ORIGINAL RESEARCH. Efficacy of Clarithromycin and Ethambutol for Mycobacterium avium Complex Pulmonary Disease A Preliminary Study.

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1 Efficacy of Clarithromycin and Ethambutol for Mycobacterium avium Complex Pulmonary Disease A Preliminary Study Seiichi Miwa 1,2, Masahiro Shirai 1,2, Mikio Toyoshima 2, Toshihiro Shirai 2, Kazumasa Yasuda 2, Koshi Yokomura 2, Takashi Yamada 2, Masafumi Masuda 2, Naoki Inui 2, Kingo Chida 2, Takafumi Suda 2, and Hiroshi Hayakawa 1,2 1 Department of Respiratory Medicine, Tenryu Hospital, National Hospital Organization, Hamamatsu, Japan; and 2 Department of Respiratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan Abstract Rationale: Patients with Mycobacterium avium complex pulmonary disease are frequently administered a combination of clarithromycin, ethambutol, and rifampicin. However, rifampicin is known to reduce the serum levels of clarithromycin. It remains unclear whether a reduction in clarithromycin serum levels influences the clinical outcome of the Mycobacterium avium complex pulmonary disease treatment regimen. Objectives: To compare a three-drug regimen (clarithromycin, ethambutol, and rifampicin) to a two-drug regimen (clarithromycin and ethambutol) for the treatment of Mycobacterium avium lung disease. Methods: In a preliminary open-label study, we randomly assigned newly diagnosed, but as-yet untreated, patients with disease caused by Mycobacterium avium complex without HIV infection to either the threedrug or the two-drug regimen for 12 months. The primary endpoint was the conversion of sputum cultures to negative after 12 months of treatment. Patient data were analyzed using the intention-to-treat method. Measurements and Main Results: Of 119 eligible patients, 59 were assigned to the three-drug regimen and 60 to the two-drug regimen. The rate of sputum culture conversion was 40.6% with the three-drug regimen and 55.0% with the two-drug regimen (difference, 214.4% [95% confidence interval, to 3.4]). The incidence of adverse events leading to the discontinuation of treatment was 37.2 and 26.6% for the three-drug and the two-drug regimens, respectively. Conclusions: This preliminary study suggests that treatment with clarithromycin and ethambutol is not inferior to treatment with clarithromycin, ethambutol, and rifampicin for Mycobacterium avium complex lung disease. Our findings justify a larger clinical trial to compare long-term clinical outcomes for the two treatment regimens. Clinical trial registered with (UMIN ). Keywords: Mycobacterium avium complex; pulmonary disease; clarithromycin; ethambutol; rifampicin (Received in original form August 12, 2013; accepted in final form November 19, 2013 ) Author Contributions: Conception and design: M.S. and H.H. Acquisition of data: M.S., M.T., T.S., K. Yasuda, K. Yokomura, T.Y., M.M., N.I., K.C., and T.S. Analysis and interpretation of data and manuscript writing: S.M. Study supervisor: H.H. Correspondence and requests for reprints should be addressed to Seiichi Miwa, M.D., Ph.D., , Hamamatsu , Japan. miwamaro11@yahoo.co.jp Ann Am Thorac Soc Vol 11, No 1, pp 23 29, Jan 2014 Copyright 2014 by the American Thoracic Society DOI: /AnnalsATS OC Internet address: Nontuberculous mycobacteria are ubiquitous in the environment and cause lung disease worldwide (1). Mycobacterium avium complex, including Mycobacterium avium and Mycobacterium intracellulare, frequently causes nontuberculous mycobacterial lung disease, and this could eventually lead to respiratory failure (1). Previous studies have indicated that newer macrolides, such as clarithromycin or azithromycin, are key drugs in the treatment of these mycobacterial infections (1 7). At present, the combination of clarithromycin or azithromycin, ethambutol, and a rifamycin (rifampicin or rifabutin) is recommended (1), but the optimal treatment is not established. Although rifampicin is known to affect the metabolism of the newer macrolides by induction of cytochrome P-450 enzymes (8 10), macrolides and rifamycins are often used concurrently. Specifically, rifampicin strongly reduces the serum concentration of clarithromycin. However, it remains unclear whether the reduction of clarithromycin in the serum has an Miwa, Shirai, Toyoshima, et al.: Efficacy of Clarithromycin and Ethambutol for MAC Pulmonary Disease 23

2 influence on the clinical efficacy of the combined treatment on Mycobacterium avium complex pulmonary disease. We conducted a randomized study of Mycobacterium avium complex pulmonary disease comparing the therapeutic efficacy of a two-drug regimen (clarithromycin and ethambutol) to that of a three-drug regimen (clarithromycin, ethambutol, and rifampicin). We also examined the serum concentrations of clarithromycin in the two groups. Methods Patients Subjects included patients with Mycobacterium avium complex lung disease who were diagnosed according to the 2007 American Thoracic Society criteria (1) at our institutions between 2009 and The criteria were as follows: (1) clinical: pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography (HRCT) scan that showed multifocal bronchiectasis with multiple small nodules; and (2) microbiologic: positive culture results from at least two separate expectorated sputum samples. None of the patients had ever been treated with Mycobacterium avium complex therapy. We excluded patients who were HIVpositive, showed poor performance status (more than a score of 2 on the Eastern Cooperative Oncology Group scale), had malignancy, or received immunosuppressant therapy. This study was approved by our hospital s ethics committee. Informed consent was obtained according to hospital guidelines. Study Design This preliminary open-label and randomized study was conducted at Tenryu Hospital and Hamamatsu University School of Medicine in Hamamatsu, Japan. Participants were randomly assigned to receive a three-drug regimen including clarithromycin, ethambutol, and rifampicin or a two-drug regimen including clarithromycin and ethambutol for 12 months. Because cavitation is reported to influence treatment response (11), randomization was stratified according to the presence of cavitation at baseline, as detected by chest HRCT. All medications were self-administered. Patient adherence was confirmed by patient interviews and by monitoring prescription refills at each visit. For patients with body weight greater than or equal to 40 kg, doses of clarithromycin, ethambutol, and rifampicin were 600 mg/ d (200 mg thrice daily), 750 mg/d (750 mg once daily), and 450 mg/d (450 mg once daily), respectively. For patients with body weight less than 40 kg, doses of clarithromycin, ethambutol, and rifampicin were 400 mg/d (200 mg twice daily), 500 mg/d (500 mg once daily), and 300 mg/d (300 mg once daily), respectively. Completion of study treatment was defined as the continuation of each medication for 12 months. The primary endpoint was sputum culture-negative conversion at the completion of treatment. Sputum conversion was defined as three consecutive cultures testing negative for Mycobacterium avium complex isolates. The time of conversion is defined as the date of the first negative culture. Secondary endpoints include improvement of clinical symptoms (e.g., chronic cough, sputum production, and hemoptysis) and HRCT findings. Patients were asked about their symptoms and medical concerns at baseline and again at each visit. Symptomatic responses to treatment were evaluated at baseline and at the completion of the study. Chest radiographs were obtained at the beginning of and every 2 to 3 months during the study, and HRCT images were obtained at the beginning of and at completion of the study. Assessment of HRCT images was performed by two respiratory physicians who were blinded to the patients group assignment. Microbiological Culture and Analysis Sputum samples were collected monthly with an ultrasonic nebulizer using sterile 3% sodium chloride solution as needed. They were decontaminated with N-acetyl-Lcysteine and sodium hydroxide. Fluorescent, acid-fast auramine-rhodamine staining was used for smear examination. Cultures were grown in a BACTEC MGIT 960 system with Oleic Albumin Dextrose Catalase growth supplement and an antimicrobial mixture PANTA (polymyxin B, amphotericin B, nalidixic acid, trimethoprim, azlocillin) (Becton Dickinson, Tokyo, Japan) for a maximum of 6 weeks. Mycobacterium avium complex was identified via a polymerase chain reaction assay using the Cobas TaqMan 48 Analyzer (Roche Diagnostics, Basel, Switzerland). Drug susceptibility testing was performed on Mycobacterium avium complex isolates of all patients before treatment. If sputum culture conversion was not achieved after 12 months of therapy, isolates from the last positive cultures collected were tested. To determine the clarithromycin susceptibility of the Mycobacterium avium complex strains, we used BrothMIC NTM (Kyokuto Pharmaceutical Industrial Co., Ltd, Tokyo, Japan). According to the standards of the Clinical Laboratory Standards Institute (12), strains with a minimum inhibitory concentration of clarithromycin (<8 mg/ ml) were considered susceptible to clarithromycin, whereas those with a minimum inhibitory concentration greater than or equal to 32 mg/ml were considered resistant. Values of 16 to 32 mg/ml were considered intermediate. Adverse Event Monitoring Adverse events in patients were assessed by means of patient-reported symptoms, complete blood counts, and blood measurements of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, bilirubin, blood urea nitrogen, and creatinine, at baseline and every month thereafter. Patients with any optic adverse events were referred to an ophthalmologist. If adverse events were considered to be related to Mycobacterium avium complex treatment and clinically significant, the treatment was discontinued at the discretion of the attending respiratory physicians. Measurement of Clarithromycin and 14-Hydroxy-Clarithromycin Serum Concentrations Analysis of blood clarithromycin concentration was conducted on patients who gave informed consent at least 2 weeks after starting treatment. Blood samples were collected immediately before and at 2, 4, and 6 hours after oral administration of clarithromycin. Serum clarithromycin and 14-hydroxy-metabolite concentrations were measured using liquid chromatography tandem mass spectrometry assay (13, 14). Data Analysis The study was designed to establish noninferiority of a two-drug regimen compared with a three-drug regimen. The primary endpoint was evaluated by 24 AnnalsATS Volume 11 Number 1 January 2014

3 Figure 1. Randomization and follow-up. intention-to-treat analysis. The noninferiority margin for the difference of efficacy was 10%. We calculated that 49 patients per regimen were needed to determine noninferiority with a power of 80% and one-sided type 1 error rate (a) of If the upper limit of 95% confidence interval (CI) was less than 10%, we accepted noninferiority of the two-drug regimen. Values are expressed as mean 6 SD. Statistical analysis was performed using the Chi-square test, Mann-Whitney U test, and logistic regression analysis. P less than 0.05 was considered statistically significant. Results Patients A total of 119 patients underwent randomization, with 59 assigned to the three-drug regimen group and 60 to the two-drug regimen group (Figure 1). The Table 1. Baseline characteristics of the study patients Characteristic Three-Drug Regimen (Clarithromycin, Ethambutol and Rifampicin) (N = 59) Two-Drug Regimen (Clarithromycin and Ethambutol) (N = 60) Age, yr Male/female, no. 19/40 20/40 Smoking status Never, no Ever and current, no Body mass index, kg/m Body weight. 40 kg, no Clinical symptoms, no. Chronic cough Sputum production Hemoptysis Cavitation on HRCT, no Bronchiectasis on HRCT, no Extension of the lesion on chest radiograph, no. Within one-third of unilateral lung field Within two-thirds of unilateral lung field Within unilateral lung field 8 8 Over unilateral lung field 2 7 White blood cells, /ml 5, ,706 5, ,945 Albumin, g/dl Definition of abbreviation: HRCT = high-resolution computed tomography. Miwa, Shirai, Toyoshima, et al.: Efficacy of Clarithromycin and Ethambutol for MAC Pulmonary Disease 25

4 Figure 2. Sputum-negative conversion rates in intention-to-treat and per-protocol populations (x-axis indicates percentage). Difference of sputumnegative conversion rates between the three-drug regimen (clarithromycin, ethambutol, and rifampicin) and the two-drug regimen (clarithromycin and ethambutol) groups; bars show 95% confidence interval. Dotted line shows noninferiority margin of 10%. two groups were well balanced with respect to the baseline characteristics (Table 1). Of the 119 patients enrolled in the study, 80 (67.2%) were women. The mean age was 68.7 years. Eleven patients (18.6%) in the three-drug regimen group and 11 patients (18.3%) in the two-drug regimen group presented with hemoptysis. Cavitation on HRCT was present in 29 patients (49.1%) in the three-drug regimen group and 28 patients (46.6%) in the two-drug regimen group, respectively. A total of 32 patients (54.2%) and 40 patients (66.6%) completed the three-drug regimen and the two-drug regimen, respectively. Efficacy and Adverse Events In the intention-to-treat analysis, 24 of 59 (40.6%) patients receiving the three-drug regimen achieved sputum-negative conversion, as did 33 of 60 (55.0%) patients receiving the two-drug regimen (difference, 214.4% [95% CI, 32.1 to 3.4%]). In the per-protocol analysis, 24 of 32 (75.0%) patients receiving the three-drug regimen achieved sputum-negative conversion, as did 33 of 40 (82.5%) patients receiving the two-drug regimen (difference, 7.5% [95% CI, 26.6 to 11.6%]). The one-sided 95% CI of the efficacy difference was less than the predefined 10% margin in the intention-totreat analysis, although more than in the per-protocol analysis (Figure 2). For patients with cavitary disease in the perprotocol population, 11 of 15 (73.3%) patients in the three-drug regimen group and 11 of 16 (68.7%) patients in the twodrug regimen group had culture-negative conversion. The period of time until negative conversion of the culture from the initiation of treatment was months in the three-drug regimen group and months in the two-drug regimen group (P = 0.297). Before treatment, all of mycobacterial isolates from 119 enrolled patients were susceptible to clarithromycin. Isolates from eight patients in three-drug regimen and seven patients in two-drug regimen who did not achieve sputum conversion remained susceptible to clarithromycin at the end of study. Improvement of clinical symptoms from baseline was observed in 56.2% of patients in the three-drug regimen group and in 75.0% of the two-drug regimen group among those who had followed the protocol. HRCT findings improved in 78.1% of patients receiving the three-drug regimen and in 85.0% of those receiving the two-drug regimen in the per-protocol population. Table 2 lists the adverse events that occurred during treatment. Rash was the Table 2. Adverse events in patients assigned to treatment Adverse Event Three-Drug Regimen (Clarithromycin, Ethambutol, and Rifampicin) (N = 59) Two-Drug Regimen (Clarithromycin and Ethambutol) (N = 60) Discontinuation of study drugs 22 (37.2) 16 (26.6) Loss of appetite 6 (10.1) 1 (1.6) Nausea 2 (3.3) 3 (5.0) Diarrhea 1 (1.6) 2 (3.3) Stomatitis 4 (6.7) 4 (6.6) Rash 8 (13.5) 9 (15.0) Fever 4 (6.7) 5 (8.3) Visual impairment 3 (5.0) 1 (1.6) Hepatitis 1 (1.6) 2 (3.3) Headache 2 (3.3) 1 (1.6) Pancytopenia 2 (3.3) 0 (0) Others 6 (10.1) 1 (1.6) Data are presented as N (%). 26 AnnalsATS Volume 11 Number 1 January 2014

5 most frequent adverse event in patients in both groups (13.5% in the three-drug regimen group and 15.0% in the two-drug regimen group). Loss of appetite occurred in 10.1% of patients receiving the three-drug regimen and in 1.6% of those receiving the two-drug regimen. In the three-drug regimengroup,22of59(37.2%)patients discontinued the treatment due to adverse events, whereas 16 of 60 (26.6%) patients discontinued the two-drug regimen. Serum Concentration of Clarithromycin and 14-Hydroxy- Clarithromycin Figure 3 shows the serum clarithromycin and 14-hydroxy-clarithromycin concentrations after oral administration in patients receiving the three-drug regimen (with rifampicin) or the two-drug regimen (without rifampicin). Clarithromycin concentration of patients in the three-drug regimen group was significantly lower than that of patients in the two-drug regimen group (Figure 3A). A similar trend was observed for the 14-hydroxy clarithromycin (Figure 3B). In the two-drug regimen group, there was no difference in serum concentration of clarithromycin and 14-hydroxy-clarithromycin between patients receiving 600 mg/d and 400 mg/d. In the three-drug regimen group, we obtained data only from patients receiving 600 mg/d clarithromycin. Discussion The present study is the first report comparing the efficacies of clarithromycincontaining double- and triple-drug therapy regimens for Mycobacterium avium Figure 3. Mean concentrations of clarithromycin (A) and 14-hydroxy-clarithromycin(B) in serum after oral administration of the three-drug regimen (clarithromycin, ethambutol, and rifampicin) and the twodrug regimen (clarithromycin and ethambutol). Open circles, three-drug regimen: clarithromycin 600 mg/day (n = 5); solid circles, two-drug regimen: clarithromycin 600 mg/day (n = 3); shaded circles, twodrug regimen: clarithromycin 400 mg/day (n = 4). complex pulmonary disease. We demonstrated that a two-drug regimen (clarithromycin and ethambutol) was not inferior to a three-drug regimen (clarithromycin, ethambutol, and rifampicin) with respect to sputumnegative conversion after 12 months of treatment in patients with Mycobacterium avium. Macrolide monotherapy should not be used for this lung disease because of the risk for developing macrolide-resistant organisms (2, 5, 15). Generally, the twodrug regimen has not been recommended either (1). Gordin and colleagues found that 14% of patients with AIDS and Mycobacterium avium bacteremia receiving the two-drug regimen (clarithromycin and ethambutol) developed clarithromycin resistance, whereas only 2% in the threedrug regimen (clarithromycin, ethambutol, and rifabutin) group did (P = 0.05), despite a bacteriologically similar response at 16 weeks between the groups (16). However, disseminated Mycobacterium avium disease in patients with AIDS and pulmonary avium disease in HIV-negative patients are very different. Nonetheless, no study has demonstrated whether clarithromycin and ethambutol regimen promotes the emergence of clarithromycin-resistant Mycobacterium avium complex isolates in lung disease. Our results show that clarithromycin-resistant Mycobacterium avium isolates were not detected in either the two-drug or the three-drug regimen during study. The current recommended treatment for Mycobacterium avium pulmonary disease results in pharmacologic interactions between macrolides and rifampicin. Specifically, rifampicin decreases serum concentrations of clarithromycin (8 10). In view of pharmacokinetics, van Ingen and colleagues stated that low concentrations of clarithromycin might at least partly explain the unsuccessful outcomes of currently recommended regimens for Mycobacterium avium complex pulmonary disease (9). The suggestion was supported by the finding that higher doses of clarithromycin improved treatment outcomes of these patients (17, 18). In contrast, there was no significant difference in the treatment response rate between the two groups in our study, despite the lower serum levels of clarithromycin in patients receiving the three-drug regimen. In a retrospective Miwa, Shirai, Toyoshima, et al.: Efficacy of Clarithromycin and Ethambutol for MAC Pulmonary Disease 27

6 study, Koh and colleagues also report that serum clarithromycin levels were commonly low in patients treated for Mycobacterium avium pulmonary disease regardless of treatment outcome (10), raising the question of serum clarithromycin levels and its antimycobacterial efficacy. Multidrug treatment related adverse events remain a major problem. In the current study, occurrence of adverse events in the two-drug regimen group tended to be lower than that in the three-drug regimen group (26.6 and 37.2%, respectively). Specifically, the percentage of patients who experienced appetite loss was lower in the two-drug regimen group than in the threedrug regimen group (1.6 and 10.1%, respectively). These results may indicate that a daily two-drug regimen is more tolerable than a daily three-drug regimen for the treatment. Our preliminary study has several limitations. First, the analysis included only a small sample size and it was not doubleblind study. Second, because our major endpoint was sputum culture negativity at completion of 12 months of treatment, we did not follow patients after a 12-month period of treatment. For that reason, we did not show data on any subsequent microbiological relapse or delineate whether there was any difference between the two regimens. In addition, duration of culture negativity was shorter than what is recommended in the American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines. Third, daily doses of medication were lower than the ATS/IDSA recommendation. This study included mostly elderly patients. Often, elderly patients with Mycobacterium avium pulmonary disease could not tolerate the medication dosage because of the gastrointestinal side effects. ATS/IDSA and Wallace and colleagues suggest that the doses of clarithromycin need to be reduced to 250 mg twice daily for patients with small body mass or those older than 70 years of age due to gastrointestinal intolerance (1, 19). Thus, daily doses of clarithromycin and rifampicin were at the lower end of the ATS/IDSA recommended range. For the same reason, although onceor twice-daily dosing of clarithromycin was desirable, clarithromycin 400 mg/d and 600 mg/d were prescribed as twice or thrice daily in small doses (200 mg). However, lower daily doses and the method of administration might have affected on our results. In conclusion, the current preliminary study suggests that clarithromycin and ethambutol is not inferior to clarithromycin, ethambutol, and rifampicin for conversion to negative sputum cultures in the treatment of Mycobacterium avium complex lung infections. In addition, the two-drug regimen may be better tolerated than the three-drug regimen. Limitations in the scope and design of our study preclude any recommendation for modification of clinical practice at this time. Further studies are required to compare the rate of emergence of resistance to macrolides, the rate of less common adverse effects, and the long-term clinical outcomes for two-drug versus three-drug treatment regimens. n Author disclosures are available with the text of this article at Acknowledgment: We thank Hiromi Ohta, Akemi Shimaya, Hiroshi Fukui, Mieko Uchida, Yuka Fujisaka, and Naomi Nakamura at Tenryu Hospital for their assistance with data collection. References 1 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175: [Published erratum appears in Am J Respir Crit Care Med 175: ] 2 Dautzenberg B, Piperno D, Diot P, Truffot-Pernot C, Chauvin JP; Clarithromycin Study Group of France. Clarithromycin in the treatment of Mycobacterium avium lung infections in patients without AIDS. Chest 1995;107: Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT, Onyi GO, Steingrube VA, Mazurek GH. Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am J Respir Crit Care Med 1994;149: Griffith DE, Brown BA, Girard WM, Murphy DT, Wallace RJ Jr. Azithromycin activity against Mycobacterium avium complex lung disease in patients who were not infected with human immunodeficiency virus. Clin Infect Dis 1996;23: Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT. Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients. Am J Respir Crit Care Med 1996;153: Griffith DE, Brown BA, Girard WM, Griffith BE, Couch LA, Wallace RJ Jr. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 2001; 32: Tanaka E, Kimoto T, Tsuyuguchi K, Watanabe I, Matsumoto H, Niimi A, Suzuki K, Murayama T, Amitani R, Kuze F. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 1999;160: Wallace RJ Jr, Brown BA, Griffith DE, Girard W, Tanaka K. Reduced serum levels of clarithromycin in patients treated with multidrug regimens including rifampin or rifabutin for Mycobacterium avium-m. intracellulare infection. J Infect Dis 1995;171: van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, Aarnoutse RE, Heifets LB, Peloquin CA, Daley CL. The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment. 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7 16 Gordin FM, Sullam PM, Shafran SD, Cohn DL, Wynne B, Paxton L, Perry K, Horsburgh CR Jr. A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis 1999;28: Hasegawa N, Nishimura T, Ohtani S, Takeshita K, Fukunaga K, Tasaka S, Urano T, Ishii K, Miyairi M, Ishizaka A. Therapeutic effects of various initial combinations of chemotherapy including clarithromycin against Mycobacterium avium complex pulmonary disease. Chest 2009;136: Kobashi Y, Abe M, Mouri K, Obase Y, Kato S, Oka M. Relationship between clinical efficacy for pulmonary MAC and drug-sensitivity test for isolated MAC in a recent 6-year period. J Infect Chemother 2012;18: Wallace RJ Jr, Brown BA, Griffith DE. Drug intolerance to high-dose clarithromycin among elderly patients. Diagn Microbiol Infect Dis 1993;16: Miwa, Shirai, Toyoshima, et al.: Efficacy of Clarithromycin and Ethambutol for MAC Pulmonary Disease 29