ABSTRACT
We investigated the treatment outcomes of patients with cavitary nodular bronchiectatic (C-NB)-type Mycobacterium avium complex (MAC) pulmonary disease (PD) via outcome comparisons between the fibrocavitary (FC) and C-NB types treated with guideline-based therapy (GBT) composed of daily three-drug oral antibiotics and injectable aminoglycoside. Additionally, we analyzed whether treatment with oral antibiotics alone would result in acceptable outcomes for the C-NB type. From 2002 to 2019, patients with cavitary MAC-PD who received three-drug oral antibiotics with or without an injectable aminoglycoside for ≥1 year were retrospectively enrolled at a tertiary referral center in South Korea. We compared the rates of culture conversion at 12 months according to the radiological type and treatment regimen. The overall culture conversion rate at 12 months of 154 patients with cavitary MAC-PD who received GBT was 75.3%. Among them, the culture conversion rates of 114 patients with the C-NB type were higher than that of 40 patients with the FC-type (80.7% versus 60.0%, respectively; P = 0.009). Of 166 patients with the C-NB-type treated with oral medications with or without an injectable drug, 83.7% achieved culture conversion at 12 months. The conversion rates of those who received oral medications alone and those treated with oral medications and an injectable aminoglycoside were similar (90.4% versus 80.7%, respectively; P = 0.117). In conclusion, the culture conversion rates of the patients with C-NB type treated with GBT were significantly higher than those of patients with the FC type. Additionally, the C-NB type could be treated with oral medications alone.
KEYWORDS: Mycobacterium avium complex, cavitary nodular bronchiectatic, fibrocavitary, treatment outcome, injectable aminoglycoside
INTRODUCTION
Mycobacterium avium complex (MAC) pulmonary disease (PD) has been traditionally categorized into two major radiological types: fibrocavitary (FC) and nodular bronchiectatic (NB) (1). However, Koh et al. reported that the treatment outcomes of the cavitary form of the NB type were similar to those of the FC type (2). Since then, the NB type has been further classified into cavitary NB (C-NB) and noncavitary NB (NC-NB) types according to the presence or absence of cavitary lesions (3, 4). Recent clinical guidelines recommend the use of different treatment modalities depending on whether patients with MAC-PD have cavitary disease (3, 5, 6). That is, an intermittent treatment with three oral antibiotics (i.e., macrolide, ethambutol, and rifampin) is recommended for patients with NC-NB-type MAC-PD, whereas a daily administration of these oral antibiotics and an injectable aminoglycoside is recommended for treating those with cavitary disease (FC or C-NB type) (3, 4).
However, all these recommendations for treating FC and C-NB types with the same treatment modality were based on only one single-center study (2), i.e., the optimal treatment regimen for C-NB-type MAC-PD has not been reevaluated or assessed via other studies. Moreover, it is noteworthy that not all patients with cavitary disease in that single-center study received an injectable agent (it was used only in 68% of patients with cavitary disease) (2). Therefore, clinical evidence regarding whether or not an injectable aminoglycoside should be included in the treatment regimen of patients with C-NB-type MAC-PD is currently insufficient. Additionally, although the FC and C-NB types have been considered to fall under a similar disease spectrum in terms of treatment regimen and subsequent treatment outcome (3, 4), no study has investigated whether guideline-based therapy (GBT) results in similar treatment outcomes for patients with FC-type and those with C-NB-type MAC-PD. Therefore, we investigated these issues in this study. First, we analyzed the treatment outcomes of patients with C-NB-type MAC-PD by comparing the treatment responses of patients with FC-type and those with C-NB-type MAC-PD who received GBT composed of daily three-drug oral antibiotics with an injectable aminoglycoside. Next, we analyzed whether treatment with oral antibiotics alone would lead to acceptable treatment outcomes for the C-NB type compared with those who received GBT.
RESULTS
Study subjects.
On conducting eligibility screening, 276 patients with C-NB-type MAC-PD were identified, including 101 patients who started receiving three-drug oral antibiotics alone and 175 patients who started receiving GBT (three-drug oral antibiotics with an injectable aminoglycoside) (Fig. 1). The baseline characteristics are shown in Table 1. The mean age (± standard deviation [SD]) of the 276 patients was 63.2 ± 11.0 years, and 68.5% of them were female. Significant differences were noted between the two groups in terms of etiologic organisms and cavity size. Among the 276 patients, 52 and 114 continued using three-drug oral antibiotics alone and GBT without any modification in medications for ≥1 year, respectively (Fig. 1).
FIG 1.
Flowchart for study subject enrollment of patients with C-NB-type MAC-PD. EMB, ethambutol; RIF, rifampin. The standard three-drug oral antibiotic regimen included macrolide, ethambutol, and rifampin.
TABLE 1.
Clinical characteristics of 276 patients with C-NB-type MAC-PD according to initial treatment regimen
| Characteristic | Total (n = 276)a | Oral medication alone (n = 101)a | Oral medication and injectable aminoglycoside (n = 175)a | P value |
|---|---|---|---|---|
| Age (yrs) | 63.2 ± 11.0 | 64.4 ± 11.1 | 62.5 ± 11.0 | 0.182 |
| Sex, female | 189 (68.5%) | 66 (65.3%) | 123 (70.3%) | 0.395 |
| Body mass index at initiation of treatment (kg/m2) | 20.1 ± 2.8 | 20.1 ± 3.0 | 20.1 ± 2.7 | 0.901 |
| Current or past smoker | 64 (23.2%) | 25 (24.8%) | 39 (22.3%) | 0.608 |
| History of tuberculosis treatment | 112 (40.6%) | 41 (40.6%) | 71 (40.6%) | 0.997 |
| Diabetes mellitus | 20 (7.2%) | 7 (6.9%) | 13 (7.4%) | 0.878 |
| Underlying disease | ||||
| Malignancy | 46 (16.7%) | 21 (20.8%) | 25 (14.3%) | 0.162 |
| Chronic liver disease | 26 (9.4%) | 13 (12.9%) | 13 (7.4%) | 0.136 |
| Chronic obstructive lung disease | 20 (7.2%) | 11 (10.9%) | 9 (5.1%) | 0.076 |
| Etiology | 0.006 | |||
| Mycobacterium avium | 131 (47.5%) | 37 (36.6%) | 94 (53.7%) | |
| Mycobacterium intracellulare | 145 (52.5%) | 64 (63.4%) | 81 (46.3%) | |
| Positive AFB smear at treatment initiation | 139 (50.4%) | 44 (43.6%) | 95 (54.3%) | 0.086 |
| No. of involved lobes | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 0.131 |
| Median no. of cavities | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 0.562 |
| No. of cavities | 0.767 | |||
| <2 | 169 (61.2%) | 63 (62.4%) | 106 (60.6%) | |
| ≥2 | 107 (38.8%) | 38 (37.6%) | 69 (39.4%) | |
| Maximum size of cavity (cm) | 1.9 (1.3–2.7) | 1.5 (1.1–2.6) | 1.9 (1.5–2.7) | 0.028 |
| Size of cavities | 0.371 | |||
| <2 cm | 157 (56.9%) | 61 (60.4%) | 96 (54.9%) | |
| ≥2 cm | 119 (43.1%) | 40 (39.6%) | 79 (45.1%) | |
| Maximum thickness of cavity (mm) | 4.1 (2.9–5.7) | 4.0 (2.7–5.6) | 4.2 (3.1–5.7) | 0.302 |
| Thickness of cavities | 0.858 | |||
| <5 mm | 173 (62.7%) | 64 (63.4%) | 109 (62.3%) | |
| ≥5 mm | 103 (37.3%) | 37 (36.6%) | 66 (37.7%) |
Data are means ± standard deviations, medians (with interquartile ranges), or number (percent) of subjects with the characteristic.
We then identified 135 patients with FC-type MAC-PD who were initially administered three-drug antibiotics (n = 43) or GBT (n = 92) (Fig. 2). As shown in Table 2, two groups were comparable except in terms of age. Of the 135 patients, 17 and 40 continued treatment with three-drug oral antibiotics alone or GBT without any modification in medications for ≥1 year, respectively (Fig. 2).
FIG 2.
Flowchart of study subject enrollment of patients with FC-type MAC-PD. EMB, ethambutol; RIF, rifampin. The standard three-drug oral antibiotic regimen included macrolide, ethambutol, and rifampin.
TABLE 2.
Clinical characteristics of 135 patients with FC-type MAC-PD according to the initial treatment regimen
| Characteristic | Total (n = 135)a | Oral medication alone (n = 43)a | Oral medication and an injectable aminoglycoside (n = 92)a | P value |
|---|---|---|---|---|
| Age (yrs) | 65.4 ± 10.2 | 69.7 ± 9.6 | 63.4 ± 10.0 | 0.001 |
| Sex, female | 32 (23.7%) | 10 (23.3%) | 22 (23.9%) | 0.933 |
| Body mass index at initiation of treatment (kg/m2) | 18.9 ± 3.0 | 18.9 ± 3.3 | 18.9 ± 2.9 | 0.994 |
| Current or past smoker | 88 (65.2%) | 30 (69.8%) | 58 (63.0%) | 0.445 |
| History of tuberculosis treatment | 101 (74.8%) | 35 (81.4%) | 66 (71.7%) | 0.229 |
| Diabetes mellitus | 17 (12.6%) | 4 (9.3%) | 13 (14.1%) | 0.431 |
| Underlying disease | ||||
| Chronic obstructive lung disease | 35 (25.9%) | 16 (37.2%) | 19 (20.7%) | 0.041 |
| Malignancy | 33 (24.4%) | 11 (25.6%) | 22 (23.9%) | 0.834 |
| Chronic liver disease | 9 (6.7%) | 2 (4.7%) | 7 (7.6%) | 0.521 |
| Etiology | 0.268 | |||
| Mycobacterium avium | 40 (29.6%) | 10 (23.3%) | 30 (32.6%) | |
| Mycobacterium intracellulare | 95 (70.4%) | 33 (76.7%) | 62 (67.4%) | |
| Positive AFB smear at treatment initiation | 105 (77.8%) | 30 (69.8%) | 75 (81.5%) | 0.126 |
| No. of involved lobes | 3.0 (2.0–4.0) | 3.0 (2.0–4.0) | 3.0 (3.0–4.0) | 0.415 |
| Median no. of cavities | 2.0 (1.0–3.0) | 1.0 (1.0–3.0) | 2.0 (1.0–3.0) | 0.815 |
| No. of cavities | 0.474 | |||
| <2 | 63 (46.7%) | 22 (51.2%) | 41 (44.6%) | |
| ≥2 | 72 (53.3%) | 21 (48.8%) | 51 (55.4%) | |
| Maximum size of cavity (cm) | 4.9 (3.9–6.1) | 4.8 (3.2–6.5) | 4.9 (4.1–6.1) | 0.638 |
| Size of cavities | 0.936 | |||
| <2 cm | 6 (4.4%) | 2 (4.7%) | 4 (4.3%) | |
| ≥2 cm | 129 (95.6%) | 41 (95.3%) | 88 (95.7%) | |
| Maximum thickness of cavity (mm) | 7.2 (5.4–9.5) | 7.9 (5.5–10.0) | 6.9 (5.2–9.5) | 0.595 |
| Thickness of cavities | 0.864 | |||
| <5 mm | 24 (17.8%) | 8 (18.6%) | 16 (17.4%) | |
| ≥5 mm | 111 (82.2%) | 35 (81.4%) | 76 (82.6%) |
Data are means ± standard deviations, medians (with interquartile ranges), or number (percent) of subjects with the characteristic.
Clinical characteristics and treatment outcomes of patients with cavitary MAC-PD receiving treatment for ≥1 year.
Table 3 presents the baseline characteristics and treatment outcomes for 223 patients who continued their initial treatment regimen (either oral drugs alone or oral drugs with an injectable agent) for ≥1 year, including 166 patients with C-NB-type MAC-PD and 57 patients with FC-type MAC-PD. Statistically significant differences were noted between the C-NB and FC groups in terms of several baseline characteristics: sex, body mass index, smoking history, tuberculosis history, underlying disease, and etiologic organisms. Additionally, patients with C-NB-type MAC-PD had less severe disease overall, which was evidenced by proportionately less smear positivity and smaller-sized or thin-walled cavities.
TABLE 3.
Clinical characteristics and treatment outcome of 223 patients with cavitary MAC-PD who received treatment with oral medication with or without aminoglycoside for ≥1 year according to radiologic subtype
| Characteristic | Totala (n = 223) | C-NB typea (n = 166) | FC typea (n = 57) | P value |
|---|---|---|---|---|
| Age (yrs) | 61.4 ± 10.4 | 60.6 ± 10.3 | 63.7 ± 10.5 | 0.050 |
| Sex, female | 137 (61.4%) | 123 (74.1%) | 14 (24.6%) | <0.001 |
| Body mass index at initiation of treatment (kg/m2) | 20.2 ± 2.6 | 20.4 ± 2.5 | 19.5 ± 2.9 | 0.029 |
| Current or past smoker | 64 (28.7%) | 30 (18.1%) | 34 (59.6%) | <0.001 |
| History of tuberculosis treatment | 109 (48.9%) | 67 (40.4%) | 42 (73.7%) | <0.001 |
| Diabetes mellitus | 10 (4.5%) | 3 (1.8%) | 7 (12.3%) | 0.001 |
| Underlying disease | ||||
| Malignancy | 41 (18.4%) | 28 (16.9%) | 13 (22.8%) | 0.318 |
| Chronic obstructive lung disease | 25 (11.2%) | 9 (5.4%) | 16 (28.1%) | <0.001 |
| Chronic liver disease | 17 (7.6%) | 12 (7.2%) | 5 (8.8%) | 0.705 |
| Etiology | <0.001 | |||
| Mycobacterium avium | 103 (46.2%) | 88 (53.0%) | 15 (26.3%) | |
| Mycobacterium intracellulare | 120 (53.8%) | 78 (47.0%) | 42 (73.7%) | |
| Positive AFB smear at treatment initiation | 118 (52.9%) | 75 (45.2%) | 43 (75.4%) | <0.001 |
| No. of involved lobes | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 3.0 (2.0–4.0) | <0.001 |
| Median no. of cavities | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–3.0) | 0.152 |
| No. of cavities | 0.308 | |||
| <2 | 134 (60.1%) | 103 (62.0%) | 31 (54.4%) | |
| ≥2 | 89 (39.9%) | 63 (38.0%) | 26 (45.6%) | |
| Maximum size of cavity (cm) | 1.9 (1.4–3.7) | 1.7 (1.2–2.3) | 4.6 (3.7–5.3) | <0.001 |
| Size of cavities | <0.001 | |||
| <2 cm | 116 (52.0%) | 113 (68.1%) | 3 (5.3%) | |
| ≥2 cm | 107 (48.0%) | 53 (31.9%) | 54 (94.7%) | |
| Maximum thickness of cavity (mm) | 4.5 (3.0–6.7) | 3.9 (2.7–5.4) | 8.3 (5.2–10.1) | <0.001 |
| Thickness of cavities | <0.001 | |||
| <5 mm | 120 (53.8%) | 113 (68.1%) | 7 (12.3%) | |
| ≥5 mm | 103 (46.2%) | 53 (31.9%) | 50 (87.7%) | |
| Treatment regimen | 0.833 | |||
| Oral medications alone | 69 (30.9%) | 52 (31.3%) | 17 (29.8%) | |
| Oral medications and injectable aminoglycoside | 154 (69.1%) | 114 (68.7%) | 40 (70.2%) | |
| Total treatment duration (mos) | 15.0 (13.7–17.0) | 15.0 (13.7–16.9) | 15.0 (13.7–17.4) | 0.901 |
| Culture conversion at 12 mos | 172 (77.1%) | 139 (83.7%) | 33 (57.9%) | <0.001 |
| Culture conversion at end of treatment | 175 (78.5%) | 142 (85.5%)b | 33 (57.9%)c | <0.001 |
| Follow-up duration after achievement of culture conversion (yrs) (n = 175) | 3.4 (1.1–6.5) | 3.5 (1.1–6.8) | 3.0 (1.2–5.2) | 0.299 |
| Recurrence rate: | ||||
| At 6 mos after end of treatment (n = 145) | 12/145 (8.3%) | 10/118 (8.5%) | 2/27 (7.4%) | >0.99 |
| At 12 mos after end of treatment (n = 133) | 18/133 (13.5%) | 16/108 (14.8%) | 2/25 (8.0%) | 0.524 |
| At 2 yrs after end of treatment (n = 108) | 21/108 (19.4%) | 19/87 (21.8%) | 2/21 (9.5%) | 0.335 |
| At 3 yrs after end of treatment (n = 94) | 25/94 (26.6%) | 23/77 (29.9%) | 2/17 (11.8%) | 0.223 |
Data are means ± standard deviations, medians (with interquartile ranges), or number (percent) of subjects with the characteristic.
Four patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, seven patients achieved culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
Three patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, three patients achieved culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
Among 223 patients, the overall rates of culture conversion at 12 months and at the end of treatment were higher in patients with the C-NB type than those with the FC type, whereas the two groups had similar recurrence rates during the follow-up period after the end of treatment.
Clinical characteristics and treatment outcomes of patients with cavitary MAC-PD receiving GBT for ≥1 year.
Next, the characteristics and treatment outcomes of 154 patients with cavitary disease who received GBT (three oral antibiotics and an injectable aminoglycoside) according to the radiological types were compared (Table 4). There were 114 patients with C-NB-type MAC-PD and 40 patients with FC-type MAC-PD. The C-NB group had a milder form of disease with regard to several characteristics, such as acid-fast bacillus (AFB) smear positivity and the size and thickness of cavities.
TABLE 4.
Clinical characteristics and treatment outcomes of 154 patients with cavitary MAC-PD who received the three-drug oral antibiotic regimen with an injectable aminoglycoside for ≥1 year, according to radiologic subtype
| Characteristic | Totala (n = 154) | C-NB typea (n = 114) | FC typea (n = 40) | P value |
|---|---|---|---|---|
| Age (yrs) | 60.3 ± 10.2 | 59.6 ± 10.0 | 62.3 ± 10.7 | 0.161 |
| Sex, female | 99 (64.3%) | 88 (77.2%) | 11 (27.5%) | <0.001 |
| Body mass index at initiation of treatment (kg/m2) | 20.2 ± 2.5 | 20.3 ± 2.3 | 19.9 ± 2.9 | 0.389 |
| Current or past smoker | 41 (26.6%) | 19 (16.7%) | 22 (55.0%) | <0.001 |
| History of tuberculosis treatment | 76 (49.4%) | 48 (42.1%) | 28 (70.0%) | 0.002 |
| Diabetes mellitus | 8 (5.2%) | 2 (1.8%) | 6 (15.0%) | 0.001 |
| Underlying disease | ||||
| Malignancy | 29 (18.8%) | 20 (17.5%) | 9 (22.5%) | 0.490 |
| Chronic liver disease | 13 (8.4%) | 8 (7.0%) | 5 (12.5%) | 0.283 |
| Chronic obstructive lung disease | 10 (6.5%) | 2 (1.8%) | 8 (20.0%) | <0.001 |
| Etiology | 0.004 | |||
| Mycobacterium avium | 80 (51.9%) | 67 (58.8%) | 13 (32.5%) | |
| Mycobacterium intracellulare | 74 (48.1%) | 47 (41.2%) | 27 (67.5%) | |
| Positive AFB smear at treatment initiation | 91 (59.1%) | 58 (50.9%) | 33 (82.5%) | <0.001 |
| No. of involved lobes | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 3.0 (2.0–4.0) | <0.001 |
| Median no. of cavities | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–3.0) | 0.313 |
| No. of cavities | 0.375 | |||
| <2 | 90 (58.4%) | 69 (60.5%) | 21 (52.5%) | |
| ≥2 | 64 (41.6%) | 45 (39.5%) | 19 (47.5%) | |
| Maximum size of cavity (cm) | 2.0 (1.5–3.9) | 1.9 (1.4–2.5) | 4.7 (3.8–5.4) | <0.001 |
| Size of cavities | <0.001 | |||
| <2 cm | 73 (47.4%) | 70 (61.4%) | 3 (7.5%) | |
| ≥2 cm | 81 (52.6%) | 44 (38.6%) | 37 (92.5%) | |
| Maximum thickness of cavity (mm) | 4.6 (3.4–6.5) | 4.1 (3.1–5.4) | 7.8 (5.2–10.0) | <0.001 |
| Thickness of cavities | <0.001 | |||
| <5 mm | 81 (52.6%) | 76 (66.7%) | 5 (12.5%) | |
| ≥5 mm | 73 (47.4%) | 38 (33.3%) | 35 (87.5%) | |
| Total treatment duration (mos) | 15.1 (13.6–17.2) | 14.9 (13.6–16.9) | 15.3 (14.1–17.6) | 0.349 |
| Duration of injectable aminoglycosides (wks) | 17.1 (14.0–23.6) | 17.0 (13.6–22.0) | 19.7 (15.9–29.1) | 0.016 |
| Culture conversion at 12 mos | 116 (75.3%) | 92 (80.7%) | 24 (60.0%) | 0.009 |
| Culture conversion at end of treatment | 119 (77.3%) | 95 (83.3%)b | 24 (60.0%)c | 0.002 |
| Follow-up duration after the achievement of culture conversion (yrs) (n = 119) | 3.4 (1.4–6.2) | 3.5 (1.5–6.3) | 2.8 (0.5–5.3) | 0.192 |
| Recurrence rate: | ||||
| At 6 mos after end of treatment (n = 102) | 7/102 (6.9%) | 6/84 (7.1%) | 1/18 (5.6%) | >0.99 |
| At 12 mos after end of treatment (n = 95) | 12/95 (12.6%) | 11/79 (13.9%) | 1/16 (6.3%) | 0.684 |
| At 2 yrs after end of treatment (n = 76) | 16/76 (21.1%) | 14/62 (22.6%) | 2/14 (14.3%) | 0.721 |
| At 3 yrs after end of treatment (n = 65) | 19/65 (29.2%) | 17/54 (31.5%) | 2/11 (18.2%) | 0.486 |
Data are means ± standard deviations, medians (with interquartile ranges), or number (percent) of subjects with the characteristic.
Two patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, five patients achieved culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
Three patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, three patients achieved culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
The median duration of treatment with an injectable aminoglycoside for the 114 patients with C-NB-type MAC-PD was 17.0 weeks (interquartile range [IQR], 13.6 to 22.0), which was significantly shorter than that for the 40 patients with FC-type MAC-PD (19.7 weeks; IQR 15.9 to 29.1) (P = 0.016). Among the patients with C-NB-type MAC-PD, 8.8% (10/114) discontinued aminoglycoside treatment due to the development of adverse events, including hearing impairment (n = 5), tinnitus (n = 3), azotemia (n = 1), and injection site pain (n = 1). Of the 40 patients with FC-type MAC-PD, treatment with an injectable aminoglycoside was interrupted due to newly occurring adverse events, including hearing impairment (n = 2), azotemia (n = 1), and injection site pain (n = 1), in 4 (10.0%) patients.
The overall culture conversion rates at 12 months and at the end of treatment for the 154 patients were 75.3% (116/154) and 77.4% (119/154), respectively. Of the 114 patients with C-NB-type MAC-PD, the number of patients who achieved culture conversion at 12 months was 92 (80.7%), which was significantly higher than the number of patients with FC-type MAC-PD who achieved culture conversion at 12 months (60.0% [24/40]; P = 0.009) (Table 4). Additionally, the rates of culture conversion achievement at the end of treatment were also significantly different between the two groups (83.3% versus 60.0%; P = 0.002) (Table 4). Of the patients who achieved culture conversion at the end of treatment, the recurrence rates were similar between the patients with the C-NB type and those with the FC type during the median follow-up duration of 3.4 years (IQR, 1.4 to 6.2).
Clinical characteristics and treatment outcomes of patients with C-NB-type MAC-PD according to treatment regimen.
Next, the baseline characteristics and treatment outcomes of the 166 patients with C-NB-type MAC-PD were compared according to treatment regimen: the three-drug oral medication alone versus oral antibiotics with an injectable agent (Table 5). Several statistically significant differences in baseline characteristics were observed between the two groups, including chronic obstructive lung disease as an underlying disease, sputum AFB smear positivity, etiology, and the size and thickness of cavity.
TABLE 5.
Clinical characteristics and treatment outcomes of 166 patients with C-NB-type MAC-PD who received treatment for ≥1 year, according to treatment regimen
| Characteristic | Totala (n = 166) | Oral medication alonea (n = 52) | Oral medication and injectable aminoglycosidea (n = 114) | P value |
|---|---|---|---|---|
| Age (yrs) | 60.6 ± 10.3 | 62.7 ± 10.8 | 59.6 ± 10.0 | 0.081 |
| Sex, female | 123 (74.1%) | 35 (67.3%) | 88 (77.2%) | 0.178 |
| Body mass index at initiation of treatment (kg/m2) | 20.4 ± 2.5 | 20.7 ± 2.8 | 20.3 ± 2.3 | 0.335 |
| Current or past smoker | 30 (18.1%) | 11 (21.2%) | 19 (16.7%) | 0.486 |
| History of tuberculosis treatment | 67 (40.4%) | 19 (36.5%) | 48 (42.1%) | 0.498 |
| Diabetes mellitus | 3 (1.8%) | 1 (1.9%) | 2 (1.8%) | 0.940 |
| Underlying disease | ||||
| Malignancy | 28 (16.9%) | 8 (15.4%) | 20 (17.5%) | 0.730 |
| Chronic liver disease | 12 (7.2%) | 4 (7.7%) | 8 (7.0%) | 0.876 |
| Chronic obstructive lung disease | 9 (5.4%) | 7 (13.5%) | 2 (1.8%) | 0.002 |
| Etiology | 0.028 | |||
| Mycobacterium avium | 88 (53.0%) | 21 (40.4%) | 67 (58.8%) | |
| Mycobacterium intracellulare | 78 (47.0%) | 31 (59.6%) | 47 (41.2%) | |
| Positive AFB smear at treatment initiation | 75 (45.2%) | 17 (32.7%) | 58 (50.9%) | 0.029 |
| No. of involved lobes | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 0.173 |
| Median no. of cavities | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) | 0.346 |
| No. of cavities | 0.550 | |||
| <2 | 103 (62.0%) | 34 (65.4%) | 69 (60.5%) | |
| ≥2 | 63 (38.0%) | 18 (34.6%) | 45 (39.5%) | |
| Maximum size of cavity (cm) | 1.7 (1.2–2.3) | 1.3 (0.9–1.9) | 1.9 (1.4–2.5) | <0.001 |
| Size of cavities | 0.006 | |||
| <2 cm | 113 (68.1%) | 43 (82.7%) | 70 (61.4%) | |
| ≥2 cm | 53 (31.9%) | 9 (17.3%) | 44 (38.6%) | |
| Maximum thickness of cavity (mm) | 3.9 (2.7–5.4) | 3.2 (2.3–5.3) | 4.1 (3.1–5.4) | 0.027 |
| Thickness of cavities | 0.565 | |||
| <5 mm | 113 (68.1%) | 37 (71.2%) | 76 (66.7%) | |
| ≥5 mm | 53 (31.9%) | 15 (28.8%) | 38 (33.3%) | |
| Total treatment duration (mos) | 15.0 (13.7–16.9) | 15.1 (13.8–16.4) | 14.9 (13.6–16.9) | 0.958 |
| Culture conversion at 12 mos | 139 (83.7%) | 47 (90.4%) | 92 (80.7%) | 0.117 |
| Culture conversion at end of treatment | 142 (85.5%) | 47 (90.4%)b | 95 (83.3%)c | 0.231 |
| Follow-up duration after achievement of culture conversion (yrs) (n = 142) | 3.5 (1.1–6.8) | 3.4 (0.5–8.4) | 3.5 (1.5–6.3) | 0.719 |
| Recurrence rate: | ||||
| At 6 mos after end of treatment (n = 118) | 10/118 (8.5%) | 4/34 (11.8%) | 6/84 (7.1%) | 0.471 |
| At 12 mos after end of treatment (n = 108) | 16/108 (14.8%) | 5/29 (17.2%) | 11/79 (13.9%) | 0.667 |
| At 2 yrs after end of treatment (n = 87) | 19/87 (21.8%) | 5/25 (20.0%) | 14/62 (22.6%) | 0.792 |
| At 3 yrs after end of treatment (n = 77) | 23/77 (29.9%) | 6/23 (26.1%) | 17/54 (31.5%) | 0.636 |
Data are means ± standard deviations, medians (with interquartile ranges), or number (percent) of subjects with the characteristic.
Two patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, two patients achieved culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
Two patients failed to achieve culture conversion at the end of treatment, even though they did so at 12 months after treatment initiation. In contrast, five patients achieved a culture conversion at the end of treatment, although they did not at 12 months after treatment initiation.
Overall, 83.7% (139/166) of patients with the C-NB type achieved culture conversion at 12 months. The 12-month culture conversion rates were similar between patients who received oral medication alone and those treated with the inclusion of an injectable agent; the 12-month culture conversion rates were 90.4% and 80.7%, respectively (P = 0.117) (Table 5). Additionally, there were no significant differences in the culture conversion rates at the end of treatment according to treatment modality (90.4% versus 83.3%, P = 0.231) (Table 5).
After the treatment completion for the patients who achieved culture conversion at the end of treatment, the follow-up period was a median of 3.5 years (IQR, 1.1 to 6.8). During this period, similar rates of recurrence were noted between the two groups.
DISCUSSION
In 2017, Koh et al. first reported the presence of the clinical phenotype of C-NB type among patients with MAC-PD by showing the similar treatment outcomes between patients with the FC or C-NB types who underwent antibiotic treatment for ≥12 months (2). However, since the publication of that study, few others have investigated the clinical characteristics, treatment outcomes, and optimal regimens of C-NB-type MAC-PD, although as many as 20% to 25% of patients have the cavitary form among those with NB type MAC-PD (2, 7, 8). In the present study, the clinical characteristics and treatment outcomes of patients with C-NB-type MAC-PD were compared with those with FC-type MAC-PD, and treatment responses were assessed based on the treatment regimen through a retrospective analysis involving patients with cavitary MAC-PD treated at a tertiary referral center in South Korea. The key findings were as follows. (i) Among the patients with cavitary MAC-PD who received daily three-drug oral antibiotics with an injectable agent, as the guidelines recommended, a distinct difference was noted in the achievement of culture conversion according to the radiological subtype. The culture conversion rates at 12 months and at the end of treatment were higher for the C-NB type than for the FC type. (ii) In patients with the C-NB type, the addition of an injectable aminoglycoside to the regimen did not show any additional effects in terms of culture conversion achievement or recurrence compared with the treatment entailing oral antibiotics alone.
In the present study, radiologically, the C-NB type had thinner cavity walls or a smaller maximum cavity diameter than the FC type. Considering that one of the reasons for the poor treatment outcomes of patients with cavitary MAC-PD is the limitation of drug supply and penetration into the cavitary lesion (9), this disparity in the characteristics of the cavities would result in differences in treatment outcomes. Moreover, as shown in Table 3, compared with those with C-NB-type MAC-PD, patients with the FC-type MAC-PD had more distinct clinical characteristics known to be associated with worse treatment outcomes or a higher mortality rate, such as older age (10, 11), male gender (2, 12), low body mass index (7, 12), chronic respiratory disease (13), Mycobacterium intracellulare as the infectious organism (11, 14), and AFB smear positivity (15). Given these distinct differences in the radiological and clinical features between the C-NB and FC types, the higher rate of achievement of culture conversion in the C-NB type in this study could be considered a plausible outcome. Our findings are consistent with those of a previous study that reported a significantly lower mortality rate in patients with C-NB-type MAC-PD than in those with FC-type MAC-PD (11).
Another important finding of the present study was that, in the patients with C-NB-type MAC-PD, treatment with daily oral three-drug antibiotics alone could lead to similar rates of culture conversion achievement compared with treatment with oral three-drug antibiotics and an injectable aminoglycoside. Additionally, there were no significant differences in recurrence rates after the achievement of culture conversion according to the treatment modality. This was in contrast with the current guidelines, which recommend treating patients with C-NB-type MAC-PD with the same treatment modality as that used for treating those with FC-type MAC-PD (3, 4). Considering the frequent development of adverse events after the use of an injectable agent (16), the result that a high rate of culture conversion can be achieved with oral drugs alone has notable clinical implications. However, it should be emphasized that we do not assert that all patients with C-NB-type MAC-PD can be treated with oral antibiotics alone. In this study, among the patients with C-NB-type MAC-PD, those who received oral medications without an injectable agent had less severe disease in terms of sputum AFB smear positivity or cavity size and thickness and tended to be older than those treated with the inclusion of an injectable agent (Table 5). Therefore, the treatment option of three daily oral antibiotics excluding an injectable aminoglycoside could be considered for patients with a milder form of the C-NB type, such as the form with small-sized cavities (17), and particularly for elderly patients who cannot tolerate injectable drugs.
This study had several limitations. First, this study was conducted at a single referral center; therefore, the number of enrolled patients with cavitary type was limited. Additionally, as the study had a retrospective design, treatment allocation of patients to treatment groups was not randomized. The decision concerning treatment regimen selection and aminoglycoside inclusion was made by the attending physician without following a pre-established protocol, which may possibly have led to a referral bias. As the patients with the C-NB type whose treatment was initiated with oral antibiotics alone had an overall milder disease severity that manifested as less smear positivity and smaller cavity size, it was likely that the attending physician tended to not prescribe an injectable aminoglycoside-containing regimen to those with a less severe form of C-NB. Finally, because we only included patients who had been treated with GBT for ≥1 year, a considerable number of patients were excluded because they had not completed ≥1 year of treatment for various reasons, such as adverse events or hospital transfer out. This inclusion criteria was used because other studies analyzing the treatment outcomes of patients with cavitary MAC-PD also only included patients who completed ≥1 year of treatment (2, 8, 18), and this enrollment process was thought to be the most suitable method to assess the effects of the treatment regimen.
In conclusion, we found that among the patients with cavitary MAC-PD who received GBT for ≥1 year, the culture conversion rates at 12 months and at the end of treatment were significantly higher for patients with C-NB-type MAC-PD than for those with FC-type MAC-PD. Moreover, patients with C-NB-type MAC-PD receiving treatment with three-drug oral antibiotics alone showed similar rates of culture conversion and recurrence compared to those receiving treatment with oral medication and an injectable aminoglycoside. These results suggest that there may be a subset of patients with C-NB-type MAC-PD who could be treated with oral three-drug antibiotics alone. Future prospective randomized trials should investigate this further to determine whether there is an objectively identifiable subset of patients with C-NB-type MAC-PD who can be treated without the use of an injectable aminoglycoside.
MATERIALS AND METHODS
Study participants.
Study patients were retrospectively selected at Asan Medical Center, a 2,700-bed referral hospital in Seoul, South Korea. From October 2002 to December 2019, 435 patients with cavitary MAC-PD (FC and C-NB types) who had received treatment were identified. Among them, after excluding patients (i) who did not receive the standard three-drug antibiotics, comprised of macrolide, ethambutol, and rifampin, and (ii) whose MAC isolates were macrolide resistant, 411 patients with macrolide-sensitive cavitary MAC-PD remained. Next, we selected patients who continued using daily standard three-drug oral medication with or without an injectable aminoglycoside for ≥1 year and excluded those (i) whose treatment duration was <1 year, (ii) who underwent lung resection surgery within 1 year after treatment initiation, and (iii) who discontinued ethambutol and/or rifampin during the treatment period due to adverse events; the treatment outcomes of these patients were significantly worse than outcomes for those who continued GBT (19, 20) (Fig. 1 and 2). All patients in the final analysis received a macrolide or azalide (i.e., clarithromycin or azithromycin) throughout their treatment. The medical records of the remaining patients were retrospectively analyzed in June 2021. The treatment outcomes were compared according to the radiological type and whether the patients received oral medication alone or oral medication with an injectable agent.
The study protocol was approved by the Institutional Review Board (IRB) of the Asan Medical Center (IRB number 2021-0912). The IRB waived the requirement for informed consent because of the retrospective nature of the study.
Radiological evaluation.
Radiographic abnormalities on chest computed tomography at the time of treatment initiation were categorized into FC and C-NB. Cases with the presence of an upper lobe predominant cavitary lesion with surrounding pleural thickening and fibrotic changes in the upper lobe were determined to be of the FC type (2, 21). Additionally, the C-NB type were those cases having bronchiectatic changes with branching centrilobular nodules in the lungs bilaterally preferentially involving the lingula segment and right middle lobe combined with the presence of a cavitary lesion (2, 4, 21). The typical presentations of FC and C-NB types are shown in Fig. S1 in the supplemental material. We measured the number and sizes of the cavities and the thickness of the thickest cavity wall. The largest cavity in any lobe of the lung was evaluated by measuring the size and thickness of the cavity. Lingula division was regarded as a separate lobe, which resulted in a total of six lung lobes for analysis (22). All the radiographic abnormalities were evaluated by two pulmonologists and one radiologist.
Microbiological examination.
Expectorated sputum or samples obtained via bronchoscopy were cultured in both solid (Ogawa medium; Korean Institute of Tuberculosis, South Korea) and liquid (Bactec 960 Mycobacterial Growth Indicator Tube; Becton, Dickinson, Sparks, MD, USA) media. AFB smears were made using Ziehl-Neelsen staining. Positive liquid cultures and colonies on solid medium were subjected to PCR assay using Seeplex tuberculosis detection (Seegen, Seoul, Korea) to differentiate M. tuberculosis complex from nontuberculous mycobacterium (NTM). NTM species were identified using reverse-blot hybridization of the rpoB gene (GenoType Mycobacterium CM/AS; HAIN Life Science, Germany).
Treatment outcome analysis.
The patients were requested to submit expectorated sputum samples with at least 1-month interval after treatment initiation, until the sputum culture conversion results were negative. After the achievement of culture negativity, sputum samples were collected at intervals of 2–3 months until treatment completion. For the patients who could not spontaneously expectorate sputum, induced sputum was collected. The induced sputum was obtained by trained health care workers in a procedure room by the administration of 3% hypertonic saline using a nebulizer over a period of 20 min. If the patient was unable to expectorate sputum even after this procedure, the sputum was considered to have converted to negative (23).
Treatment outcomes were determined as sputum culture conversion, which was defined as at least three consecutive negative sputum cultures from respiratory samples, collected at least 4 weeks apart, during antimycobacterial treatment according to the Nontuberculous Mycobacterium Network European Trials Group consensus statement (24). The time of conversion was defined as the date of obtaining the first negative culture. In light of the fact that previous studies considered cases of persistently positive cultures after >12 months of antibiotic treatment as treatment failures (25, 26), we first assessed whether the culture conversion was achieved at 12 months after treatment with GBT (2, 8, 27–29). Then, the achievement of a culture conversion at the end of treatment was evaluated. Recurrence of MAC-PD was defined as the re-emergence of at least two positive cultures with the causative MAC organism from respiratory samples after treatment completion among those who achieved a culture conversion at the end of treatment (24).
Statistical analysis.
All data are presented as the mean ± standard deviation or median with IQRs for continuous variables and as numbers (%) for categorical variables. We compared the data using Student's t test or Mann–Whitney U-test for continuous variables and chi-square or Fisher’s exact test for categorical variables. All tests of significance were two-sided; P-values of <0.05 indicated statistical significance. We performed all analyses using SPSS statistical software (version 24.0; IBM Corp., Armonk, NY, USA).
ACKNOWLEDGMENTS
This work was supported by a National Research Foundation of Korea grant funded by the Korean government (Ministry of Science and ICT number 2022R1A2C1002847) for Kyung-Wook Jo.
We have no conflicts of interest to declare.
Footnotes
Supplemental material is available online only.
REFERENCES
- 1.Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ, Winthrop K, ATS Mycobacterial Diseases Subcommittee, American Thoracic Society, Infectious Disease Society of America . 2007. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 175:367–416. doi: 10.1164/rccm.200604-571ST. [DOI] [PubMed] [Google Scholar]
- 2.Koh W-J, Moon SM, Kim S-Y, Woo M-A, Kim S, Jhun BW, Park HY, Jeon K, Huh HJ, Ki C-S, Lee NY, Chung MJ, Lee KS, Shin SJ, Daley CL, Kim H, Kwon OJ. 2017. Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype. Eur Respir J 50:1602503. doi: 10.1183/13993003.02503-2016. [DOI] [PubMed] [Google Scholar]
- 3.Kwon Y-S, Koh W-J, Daley CL. 2019. Treatment of Mycobacterium avium complex pulmonary disease. Tuberc Respir Dis (Seoul) 82:15–26. doi: 10.4046/trd.2018.0060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Pan SW, Shu CC, Feng JY, Su WJ. 2020. Treatment for Mycobacterium avium complex lung disease. J Formos Med Assoc 119(Suppl 1):S67–S75. doi: 10.1016/j.jfma.2020.05.006. [DOI] [PubMed] [Google Scholar]
- 5.Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ, Andrejak C, Böttger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. 2020. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J 56:2000535. doi: 10.1183/13993003.00535-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Griffith DE, Aksamit TR. 2021. Managing Mycobacterium avium complex lung disease with a little help from my friend. Chest 159:1372–1381. doi: 10.1016/j.chest.2020.10.031. [DOI] [PubMed] [Google Scholar]
- 7.Sadamatsu H, Takahashi K, Tashiro H, Kusaba K, Haraguchi T, Kurihara Y, Komiya N, Nakashima C, Nakamura T, Kimura S, Sueoka-Aragane N. 2021. A low body mass index is associated with unsuccessful treatment in patients with Mycobacterium avium complex pulmonary disease. J Clin Med 10:1576. doi: 10.3390/jcm10081576. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kwon YS, Han M, Kwon BS, Kim O-H, Lee H-Y, Shim TS, Chong YP, Jo K-W. 2020. Discontinuation rates attributed to adverse events and treatment outcomes between clarithromycin and azithromycin in Mycobacterium avium complex lung disease: a propensity score analysis. J Glob Antimicrob Resist 22:106–112. doi: 10.1016/j.jgar.2020.01.004. [DOI] [PubMed] [Google Scholar]
- 9.Dartois V. 2014. The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nat Rev Microbiol 12:159–167. doi: 10.1038/nrmicro3200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hwang JA, Kim S, Jo KW, Shim TS. 2017. Natural history of Mycobacterium avium complex lung disease in untreated patients with stable course. Eur Respir J 49:1600537. doi: 10.1183/13993003.00537-2016. [DOI] [PubMed] [Google Scholar]
- 11.Jhun BW, Moon SM, Jeon K, Kwon OJ, Yoo H, Carriere KC, Huh HJ, Lee NY, Shin SJ, Daley CL, Koh W-J. 2020. Prognostic factors associated with long-term mortality in 1445 patients with nontuberculous mycobacterial pulmonary disease: a 15-year follow-up study. Eur Respir J 55:1900798. doi: 10.1183/13993003.00798-2019. [DOI] [PubMed] [Google Scholar]
- 12.Kim H-J, Kwak N, Hong H, Kang N, Im Y, Jhun BW, Yim J-J. 2021. BACES score for predicting mortality in nontuberculous mycobacterial pulmonary disease. Am J Respir Crit Care Med 203:230–236. doi: 10.1164/rccm.202004-1418OC. [DOI] [PubMed] [Google Scholar]
- 13.Hayashi M, Takayanagi N, Kanauchi T, Miyahara Y, Yanagisawa T, Sugita Y. 2012. Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 185:575–583. doi: 10.1164/rccm.201107-1203OC. [DOI] [PubMed] [Google Scholar]
- 14.Koh W-J, Jeong B-H, Jeon K, Lee NY, Lee KS, Woo SY, Shin SJ, Kwon OJ. 2012. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M avium complex lung disease. Chest 142:1482–1488. doi: 10.1378/chest.12-0494. [DOI] [PubMed] [Google Scholar]
- 15.Sim YS, Park HY, Jeon K, Suh GY, Kwon OJ, Koh WJ. 2010. Standardized combination antibiotic treatment of Mycobacterium avium complex lung disease. Yonsei Med J 51:888–894. doi: 10.3349/ymj.2010.51.6.888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, Leitch A, Loebinger MR, Milburn HJ, Nightingale M, Ormerod P, Shingadia D, Smith D, Whitehead N, Wilson R, Floto RA. 2017. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax 72:ii1–ii64. doi: 10.1136/thoraxjnl-2017-210927. [DOI] [PubMed] [Google Scholar]
- 17.Kang H-R, Hwang EJ, Kim SA, Choi SM, Lee J, Lee C-H, Yim J-J, Kwak N. 2021. Clinical implications of size of cavities in patients with nontuberculous mycobacterial pulmonary disease: a single-center cohort study. Open Forum Infect Dis 8:ofab087. doi: 10.1093/ofid/ofab087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kim O-H, Kwon BS, Han M, Koh Y, Kim W-S, Song J-W, Oh Y-M, Lee S-D, Lee SW, Lee J-S, Lim C-M, Choi C-M, Huh J-W, Hong S-B, Shim TS, Jo K-W. 2019. Association between duration of aminoglycoside treatment and outcome of cavitary Mycobacterium avium complex lung disease. Clin Infect Dis 68:1870–1876. doi: 10.1093/cid/ciy804. [DOI] [PubMed] [Google Scholar]
- 19.Kim H-J, Lee JS, Kwak N, Cho J, Lee C-H, Han SK, Yim J-J. 2019. Role of ethambutol and rifampicin in the treatment of Mycobacterium avium complex pulmonary disease. BMC Pulm Med 19:212. doi: 10.1186/s12890-019-0982-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kwon YS, Kwon BS, Kim OH, Park YE, Shim TS, Chong YP, Jo KW. 2020. Treatment outcomes after discontinuation of ethambutol due to adverse events in Mycobacterium avium complex lung disease. J Korean Med Sci 35:e59. doi: 10.3346/jkms.2020.35.e59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Pennington KM, Vu A, Challener D, Rivera CG, Shweta FNU, Zeuli JD, Temesgen Z. 2021. Approach to the diagnosis and treatment of non-tuberculous mycobacterial disease. J Clin Tuberc Other Mycobact Dis 24:100244. doi: 10.1016/j.jctube.2021.100244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Park YE, Chong YP, Kim Y-J, Kim O-H, Kwon BS, Shim TS, Jo K-W. 2020. Outcome of shorter treatment duration in non-cavitary nodular bronchiectatic Mycobacterium avium complex lung disease. J Thorac Dis 12:338–348. doi: 10.21037/jtd.2020.01.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Togo T, Atsumi J, Hiramatsu M, Shimoda K, Morimoto K, Uchimura K, Shiraishi Y. 2020. Residual destructive lesions and surgical outcome in Mycobacterium avium complex pulmonary disease. Ann Thorac Surg 110:1698–1705. doi: 10.1016/j.athoracsur.2020.04.034. [DOI] [PubMed] [Google Scholar]
- 24.van Ingen J, Aksamit T, Andrejak C, Böttger EC, Cambau E, Daley CL, Griffith DE, Guglielmetti L, Holland SM, Huitt GA, Koh W-J, Lange C, Leitman P, Marras TK, Morimoto K, Olivier KN, Santin M, Stout JE, Thomson R, Tortoli E, Wallace RJ, Winthrop KL, Wagner D. 2018. Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement. Eur Respir J 51:1800170. doi: 10.1183/13993003.00170-2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Jhun BW, Kim S-Y, Moon SM, Jeon K, Kwon OJ, Huh HJ, Ki C-S, Lee NY, Shin SJ, Daley CL, Koh W-J. 2018. Development of macrolide resistance and reinfection in refractory Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 198:1322–1330. doi: 10.1164/rccm.201802-0321OC. [DOI] [PubMed] [Google Scholar]
- 26.Philley JV, Wallace RJ, Benwill JL, Taskar V, Brown-Elliott BA, Thakkar F, Aksamit TR, Griffith DE. 2015. Preliminary results of bedaquiline as salvage therapy for patients with nontuberculous mycobacterial lung disease. Chest 148:499–506. doi: 10.1378/chest.14-2764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lee JH, Park YE, Chong YP, Shim TS, Jo KW. 2022. Efficacy of fluoroquinolones as substitutes for ethambutol or rifampin in the treatment of Mycobacterium avium complex pulmonary disease according to radiologic types. Antimicrob Agents Chemother 66:e01522-21. doi: 10.1128/AAC.01522-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Moon SM, Yoo IY, Huh HJ, Lee NY, Jhun BW. 2019. Intermittent treatment with azithromycin and ethambutol for noncavitary Mycobacterium avium complex pulmonary disease. Antimicrob Agents Chemother 64. doi: 10.1128/AAC.01787-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Wallace RJ, Brown-Elliott BA, McNulty S, Philley JV, Killingley J, Wilson RW, York DS, Shepherd S, Griffith DE, Jr.. 2014. Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease. Chest 146:276–282. doi: 10.1378/chest.13-2538. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
Fig. S1 and S2. Download aac.02261-21-s0001.pdf, PDF file, 0.9 MB (946.8KB, pdf)