BEYOND THE BLUE: What Fellows Are Reading in Other Journals Inhaled Antibiotics for Refractory Nontuberculous Mycobacteria and Non–Cystic Fibrosis Bronchiectasis and the Significance of Mycobacterium abscessus subsp. abscessus Isolation during M. avium Complex Lung Disease Therapy Vikramjit Mukherjee, William S. Bender, and John P. Egan III Division of Pulmonary, Critical Care, and Sleep Medicine, New York University School of Medicine, New York, New York Recommended Reading from the New York University School of Medicine Pulmonary, Critical Care, and Sleep Medicine Fellowship Program; Doreen Addrizzo-Harris, M.D., Program Director, and Ashwin Basavaraj, M.D., Assistant Program Director
Olivier KN, et al. Inhaled Amikacin for Treatment of Refractory Pulmonary Nontuberculous Mycobacterial Disease. Ann Am Thorac Soc (1) Reviewed by Vikramjit Mukherjee
Nontuberculous mycobacteria (NTM) are naturally occurring environmental pathogens that can cause severe, persistent lung disease in certain populations. Even completion of a lengthy and potentially toxic multidrug antibiotic regimen does not result in successful treatment in up to one-third of patients (2). Olivier and colleagues studied the effect of inhaled amikacin in 20 patients who had treatment-refractory NTM disease (1). The study was designed as a retrospective review, identifying patients who had met American Thoracic Society diagnostic guidelines for NTM disease and were treated with aerosolized amikacin. Microbiological details, including serial smear quantification, subspecies-level identification, and inducible macrolide resistance, were extracted, as were details such as severity of symptoms and serial computed tomography (CT) findings. Serial audiology reports were reviewed to assess the side-effect profile of the study drug. Amikacin sulfate was started via jet nebulizer at 250 mg once daily and then titrated up, as tolerated, to a maximum dose of 500 mg twice daily. The 20 patients who met study inclusion criteria were mostly women (80%), with a mean age of 56 years. The disease in this population was markedly refractory to conventional NTM treatment; patients had received an average of 5 years of treatment and had a median of eight positive cultures before initiation of amikacin. Of note, there was a wide variation in duration and type of treatment before initiation of amikacin—up to 16 antibiotics in various combinations and with duration of treatment lasting up to
15 years. Amikacin was added to failing regimens for treatment of refractory disease. Some 75% of patients had Mycobacterium abscessus, whereas the others had M. avium infections. Symptoms were mostly nonspecific and included productive cough, shortness of breath, weight loss, and fatigue. Although eight (40%) of these patients with refractory disease had initial culture conversion, three of them relapsed to have subsequent positive cultures, despite taking inhaled amikacin. Decrease in smear quantitation was noted in nine (45%) of the patients, and total symptom score improved in nine patients as well. Of note, the symptom score also worsened in four patients. Six (30%) patients showed improvements on serial CT scans, whereas eleven (55%) showed worsening; there was no correlation between sputum conversion and CT findings. Seven (35%) stopped taking amikacin because of toxicity, which included ototoxicity, hemoptysis, and nephrotoxicity. The most common tolerated dose was 250 mg once daily. Overall, this study reemphasizes the challenges in treating patients with refractory NTM. In this study, although there was improvement in sputum culture quantitation, clinical and radiologic improvements were unpredictable. Limitations of this study include its retrospective nature, limited sample size, and lack of correlation between sputum changes and clinical and radiologic improvement. Further studies, including an ongoing randomized controlled trial of inhaled amikacin, should help guide further management. n References 1. Olivier KN, Shaw PA, Glaser TS, Bhattacharyya D, Fleshner M, Brewer CC, Zalewski CK, Folio LR, Siegelman JR, Shallom S, et al. Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc 2014; 11:30–35.
( Received in original form February 19, 2015; accepted in final form April 11, 2015 ) Correspondence and requests for reprints should be addressed to Ashwin Basavaraj, M.D., Division of Pulmonary, Critical Care, and Sleep Medicine, NYU School of Medicine, 462 1st Avenue, NBV 7N24, New York, NY 10016. E-mail: [email protected] Am J Respir Crit Care Med Vol 192, Iss 1, pp 106–108, Jul 1, 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1164/rccm.201502-0360RR Internet address: www.atsjournals.org
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American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
BEYOND THE BLUE 2. Kasperbauer SH, Daley CL. Diagnosis and treatment of infections due to Mycobacterium avium complex. Semin Respir Crit Care Med 2008;29: 569–576.
genetics of NTM and virulence factors will be needed in the future. n References
Griffith DE, et al. The Significance of Mycobacterium abscessus Subspecies abscessus Isolation during Mycobacterium avium Complex Lung Disease Therapy. Chest (3) Reviewed by: John P. Egan III
3. Griffith DE, Philley JV, Brown-Elliott BA, Benwill J, Shepherd S, York D, Wallace RJ Jr. The significance of Mycobacterium abscessus subspecies abscessus isolation during Mycobacterium avium complex lung disease therapy. Chest 2014;147:1369–1375. 4. 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. [Published erratum appears in Am J Respir Crit Care Med 175:744–745.]
Treating Mycobacterium avium complex (MAC) lung disease can be made difficult when other nontuberculous mycobacteria (NTM), such as M. abscessus abscessus (MAA), are cultured from sputum. Determining which patients with MAC also have clinically significant lung disease secondary to MAA is challenging, and committing such patients to the lengthy courses of parenteral antibiotics required to treat MAA may be potentially harmful. In this retrospective analysis, Griffith and colleagues identified patients with nodular/bronchiectatic MAC who were also found to have MAA in respiratory isolates during the course of their treatment (3). Over a 2-year period, 53 of 180 (29%) patients treated for MAC-associated lung disease were also found to have isolates of MAA. These patients were divided into two groups. Group 1 (n = 32) had no clinically significant MAA lung disease. Group 2 (n = 21) patients had clinically significant MAA lung disease as defined by American Thoracic Society (ATS)/Infectious Disease Society of America criteria, including multiple positive isolates for MAA, as well as clinical and radiographic deterioration after initial improvement on MAC therapy (4). There were no significant differences between the two groups regarding demographics, number of cultures obtained, or length of follow up. Given how the groups were defined, the results are not unexpected: Group 2 had significantly more total positive cultures for MAA (15.0 6 11.1 vs. 1.2 6 0.4; P , 0.0001; confidence interval, 217.7 to 29.9), were more likely to develop cavitary lesions on MAC therapy (P . 0.0001), and were also more likely to meet all three ATS diagnostic criteria for NTM disease (21/21 [100%] vs. 0/32 [0%]; P , 0.0001). This study underscores the need for systematic and meticulous sample collection, which will help guide therapy in patients undergoing treatment for nodular/bronchiectatic MAC, in hopes of avoiding the addition of costly and potentially toxic medications to their regimens against a bacterium that may not cause significant disease. Limitations of this paper include the lack of long-term outcome data for the groups. Although the best clinical course of action in patients who are found to have MAA during their treatment for MAC still remains unclear, Griffith and colleagues have provided evidence to help guide physicians. Regular follow up in such patients is essential to determine which truly have MAA-associated lung disease. ATS/Infectious Disease Society of America diagnostic criteria, if completely met, maybe helpful in differentiating which patients have MAA-associated lung disease and which are simply colonized. More sophisticated tests focusing on the
Bronchiectasis is a chronic lung disease characterized by airway dilation and obstructive physiology. This results in a predilection for bacterial infections, and recent evidence suggests an increased prevalence as well as resource use with the disease (6, 7). In many cases, treatment regimens, including the use of inhaled antibiotics, are extrapolated from effective cystic fibrosis (CF) regimens given the relatively similar pathophysiological and microbiological patterns. The evidence supporting this practice, however, has not been well established (5). In this study consisting of two phase 3 controlled trials (AIRBX1 and AIR-BX2), the safety and efficacy of aztreonam for inhalation (AZLI) solution in patients with non-CF bronchiectasis and gram-negative bacterial colonization were evaluated. A total of 266 patients in AIR-BX1 and 274 patients in AIR-BX2 were randomized to AZLI or placebo. Each trial consisted of two 4-week courses of inhaled treatment with ALZI at 75 mg three times per day followed by 4 weeks without treatment. The primary endpoint was change in health-related quality of life as measured by the Quality of Life–Bronchiectasis Respiratory Symptoms score (QOL-B-RSS) at baseline and then 4 weeks, with higher scores representing fewer symptoms. Secondary endpoints were change in QOL-B-RSS from baseline to Week 12 and time to first exacerbation. Numerical improvements in QOL-B-RSS were noted for both AZLI-treated patients and placebo-treated patients; the difference between groups, however, was only significant in AIR-BX2 at Week 4 of AZLI (adjusted mean change [95% confidence interval], 4.6 [1.1–8.2]; P = 0.011). This difference was less than the minimal important difference determined for this study (8.0 points; Quittner AL, personal communication) and thus not deemed clinically significant. There was also a significant reduction in sputum bacterial density in both studies, but without a significant improvement in clinical endpoints. In fact, both trials were notable
Beyond the Blue: What Fellows Are Reading in Other Journals
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Barker AF, et al. Aztreonam for Inhalation Solution in Patients with Non-Cystic Fibrosis Bronchiectasis (AIR-BX1 and AIR-BX2): Two Randomised Double-Blind, Placebo-controlled Phase 3 Trials. Lancet Respir Med (5) Reviewed by William S. Bender
BEYOND THE BLUE for more adverse events in the AZLI group, with dyspnea, cough, and increased sputum production the most prevalent. In addition, the AZLI group had more adverse event–related withdrawals, with 22% (30 of 134) in AIR-BX1 and 8% (11 of 135) in AIR-BX2. No significant differences were noted with the secondary endpoints, and a clear responder population was not delineated in subgroup analyses. AZLI treatment was not associated with significant clinical improvement in patients with non-CF bronchiectasis. There are a number of possible reasons for such a disappointing outcome. For example, the patient selection was heterogeneous, and there were a large number of patients with COPD, particularly in the treatment arm. The study was also underpowered to detect exacerbation changes; one-third of patients were without exacerbations in the previous year. The endpoint selection and drug dosages chosen may also have played a role in the outcome. Additionally, extrapolating from the CF field did not deliver a significant benefit. A major focus of future work, therefore, could be directed at delineating the
108
phenotypes of the non-CF bronchiectasis population to allow for greater treatment effects. n Author disclosures are available with the text of this article at www.atsjournals.org.
References 5. Barker AF, O’Donnell AE, Flume P, Thompson PJ, Ruzi JD, de Gracia J, Boersma WG, De Soyza A, Shao L, Zhang J, et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebocontrolled phase 3 trials. Lancet Respir Med 2014;2:738–749. 6. Seitz AE, Olivier KN, Adjemian J, Holland SM, Prevots R. Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest 2012;142:432–439. 7. Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, Prevots DR. Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993-2006. Chest 2010;138:944–949.
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
Olivier KN, et al. Inhaled Amikacin for Treatment of Refractory Pulmonary Nontuberculous Mycobacterial Disease. Ann Am Thorac Soc (1) Reviewed by Vikramjit Mukherjee
Nontuberculous mycobacteria (NTM) are naturally occurring environmental pathogens that can cause severe, persistent lung disease in certain populations. Even completion of a lengthy and potentially toxic multidrug antibiotic regimen does not result in successful treatment in up to one-third of patients (2). Olivier and colleagues studied the effect of inhaled amikacin in 20 patients who had treatment-refractory NTM disease (1). The study was designed as a retrospective review, identifying patients who had met American Thoracic Society diagnostic guidelines for NTM disease and were treated with aerosolized amikacin. Microbiological details, including serial smear quantification, subspecies-level identification, and inducible macrolide resistance, were extracted, as were details such as severity of symptoms and serial computed tomography (CT) findings. Serial audiology reports were reviewed to assess the side-effect profile of the study drug. Amikacin sulfate was started via jet nebulizer at 250 mg once daily and then titrated up, as tolerated, to a maximum dose of 500 mg twice daily. The 20 patients who met study inclusion criteria were mostly women (80%), with a mean age of 56 years. The disease in this population was markedly refractory to conventional NTM treatment; patients had received an average of 5 years of treatment and had a median of eight positive cultures before initiation of amikacin. Of note, there was a wide variation in duration and type of treatment before initiation of amikacin—up to 16 antibiotics in various combinations and with duration of treatment lasting up to
15 years. Amikacin was added to failing regimens for treatment of refractory disease. Some 75% of patients had Mycobacterium abscessus, whereas the others had M. avium infections. Symptoms were mostly nonspecific and included productive cough, shortness of breath, weight loss, and fatigue. Although eight (40%) of these patients with refractory disease had initial culture conversion, three of them relapsed to have subsequent positive cultures, despite taking inhaled amikacin. Decrease in smear quantitation was noted in nine (45%) of the patients, and total symptom score improved in nine patients as well. Of note, the symptom score also worsened in four patients. Six (30%) patients showed improvements on serial CT scans, whereas eleven (55%) showed worsening; there was no correlation between sputum conversion and CT findings. Seven (35%) stopped taking amikacin because of toxicity, which included ototoxicity, hemoptysis, and nephrotoxicity. The most common tolerated dose was 250 mg once daily. Overall, this study reemphasizes the challenges in treating patients with refractory NTM. In this study, although there was improvement in sputum culture quantitation, clinical and radiologic improvements were unpredictable. Limitations of this study include its retrospective nature, limited sample size, and lack of correlation between sputum changes and clinical and radiologic improvement. Further studies, including an ongoing randomized controlled trial of inhaled amikacin, should help guide further management. n References 1. Olivier KN, Shaw PA, Glaser TS, Bhattacharyya D, Fleshner M, Brewer CC, Zalewski CK, Folio LR, Siegelman JR, Shallom S, et al. Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am Thorac Soc 2014; 11:30–35.
( Received in original form February 19, 2015; accepted in final form April 11, 2015 ) Correspondence and requests for reprints should be addressed to Ashwin Basavaraj, M.D., Division of Pulmonary, Critical Care, and Sleep Medicine, NYU School of Medicine, 462 1st Avenue, NBV 7N24, New York, NY 10016. E-mail: [email protected] Am J Respir Crit Care Med Vol 192, Iss 1, pp 106–108, Jul 1, 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1164/rccm.201502-0360RR Internet address: www.atsjournals.org
106
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
BEYOND THE BLUE 2. Kasperbauer SH, Daley CL. Diagnosis and treatment of infections due to Mycobacterium avium complex. Semin Respir Crit Care Med 2008;29: 569–576.
genetics of NTM and virulence factors will be needed in the future. n References
Griffith DE, et al. The Significance of Mycobacterium abscessus Subspecies abscessus Isolation during Mycobacterium avium Complex Lung Disease Therapy. Chest (3) Reviewed by: John P. Egan III
3. Griffith DE, Philley JV, Brown-Elliott BA, Benwill J, Shepherd S, York D, Wallace RJ Jr. The significance of Mycobacterium abscessus subspecies abscessus isolation during Mycobacterium avium complex lung disease therapy. Chest 2014;147:1369–1375. 4. 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. [Published erratum appears in Am J Respir Crit Care Med 175:744–745.]
Treating Mycobacterium avium complex (MAC) lung disease can be made difficult when other nontuberculous mycobacteria (NTM), such as M. abscessus abscessus (MAA), are cultured from sputum. Determining which patients with MAC also have clinically significant lung disease secondary to MAA is challenging, and committing such patients to the lengthy courses of parenteral antibiotics required to treat MAA may be potentially harmful. In this retrospective analysis, Griffith and colleagues identified patients with nodular/bronchiectatic MAC who were also found to have MAA in respiratory isolates during the course of their treatment (3). Over a 2-year period, 53 of 180 (29%) patients treated for MAC-associated lung disease were also found to have isolates of MAA. These patients were divided into two groups. Group 1 (n = 32) had no clinically significant MAA lung disease. Group 2 (n = 21) patients had clinically significant MAA lung disease as defined by American Thoracic Society (ATS)/Infectious Disease Society of America criteria, including multiple positive isolates for MAA, as well as clinical and radiographic deterioration after initial improvement on MAC therapy (4). There were no significant differences between the two groups regarding demographics, number of cultures obtained, or length of follow up. Given how the groups were defined, the results are not unexpected: Group 2 had significantly more total positive cultures for MAA (15.0 6 11.1 vs. 1.2 6 0.4; P , 0.0001; confidence interval, 217.7 to 29.9), were more likely to develop cavitary lesions on MAC therapy (P . 0.0001), and were also more likely to meet all three ATS diagnostic criteria for NTM disease (21/21 [100%] vs. 0/32 [0%]; P , 0.0001). This study underscores the need for systematic and meticulous sample collection, which will help guide therapy in patients undergoing treatment for nodular/bronchiectatic MAC, in hopes of avoiding the addition of costly and potentially toxic medications to their regimens against a bacterium that may not cause significant disease. Limitations of this paper include the lack of long-term outcome data for the groups. Although the best clinical course of action in patients who are found to have MAA during their treatment for MAC still remains unclear, Griffith and colleagues have provided evidence to help guide physicians. Regular follow up in such patients is essential to determine which truly have MAA-associated lung disease. ATS/Infectious Disease Society of America diagnostic criteria, if completely met, maybe helpful in differentiating which patients have MAA-associated lung disease and which are simply colonized. More sophisticated tests focusing on the
Bronchiectasis is a chronic lung disease characterized by airway dilation and obstructive physiology. This results in a predilection for bacterial infections, and recent evidence suggests an increased prevalence as well as resource use with the disease (6, 7). In many cases, treatment regimens, including the use of inhaled antibiotics, are extrapolated from effective cystic fibrosis (CF) regimens given the relatively similar pathophysiological and microbiological patterns. The evidence supporting this practice, however, has not been well established (5). In this study consisting of two phase 3 controlled trials (AIRBX1 and AIR-BX2), the safety and efficacy of aztreonam for inhalation (AZLI) solution in patients with non-CF bronchiectasis and gram-negative bacterial colonization were evaluated. A total of 266 patients in AIR-BX1 and 274 patients in AIR-BX2 were randomized to AZLI or placebo. Each trial consisted of two 4-week courses of inhaled treatment with ALZI at 75 mg three times per day followed by 4 weeks without treatment. The primary endpoint was change in health-related quality of life as measured by the Quality of Life–Bronchiectasis Respiratory Symptoms score (QOL-B-RSS) at baseline and then 4 weeks, with higher scores representing fewer symptoms. Secondary endpoints were change in QOL-B-RSS from baseline to Week 12 and time to first exacerbation. Numerical improvements in QOL-B-RSS were noted for both AZLI-treated patients and placebo-treated patients; the difference between groups, however, was only significant in AIR-BX2 at Week 4 of AZLI (adjusted mean change [95% confidence interval], 4.6 [1.1–8.2]; P = 0.011). This difference was less than the minimal important difference determined for this study (8.0 points; Quittner AL, personal communication) and thus not deemed clinically significant. There was also a significant reduction in sputum bacterial density in both studies, but without a significant improvement in clinical endpoints. In fact, both trials were notable
Beyond the Blue: What Fellows Are Reading in Other Journals
107
Barker AF, et al. Aztreonam for Inhalation Solution in Patients with Non-Cystic Fibrosis Bronchiectasis (AIR-BX1 and AIR-BX2): Two Randomised Double-Blind, Placebo-controlled Phase 3 Trials. Lancet Respir Med (5) Reviewed by William S. Bender
BEYOND THE BLUE for more adverse events in the AZLI group, with dyspnea, cough, and increased sputum production the most prevalent. In addition, the AZLI group had more adverse event–related withdrawals, with 22% (30 of 134) in AIR-BX1 and 8% (11 of 135) in AIR-BX2. No significant differences were noted with the secondary endpoints, and a clear responder population was not delineated in subgroup analyses. AZLI treatment was not associated with significant clinical improvement in patients with non-CF bronchiectasis. There are a number of possible reasons for such a disappointing outcome. For example, the patient selection was heterogeneous, and there were a large number of patients with COPD, particularly in the treatment arm. The study was also underpowered to detect exacerbation changes; one-third of patients were without exacerbations in the previous year. The endpoint selection and drug dosages chosen may also have played a role in the outcome. Additionally, extrapolating from the CF field did not deliver a significant benefit. A major focus of future work, therefore, could be directed at delineating the
108
phenotypes of the non-CF bronchiectasis population to allow for greater treatment effects. n Author disclosures are available with the text of this article at www.atsjournals.org.
References 5. Barker AF, O’Donnell AE, Flume P, Thompson PJ, Ruzi JD, de Gracia J, Boersma WG, De Soyza A, Shao L, Zhang J, et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebocontrolled phase 3 trials. Lancet Respir Med 2014;2:738–749. 6. Seitz AE, Olivier KN, Adjemian J, Holland SM, Prevots R. Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest 2012;142:432–439. 7. Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, Prevots DR. Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993-2006. Chest 2010;138:944–949.
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
