Antibiotic Treatment of Mycobacterium abscessus Lung Disease A Retrospective Analysis of 65 Patients

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1 Antibiotic Treatment of Mycobacterium abscessus Lung Disease A Retrospective Analysis of 65 Patients Kyeongman Jeon 1, O Jung Kwon 1, Nam Yong Lee 2, Bum-Joon Kim 3, Yoon-Hoh Kook 3, Seung-Heon Lee 4, Young Kil Park 4, Chang Ki Kim 4, and Won-Jung Koh 1 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and 2 Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3 Department of Microbiology, Seoul National University College of Medicine, Seoul, Republic of Korea; and 4 Korean Institute of Tuberculosis, Seoul, Republic of Korea Rationale: The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. Objectives: To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease. Methods: Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization. Measurements and Main Results: Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P ). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days. Conclusions: Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved. Keywords: atypical mycobacteria; lung diseases; Mycobacterium abscessus; treatment outcome Rapidly growing mycobacteria (RGM), which are characterized by visible growth on solid media within 7 days, are ubiquitous environmental organisms that are increasingly recognized as important human pathogens (1 4). Mycobacterium abscessus accounts for approximately 65 to 80% of lung disease caused by RGM (5 8). M. abscessus is resistant to many antibiotics and thus is very difficult to treat. Isolates are usually susceptible only in vitro to the parenteral agents amikacin, cefoxitin, and imipenem, and to (Received in original form May 10, 2009; accepted in final form August 5, 2009) Supported by a grant of the Korea Science and Engineering Foundation (R ) and the Samsung Biomedical Research Institute grant (#SBRI C-A ). 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, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea. wjkoh@skku.edu This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 180. pp , 2009 Originally Published in Press as DOI: /rccm OC on August 6, 2009 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. What This Study Adds to the Field Standardized combination antibiotic regimen, which is largely based on clarithromycin use, together with an initial 4-week administration of cefoxitin and amikacin, is moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential need for prolonged hospitalization are important issues that remain to be resolved. oral macrolides (clarithromycin and azithromycin) (1, 2). Combination therapy of intravenous amikacin with cefoxitin or imipenem and an oral macrolide have been recommended by the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) and many other experts (1 4). However, there are very limited data in the literature regarding the clinical efficacy of this combination antibiotic therapy for M. abscessus lung disease. Specifically, optimal therapeutic regimens and treatment durations are not well established. In South Korea, M. abscessus is the second most common pathogen responsible for lung disease caused by nontuberculous mycobacteria (NTM), after Mycobacterium avium-intracellulare complex (9, 10). To gain greater insight into the optimal therapeutic strategy for M. abscessus lung disease, we retrospectively assessed the efficacy of a combination antibiotic therapy, which included a clarithromycin-containing three-drug regimen along with an initial 4-week course of intravenous cefoxitin and amikacin. The patients were treated over an 8- year period at a tertiary referral hospital in South Korea. Some of the results of this study have been previously reported in the form of abstracts (11, 12). METHODS Study Population We retrospectively reviewed the medical records of all patients with M. abscessus lung disease at the Samsung Medical Center (a 1,250-bed referral hospital in Seoul, South Korea) between January 2000 and December During this period, 188 patients were newly diagnosed with M. abscessus lung disease. All patients met the diagnostic criteria for NTM lung disease, according to the ATS guidelines in 1997 (1). The diagnosis was based on repeated sputum culture positivity in 167 patients (89%) and on bronchial washing or bronchoalveolar lavage

2 Jeon, Kwon, Lee, et al.: Treatment of M. abscessus Disease 897 fluid culture positivity in the remaining 21 patients (11%) who were either unable to produce sputum or had negative sputum cultures. M. abscessus lung disease may progress very 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 to 12 months without antibiotic treatment. When the disease was clearly recognized as being progressive, the patients received a standardized combination antibiotic therapy after hospitalization. In patients with substantial symptoms and/or advanced or progressive radiographic abnormalities, antibiotic therapy was initiated immediately. Out of 188 patients with M. abscessus lung disease, 102 (54%) patients did not receive antibiotic therapy for the following reasons: mild symptoms and no clear evidence of disease progression during the observation period (n 5 83; median follow-up duration, 20.5 mo; interquartile range [IQR, 25th and 75th percentiles] mo); lost to follow-up (n 5 8; median follow-up duration, 17.7 mo; IQR mo); transfer to another hospital after diagnosis of M. abscessus lung disease (n 5 6; median follow-up duration, 11.2 mo; IQR mo); or death due to another disease (n 5 5; median follow-up duration, 24.5 mo; IQR mo). Patients who received antibiotic therapy tended to be younger and mostly female and were more likely to have respiratory symptoms, positive sputum specimens based on acid-fast bacilli smears, and cavitation on chest radiography, compared with those who did not receive antibiotic therapy (Table 1). Of 86 (46%) patients who initiated combination antibiotic therapy, 21 patients were excluded because they had received antibiotic therapy for less than 12 months at the time of analysis. Therefore, a total of 65 patients who received antibiotic therapy for more than 12 months were included in the study. 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. Microbiological Examination Sputum smears and mycobacterial cultures were performed with standard methods (13). Additional detail on the method is provided in an online data supplement. NTM species were identified using a polymerase chain reaction and restriction length polymorphism method based on the rpob gene, as previously described (9). Antimicrobial susceptibility testing was performed at the Korean Institute of Tuberculosis. Minimum inhibitory concentrations (MICs) of oral antimicrobials (clarithromycin, ciprofloxacin, and doxycycline) and parenteral antimicrobials (amikacin, cefoxitin, and imipenem) were determined using the broth microdilution method and interpreted according to the National Committee for Clinical Laboratory Standards guidelines (14). Isolates were considered resistant if the MIC of clarithromycin was 8 mg/ml or greater and susceptible if the MIC of clarithromycin was 2 mg/ml or less (14). The broth microdilution MIC determination was not established in Korea during the early study period. Therefore, the isolates recovered from only 45 (69%) of 65 patients could be tested for susceptibility to antibiotics. Radiological Examination Chest radiography and high-resolution computed tomography (HRCT) findings were classified as showing either upper lobe cavitary disease or nodular bronchiectatic disease (15). Additional detail on the method is provided in the online supplement. Follow-up HRCT scans were performed at a median 12.2 months (IQR, mo) after the start of antibiotic therapy. Initial and follow-up HRCT scans were available for all patients, and these images were reviewed by two of the authors (K. Jeon and W-J. Koh). Differences in observed findings were resolved by consensus based on five radiographic features: cavitary disease, bronchiectasis, nodules, consolidation, and tree-in-bud appearance (16). Treatment Protocol All patients who were chosen to begin antibiotic therapy were hospitalized for 4 weeks and received a clarithromycin-containing three-drug oral regimen that included 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) (17). Peak serum levels of amikacin (. 20 mg/ml) were achieved using therapeutic drug monitoring. Complete blood cell counts, serum creatinine, and liver function test results were monitored twice a week during hospitalization. If an adverse reaction associated with cefoxitin occurred, imipenem (750 mg, three times a day) (3) 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. Assessment of Microbiologic Response Sputum conversion was defined as three consecutive negative cultures within 6 months, with the time of conversion defined as the date of the first negative culture. If the patient could not expectorate sputum during treatment, the sputum was considered to have converted. Sputum relapse was defined as two consecutive positive cultures after sputum conversion (18). TABLE 1. COMPARISON OF THE CLINICAL AND RADIOGRAPHIC CHARACTERISTICS OF PATIENTS WITH MYCOBACTERIUM ABSCESSUS LUNG DISEASE WHO RECEIVED ANTIBIOTIC THERAPY WITH THOSE WHO DID NOT RECEIVE ANTIBIOTIC THERAPY Characteristics Patients Who Received Antibiotic Therapy (n 5 86) Patients Who Did Not Receive Antibiotic Therapy (n 5 102) P Value Age, yr, median (IQR) 55 (43 63) 58 (50 67) Sex, female 72 (84%) 68 (67%) Body mass index, kg/m 2, median (IQR) 20.1 ( ) 20.7 ( ) Nonsmoker 78 (91%) 85 (83%) Respiratory symptoms Cough 81 (94%) 81 (80%) Sputum 78 (91%) 83 (81%) Hemoptysis 46 (54%) 32 (31%) Positive sputum AFB smear 71 (83%)* 63 (62%) Type of disease Nodular bronchiectatic form 62 (72%) 83 (81%) Upper lobe cavitary form 21 (24%) 9 (9%) Unclassifiable form 3 (4%) 10 (10%) Definition of abbreviations: AFB 5 acid-fast bacilli; IQR 5 interquartile range. * At the time of antibiotic therapy initiation. At the time of diagnosis.

3 898 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Data Analysis Because the majority of the data did not follow a normal distribution, all results in the text or tables are expressed as the median and IQR, or as the number (percentage) of patients. Categorical variables were analyzed using the Pearson x 2 -test or Fisher exact test. Continuous variables were analyzed using a Mann-Whitney U test. A nonparametric repeated-measures analysis of variance (Friedman test) was performed to test for changes in erythrocyte sedimentation rates (ESR) with time. RESULTS Patient Characteristics A total of 65 patients (10 males and 55 females; median age, 55 yr [IQR yr]) with M. abscessus lung disease who received combination antibiotic therapy for more than 12 months were included in the study. None of the 65 patients tested positive for human immunodeficiency virus. Baseline characteristics of the patients are summarized in Table 2. Fifty-seven (88%) patients had a positive acid-fast bacilli smear. Four (6%) patients were either unable to produce sputum or had negative sputum cultures and subsequently underwent bronchoscopy. A diagnosis in these cases was established via culture from bronchial washing or bronchoalveolar lavage. Forty-eight (74%) patients had the nodular bronchiectatic form, 15 (23%) had the upper lobe cavitary form, and 2 (3%) had unclassifiable variants. Female patients were more likely to be nonsmokers (100 vs. 30%, P, 0.001) and to have nodular bronchiectatic form (84 vs. 20%, P, 0.001) compared with male patients. Age and body mass index did not differ significantly between female and male patients. Drug susceptibility tests were performed on M. abscessus isolates recovered from 45 patients as described above. Of the parenteral antibiotics, cefoxitin (98%, 44/45) and amikacin (96%, 43/45) were active against most isolates. Imipenem displayed in vitro activity against a moderate number of isolates (48%, 20/ 42). Of the oral antibiotics, clarithromycin showed moderate in vitro activity against the isolates (73%, 33/45), but demonstrated better in vitro activity than ciprofloxacin (47%, 21/45). None of the examined isolates was susceptible to doxycycline (Table 3). Combination Antibiotic Treatment Out of 65 patients, 41 (63%) patients completed the treatment. The median duration of antibiotic treatment was 24.4 months TABLE 2. CHARACTERISTICS OF 65 PATIENTS WITH MYCOBACTERIUM ABSCESSUS LUNG DISEASE WHO RECEIVED COMBINATION ANTIBIOTIC THERAPY FOR MORE THAN 12 MONTHS Characteristics No. (%) or Median (IQR) Age, yr 55 (43 63) Sex, female 55 (85) Body mass index, kg/m ( ) Smoking history Nonsmoker 58 (89) Ex-smoker 6 (9) Current smoker 1 (2) Respiratory symptoms Cough 64 (99) Sputum 61 (94) Hemoptysis 35 (54) Dyspnea 20 (31) Chest pain 5 (8) Positive sputum AFB smear 57 (88) Type of disease Nodular bronchiectatic form 48 (74) Upper lobe cavitary form 15 (23) Unclassifiable form 2 (3) For definition of abbreviations, see Table 1. TABLE 3. MINIMUM INHIBITORY CONCENTRATIONS BREAKPOINTS AND IN VITRO SUSCEPTIBILITY OF MYCOBACTERIUM ABSCESSUS (N 5 45) No. of Strains Distributed at the MIC (mg/ml) Drug Amikacin Cefoxitin Imipenem* Clarithromycin Doxycycline Ciprofloxacin 2* Definition of abbreviation: MICS 5 minimum inhibitory concentrations. In vitro susceptibility test results to imipenem were available in 42 M. abscessus isolates. Italic and bold type indicate susceptible and resistant categories of interpretive criteria to each antimicrobial agent, respectively. * Low off-scale MICs were converted to the next-lowest concentration. High off-scale MICs were converted to the next-highest concentration. (IQR, mo; Table 4). Thirty-seven patients received antibiotic therapy for 24 months or more. In three patients who underwent surgical resection of localized disease and achieved sputum negative conversion, treatment finished at 13, 19, and 20 months, respectively. One patient, whose sputum cultures had converted to negative for 18 months, refused further therapy at 19 months. Out of 24 (37%) patients who did not complete the full course of treatment, 3 patients refused further therapy due to adverse reactions at 15, 15, and 39 months, respectively. Four patients were transferred to another hospital or were lost to follow-up. Two patients died due to disease progression at 18 and 30 months, respectively. The remaining 15 patients continued antibiotic therapy until the end of December 2008 (median duration of treatment, 21.0 mo; IQR, mo). Clinical, Radiographic, and Microbiologic Responses As shown in Table 5, response rates were 83% based on symptoms and 74% based on HRCT findings. At the start of treatment, the median ESR was 45.0 mm/h (IQR, mm/h). ESR levels decreased to a median of 26.0 mm/h (IQR, mm/h) after an initial 4 weeks of treatments and further decreased to a median of 17.5 mm/h (IQR, mm/h) after 12 months of treatment (P, 0.001). The initial sputum conversion rate was 72% (47/65), and the median time until sputum conversion was 1 month (IQR, 1 1 mo). The other 18 (28%) patients, including 2 patients who died of disease progression, failed to achieve sputum conversion. Sputum relapse occurred in 9 (19%) of 47 patients who achieved initial sputum conversion. For these patients, relapse occurred at a median time point of 12 months (IQR, 5 30 mo) after sputum conversion. Furthermore, of these nine patients, sputum relapse occurred during antibiotic treatment in five patients and after completion of treatment in four patients (5, 6, 7, and 40 mo after treatment completion, respectively). Therefore, 38 (58%) of the 65 patients sputum converted and remained culture negative until the end of December Of these 38 patients, 32 patients completed antibiotic treatment and were followed for a median of 11.9 months (IQR, mo) without relapse. Six patients underwent treatment for 19.2 months (IQR, mo). Sputum conversion rates were lower in patients whose isolates were resistant to clarithromycin (42%, 5/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (76%, 25/33). In addition, sputum relapse after initial negative conversion was higher in patients infected with clarithromycin-resistant isolates (60%, 3/5) compared with

4 Jeon, Kwon, Lee, et al.: Treatment of M. abscessus Disease 899 TABLE 4. TREATMENT OF 65 PATIENTS WITH MYCOBACTERIUM ABSCESSUS LUNG DISEASE Treatment those infected with clarithromycin-susceptible or intermediate isolates (16%, 4/25). Therefore, the microbiologic response rate, which was defined as sputum conversion and the maintenance of negative sputum cultures for more than 12 months, was significantly lower in patients infected with clarithromycinresistant isolates (17%, 2/12) compared with patients infected with clarithromycin-susceptible or intermediate isolates (64%, 21/33; P ) (Table 6). A multiple logistic regression model revealed that resistance to clarithromycin was independently associated with failure to conversion or relapse (odds ratio, 0.03; 95% CI, ; P ) (Table 6). Adverse Reactions No. (%) of Patients Treatment completion 41 (63%) Treatment for > 24 mo 37 Treatment for, 24 mo 4 Treatment incompletion 24 (37%) On the treatment 15 Refused further therapy before treatment completion 3 Transfer out or follow-up loss 4 Death due to disease progression during the treatment 2 Adverse reactions associated with cefoxitin occurred frequently. Leukopenia (white blood cell counts, 3,000/ml) and thrombocytopenia (platelet counts, 100,000/ml) developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity (aspartate aminotransferase or alanine aminotransferase levels > 120 IU/L) occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days (IQR, d). After the discontinuation of cefoxitin, the above adverse reactions resolved completely. In 28 of these 39 patients, imipenem was administered as a substitute for cefoxitin during the remaining 4 weeks of hospitalization. There were no complaints of vestibular dysfunction or hearing difficulties was attributable to the 4-week administration of amikacin. Gastrointestinal symptoms (e.g., anorexia, nausea, or diarrhea) associated with oral antibiotic usage after discharge from the hospital occurred in 14 (22%) patients. In these 14 patients, 5 patients continued clarithromycin and ciprofloxacin after discontinuation of doxycycline. Three patients were able to continue antibiotic therapy after reduction of the clarithromycin dosage (500 mg/d). One patient discontinued clarithromycin and one patient required the substitution of clarithromycin with azithromycin. Four patients completely discontinued antibiotic therapy because of severe gastrointestinal symptoms after a median period of 15 months (IQR, mo). Three (5%) patients, who presented with the upper lobe cavitary form of M. abscessus lung disease had complications of chronic necrotizing pulmonary aspergillosis. Two patients were diagnosed at 14 and 26 months, respectively, after the initiation of antibiotic therapy, and one patient was diagnosed at 9 months after the completion of antibiotic treatment for M. abscessus lung disease. A positive culture for Aspergillus fumigatus from sputum samples and clinical and radiographic evidence of a chronic infective process were recognized in all three patients. Adjunctive Surgical Resection Surgical resection was performed in 14 (22%) patients. The indications for surgery included failure of sputum conversion (n 5 6), sputum relapse after initial conversion (n 5 2), and complications such as recurrent hemoptysis despite negative sputum conversion (n 5 6). Pulmonary resections included lobectomy in six patients, pneumonectomy in three patients, bilobectomy in two patients, segmentectomy in one patient, and lobectomy plus segmentectomy in two patients. Negative sputum culture conversion was achieved within a median duration of 1.5 months (IQR, mo) postoperatively and was maintained in seven (88%) of eight patients with preoperative culture-positive sputum. DISCUSSION The optimal therapeutic regimen and duration of treatment for M. abscessus lung disease has not been established. The ATS guidelines (1997) and ATS/IDSA guidelines (2007) recommend treating patients with clarithromycin in combination with highdose cefoxitin and low-dose amikacin (1, 2). The guidelines state that administration of this combination therapy for 2 to 4 weeks (1) or 2 to 4 months (2) usually produces clinical and microbiologic improvement; however, cost and morbidity are significant impediments to a curative course of therapy (likely 4 6 mo). Surprisingly, limited data are available in the literature regarding the clinical efficacy of this combination antibiotic therapy for M. abscessus lung disease. In a large study of 154 patients with RGM-associated lung disease, in which more than 80% of patients were infected by M. abscessus, Griffith and colleagues concluded that M. abscessus was extremely difficult to eradicate by antibiotic therapy (6). However, the patients did not receive the currently recommended TABLE 5. TREATMENT RESPONSES OF 65 PATIENTS WITH MYCOBACTERIUM ABSCESSUS LUNG DISEASE Radiographic Responses on HRCT Symptomatic Responses Improved Unchanged Worsened Total Initial sputum conversion and maintenance of conversion Initial sputum conversion, with sputum relapse Improved Unchanged 2 2 Worsened 1 1 Total (58%) Improved Unchanged 1 1 Worsened Total (14%) Failure to sputum conversion Improved Unchanged Worsened Total (28%) Total 54 (83%) 3 (5%) 8 (12%) 65 (100%) Definition of abbreviations: HRCT 5 high-resolution computed tomography.

5 900 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 6. ASSOCIATIONS BETWEEN DRUG RESISTANCES AND MICROBIOLOGIC RESPONSE* (N 5 45) No. of Patients with Favorable Microbiologic Response Logistic Regression Univariate Analysis Drug Resistance No Resistance P Value OR (95% CI) P Value Amikacin 1/2 (50%) 22/43 (51%) ( ) Cefoxitin 1/1 (100%) 22/44 (50%) 1.0 NA 1.0 Clarithromycin 2/12 (17%) 21/33 (64%) ( ) Doxycycline 21/42 (50%) 2/3 (67%) ( ) Ciprofloxacin 13/24 (54%) 10/21 (48%) ( ) Definition of abbreviations: CI 5 confidence interval; OR 5 odds ratio. * Favorable microbiologic response was defined as sputum conversion and the maintenance of negative sputum cultures for more than 12 months. combination of antibiotics, which includes newer macrolides such as clarithromycin. The administered drugs included amikacin (58%), cefoxitin (43%), erythromycin (31%), and antituberculosis agents (37%) (6). To our knowledge, there has been no published study for more than 15 years that has focused on the antibiotic treatment of M. abscessus lung disease in a large sample of patients. Our study found that a combination antibiotic therapy is modestly effective in producing a favorable microbiologic response. Furthermore, both sputum conversion rates and relapse rates were significantly associated with clarithromycin resistance in this study. ATS/IDSA recommendations suggest that susceptibility to some agents, such as amikacin, cefoxitin, clarithromycin, ciprofloxacin, and doxycycline, should be reported and used to guide treatment (1, 2). However, the relationship between in vitro susceptibility results for M. abscessus and clinical responses to these agents has not been established. Our study results suggest that, for clarithromycin, there is a strong correlation between in vitro and in vivo results. In contrast to clarithromycin, no such relationship was found for amikacin, cefoxitin, ciprofloxacin, or doxycycline in this study. Our treatment regimen included an initial 4-week regimen of intravenous cefoxitin and amikacin administration. This approach usually requires placement of a long-term indwelling intravenous access with the potential for morbidity. In addition, the administration of intravenous cefoxitin for 4 weeks was frequently associated with adverse reactions, such as neutropenia. The incidence of b-lactam antibiotic-induced neutropenia increases when parenteral treatment is used in higher doses and extends beyond 2 weeks (19, 20). Therefore, these side effects may limit the feasibility of the suggested prolonged treatment duration (i.e., 2 4 mo) of parenteral antibiotic therapy, including cefoxitin (1, 2). Imipenem may be a reasonable alternative to cefoxitin (2), but neutropenia can also occur with prolonged administration. We continue to use cefoxitin in the initial 4-week treatment period because of high in vitro susceptibility of M. abscessus isolates to cefoxitin and low reproducibility of susceptibility results for imipenem (1, 2). For the treatment of M. abscessus lung disease, clarithromycin administration plus at least one other agent to which the organism is susceptible may follow initial therapy. However, this option is limited because of high in vitro resistance rates to the various oral agents used against M. abscessus isolates. We used a clarithromycin-containing three-drug oral regimen because of our concern for the emergence of clarithromycin resistance during clarithromycin monotherapy after discharge from the hospital after the initial 4-week therapy (21, 22). In addition, the broth microdilution MIC determination method had not yet been established in Korea during the early study period. After the establishment of a reliable drug susceptibility test, we found that the fluoroquinolones, such as ciprofloxacin and moxifloxacin, showed moderate in vitro activity against M. abscessus isolates from patients, whereas doxycycline showed very weak in vitro activity (23). Currently, we are using two-drug regimens including clarithromycin and moxifloxacin after the initial parenteral therapy. The roles of combined activities of fluoroquinolones with clarithromycin against M. abscessus are controversial. Interestingly, some experts suggest that holding regimens of a macrolide plus a fluoroquinolone may be helpful for periods between the pulsed intravenous antibiotic therapies, even if in vitro susceptibility results reveal resistance to the fluoroquinolones (24). Moreover, a study showed that moxifloxacin has a good activity against M. abscessus and combinations of clarithromycin and moxifloxacin were effective against M. abscessus strains in in vitro models (25). However, another recent study revealed that the activity of clarithromycin against M. avium complex strains could be attenuated by combination with a fluoroquinolone in both in vitro and in vivo models (26). Thus, further studies are required to evaluate active combinations of oral antibiotics and determine their clinical importance. Some M. abscessus isolates are susceptible to linezolid, which is an oxazolidinone that is available as an oral drug (27, 28). The combination of clarithromycin and linezolid exhibits good in vitro activity against M. abscessus isolates (25, 29). However, linezolid was not used at our institution for the treatment of NTM lung disease because of high costs and side effects such as peripheral neuropathy and bone marrow suppression (30, 31). One of the most difficult questions regarding the treatment of NTM lung disease, including M. abscessus lung disease, is when to start antibiotic therapy and how to construct treatment regimens (i.e., standardized treatment regimens vs. personalized treatment regimens). The decision to start antibiotic therapy is made by weighing the anticipated benefits and risks. The decision is relatively easy in patients with profound symptoms and destructive lesions; however, the decision is difficult in patients with mild symptoms and non-advanced lesions. Factors to consider must include the patient s age, severity of symptoms, and presence of comorbidities (32). Close observation is indicated if the decision is made not to treat. However, few studies have shown that patients with certain characteristics show disease progression (33). Optimal therapeutic regimens have not been established for M. abscessus lung disease. Clinicians have the choice between personalized treatment regimens and standardized treatment regimens. Personalized treatment regimens could be designed based on in vitro drug susceptibility testing results of bacilli in an individual patient. Our treatment strategy for patients with M. abscessus lung disease is divided into two paths: reservation of antibiotic therapy for patients with mild forms of the disease and initiation of aggressive antibiotic therapy with standardized regimens for patients with severe or progressive forms of the disease. However, standardized regimens could fail to acknowledge the wide divergence in in vitro drug susceptibility testing results of M. abscessus organisms.

6 Jeon, Kwon, Lee, et al.: Treatment of M. abscessus Disease 901 The frequently changing nomenclature to describe RGM is a source of confusion for clinicians. For instance, M. abscessus has been labeled as Mycobacterium cheloneii subspecies abscessus, Mycobacterium chelonae subspecies abscessus, and finally, in 1992, as M. abscessus (34). In recent years, Mycobacterium massiliense and Mycobacterium bolletii have been newly identified within the M. abscessus group (35, 36). Thus, the nomenclature of M. abscessus in the present study was referred to the M. abscessus group, which is now divided into three species: M. abscessus, M. massiliense and M. bolletii. Recent studies showed that low MIC of clarithromycin was observed for M. massiliense compared with M. abscessus (37, 38). In addition, M. bolletii was reported to be naturally resistant to clarithromycin (36, 39). These results suggest that accurate species identification and in vitro clarithromycin susceptibility testing are important for the treatment of lung disease caused by M. abscessus group and treatment outcomes may be different depending on the precise species obtained. The present study has several limitations. First, our study is a retrospective case study that was conducted at a single center. Treatment regimens cannot be optimized solely on the basis of retrospective studies with limited follow-up data; prospective clinical trials would be the proper approach. Second, the number of sputum specimens collected over time was relatively low. If the sputum samples are examined more frequently, we might find more frequent relapses and earlier ones. Third, bacterial genotyping was not performed in nine patients who became culture positive again after initial sputum conversion. Thus, we are not sure whether the recurrence was due to relapse with the original strain or reinfection with a genetically different strain (40, 41). Fourth, drug susceptibility results were available in only 69% (45/ 65) of patients. In addition, the inducible macrolide resistance and inducible erm gene, which provide an explanation for the lack of efficacy of macrolide-based treatments (42), were not determined in our study. Most importantly, whether or not a favorable microbiologic response will continue cannot be readily determined. Of the 38 patients who achieved culturenegative sputum for more than 12 months, 32 patients completed their antibiotic therapy and were followed up for only a median of 12 months. This follow-up duration after treatment completion was insufficient to detect sputum relapse in many patients. Therefore, further follow-up data are essential. In conclusion, a standardized combination therapy of antibiotics, which includes a clarithromycin-containing drug regimen, along with an initial 4-week course of cefoxitin and amikacin, is moderately effective in treating M. abscessus lung disease. Negative conversion of sputum was achieved and maintained for more than 12 months in 58% (38/65) of patients. However, frequent adverse reactions and a long duration of hospitalization are problems that remain to be solved. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The authors thank Ms. Shinok Kim of the Korean Institute of Tuberculosis and Ms. Eun Mi Park of Samsung Medical Center for their assistance and technical support. References 1. Wallace RJ Jr, Cook JL, Glassroth J, Griffith DE, Olivier KN, Gordin F. 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