Abstract
Rationale: Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation.
Objectives: To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease.
Methods: We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease.
Measurements and Main Results: The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28).
Conclusions: Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.
Mycobacterium abscessus is resistant to many antibiotics and is difficult to treat. Mycobacterium massiliense has been recognized as a separate species from M. abscessus; however, little is known regarding the clinical impact of this differentiation.
Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.
M. abscessus is resistant in vitro to many antibiotics and thus is difficult to treat. Isolates are usually susceptible in vitro to some parenteral agents (amikacin, cefoxitin, imipenem) and to the macrolides (clarithromycin, azithromycin) (1, 2). Combination therapy of intravenous amikacin with cefoxitin or imipenem and an oral macrolide has been recommended by the American Thoracic Society/Infectious Diseases Society of America and many other experts (1–4). However, treatment response rates are not satisfactory and optimal therapeutic regimens and treatment durations are not well established (12).
Inducible resistance to clarithromycin has been suggested as an explanation for the lack of efficacy of clarithromycin-based treatments against M. abscessus infection (13). An erythromycin ribosomal methylase gene, erm(41), has been identified in several isolates of M. abscessus and the presence of the gene was associated with inducible resistance to macrolides. The induction of resistance was shown to result from increased expression of erm(41) as demonstrated by an increase in erm(41) RNA levels after exposure to macrolides.
M. abscessus (now M. abscessus sensu lato, or M. abscessus complex) was shown to comprise three closely related species: M. abscessus (sensu stricto) (hereafter referred to as M. abscessus), Mycobacterium massiliense, and Mycobacterium bolletii (14, 15). The isolation of M. massiliense and M. bolletii from patients with lung disease has been reported in many countries such as the United States (16, 17), the Netherlands (18), France (19), and Korea (20). However, little is known regarding the clinical impact of this species differentiation within the M. abscessus complex.
In Korea, M. abscessus is the second most common pathogen responsible for lung disease caused by nontuberculous mycobacteria (NTM), following the Mycobacterium avium-intracellulare complex (21, 22). In addition, M. abscessus and M. massiliense are isolated in almost equal numbers among M. abscessus complex infections, whereas M. bolletii is rare (20). The purpose of the present study was to compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease and to determine whether M. abscessus and M. massiliense isolates demonstrated inducible resistant to clarithromycin. Some of the results of this study have been previously reported in the form of an abstract (23).
We retrospectively reviewed the medical records of all patients with M. abscessus complex lung disease at the Samsung Medical Center (Seoul, Korea) between January 2004 and December 2008. During this 5-year period, 185 patients were newly diagnosed with M. abscessus complex lung disease. All patients met the diagnostic criteria for NTM lung disease according to the American Thoracic Society guidelines (1). Among the 185 patients, the isolates from 158 patients (85%) were kept in storage and were available for further species identification.
Permission was obtained from the institutional review board of Samsung Medical Center to review and publish information from the patients' records. Informed consent was waived because of the retrospective nature of the study.
Sputum smears and mycobacterial cultures were performed by standard methods, as described previously (12). During the study period, NTM species were identified by a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method based on the rpoB gene, as described previously (21). Further differentiation among M. abscessus complex members was done at the Department of Microbiology, Seoul National University College of Medicine (Seoul, Korea), using sequence analysis targeting the rpoB and hsp65 genes (20, 24).
Antimycobacterial susceptibility testing was performed at the Korean Institute of Tuberculosis (Seoul, Korea). Minimal inhibitory concentrations (MICs) of oral antimicrobials (clarithromycin, ciprofloxacin, doxycycline) and parenteral antimicrobials (amikacin, cefoxitin, imipenem) were determined by the broth microdilution method and were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) document M24-A of 2003 (25). Isolates were considered resistant if the MIC of clarithromycin was 8 μg/ml or greater and as susceptible if the MIC of clarithromycin was 2 μg/ml or less (25). The MIC of moxifloxacin for the M. abscessus group has not yet been described by the CLSI. In its place, we followed the recommendation for aerobic organisms in CLSI M100-S11 of 2001 (26).
To test for inducible resistance to clarithromycin, clarithromycin susceptibility assays were performed by a broth microdilution method without preincubation with clarithromycin (13). The MICs were determined on Days 3, 7, and 14 after incubation. The tests were performed without knowledge of the identification results of the clinical isolates. For analysis of the erm(41) gene in M. abscessus and M. massiliense, mycobacterial DNA preparations for PCR were obtained by a heating method. For cloning of the resistance gene element, M. abscessus and M. massiliense DNA amplification was performed according to protocols described by Nash and colleagues (13). Briefly, the PCR products were sequenced, using a BigDye terminator v3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA), and sequencing was performed on a 3730xl DNA analyzer (Applied Biosystems). The erm(41) gene sequences from clinical isolates were analyzed for homology by BLAST with the erm(41) gene sequence from M. abscessus (19977; American Type Culture Collection [ATCC], Manassas, VA), which is susceptible to clarithromycin.
NTM lung disease may progress slowly; furthermore, some patients do not require treatment, whereas others require combination antibiotic therapy, including parenteral agents. After discussing this information with the patients, we implemented an observation period of at least 6−12 months with no antibiotic treatment. When the disease was clearly recognized as being progressive, patients received standardized combination antibiotic therapy after hospitalization. In patients with substantial symptoms and/or advanced or progressive radiographic abnormalities, antibiotic therapy was initiated immediately (12).
As described in a previous report (12, 27), all patients who were chosen to begin antibiotic therapy were hospitalized for 4 weeks and received a clarithromycin-containing three-drug oral regimen, clarithromycin (1,000 mg/d), ciprofloxacin (1,000 mg/d), and doxycycline (200 mg/d), along with an initial 4-week course of amikacin (15 mg/kg/d in two divided doses) and cefoxitin (200 mg/kg/d; maximum, 12 g/d in three divided doses). If an adverse reaction associated with cefoxitin occurred, imipenem (750 mg, three times per day) was substituted for cefoxitin.
After discharge, patients took a three-drug oral regimen for a total treatment duration of 24 months. This regimen continued for at least 12 months after sputum culture conversion. Sputum smear and culture examinations were performed monthly for the first 6 months and then at 2- to 3-month intervals until the end of treatment.
Results presented in text and tables are expressed as means and standard deviations, or as the number (percentage) of patients. Categorical variables were analyzed by Pearson χ2 test or Fisher exact test. Continuous variables were analyzed by t test. All P values were two-sided; P < 0.05 were deemed to indicate statistical significance. Analyses were conducted with PASW (version 17.0 for Windows; SPSS Inc., Chicago, IL).
Of 185 patients who were newly diagnosed with M. abscessus complex lung disease, clinical isolates from 158 (85%) were kept in storage. The patients with isolates available for further species identification were similar to those without stored isolates in terms of demographic characteristics such as age, sex, sputum smear results, type of disease, and microbiologic responses (data not shown).
Sequence analysis of the rpoB and hsp65 genes of these 158 clinical isolates of M. abscessus complex led to the identification of 64 (44%) M. abscessus isolates, 81 (55%) M. massiliense isolates, and two (1%) M. bolletii isolates. Eleven isolates were nontypeable. We compared clinical characteristics and treatment outcomes between the 64 patients with M. abscessus and 81 patients with M. massiliense. Some clinical data for these 147 patients were included in an article published in 2009 (12). However, we reanalyzed these data after differentiating between M. abscessus and M. massiliense.
Baseline characteristics of the patients are summarized in Table 1. No significant difference was found between the groups in any of the baseline characteristics, including demographic data, underlying conditions, and respiratory symptoms. Distributions of radiographic type of disease were also similar; the majority of the patients had the nodular bronchiectatic form of disease in both groups. None of these patients tested positive for human immunodeficiency virus or were organ transplant recipients.
M. abscessus (n = 64) | M. massiliense (n = 81) | P Value | |
|---|---|---|---|
| Age, yr | 57.6 (13.0) | 56.0 (12.9) | 0.467 |
| Sex, female | 47 (71) | 61 (75) | 0.545 |
| Body mass index, kg/m2 | 20.5 (3.1) | 20.8 (2.8) | 0.566 |
| Smoking | |||
| Nonsmoker | 56 (88) | 69 (85) | 0.923 |
| Current or ex-smoker | 8 (12) | 12 (15) | |
| Underlying disease | |||
| Previous tuberculosis | 33 (52) | 44 (54) | 0.741 |
| COPD | 3 (5) | 8 (10) | 0.347 |
| Diabetes mellitus | 3 (5) | 1 (1) | 0.321 |
| Lung cancer | 6 (9) | 5 (6) | 0.537 |
| Other malignancy | 8 (13) | 5 (6) | 0.185 |
| Symptoms | |||
| Cough | 55 (86) | 73 (90) | 0.437 |
| Sputum | 55 (86) | 68 (84) | 0.741 |
| Hemoptysis | 27 (42) | 27 (33) | 0.273 |
| Positive AFB smear | 44 (69) | 47 (58) | 0.185 |
| Type of disease | |||
| Nodular bronchiectatic form | 53 (83) | 56 (69) | |
| Upper lobe cavitary form | 8 (12) | 17 (21) | 0.161 |
| Unclassifiable form | 3 (5) | 8 (10) |
Drug susceptibility results for 64 patients with M. abscessus and 79 patients with M. massiliense infection are shown in Table 2. Of the parenteral antibiotics, amikacin and cefoxitin were active against most M. abscessus isolates (61 [95%] for amikacin, 64 [100%] for cefoxitin) and M. massiliense isolates (73 [92%] for amikacin, 78 [99%] for cefoxitin), with no difference between the species (P = 0.731 and P = 1.0, respectively). However, drug resistance rates to imipenem were higher in patients with M. massiliense infection (67%, 50 of 75) than in those with M. abscessus infection (44%, 27 of 62; P = 0.007). No significant difference was observed in drug resistance rates to oral antibiotics, including clarithromycin, doxycycline, ciprofloxacin, and moxifloxacin (P = 1.0, P = 0.152, P = 0.467, and P = 0.457, respectively).
No. of Strains Distributed at MIC (μg/ml) | Resistance Rate | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Etiology | Drug | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | 128 | 256 | ||||||||||||
| M. abscessus | Amikacin | 4 | 14 | 24 | 14 | 5 | 2 | 1* | 3 (5%) | ||||||||||||||||
| Cefoxitin | 1† | 3 | 4 | 24 | 31 | 1 | 0 | ||||||||||||||||||
| Imipenem | 1 | 2 | 1 | 7 | 24 | 12 | 6 | 2 | 7* | 27 (44%) | |||||||||||||||
| Clarithromycin | 30† | 18 | 10 | 3 | 2 | 1* | 3 (5%) | ||||||||||||||||||
| Doxycycline | 1† | 1 | 2 | 4 | 3 | 3 | 11 | 39* | 53 (83%) | ||||||||||||||||
| Ciprofloxacin | 1† | 2 | 5 | 19 | 17 | 9 | 5 | 6* | 37 (58%) | ||||||||||||||||
| Moxifloxacin | 1† | 2 | 5 | 9 | 17 | 17 | 9 | 2 | 2* | 30 (47%) | |||||||||||||||
| M. massiliense | Amikacin | 5 | 14 | 24 | 17 | 13 | 5 | 1* | 6 (8%) | ||||||||||||||||
| Cefoxitin | 1 | 4 | 37 | 31 | 5 | 1 | 1 (1%) | ||||||||||||||||||
| Imipenem‡ | 4 | 3 | 18 | 30 | 8 | 5 | 7* | 50 (67%) | |||||||||||||||||
| Clarithromycin | 36† | 38 | 2 | 3* | 3 (4%) | ||||||||||||||||||||
| Doxycycline | 1 | 1 | 6 | 9 | 4 | 6 | 8 | 44* | 58 (73%) | ||||||||||||||||
| Ciprofloxacin | 1 | 4 | 4 | 22 | 19 | 17 | 5 | 7* | 48 (61%) | ||||||||||||||||
| Moxifloxacin | 3 | 5 | 16 | 13 | 20 | 14 | 4 | 4* | 42 (53%) | ||||||||||||||||
Of the 145 patients enrolled in the study, 30 patients (47%) with M. abscessus infection and 37 patients (46%) with M. massiliense infection received antibiotic treatment for a mean duration of 23.1 ± 12.9 and 21.6 ± 7.7 months, respectively. In these 67 patients who initiated combination antibiotic therapy, 57 patients (24 with M. abscessus infection and 33 with M. massiliense infection) who received antibiotic therapy for more than 12 months were included in the analysis of treatment response (Table 3).
M. abscessus (n = 24) | M. massiliense (n = 33) | P Value | |
|---|---|---|---|
| Symptomatic response | 0.040 | ||
| Improved | 18 (75%) | 32 (97%) | |
| Unchanged | 4 (17%) | 1 (3%) | |
| Worsened | 2 (8%) | — | |
| Radiographic response on HRCT | 0.003 | ||
| Improved | 10 (42%) | 27 (82%) | |
| Unchanged | 7 (29%) | 5 (15%) | |
| Worsened | 7 (29%) | 1 (3%) | |
| Microbiologic response | <0.001 | ||
| Initial sputum conversion and maintenance of conversion | 6 (25%) | 29 (88%) | |
| Initial sputum conversion, with sputum relapse | 4 (17%) | 3 (9%) | |
| Failure to sputum conversion | 14 (58%) | 1 (3%) |
Clarithromycin Resistance (MIC, μg/ml) | No. of Clinical Isolates | |||||
|---|---|---|---|---|---|---|
| Isolate | Day 3 | Day 7 | Day 14 | |||
| M. abscessus (n = 19) | Susceptible | |||||
| ≤0.5 | 9 (47%) | — | — | |||
| 1 | 6 (32%) | — | — | |||
| 2 | 4 (21%) | — | — | |||
| Intermediate | ||||||
| 4 | — | — | — | |||
| Resistant | ||||||
| 8 | — | 1 (5%) | — | |||
| 16 | — | 8 (42%) | — | |||
| 32 | — | 4 (21%) | 3 (16%) | |||
| ≥64 | — | 6 (32%) | 16 (84%) | |||
| M. massiliense (n = 28) | Susceptible | 20 (71%) | 20 (71%) | 20 (71%) | ||
| ≤0.5 | ||||||
| 1 | 8 (29%) | 8 (29%) | ||||
| 2 | — | — | — | |||
| Intermediate | ||||||
| 4 | — | — | — | |||
| Resistant | ||||||
| ≥8 | — | — | — | |||
Symptomatic improvement rates were higher in patients with M. massiliense infection (97%) than in those with M. abscessus infection (75%; P = 0.040). Radiographic improvement rates were higher in patients with M. massiliense infection (82%) than in those with M. abscessus infection (42%; P = 0.003). Microbiologic responses also differed between the two groups. The initial sputum conversion rates were lower in patients with M. abscessus infection (42%, 10 of 24) than in those with M. massiliense infection (97%, 32 of 33). Sputum relapse rates after initial conversion to negative were higher in patients with M. abscessus infection (40%, 4 of 10) compared with those with M. massiliense infection (9%, 3 of 33). Thus, the proportion of patients whose sputum converted and remained culture-negative during the follow-up period was significantly lower in patients with M. abscessus infection (25%, 6 of 24) than in patients with M. massiliense infection (88%, 29 of 33; P < 0.001; Table 3).
To determine whether M. abscessus and M. massiliense contained an inducible clarithromycin resistance element, 19 clinical isolates of M. abscessus and 28 clinical isolates of M. massiliense were chosen from organisms from 57 patients who received combination antibiotic therapy for more than 12 months and had treatment outcome data available. Ten clinical isolates were not included in this test because of initial resistance to clarithromycin and loss of isolates. All 19 M. abscessus isolates had clarithromycin MICs not exceeding 2 μg/ml when the broth susceptibility tests were read on Day 3. However, all M. abscessus isolates showed MICs of at least 8 μg/ml to clarithromycin on Day 7, that is, these isolates developed in vitro resistance to clarithromycin. On Day 14, all M. abscessus isolates became further highly resistant to clarithromycin (MICs ≥ 32 μg/ml). In contrast, clarithromycin MICs of all 29 M. massiliense isolates were not more than 1 μg/ml when the broth susceptibility tests were read on Day 3 and remained at 1 μg/ml or less during the 14-day observation (Table 4).
The erm(41) gene, which is 522 bp, was present in all M. abscessus isolates, but was partially deleted in all M. massiliense isolates. Of 19 inducibly resistant isolates of M. abscessus, 11 isolates (58%) were mutants and 8 isolates (42%) were nonmutants. When the DNA sequences of the 11 mutant isolates were compared with the reference sequence (M. abscessus, cat. no. 19977; ATCC), 10 base substitutions were observed, of which 4 resulted in a change of amino acid.
This is the first study to focus primarily on the clinical relevance of the species differentiation between M. abscessus and M. massiliense, and the largest study of its kind, with almost 150 patients included. The important finding from our study was that favorable microbiologic response rates to the same combination antibiotic therapy were much higher in patients with M. massiliense lung disease (88%) than in those with M. abscessus lung disease (25%). In addition, inducible resistance to clarithromycin (MIC ≥ 32 μg/ml) was found in all M. abscessus clinical isolates tested, but in none of the M. massiliense isolates.
The nomenclature used to describe RGM has changed frequently, and these changes have been a source of confusion for clinicians. For instance, M. abscessus has been labeled as M. chelonei subspecies abscessus, M. chelonae subspecies abscessus, and finally, in 1992, as M. abscessus (28). Two new related species, M. massiliense and M. bolletii, have been reported (14, 15). However, the clinical significance of these species distinction is still unclear (29), although some small studies have suggested the possible differences in the characteristics of patients infected with M. abscessus compared with those infected with M. massiliense (17, 18).
The proportions of M. massiliense and M. bolletii among M. abscessus complex are variable, according to geographical distribution. Among 40 patients monitored at the National Institutes of Health (Bethesda, MD), the prevalence of M. massiliense and M. bolletii was 28% and 5%, respectively (17). In the Netherlands, 21% of 39 clinical isolates of M. abscessus complex were identified as M. massiliense and 15% were M. bolletii (18). In France, M. massiliense and M. bolletii accounted for 22 and 18% of 50 patients with cystic fibrosis infected with M. abscessus complex, respectively (19). In Korea, a previous study showed that nearly half (47%) of all M. abscessus complex clinical isolates were identified as M. massiliense, although the prevalence of M. bolletii was low (2%) (20). The present study included almost 150 patients with M. abscessus complex lung disease and reconfirmed the relatively high prevalence of M. massiliense among M. abscessus complex in Korea. Actually, the proportion of M. massiliense (55%) was higher than that of M. abscessus (44%) in this study, when nontypeable isolates were excluded. Because the proportion of M. bolletii was low (1%) in this study, we compared the characteristics of patients with M. abscessus lung disease and those with M. massiliense lung disease.
The clinical characteristics of patients with M. abscessus lung disease, compared with those with M. massiliense lung disease, were similar regarding age, sex, smoking status, and underlying disease. Most patients had the nodular bronchiectatic form of NTM lung disease. Interestingly, the most common type of underlying lung disease in this study was prior tuberculosis. However, it was unclear whether these patients had culture-confirmed pulmonary tuberculosis previously, because patients with AFB-positive sputum or those displaying chest radiographic findings that suggested active tuberculosis had generally been presumed to have pulmonary tuberculosis and were treated empirically with antituberculous drugs. Although NTM lung disease, including M. abscessus complex, has been reported increasingly in patients with cystic fibrosis in the United States and Western Europe (9–11), cystic fibrosis is quite rare in Asians (30, 31). Underlying predisposing factors are still unclear in these patients with M. abscessus and M. massiliense lung disease.
Data regarding in vitro drug susceptibility results of M. massiliense are limited. Initial studies reported low MICs for clarithromycin (0.125 μg/ml) in M. massiliense isolates (14, 24). One study from Korea showed that M. massiliense was either markedly susceptible (MICs, 0.125–0.5 μg/ml) or highly resistant (MICs, >256 μg/ml) to clarithromycin, although general resistance rates against clarithromycin were similar between M. abscessus (4 of 9, 44%) and M. massiliense (3 of 9, 33%) (20). In another study from the Netherlands, M. abscessus isolates (44%, 8 of 18) were more resistant to clarithromycin than were M. massiliense isolates (17%, 1 of 6) (18). In the present study, which tested more than 140 clinical isolates from newly diagnosed patients, the resistant rates were less than 5% against amikacin, cefoxitin, and clarithromycin in both M. abscessus and M. massiliense. Interestingly, the in vitro susceptible rates to ciprofloxacin or moxifloxacin were about 40–50% in both M. abscessus and M. massiliense. M. abscessus complex has usually been regarded as resistant to fluoroquinolones (3). However, there have been reports demonstrating moderate in vitro activity of some fluoroquinolones against M. abscessus complex (32–34). The possibility that fluoroquinolones could be used as alternative oral agents during combination antibiotic therapy for M. abscessus and M. massiliense infection should be studied further.
One of the most important findings of our study was the difference in inducible resistance to clarithromycin between M. abscessus and M. massiliense. Studies have shown that some RGM, such as M. abscessus and M. fortuitum, but not M. chelonae, had an erm gene that induced macrolide resistance (13, 35). However, it is unknown whether other RGM such as M. massiliense have an erm gene. This study demonstrated that high resistance to clarithromycin was induced in M. abscessus isolates, but not in M. massiliense isolates. Interestingly, M. abscessus isolates, which appeared to be susceptible to clarithromycin on Day 3, showed much higher MICs on Day 14 versus those on Day 7. In contrast, M. massiliense isolates remained susceptible to clarithromycin during the 14-day observation period. These findings may explain the significant difference in treatment outcomes between M. abscessus and M. massiliense lung disease. We reported that sputum conversion and maintenance of negative cultures were achieved in 58% of patients with M. abscessus lung disease (12). These relatively high sputum conversion rates may have been due to the inclusion of patients with M. massiliense lung disease.
The sequence and function of the erm(41) gene, which confers inducible macrolide resistance in M. abscessus, was reported by Nash and colleagues (13). For seven inducibly resistant M. abscessus isolates, eight base substitutions were observed, with three resulting in amino acid changes in that study (13). In our study, 10 base substitutions with 4 amino acid changes were found in 11 inducibly resistant M. abscessus isolates, whereas 8 other inducibly resistant M. abscessus isolates had erm(41) gene sequences identical to that of a susceptible reference strain. These results suggest the presence of mechanisms other than the erm(41) gene for inducible resistance to clarithromycin in M. abscessus, and further studies are needed to investigate these mechanisms (36).
From a clinical standpoint, our study has some important therapeutic implications. The inducible resistance to clarithromycin of M. abscessus isolates means that it can be much more difficult to treat M. abscessus lung disease. A much longer duration of intravenous antibiotic therapy and more effective oral antibiotics may be needed to improve treatment outcomes in M. abscessus lung disease. The low MIC for clarithromycin and the absence of inducible resistance to clarithromycin suggest that M. massiliense lung disease may be more effectively treated with a clarithromycin-based antibiotic regimen.
Species-level identification is important because antibiotic susceptibility and therapies differ significantly depending on the RGM species obtained (1, 2). In fact, M. abscessus lung disease has been regarded as a chronic incurable infection for most patients given the current antibiotic options (2). This may be true in patients with M. abscessus lung disease; however, this may not be the case in patients with M. massiliense lung disease who were previously diagnosed as having M. abscessus lung disease.
In conclusion, this study found clinically significant differences between M. abscessus and M. massiliense lung infections. Treatment response rates to clarithromycin-based antibiotic therapy were higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of antibiotic therapy against M. abscessus infections. Although an erm(41) gene was identified in approximately 50% of the M. abscessus isolates, other mechanisms may be important in the development of inducible macrolide resistance.
The authors thank Drs. Christopher Czaja, Shannon Kasperbauer, and Carlos Perez-Velez (National Jewish Health, Denver, CO) and Su-Young Kim (Samsung Medical Center, Seoul, Korea) for critical reading and helpful comments in the preparation of this manuscript. The authors also thank Ms. Eun Mi Park (Samsung Medical Center) for assistance and technical support.
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