EDITORIALS Treatment of Pulmonary Nontuberculous Mycobacterial Infections: Many Questions Remain The more than 160 species collectively referred to as nontuberculous mycobacteria (NTM) are now more commonly isolated in some parts of the world than Mycobacterium tuberculosis. While NTM are generally considered less virulent than M. tuberculosis and some species are usually regarded as nonvirulent, others can and do cause disease including pulmonary disease. Despite their perceived clinical importance, our understanding of these organisms is still limited. There is debate about how they are transmitted, the true incidence/prevalence of NTM pulmonary disease, when to treat them, what drugs to use, how long to continue treatment, and even how best to design clinical studies to advance our knowledge. Indeed, much of what we do clinically with NTM is based on experience with a relatively few species such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus. Expert groups have developed guidelines based on the relatively limited data available to assist clinicians in managing NTM (1). This issue of AnnalsATS offers a series of articles that try to advance our knowledge. While these are provocative and welcome for the information they provide, they also illustrate some problems with studying NTM. Successful treatment of NTM infections is limited by the need for multidrug regimens administered for long durations and often associated with adverse reactions. Current expert guidelines (1) recommend a three-drug treatment regimen for pulmonary MAC infection, including a macrolide (azithromycin or clarithromycin), rifamycin (rifampin or rifabutin), and ethambutol. The regimen should be given for 12 months of culture negativity, often resulting in treatment courses of 18 or more months. Despite these long durations of treatment, cure rates for pulmonary MAC and M. abscessus infections are disappointingly low and adverse reactions disappointingly high. The most effective drugs, optimal drug doses, and drug combinations are simply not known. To date there have been only two randomized trials published that related to treatment of MAC pulmonary infections (2, 3). In this issue of AnnalsATS, Miwa and coworkers (pp. 23–29) from Japan attempt to find a better tolerated regimen through conducting a randomized, open-label study comparing a two-drug (clarithromycin and ethambutol) versus a three-drug (clarithromycin, ethambutol, and rifampin) treatment regimen (4). In this study, 119 of 123 patients assessed for eligibility with MAC lung disease were randomized to the three-drug regimen (n = 59) or the two-drug regimen (n = 60). The subjects were well matched in terms of demographics, but the extent of disease is not well described, nor are co-morbidities that could affect treatment outcomes or drug tolerance. The investigators in this study chose to use dosages and administration schedules that are not currently recommended (1). Although difficult to discern from the study, the drug exposures were likely lower than in some previous studies and clarithromycin was given three times a day (a dosing schedule that is not recommended). This latter dosing schedule contributed to very low serum drug concentrations when given with rifampin, but this is unlikely to have been as dramatic with once- or twicedaily dosing (5–7). While serum drug concentrations may not 96
correlate with treatment outcomes (8), drug dosages may. These important decisions reduce the external validity (generalizability) of the study, make it difficult to compare with previous studies, and highlight the need to establish evidence-based dosing for NTM. Importantly, the authors report no difference in culture conversion between the regimens at 12 months, and conclude that the two-drug regimen is not inferior to the three-drug regimen. The trial is described as a noninferiority trial, but it is adequately powered only for the aggregate group of 119 participants, leaving open the question of whether issues of extent of disease or cavitary and noncavitary forms of disease affect response. In an intention-totreat analysis, 40.6% of those receiving the three-drug regimen converted their culture to negative after 12 months of therapy, compared with 55.0% with the two-drug regimen. In addition, 22/ 59 (37%) discontinued treatment in the three-drug arm and 16/60 (27%) in the two-drug arm because of adverse reactions. In a “per protocol” analysis, 24/32 (75%) patients receiving the three-drug regimen had negative cultures at 12 months compared with 33/40 (82.5%) in the two-drug arm; durability of these responses was not reported. The difference reported between the intention-to-treat analysis and the “per protocol” analysis, the former showing statistical “noninferiority” and the latter failing that test, is likely due to the high rate of discontinuation from the study primarily because of adverse reactions, a very common scenario in clinical practice. Whether a two-drug regimen is truly noninferior to a three-drug regimen cannot be definitively determined from this trial and a two-drug regimen should not be used at this time. However, what is clearly evident from this trial, as well as from previous trials, is that treatment outcomes are poor and drug-related toxicity is very common. Sadly, with our current antimycobacterial drugs and approach to treatment we are unlikely to significantly improve treatment outcomes, although we may be able develop regimens that are better tolerated. Drugs that are being developed for treatment of tuberculosis often have in vitro activity against NTM, but it will require rigorous clinical trials and years before these drugs make their way into clinical practice (6). In the meantime, we should look to repurpose our current drugs and determine the optimal drug dosages and combinations and methods of delivery for improved treatment outcomes. In this issue of AnnalsATS, Olivier and coworkers (pp. 30–35) report the results of another singlecenter study of therapy for two species of NTM, M. abscessus (n = 15) and MAC (n = 5), associated with bronchiectatic pulmonary disease in patients who had been failing treatment and who had inhaled amikacin added to their multidrug regimens (9). Clinical responses (i.e., microbiologic, symptomatic, and/or chest imaging) were noted, as were adverse reactions potentially related to amikacin. Patients were treated with a variety of inhaled amikacin doses, and treatment frequencies and the duration of treatment and follow-up varied widely. The authors report that 8 (40%) patients had a least one negative culture, 5 (25%) had persistently negative cultures, symptoms scores improved in 9 (45%), and computed tomography (CT) scores improved in 6 (30%). Because of the frequently changing dose, it is not possible to determine which of the different dosing schemes were associated with better treatment outcomes. Importantly, 7 (35%) of the patients had to stop the medication due to side effects and many others had to have the dose adjusted downward. Based on these results it AnnalsATS Volume 11 Number 1 | January 2014
EDITORIALS appears that inhaled amikacin may result in some improvement in bacteriology, symptoms, and CT abnormalities. Whether the drug is better than placebo is not known, and a prolonged response is seen in a minority of patients. Unfortunately, inhaled amikacin was associated with a high frequency of adverse reactions. Which dose and frequency of administration would provide the best balance between effectiveness and toxicity is unclear, as is the question of whether earlier use of inhaled amikacin might be a useful strategy. Enrollment into a Phase II randomized, placebo-controlled trial evaluating inhaled liposomal amikacin (Insmed) has just been completed, creating the potential for answering some of these questions. These and previous studies highlight many of the difficulties encountered in attempting to conduct rigorous clinical trials in patients with NTM infections. First, few centers, if any, have enough patients to conduct adequately powered clinical trials; robust trials will have to be multi-center studies that will be costly to conduct. Second, patients with NTM represent a broad group of patients with various comorbidities, different clinical presentations, and extent of disease. Previous studies have demonstrated that treatment outcomes are worse in patients who have acid-fast bacilli smear–positive disease (10) and those with cavitary disease (11), so it is important for studies to analyze trial results stratified by factors that are known to affect outcomes. Third, there are over 160 different species of NTM, and the treatment of these infections varies. It will not be possible to provide evidence-based treatment recommendations for all pathogenic species. Therefore, limited resources will need to be focused on the most clinically relevant species such as MAC and M. abscessus. Fourth, precise speciation is very important, as outcomes of treatment vary by species and even subspecies. Although MAC organisms (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, and others) are typically considered similar in their clinical presentation and response to therapy, a recent study reported worse outcomes with treatment of M. intracellulare compared with M. avium (12). Similarly, patients with M. abscessus ssp. massiliense have better treatment outcomes than those with M. abscessus ssp. abscessus (13). Fifth, the best measure of treatment success is not known. For tuberculosis, numerous studies have documented that 2-month culture status is a useful biomarker for cure/relapse (14). However, no such biomarker exists for pulmonary NTM infections. Is a 12-month culture result that was used by Miwa and colleagues meaningful? We cannot currently determine the answer to this question because of another issue that affects clinical trials with NTM to date: the lack of long-term follow-up. At some point, the rate of recurrence needs to be evaluated in a large cohort of patients and reinfection will need to be distinguished from true relapse. We applaud the attempts by investigators to improve the outcomes of our patients with NTM and appreciate the many barriers they face. However, the only way we can truly affect our practice is through the conduct of rigorous clinical trials using recommended approaches to design, reporting, and analysis (15). New drugs, new regimens, and new approaches are greatly needed if we are to improve treatment outcomes in our patients with NTM infections. However, many questions remain. The answers remain elusive, but clarity may be a clinical trial away. Author disclosures are available with the text of this article at www.atsjournals.org.
Editorials
Charles L. Daley, M.D. National Jewish Health and the University of Colorado Denver, Colorado Jeffrey Glassroth, M.D. University of Chicago Pritzker School of Medicine Chicago Illinois
References 1 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 2 Research Committee of the British Thoracic Society. First randomized trial for pulmonary disease caused by M. avium intracellulare, M. malmoense, and M. xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax 2001;56:67–72. 3 Jenkins PA, Campbell IA, Banks J, Gelder CM, Prescott RJ, Smith AP. Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy. Thorax 2008;63:627–634. 4 Miwa S, Shirai M, Toyoshima M, Shirai T, Yasuda K, Yokomura K, Yamada T, Masuda M, Inui N, Chida K, et al. Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. Ann Am Thorac Soc 2014;11:23–29. 5 Magis-Escurra C, Alffenaar JW, Hoefnagels I, Dekhuijzen PN, Boeree MJ, van Ingen J, Aarnoutse RE. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections. Int J Antimicrob Agents 2013;42:256–261. 6 van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, Aarnoutse RE, Heifets LB, Peloquin CA, Daley CL. The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment. Am J Respir Crit Care Med 2012;186:559–565. 7 Koh WJ, Jeong BH, Jeon K, Lee SY, Shin SJ. Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2012;186:797–802. 8 Andries K, Verhasselt P, Guillemont J, Gohlmann ¨ HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223–227. 9 Olivier KN, Shaw PA, Glaser TS, Bhattacharyya D, Fleshner M, Brewer CC, Zalewski CK, Folio LR, Siegelman JR, Holland SM, et al. Inhaled amikacin for treatment of pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc 2014;11:30–35. 10 Sim YS, Park HY, Jeon K, Suh GY, Kwon OJ, Koh WJ. Standardized combination antibiotic treatment of Mycobacterium avium complex lung disease. Yonsei Med J 2010;51:888–894. 11 Kuroishi S, Nakamura Y, Hayakawa H, Shirai M, Nakano Y, Yasuda K, Suda T, Nakamura H, Chida K. Mycobacterium avium complex disease: prognostic implication of high-resolution computed tomography findings. Eur Respir J 2008;32:147–152. 12 Koh WJ, Jeong BH, Jeon K, Lee NY, Lee KS, Woo SY, Shin SJ, Kwon OJ. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M. avium complex lung disease. Chest 2012;142:1482–1488. 13 Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, Park YK, Kim CK, Shin SJ, Huitt GA, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 2011;183:405–410. 14 Wallis RS, Kim P, Cole S, Hanna D, Andrade BB, Maeurer M, Schito M, Zumla A. Tuberculosis biomarkers discovery: developments, needs, and challenges. Lancet Infect Dis 2013;13:362–372. 15 Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7:e1000251. Copyright © 2014 by the American Thoracic Society
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correlate with treatment outcomes (8), drug dosages may. These important decisions reduce the external validity (generalizability) of the study, make it difficult to compare with previous studies, and highlight the need to establish evidence-based dosing for NTM. Importantly, the authors report no difference in culture conversion between the regimens at 12 months, and conclude that the two-drug regimen is not inferior to the three-drug regimen. The trial is described as a noninferiority trial, but it is adequately powered only for the aggregate group of 119 participants, leaving open the question of whether issues of extent of disease or cavitary and noncavitary forms of disease affect response. In an intention-totreat analysis, 40.6% of those receiving the three-drug regimen converted their culture to negative after 12 months of therapy, compared with 55.0% with the two-drug regimen. In addition, 22/ 59 (37%) discontinued treatment in the three-drug arm and 16/60 (27%) in the two-drug arm because of adverse reactions. In a “per protocol” analysis, 24/32 (75%) patients receiving the three-drug regimen had negative cultures at 12 months compared with 33/40 (82.5%) in the two-drug arm; durability of these responses was not reported. The difference reported between the intention-to-treat analysis and the “per protocol” analysis, the former showing statistical “noninferiority” and the latter failing that test, is likely due to the high rate of discontinuation from the study primarily because of adverse reactions, a very common scenario in clinical practice. Whether a two-drug regimen is truly noninferior to a three-drug regimen cannot be definitively determined from this trial and a two-drug regimen should not be used at this time. However, what is clearly evident from this trial, as well as from previous trials, is that treatment outcomes are poor and drug-related toxicity is very common. Sadly, with our current antimycobacterial drugs and approach to treatment we are unlikely to significantly improve treatment outcomes, although we may be able develop regimens that are better tolerated. Drugs that are being developed for treatment of tuberculosis often have in vitro activity against NTM, but it will require rigorous clinical trials and years before these drugs make their way into clinical practice (6). In the meantime, we should look to repurpose our current drugs and determine the optimal drug dosages and combinations and methods of delivery for improved treatment outcomes. In this issue of AnnalsATS, Olivier and coworkers (pp. 30–35) report the results of another singlecenter study of therapy for two species of NTM, M. abscessus (n = 15) and MAC (n = 5), associated with bronchiectatic pulmonary disease in patients who had been failing treatment and who had inhaled amikacin added to their multidrug regimens (9). Clinical responses (i.e., microbiologic, symptomatic, and/or chest imaging) were noted, as were adverse reactions potentially related to amikacin. Patients were treated with a variety of inhaled amikacin doses, and treatment frequencies and the duration of treatment and follow-up varied widely. The authors report that 8 (40%) patients had a least one negative culture, 5 (25%) had persistently negative cultures, symptoms scores improved in 9 (45%), and computed tomography (CT) scores improved in 6 (30%). Because of the frequently changing dose, it is not possible to determine which of the different dosing schemes were associated with better treatment outcomes. Importantly, 7 (35%) of the patients had to stop the medication due to side effects and many others had to have the dose adjusted downward. Based on these results it AnnalsATS Volume 11 Number 1 | January 2014
EDITORIALS appears that inhaled amikacin may result in some improvement in bacteriology, symptoms, and CT abnormalities. Whether the drug is better than placebo is not known, and a prolonged response is seen in a minority of patients. Unfortunately, inhaled amikacin was associated with a high frequency of adverse reactions. Which dose and frequency of administration would provide the best balance between effectiveness and toxicity is unclear, as is the question of whether earlier use of inhaled amikacin might be a useful strategy. Enrollment into a Phase II randomized, placebo-controlled trial evaluating inhaled liposomal amikacin (Insmed) has just been completed, creating the potential for answering some of these questions. These and previous studies highlight many of the difficulties encountered in attempting to conduct rigorous clinical trials in patients with NTM infections. First, few centers, if any, have enough patients to conduct adequately powered clinical trials; robust trials will have to be multi-center studies that will be costly to conduct. Second, patients with NTM represent a broad group of patients with various comorbidities, different clinical presentations, and extent of disease. Previous studies have demonstrated that treatment outcomes are worse in patients who have acid-fast bacilli smear–positive disease (10) and those with cavitary disease (11), so it is important for studies to analyze trial results stratified by factors that are known to affect outcomes. Third, there are over 160 different species of NTM, and the treatment of these infections varies. It will not be possible to provide evidence-based treatment recommendations for all pathogenic species. Therefore, limited resources will need to be focused on the most clinically relevant species such as MAC and M. abscessus. Fourth, precise speciation is very important, as outcomes of treatment vary by species and even subspecies. Although MAC organisms (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, and others) are typically considered similar in their clinical presentation and response to therapy, a recent study reported worse outcomes with treatment of M. intracellulare compared with M. avium (12). Similarly, patients with M. abscessus ssp. massiliense have better treatment outcomes than those with M. abscessus ssp. abscessus (13). Fifth, the best measure of treatment success is not known. For tuberculosis, numerous studies have documented that 2-month culture status is a useful biomarker for cure/relapse (14). However, no such biomarker exists for pulmonary NTM infections. Is a 12-month culture result that was used by Miwa and colleagues meaningful? We cannot currently determine the answer to this question because of another issue that affects clinical trials with NTM to date: the lack of long-term follow-up. At some point, the rate of recurrence needs to be evaluated in a large cohort of patients and reinfection will need to be distinguished from true relapse. We applaud the attempts by investigators to improve the outcomes of our patients with NTM and appreciate the many barriers they face. However, the only way we can truly affect our practice is through the conduct of rigorous clinical trials using recommended approaches to design, reporting, and analysis (15). New drugs, new regimens, and new approaches are greatly needed if we are to improve treatment outcomes in our patients with NTM infections. However, many questions remain. The answers remain elusive, but clarity may be a clinical trial away. Author disclosures are available with the text of this article at www.atsjournals.org.
Editorials
Charles L. Daley, M.D. National Jewish Health and the University of Colorado Denver, Colorado Jeffrey Glassroth, M.D. University of Chicago Pritzker School of Medicine Chicago Illinois
References 1 Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 2 Research Committee of the British Thoracic Society. First randomized trial for pulmonary disease caused by M. avium intracellulare, M. malmoense, and M. xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax 2001;56:67–72. 3 Jenkins PA, Campbell IA, Banks J, Gelder CM, Prescott RJ, Smith AP. Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy. Thorax 2008;63:627–634. 4 Miwa S, Shirai M, Toyoshima M, Shirai T, Yasuda K, Yokomura K, Yamada T, Masuda M, Inui N, Chida K, et al. Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. Ann Am Thorac Soc 2014;11:23–29. 5 Magis-Escurra C, Alffenaar JW, Hoefnagels I, Dekhuijzen PN, Boeree MJ, van Ingen J, Aarnoutse RE. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections. Int J Antimicrob Agents 2013;42:256–261. 6 van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, Aarnoutse RE, Heifets LB, Peloquin CA, Daley CL. The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment. Am J Respir Crit Care Med 2012;186:559–565. 7 Koh WJ, Jeong BH, Jeon K, Lee SY, Shin SJ. Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2012;186:797–802. 8 Andries K, Verhasselt P, Guillemont J, Gohlmann ¨ HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223–227. 9 Olivier KN, Shaw PA, Glaser TS, Bhattacharyya D, Fleshner M, Brewer CC, Zalewski CK, Folio LR, Siegelman JR, Holland SM, et al. Inhaled amikacin for treatment of pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc 2014;11:30–35. 10 Sim YS, Park HY, Jeon K, Suh GY, Kwon OJ, Koh WJ. Standardized combination antibiotic treatment of Mycobacterium avium complex lung disease. Yonsei Med J 2010;51:888–894. 11 Kuroishi S, Nakamura Y, Hayakawa H, Shirai M, Nakano Y, Yasuda K, Suda T, Nakamura H, Chida K. Mycobacterium avium complex disease: prognostic implication of high-resolution computed tomography findings. Eur Respir J 2008;32:147–152. 12 Koh WJ, Jeong BH, Jeon K, Lee NY, Lee KS, Woo SY, Shin SJ, Kwon OJ. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M. avium complex lung disease. Chest 2012;142:1482–1488. 13 Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, Park YK, Kim CK, Shin SJ, Huitt GA, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 2011;183:405–410. 14 Wallis RS, Kim P, Cole S, Hanna D, Andrade BB, Maeurer M, Schito M, Zumla A. Tuberculosis biomarkers discovery: developments, needs, and challenges. Lancet Infect Dis 2013;13:362–372. 15 Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7:e1000251. Copyright © 2014 by the American Thoracic Society
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