American Journal of Respiratory and Critical Care Medicine

Rationale: Although intermittent, three-times-weekly therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic Mycobacterium avium complex (MAC) lung disease, supporting data are limited.

Objectives: To evaluate the clinical efficacy of intermittent therapy compared with daily therapy for nodular bronchiectatic MAC lung disease.

Methods: A retrospective cohort study of 217 patients with treatment-naive noncavitary nodular bronchiectatic MAC lung disease. All patients received either daily (n = 99) or intermittent therapy (n = 118) that included clarithromycin or azithromycin, rifampin, and ethambutol.

Measurements and Main Results: Modification of the initial antibiotic therapy occurred more frequently in the daily therapy group than in the intermittent therapy group (46 vs. 21%; P < 0.001); in particular, ethambutol was more frequently discontinued in the daily therapy group than in the intermittent therapy group (24 vs. 1%; P ≤ 0.001). However, the rates of symptomatic improvement, radiographic improvement, and sputum culture conversion were not different between the two groups (daily therapy vs. intermittent therapy: 75 vs. 82%, P = 0.181; 68 vs. 73%, P = 0.402; 76 vs. 67%, P = 0.154, respectively). In addition, the adjusted proportion of sputum culture conversion was similar between the daily therapy (71.3%; 95% confidence interval, 59.1–81.1%) and the intermittent therapy groups (73.6%; 95% confidence interval, 62.9–82.2%; P = 0.785).

Conclusions: These results suggest that intermittent three-times-weekly therapy with a macrolide, rifampin, and ethambutol is a reasonable initial treatment regimen for patients with noncavitary nodular bronchiectatic MAC lung disease.

Clinical trial registered with www.clinicaltrials.gov (NCT 00970801).

Scientific Knowledge on the Subject

The revised 2007 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines recommend intermittent, three-times-weekly antibiotic therapy for the initial treatment for patients with the noncavitary nodular bronchiectatic form of Mycobacterium avium complex (MAC) lung disease. However, only limited data support the current recommendation for intermittent therapy in these patients.

What This Study Adds to the Field

Patients receiving intermittent therapy were more able to tolerate long-term multidrug antibiotic treatment and had similar response rates with respect to symptomatic improvement, radiographic improvement, and sputum culture conversion compared with patients receiving daily therapy. Therefore, intermittent therapy should be considered as a first-choice antibiotic regimen in treatment-naive patients with the noncavitary nodular bronchiectatic form of MAC lung disease, as recommended in the 2007 ATS/IDSA guidelines.

Mycobacterium avium complex lung disease (MAC-LD) is the most common form of lung disease caused by nontuberculous mycobacteria (NTM), and the prevalence of MAC-LD is increasing worldwide (19). The traditionally recognized clinical presentation of MAC-LD is apical fibrocavitary disease. This type of disease usually develops in older males with a history of lung disease, such as previous pulmonary tuberculosis (TB) (10). MAC-LD can also present with nodular infiltrates, frequently involving the right middle lobe and the lingular segment of the left upper lobe. This form of disease is termed nodular bronchiectatic (NB) disease and occurs predominantly in postmenopausal, nonsmoking females (1113).

In 1997, the American Thoracic Society (ATS) guidelines recommended a daily macrolide-based multidrug regimen consisting of a macrolide (clarithromycin [CLR] or azithromycin [AZM]), rifamycin (rifampin [RIF] or rifabutin [RFB]), and ethambutol (EMB) with or without the initial use of streptomycin for the treatment of MAC-LD (14). However, this regimen is poorly tolerated and can lead to a variety of side effects such as gastrointestinal symptoms and ocular toxicity (1517).

In 2007 revised guidelines issued by the ATS and the Infectious Diseases Society of America (IDSA) recommended intermittent, three-times-weekly therapy for the initial treatment of the noncavitary NB form of MAC-LD (1). Such intermittent therapy has potential advantages in reducing drug side effects, treatment discontinuation, and medication costs. However, there are limited data in support of the current recommendation for intermittent therapy for NB MAC-LD. Three previous studies published before the 2007 ATS/IDSA guidelines suggested that intermittent therapy may be as effective as a daily regimen (1820). However, all these studies included a substantial proportion of patients with a history of prior therapy for MAC-LD or cavitary disease (1820).

Intermittent antibiotic treatment for MAC-LD was previously not popular in Asian countries including Korea and Japan, although such patients are common in these areas (2129). In our institution (Samsung Medical Center, Seoul, Korea), until December 2010, all patients with MAC-LD were treated with a daily regimen. Then, beginning in January 2011, the treatment protocol was changed, and intermittent therapy was introduced for all patients with noncavitary NB MAC-LD. The purpose of the current study was to compare the clinical efficacy of intermittent therapy with daily therapy in a relatively large number of patients with NB MAC-LD.

Study Populations

Consecutive patients with MAC-LD who initiated antibiotic treatment between January 2005 and December 2012 were identified from the NTM Registry of Samsung Medical Center (a 1,961-bed referral hospital in Seoul, Korea) (21, 23, 30). The data since January 2008 were from an ongoing institutional review board–approved prospective observational cohort study to investigate NTM lung disease, and written informed consent was obtained from all participants (clinicaltrials.gov identifier NCT00970801).

During this 8-year period, 573 patients initiated antibiotic treatments for MAC-LD. All patients met the standard diagnostic criteria for NTM lung disease according to the ATS/IDSA guidelines (1). Of these patients, 380 patients were diagnosed with NB MAC-LD based on high-resolution computed tomography (HRCT) findings. After exclusion of patients with cavitation on HRCT (n = 95), previous macrolide treatment for at least 1 month before transfer to our institution (n = 76), history of completion of prior therapy for NTM lung disease (n = 48), and intermediate or higher-level resistance to CLR on drug susceptibility tests (n = 19), 217 patients with noncavitary NB MAC-LD were included in this study (Figure 1).

Antibiotic Treatment

All patients with MAC-LD who began antibiotic therapy received the standard combination antibiotic therapy consisting of an oral macrolide, RIF, and EMB (1). In our institution, all patients were treated with daily therapy regimens before January 2011 (21). After January 2011, all patients with noncavitary NB MAC-LD without previous treatment history for NTM lung disease were treated with intermittent therapy regimens.

The regimen for the daily therapy included the following components: (1) 1,000 mg of CLR or 250 mg of AZM, (2) EMB at 15 mg/kg, and (3) RIF at 450 mg/day (body weight ≤ 50 kg) or 600 mg/day (body weight ≥ 50 kg). Streptomycin was given intramuscularly at 10–15 mg/kg (500–1,000 mg) three times per week for the first 3 months at the discretion of the attending physician, especially in patients with acid-fast bacilli (AFB) smear-positive sputum. This regimen usually continued for a total treatment duration of 24 months (21).

The regimen for the intermittent therapy included the following components: (1) 500 mg of AZM or 1,000 mg of CLR, (2) EMB at 25 mg/kg, and (3) 600 mg of RFP three times weekly. In Korea, AZM was approved in 2011 for the treatment of NTM lung disease under coverage from the National Health Insurance. Therefore, CLR was usually administered before 2011 and AZM was the preferred treatment after 2011 in our institution, due to potential gastrointestinal side effects of CLR. Patients with noncavitary NB MAC-LD were generally treated until culture negative for 12 months.

Treatment Outcomes

To compare the treatment outcomes between daily therapy and intermittent therapy, we assessed whether the symptoms and HRCT findings improved and sputum AFB cultures were negative within 12 months after treatment initiation. Symptomatic responses were determined by the attending physicians. Physician’s subjective assessment of change in the patient’s respiratory condition was made and recorded at 12 months after antibiotic treatment. HRCT scans were obtained at the beginning of antibiotic therapy and at 12 months after initiation of antibiotic therapy in all patients (31) and chest radiologists’ interpretations were analyzed.

Sputum examinations were performed 1, 3, and 6 months after initiation of antibiotic treatment and then at 2- to 3-month intervals until the end of treatment during the study period. Sputum conversion was defined as three consecutive negative cultures, with the time of conversion defined as the date of the first negative culture (21, 23). A favorable treatment outcome was defined as sputum culture conversion and maintenance of negative sputum cultures for more than 12 months. An unfavorable treatment outcome was defined as follows: (1) early discontinuation of antibiotic therapy due to adverse effects and a total treatment duration of less than 12 months, (2) no sputum culture conversion, or (3) microbiological recurrence of two or more positive cultures after an initial negative conversion during antibiotic therapy.

Statistical Analyses

Data are presented as medians and interquartile range (IQR) for continuous variables and as numbers (percentage) for categorical variables. Data were compared by Mann–Whitney U test for continuous variables and by Pearson χ2 test or Fisher exact test for categorical variables. To compare the outcome of daily therapy versus intermittent therapy, adjustments were performed for age, sex, positive sputum AFB smear at treatment initiation, use of streptomycin, and factors with P values less than 0.2 in the baseline characteristics between the two groups. The adjusted proportion of patients with favorable outcomes was calculated by logistic regression analysis.

To identify the independent prognostic factors associated with unfavorable outcomes in intermittent therapy, we conducted a multiple logistic regression analysis with backward stepwise selection with P ≤ 0.05 for entry of variables and P > 0.10 for removal of variables. Initial candidate variables were those tested before starting treatment, including age, sex, body mass index, etiologic organism, smoking, history of previous TB treatment, comorbidities, positive sputum AFB smear, and time interval between diagnosis and treatment. All tests were two-sided, and a P value less than 0.05 was considered significant. Data were analyzed with PASW Statistics 18 (SPSS Inc., Chicago, IL) and STATA version 11 (STATA Corp., College Station, TX).

Baseline Characteristics

Baseline characteristics of the patients are summarized in Table 1. None of the patients tested positive for human immunodeficiency virus. There were no significant differences in age, sex, body mass index, etiologic organism, smoking history, or history of TB treatment between the daily therapy and intermittent therapy groups. The frequency of comorbidities was similar except for diabetes mellitus, which was more prevalent in the daily therapy group (11 of 99, 11%) than in the intermittent therapy group (4 of 118, 3%). The positivity of the sputum AFB smear at treatment initiation (46 of 99, 47% vs. 47 of 118, 40%) and the time interval between the diagnosis of MAC-LD and start of antibiotic therapy (8.7 mo; IQR, 2.9–14.8 mo vs. 6.6 mo; IQR, 1.8–30.4 mo) were not different between the daily therapy and intermittent therapy groups. Drug susceptibility tests were performed on MAC isolates recovered from patients before antibiotic treatment, and all MAC isolates were found to be susceptible to CLR (minimal inhibitory concentrations, ≤8 μg/ml) (32).

Table 1. Baseline Characteristics

 Daily Therapy (n = 99)Intermittent Therapy (n = 118)P Value
Age, yr59 (51–67)57 (50–66)0.223
Sex, female61 (62%)85 (72%)0.103
Body mass index, kg/m220.2 (18.8–21.5)20.4 (19.0–22.1)0.195
Etiologic organism   
Mycobacterium avium60 (61%)60 (51%)0.150
Mycobacterium intracellulare39 (39%)58 (49%) 
Nonsmoker82 (83%)99 (84%)0.833
History of TB treatment*38 (38%)31 (26%)0.056
Comorbidities   
 Chronic heart disease18 (18%)20 (17%)0.812
 Malignancy13 (13%)20 (17%)0.435
 Diabetes mellitus11 (11%)4 (3%)0.026
 Cerebrovascular disease5 (5%)3 (3%)0.474
 Chronic liver disease1 (1%)7 (6%)0.074
Positive sputum AFB smear46 (47%)47 (40%)0.325
Time interval between diagnosis and treatment, mo8.7 (2.9–14.8)6.6 (1.8–30.4)0.816

Definition of abbreviations: AFB = acid-fast bacilli; TB = tuberculosis.

* Patients had been diagnosed and treated for TB. However, it was unclear whether the patients had culture-confirmed pulmonary TB previously, because patients with AFB-positive sputum had frequently been presumed to have pulmonary TB and were treated empirically with anti-TB drugs.

At treatment initiation.

Initial Antibiotic Treatment

Most patients receiving intermittent therapy were prescribed AZM (115 of 118, 97%), compared with 12 of 99 patients (12%) receiving daily therapy (Table 2). Whereas all patients in the intermittent therapy group received RIF, four patients in the daily therapy group received RFB instead of RIF because of drug interactions with immunosuppressant drugs (n = 3) and drug intolerances (n = 1). In the daily therapy group, streptomycin was used in 60 patients (61%) for a median of 3.0 months (IQR, 2.3–4.0 mo). Antibiotic treatment duration was longer in the daily therapy group than in the intermittent therapy group (24.3 mo; IQR, 23.8–24.5 mo vs. 16.6 mo; IQR, 15.2–18.4 mo, respectively; P ≤ 0.001).

Table 2. Initial Antibiotic Treatment

 Daily Therapy (n = 99)Intermittent Therapy (n = 118)
Macrolide  
 CLR87 (88%)2 (2%)
 AZM4 (4%)92 (78%)
 CLR, followed by AZM8 (8%)23 (19%)
 AZM, followed by CLR1 (1%)
Rifamycin  
 RIF95 (96%)118 (100%)
 RFB2 (2%)
 RIF, followed by RFB2 (2%)
EMB99 (100%)118 (100%)
Streptomycin60 (61%)

Definition of abbreviations: AZM = azithromycin; CLR = clarithromycin; EMB = ethambutol; RFB = rifabutin; RIF = rifampin.

Modification of Initial Antibiotic Treatment

Modification of the initial antibiotic treatment due to medication intolerance is summarized in Table 3. The rate of early discontinuation of antibiotic therapy at less than 12 months of treatment due to adverse effects did not differ between the daily therapy group (15 of 99, 15%) and the intermittent therapy group (13 of 118, 11%; P = 0.366). Dose reduction of CLR was needed in 12% (11 of 92 patients) in the daily therapy group versus 4% (1 of 26 patients) in the intermittent therapy group, mainly due to gastrointestinal symptoms (P = 0.458). Discontinuation of RIF or RFB occurred in 4% of patients (4 of 99) in the daily therapy group and 6% of patients (7 of 118) in the intermittent therapy group (P = 0.527). However, discontinuation of EMB occurred more frequently in the daily therapy group than in the intermittent therapy group, primarily due to visual disturbances (24% [24/99] vs. 1% [1/118]; P ≤ 0.001). Patients with visual impairment developed symptoms after a median of 12.3 months (IQR, 8.7–17.8 mo) of EMB treatment. Of 25 patients who discontinued EMB, 8 patients received an additional drug (moxifloxacin in 6 patients and streptomycin in 2 patients). Therefore, any modification of the initial antibiotic therapy occurred more frequently in the daily therapy group than in the intermittent therapy group (46 of 99 [46%] vs. 25 of 118 [21%], respectively; P ≤ 0.001).

Table 3. Modification of Initial Antibiotic Treatment

 Daily Therapy (n = 99)Intermittent Therapy (n = 118)P Value
Early discontinuation of antibiotic treatment15 (15%)13 (11%)0.366
Dose reduction of CLR11/95 (12%)1/26 (4%)0.458
Change from AZM to CLR0/12 (0%)3/116 (3%)NA
Discontinuation of RIF or RFB4/99 (4%)7/118 (6%)0.527
Discontinuation of EMB24/99 (24%)1/118 (1%)<0.001
Discontinuation of streptomycin4/60 (7%)NA
Total46/99 (46%)*25/118 (21%)<0.001

Definition of abbreviations: AZM = azithromycin; CLR = clarithromycin; EMB = ethambutol; NA = not applicable; RFB = rifabutin; RIF = rifampin.

* Because some cases were included in more than one category, the sum of the the individual categories exceeds the total.

Treatment Outcomes

After 12 months of antibiotic treatment, there were no differences in symptom improvement (75 vs. 82%; P = 0.181) or HRCT improvement (68 vs. 73%; P = 0.402) between the daily therapy and intermittent therapy groups (Table 4). Although the sputum culture conversion rate was slightly lower in the intermittent therapy group (67%) than in the daily therapy group (76%), the difference was not statistically significant (P = 0.154). In addition, there was no difference in duration between treatment initiation and the time of sputum culture conversion between the daily therapy group (34 d; IQR, 27–68 d) and the intermittent therapy group (35 d; IQR, 28–85 d; P = 0.141). Microbiological recurrence of two or more positive cultures after an initial negative conversion during antibiotic therapy occurred in one patient (1.3%, 1 of 76) in the daily therapy group and three patients (3.7%, 3 of 82) in the intermittent therapy group (P = 0.621).

Table 4. Treatment Outcomes

 Daily Therapy (n = 99)Intermittent Therapy (n = 118)P Value
Improvement of symptom74 (75%)97 (82%)0.181
Improvement of HRCT67 (68%)86 (73%)0.402
Sputum culture conversion75 (76%)79 (67%)0.154
Time of sputum culture conversion, d34 (27–68)35 (28–85)0.149

Definition of abbreviation: HRCT = high-resolution computed tomography.

Among 63 patients (24 in the daily therapy group and 39 in the intermittent therapy group) who had unfavorable outcomes, 28 patients discontinued antibiotic therapy at less than 12 months because of adverse effects, as did 35 patients who failed to convert cultures to negative or had a microbiological recurrence during antibiotic therapy. Follow-up data on the CLR susceptibility were available for 34 (97%) of these 35 patients. Although the development of CLR resistance occurred more frequently in the daily therapy group (33%, 3 of 9) than in the intermittent therapy group (12%, 3 of 25), the difference was not statistically significant (P = 0.306). This may be influenced by the timing of the CLR susceptibility test after initiation of treatment. However, there is also no significant difference in the probability of development of drug resistance over time (P = 0.151, log-rank test).

Table 5 shows the crude and adjusted proportions and odds ratio (OR) of favorable treatment outcomes. Although the crude proportion of favorable outcomes was slightly higher in the daily therapy group (75.8%; 95% confidence interval [CI], 66.4–83.2%) than in the intermittent therapy group (66.9%; 95% CI, 58.0–74.8%), this difference was not statistically significant (8.8%; 95% CI, –3.3 to 20.9%; P = 0.156). After adjusting for confounding factors, the adjusted proportion of favorable outcomes for daily therapy was 71.3% (95% CI, 59.1–81.1%), and that for intermittent therapy was 73.6% (95% CI, 62.9–82.2%). Finally, the adjusted difference of proportion was –2.3% (–19.5 to 15.0%; P = 0.785).

Table 5. Crude and Adjusted Proportions and Odds Ratios for Favorable Treatment Outcomes

 Crude or Adjusted Proportion of Favorable OutcomesDifferences of Proportion*OR95% CIP Value
Daily TherapyIntermittent Therapy
Crude state75.8% (66.4–83.2)66.9% (58.0–74.8)8.8% (–3.3 to 20.9)1.5430.848–2.8070.156
Adjusted state71.3% (59.1–81.1)73.6% (62.9–82.2)−2.3% (–19.5 to 15.0)0.8910.387–2.0500.785

Definition of abbreviations: CI = confidence interval; OR = odds ratio.

* Calculated by (proportion of favorable outcomes in patients with daily therapy) − (proportion of favorable outcomes in patients with intermittent therapy). Therefore, positive values mean that daily therapy was more effective than intermittent therapy, and negative values mean the opposite.

Calculated using ratio of odds of favorable outcomes in daily therapy to those in intermittent therapy. Therefore, values greater than one mean that daily therapy was more effective than intermittent therapy, and values less than one mean the opposite.

Adjusted for age, sex, positive sputum smear, use of streptomycin, and factors with a P value less than 0.2 at baseline (body mass index, etiologic organism, history of TB treatment, and comorbidities [diabetes mellitus and chronic liver disease]).

Among patients receiving intermittent therapy, univariate and multivariate logistic analyses were performed to identify the independent prognostic factors associated with unfavorable outcomes (Table 6). After adjusting for potential confounding factors, the final multiple logistic regression model revealed that being male (adjusted OR, 2.462; 95% CI, 1.051–5.764; P = 0.038) and having a positive AFB sputum smear at treatment initiation (adjusted OR, 2.312; 95% CI, 1.038–5.151; P = 0.040) were independently associated with unfavorable outcomes.

Table 6. Factors Associated with Unfavorable Outcomes in Patients Receiving Intermittent Therapy

 Univariable AnalysisMultivariable Analysis
Favorable (n = 79)Unfavorable (n = 39)P ValueAdjusted OR (95% CI)P Value
Age, yr57 (49–65)57 (50–68)0.598  
Sex, male17 (22)16 (41)0.0262.462 (1.051–5.764)0.038
Body mass index, kg/m220.5 (19.0–22.1)20.4 (19.4–22.2)0.966  
Etiologic organism  0.268  
Mycobacterium avium43 (54)17 (44)
Mycobacterium intracellulare36 (46)22 (56)
Nonsmoker69 (87)30 (77)0.147  
History of TB treatment22 (28)9 (23)0.580  
Comorbidities     
 Chronic heart disease14 (18)6 (15)0.750
 Malignancy14 (18)6 (15)0.750
 Diabetes mellitus3 (4)1 (3)1.000
 Cerebrovascular disease2 (3)1 (3)1.000
 Chronic liver disease5 (6)2 (5)1.000
Positive sputum AFB smear*26 (33)21 (54)0.0292.312 (1.038–5.151)0.040
Time interval between diagnosis and treatment, mo6.5 (1.7–27.8)6.7 (2.1–44.8)0.611  

Definition of abbreviations: AFB = acid-fast bacilli; CI = confidence interval; OR = odds ratio; TB = tuberculosis.

* At the time of initiation of treatment.

We investigated the clinical efficacy of intermittent therapy compared with daily therapy for noncavitary NB MAC-LD. Our study included more than 200 patients without any prior treatment history of MAC-LD, and about half of the patients were treated with daily, and half with intermittent, antibiotic treatment. We found that patients receiving intermittent therapy were more able to tolerate long-term combination antibiotic treatment and had similar response rates with respect to symptomatic improvement, HRCT improvement, and sputum culture conversion compared with those receiving daily therapy. In addition, our results suggested that male patients or patients with a positive sputum AFB smears at the initiation of treatment should be carefully monitored because of an association of these traits with unfavorable outcomes.

The treatment success rate with combination antibiotic treatment for MAC-LD has been unsatisfactory (16, 33). In addition, many patients drop out of treatment due to the adverse effects of multidrug macrolide-containing antibiotic regimens (16). In one study, the dosage of at least one oral drug was altered or discontinued during daily therapy in up to 40% of patients (34). Intermittent antibiotic therapy for MAC-LD can offer the potential advantage of fewer medication side effects. Therefore, three-times-weekly antibiotic therapy was recommended in the 2007 ATS/IDSA guidelines as an initial treatment for patients with noncavitary NB MAC-LD without prior treatment history (1). However, data supporting such intermittent therapy in these patients were limited.

In their first trial, Griffith and colleagues evaluated the clinical efficacy of intermittent therapy for MAC-LD (18). The regimen consisted of three-times-weekly AZM (600 mg), EMB (25 mg/kg), and RFB (300–600 mg), with additional streptomycin usually included for the first 2 months of therapy (18). The study enrolled 47 patients and 8 (17%) received less than 6 months of therapy because of noncompliance or intolerance to medication. Sputum culture conversion at 6 months was achieved in 24 (62%) of the remaining 39 patients (this represents 51% of the 47 patients initially enrolled). This was the first study to show the efficacy of intermittent therapy in patients with MAC-LD. However, their study included patients with the fibrocavitary form of MAC-LD or prior treatment for MAC-LD, and some patients underwent surgical resection (18). In an additional study, Griffith and colleagues evaluated the efficacy of intermittent therapy including CLR (1,000 mg), RFB (150–300 mg), and EMB (25 mg/kg) in 59 patients with MAC-LD (19). In their trial, 18 (31%) patients did not complete the 6 months of therapy. Sputum culture was negative at 6 months in 32 (78%) of the remaining 41 patients (only 54% of the 59 patients initially enrolled). Again, in that study, many patients had the fibrocavitary form of MAC-LD (n = 30), or previous therapy for MAC-LD (n = 17) (19).

Lam and colleagues evaluated the treatment response to intermittent therapy including CLR (750–1,000 mg) or AZM (375–600 mg), EMB (25 mg/kg), and RIF (450–600 mg) or RFB (5–10 mg/kg) with or without inhaled IFN-γ for severe and/or previously treated MAC-LD (20). In this study, 91 patients were initially enrolled and 58 (64%) completed the 52 weeks of treatment. Contrary to previous works, Lam and colleagues reported treatment response rates including lost patients. The sputum culture conversions rate was only 13% (4% of patients with cavitary disease and 24% of patients with noncavitary disease). In their study, 49 patients (54%) had cavitary disease, and a history of MAC treatment was also frequently found (59% of cavitary disease and 48% of noncavitary disease) (20).

Although these previous studies included a substantial proportion of patients with cavitary MAC-LD or prior treatment for MAC-LD (1820) and excluded lost patients when evaluating treatment responses (18, 19), the revised 2007 ATS/IDSA guidelines recommended intermittent therapy as an initial treatment for patients with noncavitary NB MAC disease (1), because a previous multicenter study found that intermittent therapy was less effective for patients with MAC-LD with cavitary disease and a history of previous treatment for MAC-LD (20).

Compared with the previous studies, our study included only patients with noncavitary NB MAC-LD and without a history of previous therapy for NTM lung disease. To our knowledge, this is the first study to evaluate the clinical efficacy of initial intermittent antibiotic treatment for noncavitary NB MAC-LD. Our study population was suitable for evaluation of the current ATS/IDSA guidelines for NB MAC-LD.

An important benefit of intermittent therapy was an improvement in drug tolerance compared with that seen with daily treatment regimens. The present study demonstrated that modification of the initial antibiotic therapy occurred more frequently in the daily therapy group than in the intermittent therapy group (46 vs. 21%; P ≤ 0.001) and found that this difference was due mainly to the adverse effects of EMB. These findings are consistent with a previous report that showed that intermittent EMB administration was associated with less ocular toxicity than daily EMB administration in elderly patients with MAC-LD (17). EMB is an important component, second only to macrolides, in the current multidrug regimens for treatment of patients with MAC-LD (17), and the microbiological response was significantly related to the duration of EMB use (20).

Although intermittent therapy was tolerated better in patients with MAC-LD, the treatment response rates in the intermittent therapy group were comparable to the daily therapy group in terms of sputum culture conversion, as well as symptomatic and HRCT improvements. Therefore, the current ATS/IDSA guideline–recommended intermittent therapy is a reasonable option for patients with the less severe forms of MAC-LD, such as noncavitary NB.

Wallace and colleagues reported that intermittent therapy was effective and significantly better tolerated than daily therapy in patients with NB MAC-LD (35). Although there was no difference in culture conversion rates (85% [147 of 172] in intermittent therapy vs. 88% [7 of 8] in daily therapy), treatment regimen modification occurred substantially less frequently (1%) in the intermittent therapy group than in the daily therapy group (80%) (35). Compared with our study, there were some differences in the enrolled population in this study. The study by Wallace and colleagues included a small number of patients receiving daily therapy and excluded 27 (13%) patients who did not receive at least 12 months of antibiotic therapy among 207 patients who started on MAC therapy for NB MAC-LD. However, our study analyzed the treatment response of all patients who initiated MAC therapy, including all 28 patients (13%) who received less than 12 months of therapy. Among the 105 patients in our study who received at least 12 months of therapy, the sputum conversion rate was 71% (75 of 105). In addition, 21 patients (15%) received either streptomycin or amikacin for 2–3 months in the study by Wallace and colleagues (35), whereas three macrolide-based oral drugs were used in the intermittent therapy group in our study. These differences might contribute to the slightly lower microbiologic response rate in our intermittent therapy group (67%) compared with that in the study by Wallace and colleagues (85%). Moreover, 55 patients (31%) had a history of prior treatment for longer than 6 months and cavitating lesions were present in 4 patients (2%) in the study by Wallace and colleagues (35).

Previous studies identified some prognostic factors that were associated with sputum culture conversion in the treatment for MAC-LD such as old age (20), prior therapy for MAC-LD (18, 20, 25, 34, 36), positive AFB smear (20, 21, 23, 25), M. intracellulare infection (23), CLR resistance (25, 27, 37), extent of lesion (38), cavitation (20, 23, 39), low dose of CLR (22, 26, 27), short duration (<5 mo) of EMB use (20), and less than 12 months of treatment after sputum conversion (38). However, no study has evaluated the prognostic factors for the initial intermittent treatment of patients with noncavitary NB MAC-LD. We found that male patients and those having a positive AFB smear at treatment initiation were more likely to demonstrate an unfavorable microbiological response. Therefore, such patients should be closely monitored during intermittent therapy, and intermittent therapy may be switched to daily therapy when there is evidence of development of cavitation or failure to achieve sputum culture conversion (40).

The present study has several limitations. First, it was conducted at a single referral center. Second, this study was not a randomized controlled study comparing the clinical efficacy of daily versus intermittent therapy. As patients were treated with daily therapy or intermittent therapy during different time periods, according to our treatment protocols, there could be differences in the baseline characteristics and the severity of disease between the groups. In particular, streptomycin was used only in the daily therapy group and thus it might have influenced the microbiological outcomes in favor of the daily regimen. To reduce the selection bias, we analyzed the data using an adjusted proportion of favorable outcomes and multiple logistic regression analysis after adjustment of the basic demographic data and the factors that influence treatment outcomes. However, the potential for a bias of unmeasured confounder remains, such as adherence to treatment, which may contribute to treatment outcomes. Third, genotyping data were not available in patients who failed sputum culture conversion in this study. Therefore, we could not differentiate between persistent infection with the initial MAC stain and reinfection with a new MAC strain in these patients. Fourth, this study did not assess long-term patient outcomes such as the relapse rate after treatment completion. However, clinical and radiographic improvements and 12 months of sputum culture negativity could be considered to be reasonable treatment goals for MAC-LD (40), because the subsequent isolation of MAC from sputum is more likely to represent reinfection with a new MAC infection than a true relapse with recurrent isolation of the previous MAC strains (35, 41, 42).

In summary, intermittent three-times-weekly therapy with macrolide, RIF, and EMB is effective and better tolerated compared with daily therapy in patients with noncavitary NB MAC-LD without prior treatment history of MAC-LD. Adherence to the current treatment guidelines is important to improve patient outcomes and reduce medication intolerance in elderly patients with MAC-LD.

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* These authors contributed equally to this work.

Correspondence and requests for reprints should be addressed to Won-Jung Koh, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul 135-710, Korea. E-mail:

Supported by a grant of the Korean Health Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A120647).

Author Contributions: Conception and design: B.-H.J., K.J., C.L.D., and W.-J.K. Analysis, interpretation, and manuscript writing: B.-H.J., K.J., and W.-J.K. Revision of the manuscript and contribution to intellectual content: B.-H.J., K.J., H.Y.P., S.-Y.K., K.S.L., H.J.H., C.-S.K., N.Y.L., S.J.S., C.L.D., and W.-J.K.

Author disclosures are available with the text of this article at www.atsjournals.org.

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