Clinical Outcome with Standard Regimen plus Clofazimine or Moxifloxacin in Cavitary Mycobacterium avium Complex Pulmonary Disease

ABSTRACT

In this retrospective analysis including 173 patients in a tertiary referral center in South Korea, compared with the standard therapeutic regimen, clofazimine or moxifloxacin plus standard treatment regimen potentially did not induce a higher 1-year culture conversion rate in patients with Mycobacterium avium complex pulmonary disease who present with cavitary lesions (fibrocavitary or cavitary nodular bronchiectatic type).

INTRODUCTION

Patients with Mycobacterium avium complex (MAC)-pulmonary disease (PD) who present with cavitary lesions (fibrocavitary or cavitary nodular bronchiectatic type) have a poor treatment outcome, with only 60% to 80% achieving culture conversion with the recommended therapy (1, 2).

Clofazimine or broader-spectrum fluoroquinolone have been reported to have a therapeutic role in inducing culture conversion among patients with refractory MAC-PD, with persistent culture positivity after treatment initiation (3–6). However, no study has confirmed this inferred beneficial treatment outcome through the incorporation of the above-mentioned drugs in the initial treatment regimen. Therefore, we aimed to investigate whether an initial treatment regimen comprising standard therapy plus clofazimine or a fluoroquinolone would improve clinical outcomes in patients with cavitary MAC-PD.

In January 2022, medical records were examined and this analysis retrospectively enrolled patients treated at the Asan Medical Center in Seoul, Republic of Korea from 2001 to 2020. The study protocol was approved by the Institutional Review Board of the Asan Medical Center (No.: 2022-0241). The requirement for informed consent was waived because of the retrospective study design. Among the 341 patients with cavitary MAC-PD who received a macrolide- and injectable aminoglycoside-containing regimen at least once, those who were initially treated with either the standard (macrolide, ethambutol, and rifampin with injectable aminoglycoside) or intensified (clofazimine or fluoroquinolone plus standard) regimens for ≥1 year were identified (Fig. 1).

FIG 1.

Flowchart depicting participant selection and disposition in the study. MAC, Mycobacterium avium complex; PD, pulmonary disease; MIC, minimal inhibitory concentration; EMB, ethambutol; RIF, rifampin.

Eligibility screening identified 187 participants, comprising 14 and 173 patients who were treated with the intensified or standard regimen, respectively, for ≥1 year (Fig. 1). Both groups had similar clinical characteristics, except for a history of nontuberculous mycobacteria (NTM)-PD treatment, the number of involved lobes, and the treatment duration with injectable aminoglycoside (Table 1).

TABLE 1.

Clinical characteristics of 187 patients with cavitary Mycobacterium avium complex pulmonary disease according to the treatment regimen^a

Characteristics	Total (n = 187)	Intensified regimen (n = 14)	Standard regimen (n = 173)	P-valueb
Age (yrs)	60.6 ± 9.9	62.4 ± 8.2	60.4 ± 10.1	0.472
Age ≥65 yrs	63 (33.7%)	6 (42.9%)	57 (32.9%)	0.451
Sex, female	120 (64.2%)	7 (50.0%)	113 (65.3%)	0.250
Body mass index (kg/m2)	20.1 ± 2.5	19.9 ± 2.5	20.1 ± 2.5	0.758
Body mass index <18.5 kg/m2	46 (24.6%)	4 (28.6%)	42 (24.3%)	0.749
Current or past smoker	50 (26.7%)	4 (28.6%)	46 (26.6%)	>0.999
History of tuberculosis treatment	95 (50.8%)	10 (71.4%)	85 (49.1%)	0.164
History of NTM treatment	28 (15.0%)	13 (92.9%)	15 (8.7%)	<0.001
Comorbidity
Malignancy	29 (15.5%)	0 (0.0%)	29 (16.8%)	0.132
Chronic liver disease	15 (8.0%)	1 (7.1%)	14 (8.1%)	>0.999
Diabetes mellitus	12 (6.4%)	2 (14.3%)	10 (5.8%)	0.223
COPD	11 (5.9%)	0 (0.0%)	11 (6.4%)	>0.999
Radiologic type				>0.999
Fibrocavitary type	47 (25.1%)	3 (21.4%)	44 (25.4%)
Cavitary nodularbronchiectatic type	140 (74.9%)	11 (78.6%)	129 (74.6%)
Etiology				0.051
Mycobacterium avium	90 (48.1%)	3 (21.4%)	87 (50.3%)
Mycobacterium intracellulare	97 (51.9%)	11 (78.6%)	86 (49.7%)
Positive AFB smear at treatment initiation	112 (59.9%)	10 (71.4%)	102 (59.0%)	0.411
No. of involved lobes ≥4c	117 (62.6%)	13 (92.9%)	104 (60.1%)	0.019
Duration of administration of injectable agents (wks)	17.3 (14.0–25.1)	30.4 (21.4–56.6)	17.1 (13.9–23.6)	0.001
Culture conversion at 1 yr	136 (72.7%)	9 (64.3%)	127 (73.4%)	0.461

^aData are presented as mean ± standard deviation or frequencies (%) or median (interquartile range). nontuberculous mycobacteria, NTM; COPD, chronic obstructive pulmonary disease; AFB, acid-fast bacillus.

^bContinuous variables were compared using the Student's t test or Mann–Whitney test, whereas categorical variables were analyzed using the chi-square or Fisher’s exact test.

^cIn radiologic evaluation, the lingula was considered a separate lobe, and thus, a total of six lung lobes were counted in the analysis.

A history of NTM treatment was the most frequent reason for prescription of intensified regimen in the 14 patients. In all cases, moxifloxacin was the prescribed fluoroquinolone. The detailed composition of intensified regimen in 14 patients is as follows: standard regimen with clofazimine and moxifloxacin (n = 5), standard regimen with moxifloxacin (n = 5), and standard regimen with clofazimine (n = 4). Clofazimine and moxifloxacin were administered for a median duration of 65.1 (interquartile range [IQR], 60.6 to 67.3) and 64.9 (IQR, 49.1 to 66.9) weeks, respectively.

The overall 1-year culture conversion rate was 72.7% in 187 participants and was similar for the intensified and standard regimen study groups (64.3% versus 73.4%, respectively; P = 0.461, Table 1).

This is the first study to investigate whether the initial incorporation of clofazimine or moxifloxacin to the standard regimen could lead to a better treatment response in cavitary MAC-PD. We found that the intensified regimen may not achieve a higher 1-year culture conversion rate. Considering that clofazimine or moxifloxacin has distinct adverse events (7), our finding has clinical relevance for selecting a therapeutic regimen for patients with cavitary MAC-PD.

Current guidelines recommend that patients who were previously treated for NTM disease should be treated with a three-drug oral antibiotic regimen and an injectable aminoglycoside, regardless of the presence of cavitary lesions (8, 9). Therefore, as the treatment outcome of cavitary MAC-PD is poor even in treatment-naive cases, the attending physician should reasonably consider prescribing a more potent treatment regimen (standard regimen plus other potent drugs) for patients with cavitary disease and recurrence, which seems to be the main reason for prescribing the intensified regimen in 14 patients in the present study as 92.9% had recurrent infection. However, there is insufficient evidence to support the selection of a more potent treatment regimen for all cases of recurrence, as a MIC of macrolide in the recurrent-infection cases increased only in the isolates of patients with relapse but not in those with reinfection (10). Although neither relapse nor reinfection was distinguished as the cause of recurrence in 14 patients, a substantial proportion of the recurrence may be attributable to reinfection as the median interval between the completion of the previous NTM treatment and the subsequent treatment initiation of the 14 patients was 3.6 (IQR, 2.0 to 5.3) years. In previous studies, the median interval between treatment completion and recurrence was approximately 6 months or 1 to 2 years in cases of relapse or reinfection, respectively (2, 10).

Nevertheless, the initial combination of clofazimine or moxifloxacin with the standard regimen did not show a distinct therapeutic effect in our participants, in contrast to the efficacy in refractory cases (3–6). The most plausible explanation of this disparity is that we only included patients with cavitary lesion, whereas the earlier studies also enrolled patients with noncavitary MAC-PD. The presence of cavitary lesions could limit the supply and penetration of the drug and, accordingly, compared with the serum concentrations, moxifloxacin or clofazimine concentrations steeply decreased in the wall or inside the cavitary lesion (11).

In contrast to our findings, Zweijpfenning et al. recently reported a tendency toward a higher rate of cure and faster time to culture conversion with the addition of amikacin and clofazimine to the three-drug (macrolide, ethambutol, and rifampin) oral antibiotic therapy, compared with the use of three-drug oral therapy alone, in patients with fibrocavitary MAC-PD (12). However, considering that the “standard” three-drug antibiotics include an injectable aminoglycoside protocol for the treatment of fibrocavitary MAC-PD (8, 9), their results should have limited interpretability, as their control group did not receive an injectable aminoglycoside.

This study had some limitations; first, this study was retrospectively conducted at a single center with a small number of patients. Therefore, future prospective trials with a large number of participants are needed to confirm our findings. Second, the treatment regimen was determined by the attending physician without any preestablished protocol. Third, although previous studies implied that culture conversion with clofazimine use was related to a lower MIC, we did not measure the MIC of clofazimine (5).

In conclusion, we showed that the addition of clofazimine or moxifloxacin to the initial standard therapeutic regimen may not improve the therapeutic outcomes in patients with cavitary MAC-PD.