μg/ml or less and resistant if they had MICs of >32 μg/ml. Values of 16–32 μg/ml were considered intermediate .
All results are presented as means ± SD. A comparison of the characteristics of the patients was done using the unpaired Student’s t test. A value of p < 0.05 was considered statistically significant. Multivariate analysis was not performed because of the small sample size .
Between April 1998 and March 2004, 73 HIV-negative patients were diagnosed with pulmonary MAC disease and included in this study. Among these 73 patients, 8 became ineligible for the present study because it was difficult for them to visit the hospital regularly (geographic distance) or because they had to stop treatment within 24 months. However, the remaining 65 patients (89%) fulfilled the eligibility criteria and were enrolled in this protocol. The characteristics of the 65 eligible patients are shown in table 1. All patients were Japanese with a mean age of 64.8 ± 10.5 years. The ratio of males to females was 25:40. Eighteen patients were current smokers, 17 were exsmokers, and 10 suffered from chronic alcoholism. Fifty-one patients had underlying diseases. Corticosteroid drugs were administered to 4 patients (6%). Seventeen patients (26%) had received prior antituberculous drugs excluding CAM, and all patients had resistant MAC strains for antituberculous drugs before admission.
|Table 1. Patient characteristics (65 patients)|
Of the 65 patients who received over 24 months of treatment, the distribution of lesions was bilateral in 51 patients, right in 9, and left in 5. Forty-two patients (65%) had small nodules and/or bronchiectasis and 34 (52%) had cavitary lesions. In 27 patients (41%), the extent of the lesions was minimal, being within one third of the unilateral lung field. The disease was considered moderately advanced within the unilateral lung field in 31 patients (48%), and far advanced beyond the unilateral lung field in 7 patients (11%).
Regarding the microbiological findings of the strains isolated from the 65 patients, 31 strains were M. avium, 29 were M. intracellulare and 5 were MAC (not identified). A positive smear was found in 44 of the 65 patients (68%). Of the 65 isolates before the administration of CAM, the MIC to CAM was measured in 48 patients (74%). Among them, 38 strains were susceptible, 7 were intermediate, and 3 were resistant (MIC >32 μg/ml) to CAM.
Treatment of the 65 patients with pulmonary MAC disease was begun based on the regimen of this protocol according to ATS and JST guidelines. The dose of CAM was 400 mg/day for 28 patients and 600 mg/day for 37 patients.
Sputum conversion rates for the two different doses of CAM (400 and 600 mg/day), which are shown in figure 1, were measured. The most significant improvement was seen in the group receiving 600 mg/day (68%). The patients were also separated into M. avium (56%) and M. intracellulare (57%) strain groups, but there was no significant difference in the sputum conversion rates between the two groups. However, there were significant differences in the rates between patients with primary infections (29 patients with underlying respiratory diseases; 65%) and secondary infections (36 patients without underlying respiratory diseases; 45%), extension of lesions within one third of the unilateral lung field (67%), within the unilateral lung field (54%), and beyond the unilateral lung field (30%). Patients with secondary infections and/or far advanced disease beyond the unilateral lung field had significantly lower sputum conversion rates.
|Fig. 1. Sputum converting rate for pulmonary MAC disease at the completion of treatment.|
The sputum relapse rates according to the dose of CAM, which were not significantly different, are shown in figure 2. There were also no significant differences between the patients with the two kinds of strains, M. avium (42%) and M. intracellulare (38%), or between those with primary (38%) and secondary (44%) infections. However, a comparison of the rates for patients with extension of lesions within one third of the unilateral lung field (30%), for those with extension within the unilateral lung field (47%), and for those with extension beyond the unilateral lung field (67%), showed that the patients with far advanced disease beyond the unilateral lung field had significantly higher sputum relapse rates.
|Fig. 2. Sputum relapsing rate for pulmonary MAC disease until the completion of treatment. ns = Nonsignificant.|
The clinical efficacy of this regimen is shown in table 2; 20 patients (31%) improved, 24 (37%) were unchanged, 19 (29%) worsened and 2 (3%) died. Clinical improvement according to the dose of CAM was better in the group receiving 600 mg/day (35%) than in the group receiving 400 mg/day (25%). There were no significant differences in clinical improvement between the two groups with the two strains, M. avium (31%) and M. intracellulare (30%), or those with primary (36%) or secondary (24%) infections. However, differences in the rates of clinical improvement for patients with extension of lesions within one third of the unilateral lung field (40%) compared with those within the unilateral lung field (28%), and beyond the unilateral lung field (10%) were significant. Patients with far advanced disease beyond the unilateral lung field showed significantly lower clinical improvement.
|Table 2. Clinical efficacy of treatment for pulmonary MAC disease|
Adverse reactions according to the dose of CAM are shown in table 3. On a regimen of CAM 400 mg/day, adverse reactions appeared in 6 of 28 patients (21%), while on a regimen of 600 mg/day, 10 of 37 patients (27%) had adverse reactions. All 16 patients were able to continue a four-drug regimen with a modification of concomitant drugs. CAM caused no adverse reactions. Among companion drugs, SM caused vertigo in 4 patients, EB caused visual disturbance in 3 and RFP caused liver dysfunction in 5, gastrointestinal symptoms in 3, fever in 2 and eruption in 1 patient. However, there were no significant differences between the two groups with regard to the incidence and number of adverse reactions.
|Table 3. Adverse reactions and abnormal laboratory findings|
The duration of treatment in this regimen was 24–30 months in 50 patients, 30–36 months in 9, and over 36 months in 6. The duration of follow-up including the duration of treatment was 36–42 months in 37 patients, 42–48 months in 18, and over 48 months in 10. Despite long-term combined therapy of ≥24 months according to the guidelines, sputum relapse or clinical worsening in patients with sputum conversion or clinical improvement at the completion of treatment was recognized in over half of the patients (tables 4, 5). Although retreatment with the same regimen including new quinolones was performed for these patients, sputum negative conversion and/or clinical improvement could not be achieved in all patients. Twenty-four patients who were unchanged after the clinical regimen underwent follow-up. Some underwent the regimen including new quinolones. There was no change or worsening after further treatment in any of the patients. Nineteen patients whose condition worsened on the clinical regimen received the regimen including new quinolones or other antituberculous drugs. However, the clinical efficacy including sputum negative conversion was poor with the change to the new treatment.
|Table 4. Clinical course after the completion of treatment for patients achieving sputum conversion (over 24 months)|
|Table 5. Clinical course after the completion of treatment for patients achieving clinical improvement (over 24 months)|
Prospective studies that substantiate the clinical efficacy of the regimen set up in the guidelines of the ATS and JST have been few. Wallace et al. [8 ] were the first to initiate clinical trials of a regimen including CAM, EB, RBT or RFP, and initial SM for pulmonary MAC disease without AIDS. They reported the use of 1,000 mg/day (from 15 to 20 mg/kg/day) of CAM. Subsequently, the sputum conversion rate was significantly higher in their study than that in ours (92 vs. 57%). Tanaka et al.  reported on the clinical efficacy of a four-drug regimen including CAM, RFP, EB, and an initial aminoglycoside (kanamycin) in Japan. They used 10 mg/kg/day of CAM, which was similar to that of our protocol. However, the sputum conversion rate in their study was significantly higher (72 vs. 57%). We think this difference may be due to the severity of the pulmonary MAC diseases in the registered patients at the initiation of treatment. In fact, the extension of lesions due to MAC was moderately advanced within the unilateral lung field or far advanced beyond the unilateral lung field in over half of the patients in our study. In previous reports, the severity of pulmonary MAC disease was not noted. Other reasons for the difference include the lower dose of CAM and the resistance to CAM of isolated MAC(7 intermediate and 3 resistant). Regarding the dose of CAM, Wallace et al. [10 ] reported intolerance to high doses of CAM (2,000 mg/day). A potential disadvantage of the higher dose is a high incidence of limiting side effects, especially gastrointestinal symptoms, in most patients. However, it has been commonly difficult to administer CAM for patients with pulmonary MAC disease in Japan because CAM >600 mg/day has not yet been approved for clinical use by the Japanese Ministry of Health and Welfare. In addition, we compared the microbiological and clinical efficacy of the two doses of CAM, 400 and 600 mg/day, in our study and found that the sputum conversion rate of the group receiving 600 mg/day was significantly better than that of the one receiving 400 mg/day. Although we separated into two CAM groups (CAM 400 mg/day: weight <50 kg, and CAM 600 mg/day: weight ≥50 kg) according to body weight before treatment and compared the efficacy with respect to adverse reactions, we think that the separation due to body weight did not affect the efficacy because the number of patients with significant weight loss (≥5 kg during 3 months) was 2 of 28 patients (7%) receiving 400 mg/day and 3 of 37 patients (8%) receiving 600 mg/day.
Concerning CAM susceptibility, it is obvious that CAM monotherapy is ineffective for the treatment of pulmonary MAC disease with CAM-resistant strains . In this study, the sputum conversion rate was significantly lower in patients infected with CAM-resistant strains (0%) and intermediate strains (29%) than in those infected with susceptible strains (66%, p < 0.05), as in previous reports [9, 10]. The clinical improvement was also significantly lower in patients with CAM-resistant strains (0%) and intermediate strains (14%) than in those infected with susceptible strains (37%; p < 0.05). These results suggest a lack of synergism of the multidrug regimen. On the other hand, 13 of 38 patients infected with CAM-susceptible strains failed to convert the sputum to negative. These patients had extensive disease due to pulmonary MAC disease, or CAM resistance was induced during treatment with the multidrug regimen.
Regarding the relationships between causative pathogens, types of infection, underlying diseases and the extension of lesions on chest roentgenograms and clinical efficacy, although there were no significant differences in the causative pathogens (M. avium and M. intracellulare), patients who had secondary infections with an underlying respiratory disease or far advanced disease beyond the unilateral lung field had statistically significantly poorer clinical efficacy in the sputum converting rate and clinical improvement. This finding was first made in our study. There were no significant differences in the study by Tanaka et al. . The most important and difficult problem left unsolved is when to start therapy, as the ATS has also pointed out . The results suggest that the earlier therapy is begun to treat minimum lesions, the better clinical efficacy will be. We could not decide on the timing for initiating treatment in our study. In addition, regarding the problem of when to stop therapy, although the ATS has recommended continuation of the therapy for 19–24 months , we consequently continued the treatment according to both sets of guidelines even when the sputum was converted to negative because half of our patients with sputum conversion to negative and clinical improvement relapsed within 1 year after the completion of treatment (tables 4, 5).
RBT is more active than RFP against MAC in vitro . Moreover, RFP is known to accelerate the metabolic rate of CAM and to reduce CAM concentration compared to RBT . Wallace et al.  observed that RBT appears to be slightly better than RFP. However, the disadvantage of RBT is that it causes adverse reactions, which are infrequent with RFP . Therefore, we think that a double-blind randomized trial of an RBT-containing regimen versus an RFP-containing regimen is necessary in Japan.
Finally, because the method of assessment was restricted to the sputum conversion rates of MAC strains before and after treatment in previous reports, we think it is difficult to grasp the clinical effect of the treatment for the patients in those studies. Therefore, in assessing clinical efficacy, we considered the clinical symptoms which are considered comparatively characteristic of pulmonary MAC disease (continuous cough, weight loss, hemoptysis or hemosputum and fever) and/or the extent of lesions on chest roentgenogram or chest CT instead of including subjective assessments by several respiratory specialists. Subsequently, clinical improvement (31%) was poorer than the sputum converting rate (57%). There was not always a correlation between clinical improvement and the sputum converting rate, although we obtained microbiological improvement in most cases of sputum conversion of MAC. The difference may be due to two factors. The first factor is that many cases with no clinical improvement in whom sputum conversion was obtained showed a relapse of MAC during the combined therapy after judgment of the sputum conversion rate. Secondly, there is a possibility that the difference occurred because they could not expectorate sputum.
In conclusion, the four-drug regimen including CAM recommended in both guidelines was comparatively effective for the initial treatment of pulmonary MAC disease. However, even when the regimen for pulmonary MAC disease was completed and sputum conversion to negative and/or clinical improvement were achieved, it was extremely difficult to determine when to stop the therapy because there were high percentages of sputum relapse and/or clinical worsening within 1 year after the completion of treatment in our study. In addition, the dose of CAM (>600 mg) for pulmonary MAC disease has not been approved for clinical use by the Ministry of Health and Welfare in Japan. Therefore, we suggest that the dose of CAM administered for pulmonary MAC disease may be increased and recommend surgery for patients with a localized lesion at early-stage MAC disease to prevent a high rate of relapse.
Yoshihiro Kobashi, MD
Division of Respiratory Diseases, Department of Medicine
Kawasaki Medical School, 577 Matsushima
Kurashiki 701-0192 (Japan)
Tel. +81 86 462 1111, Fax +81 86 464 1041, E-Mail resp@med.Kawasaki-m.ac.jp
Received: June 7, 2005
Accepted after revision: March 29, 2006
Published online: September 5, 2006
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 5, Number of References : 13
Respiration (International Journal of Thoracic Medicine)
Vol. 74, No. 4, Year 2007 (Cover Date: July 2007)
Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)
For additional information: http://www.karger.com/RES