- Email: [email protected]
Actual practice of standard treatment for pulmonary nontuberculous mycobacteriosis in Japan
Respiratory Medicine 158 (2019) 67–69
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed
Short communication
Actual practice of standard treatment for pulmonary nontuberculous mycobacteriosis in Japan Kozo Morimoto a, b, *, 1, Kiyohiko Izumi b, 1, Manabu Ato c, Naoki Hasegawa d, Satoshi Mitarai b, e a
Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Japan c National Institute of Infectious Diseases, Japan d Keio University School of Medicine, Japan e Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan b
A R T I C L E I N F O
A B S T R A C T
Keywords: Treatment Clarithromycin resistant Guideline Insurance claim
Introduction: The details of the practice of treating nontuberculous mycobacterial pulmonary disease (NTMPD) have not been studied in Japan. Methods: We studied a random sample of 2% (184) of the 9,200 patients with incident NTM-PD in 2010 who received standard three-drug therapy for at least some of their treatment between 2010 and 2014. Results: The median duration of the standard treatment period was 248 days (IQR 56–540 days). Although 59% of the patients were treated with standard therapy for more than 6 months, only 41% were treated for 12 months. Fifty-three patients (29%) initiated treatment with substandard regimen, and 18 (34%) of those patients received treatment regimens that can lead to the development of macrolide resistance (MR)(CLR monotherapy or CLR þ RIF). Furthermore, initially, 184 receiving the standard treatment, 49 patients (27%) eventually deviated from it, and 31 patients (63%) received regimens increasing the risk of developing MR. The sporadic administration of macrolide monotherapy was observed before and after the administration of the standard treatment for 50 pa tients (27.7%) and 41 patients (27.2%), respectively. Conclusions: Approximately 60% of the treated patients did not continue the standard regimen for more than 12 months and 42% were at risk for developing MR before and after receiving the standard treatment. It is important to educate physicians and patients about the correct and safe management of NTMPD.
1. Introduction Macrolide-resistant Mycobacterium avium complex pulmonary dis ease (MAC-PD) is associated with a long course of treatment with toxic medications and a high mortality rate [1–4]. Although MAC can acquire resistance through inappropriate treatment, only 13% of clinicians follow the macrolide-containing recommended treatment, and 30% of these used regimens that have been shown to induce macrolide resis tance in the US [5]. In Japan, clarithromycin (CLR) monotherapy and deviations from the standard regimens, especially the cessation of ethambutol (EMB) due to side effects, including visual disturbances and skin eruptions, were commonly observed among macrolide-resistant MAC patients [1]. We previously reported that mortality due to non tuberculous mycobacteriosis (NTM) has been increasing over the past 40
years, and this trend may be partially explained by the accumulation of severe cases, including those with CLR resistance caused by inappro priate treatment [6]. However, little is known about the actual treat ment of MAC-PD patients who started with the standard treatment. Therefore, we evaluated treatment duration and pre- and post-standard treatment medication using representative nationwide data. 2. Material and methods We extracted the incident cases in 2010 (64,884 cases, the look-back window was three months) with at least one insurance claim with ICD10 codes associated with NTM pulmonary disease (NTM-PD) (A310 and A319) from the national health insurance database, which includes data from the entire Japanese population covered under the universal health
* Corresponding author. Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, 3-1-24, Matsuyama, Kiyose City, Tokyo, 204-8522, Japan. E-mail address: [email protected] (K. Morimoto). 1 The first two authors contributed equally to this article. https://doi.org/10.1016/j.rmed.2019.10.002 Received 3 February 2019; Received in revised form 2 September 2019; Accepted 4 October 2019 Available online 4 October 2019 0954-6111/© 2019 Published by Elsevier Ltd.
K. Morimoto et al.
Respiratory Medicine 158 (2019) 67–69
insurance system. Among the extracted cases, 9,200 were identified as receiving the CLR-based three-drug standard treatment at some point during the observation period from 2010 to 2014 [CLR þ EMB þ rifampicin (RIF)]. To focus on analysing the detailed treatment course, we then randomly selected two percent of the cases and eventually enrolled a total of 184 cases [133 in females (72.3%)] in the analysis (Fig. 1). Because MAC-PD comprises more than 90% of all NTM-PD cases in Japan [7], the vast majority of NTM-PD cases treated with the three-drug standard treatment could be regarded as MAC-pulmonary disease. Sub-standard treatment was defined as any single or two-drug combination of the standard three drugs. Fluoroquinolones (FQs) included when used together with these one or two drugs. CLR, CLR þ RIF, CLR þ FQs, and CLR þ RIF þ FQs were regarded as prescription inducing macrolide resistance. 3. Results We reviewed the course of treatment of the selected cases from January 2010 to December 2014, dividing the period into the following five categories (Fig. 2): “A-1” was the standard treatment period; “A-2” was the period of initial sub-standard treatment, e.g., CLR þ EMB or CLR þ RIF, prior to the initiation of standard treatment (A-1); “A3” was the period of subsequent sub-standard treatment after standard treat ment; “B” was the period from January 2010 to the initiation of any treatment; and “C” was the period from the end of the standard or subsequent sub-standard treatment to the end of the observation period. Category A-1. The median duration of the standard treatment was 248 days (IQR 56–540). While 59% of the patients were treated for more than six months, fewer patients were treated more than one year (41%) and even fewer for more than 18 months (25%). During this period, 14 patients (7.6%) were administered aminoglycosides. Category A-2. A total of 53 patients (28.8%) underwent initial substandard treatment before the initiation of standard treatment (A-1). Among them, 28 patients (52.8%) were administered CLR þ EMB, 15 patients (28.3%) were administered CLR, and 3 patients (5.7%) were administered CLR þ RIF. Category A-3. Among the patients who initiated standard treatment, 49 (26.6%) changed regimens, and 31 (63.3%) used regimens that may induce macrolide resistance. Category A1-A3. Throughout the entire observation period, 23 pa tients (12.5%) used fluoroquinolone together with their standard or substandard treatment regimen for a median of 300 days (IQR 161–524), and 23 patients (21.1%) sporadically used FQ for a median of five days (IQR 5–28.5). Category B. The median duration of the period from January 2010
Fig. 2. Treatment course for standard treatment for pulmonary nontuberculous mycobacteriosis from 2010 to 2014. CLR, clarithromycin; AZM, azithromycin; EMB, ethambutol; RIF, rifamycin; FQs, fluoroquinolones.
to the initiation of standard or initial sub-standard treatment was 213 days (IQR 61–488). There was no case that had already on treatment in 2010. Macrolide was prescribed for 50 patients (27.2%). CLA was pre scribed for 40 patients for a total of 20 days (IQR 6–67), and azi thromycin was prescribed for 10 patients for three days (IQR 3–6). FQs were prescribed for 33 patients (17.9%) for a total of 19 days. Category C. After excluding 33 patients who continued their first treatment regimens through the period, 151 patients were evaluated for the period from the end of the standard or subsequent sub-standard treatment to the end of the observation period. Macrolide mono therapy was provided to 41 patients (27.2%), including duplication. Among them, CLR was prescribed for 39 patients (95.1%) for a median of 23 days (IQR 8–107) and azithromycin for less than 10 patients for a median of three days (IQR 3–3.8). FQs were prescribed for 26 patients (17.2%) for a total of 73 days. A second treatment regimen was initiated for 29 patients during this period, and 24 patients started the standard treatment. Among the seven patients (24.1%) who changed regimens, six changed to regimens that had a risk of macrolide resistance. Overall, 76 cases (42%) received at leaset one prescription that has the risk of macrolide resistance during the observation period. 4. Discussion A previous survey reported that 40% of NTM-PD cases continued standard treatment for more than 6 months in Japan [8]. Although our study showed a higher proportion of 58.9%, many MAC-PD cases did not receive standard treatment for the duration recommended by the guideline, a minimum of 12 months culture negativity, possibly causing relapse of the disease [9]. Intermittent treatment has been globally recommended for patients with the nodular-bronchiectatic form, which is characterized by an indolent clinical course, while daily treatment has been recommended in Japan [10–12]. Consequently, adverse events caused by EMB constitute a significant issue for MAC-PD treatment. In this study, we found that 26.6% (49) of the patients deviated from the standard
Fig. 1. Flow diagram of the study. 68
K. Morimoto et al.
Respiratory Medicine 158 (2019) 67–69
treatment, among whom 31 (63.3%) received treatment without EMB, associated with a risk of developing macrolide resistance. The sporadic and insufficient duration of CLR administration was commonly observed before and after the standard regimen. This might be because many patients seek care for acute respiratory infection (common cold, etc.) in local clinics where physicians may casually prescribe a single macrolide drug instead of visiting their regular doctor for MAC-PD even after diagnosis of NTM. To change this patient behaviour and prevent the development of resistant cases, education needs to be provided to both patients and health care providers. Twenty-seven percent of the patients in this study were prescribed FQ in combination with standard or sub-standard treatment; this pro portion was higher than that of aminoglycoside (7.6%). Although these prescriptions could have been given to patients with moderate to severe disease or substitution of any standard drugs, aminoglycosides should have been selected instead of FQ because they are strongly recom mended according to previous studies of the minimum inhibitory con centration (MIC) and clinical responses [13]. The present study has some limitations. Because we included only two percent of the cases who initially received the standard treatment when we performed the detailed analysis, the amount of random vari ation was relatively high. Second, the dataset did not include the data on the treatment regimens for other species, such as Mycobacterium abscessus complex.
Japan Agency for Medical Research and Development, AMED, under grant number JP18fk0108043. References [1] K. Morimoto, H. Namkoong, N. Hasegawa, T. Nakagawa, E. Morino, Y. Shiraishi, K. Ogawa, K. Izumi, J. Takasaki, T. Yoshiyama, Y. Hoshino, S. Matsuda, Y. Hayashi, Y. Sasaki, M. Ishii, A. Kurashima, T. Nishimura, T. Betsuyaku, H. Goto, Macrolideresistant Mycobacterium avium complex lung disease: analysis of 102 consecutive cases, Ann. Am. Thorac. Soc. 13 (2016) 1904–1911. [2] D.E. Griffith, B.A. Brown-Elliott, B. Langsjoen, Y. Zhang, X. Pan, W. Girard, K. Nelson, J. Caccitolo, J. Alvarez, S. Shepherd, R. Wilson, E.A. Graviss, R. J. Wallace Jr., Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease, Am. J. Respir. Crit. Care Med. 174 (2006) 928–934. [3] T. Kadota, H. Matsui, T. Hirose, J. Suzuki, M. Saito, T. Akaba, K. Kobayashi, S. Akashi, M. Kawashima, A. Tamura, H. Nagai, S. Akagawa, N. Kobayashi, K. Ohta, Analysis of drug treatment outcome in clarithromycin-resistant Mycobacterium avium complex lung disease, BMC Infect. Dis. 16 (2016) 31. [4] S.M. Moon, H.Y. Park, S.Y. Kim, B.W. Jhun, H. Lee, K. Jeon, D.H. Kim, H.J. Huh, C. S. Ki, N.Y. Lee, H.K. Kim, Y.S. Choi, J. Kim, S.H. Lee, C.K. Kim, S.J. Shin, C.L. Daley, W.J. Koh, Clinical characteristics, treatment outcomes, and resistance mutations associated with macrolide-resistant Mycobacterium avium complex lung disease, Antimicrob. Agents Chemother. 60 (2016) 6758–6765. [5] J. Adjemian, D.R. Prevots, J. Gallagher, K. Heap, R. Gupta, D. Griffith, Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease, Ann. Am. Thorac. Soc. 11 (2014) 9–16. [6] K. Morimoto, K. Iwai, K. Uchimura, M. Okumura, T. Yoshiyama, K. Yoshimori, H. Ogata, A. Kurashima, A. Gemma, S. Kudoh, A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan, Ann. Am. Thorac. Soc. 11 (2014) 1–8. [7] K. Morimoto, N. Hasegawa, K. Izumi, H. Namkoong, K. Uchimura, T. Yoshiyama, Y. Hoshino, A. Kurashima, J. Sokunaga, S. Shibuya, M. Shimojima, M. Ato, S. Mitarai, A laboratory-based analysis of nontuberculous mycobacterial lung disease in Japan from 2012 to 2013, Ann. Am. Thorac. Soc. 14 (2017) 49–56. [8] J. van Ingen, D. Wagner, J. Gallagher, K. Morimoto, C. Lange, C.S. Haworth, R. A. Floto, J. Adjemian, D.R. Prevots, D.E. Griffith, NTM-NET., Poor adherence to management guidelines in nontuberculous mycobacterial pulmonary diseases. Eur. Respir. J. 49 (2017). [9] D.E. Griffith, T. Aksamit, B.A. Brown-Elliott, A. Catanzaro, C. Daley, F. Gordin, S. M. Holland, R. Horsburgh, G. Huitt, M.F. Iademarco, M. Iseman, K. Olivier, S. Ruoss, C.F. von Reyn, R.J. Wallace Jr., K. Winthrop, An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Am. J. Respir. Crit. Care Med. 175 (2007) 367–416. [10] R.J. Wallace Jr., B.A. Brown-Elliott, S. McNulty, J.V. Philley, J. Killingley, R. W. Wilson, D.S. York, S. Shepherd, D.E. Griffith, Macrolide/Azalide therapy for nodular/bronchiectatic mycobacterium avium complex lung disease, Chest 146 (2014) 276–282. [11] B.H. Jeong, K. Jeon, H.Y. Park, S.Y. Kim, K.S. Lee, H.J. Huh, C.S. Ki, N.Y. Lee, S. J. Shin, C.L. Daley, W.J. Koh, Intermittent antibiotic therapy for nodular bronchiectatic Mycobacterium avium complex lung disease, Am. J. Respir. Crit. Care Med. 191 (2015) 96–103. [12] D.E. Griffith, B.A. Brown, P. Cegielski, D.T. Murphy, R.J. Wallace Jr., Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex, Clin. Infect. Dis.: Infect. Dis. Soc. Am. 30 (2000) 288–292. [13] Y. Kobashi, T. Matsushima, M. Oka, A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease, Respir. Med. 101 (2007) 130–138.
5. Conclusions In summary, this study revealed that the actual treatment practices for NTM-PD cases were vastly different from the guidelinerecommended standard. These deviations from the standard treatment may increase the number of problematic cases, increase the incidence of relapse after treatment completion, and induce macrolide resistance. To decrease these issues, the development of a patient-friendly standard regimen with new antimicrobial agents with lower toxicity and the implementation of countermeasures, including educational efforts and local guidelines, are essential. Declaration of competing interest The authors have no potential conflicts of interest that influence on the content of this study. Acknowledgement Funding: We would like to thank BIO Communications Inc. for pre paring the dataset. This work was supported by the Research Pro gramme on Emerging and Re-emerging Infectious Diseases from the
69
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed
Short communication
Actual practice of standard treatment for pulmonary nontuberculous mycobacteriosis in Japan Kozo Morimoto a, b, *, 1, Kiyohiko Izumi b, 1, Manabu Ato c, Naoki Hasegawa d, Satoshi Mitarai b, e a
Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Japan c National Institute of Infectious Diseases, Japan d Keio University School of Medicine, Japan e Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan b
A R T I C L E I N F O
A B S T R A C T
Keywords: Treatment Clarithromycin resistant Guideline Insurance claim
Introduction: The details of the practice of treating nontuberculous mycobacterial pulmonary disease (NTMPD) have not been studied in Japan. Methods: We studied a random sample of 2% (184) of the 9,200 patients with incident NTM-PD in 2010 who received standard three-drug therapy for at least some of their treatment between 2010 and 2014. Results: The median duration of the standard treatment period was 248 days (IQR 56–540 days). Although 59% of the patients were treated with standard therapy for more than 6 months, only 41% were treated for 12 months. Fifty-three patients (29%) initiated treatment with substandard regimen, and 18 (34%) of those patients received treatment regimens that can lead to the development of macrolide resistance (MR)(CLR monotherapy or CLR þ RIF). Furthermore, initially, 184 receiving the standard treatment, 49 patients (27%) eventually deviated from it, and 31 patients (63%) received regimens increasing the risk of developing MR. The sporadic administration of macrolide monotherapy was observed before and after the administration of the standard treatment for 50 pa tients (27.7%) and 41 patients (27.2%), respectively. Conclusions: Approximately 60% of the treated patients did not continue the standard regimen for more than 12 months and 42% were at risk for developing MR before and after receiving the standard treatment. It is important to educate physicians and patients about the correct and safe management of NTMPD.
1. Introduction Macrolide-resistant Mycobacterium avium complex pulmonary dis ease (MAC-PD) is associated with a long course of treatment with toxic medications and a high mortality rate [1–4]. Although MAC can acquire resistance through inappropriate treatment, only 13% of clinicians follow the macrolide-containing recommended treatment, and 30% of these used regimens that have been shown to induce macrolide resis tance in the US [5]. In Japan, clarithromycin (CLR) monotherapy and deviations from the standard regimens, especially the cessation of ethambutol (EMB) due to side effects, including visual disturbances and skin eruptions, were commonly observed among macrolide-resistant MAC patients [1]. We previously reported that mortality due to non tuberculous mycobacteriosis (NTM) has been increasing over the past 40
years, and this trend may be partially explained by the accumulation of severe cases, including those with CLR resistance caused by inappro priate treatment [6]. However, little is known about the actual treat ment of MAC-PD patients who started with the standard treatment. Therefore, we evaluated treatment duration and pre- and post-standard treatment medication using representative nationwide data. 2. Material and methods We extracted the incident cases in 2010 (64,884 cases, the look-back window was three months) with at least one insurance claim with ICD10 codes associated with NTM pulmonary disease (NTM-PD) (A310 and A319) from the national health insurance database, which includes data from the entire Japanese population covered under the universal health
* Corresponding author. Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, 3-1-24, Matsuyama, Kiyose City, Tokyo, 204-8522, Japan. E-mail address: [email protected] (K. Morimoto). 1 The first two authors contributed equally to this article. https://doi.org/10.1016/j.rmed.2019.10.002 Received 3 February 2019; Received in revised form 2 September 2019; Accepted 4 October 2019 Available online 4 October 2019 0954-6111/© 2019 Published by Elsevier Ltd.
K. Morimoto et al.
Respiratory Medicine 158 (2019) 67–69
insurance system. Among the extracted cases, 9,200 were identified as receiving the CLR-based three-drug standard treatment at some point during the observation period from 2010 to 2014 [CLR þ EMB þ rifampicin (RIF)]. To focus on analysing the detailed treatment course, we then randomly selected two percent of the cases and eventually enrolled a total of 184 cases [133 in females (72.3%)] in the analysis (Fig. 1). Because MAC-PD comprises more than 90% of all NTM-PD cases in Japan [7], the vast majority of NTM-PD cases treated with the three-drug standard treatment could be regarded as MAC-pulmonary disease. Sub-standard treatment was defined as any single or two-drug combination of the standard three drugs. Fluoroquinolones (FQs) included when used together with these one or two drugs. CLR, CLR þ RIF, CLR þ FQs, and CLR þ RIF þ FQs were regarded as prescription inducing macrolide resistance. 3. Results We reviewed the course of treatment of the selected cases from January 2010 to December 2014, dividing the period into the following five categories (Fig. 2): “A-1” was the standard treatment period; “A-2” was the period of initial sub-standard treatment, e.g., CLR þ EMB or CLR þ RIF, prior to the initiation of standard treatment (A-1); “A3” was the period of subsequent sub-standard treatment after standard treat ment; “B” was the period from January 2010 to the initiation of any treatment; and “C” was the period from the end of the standard or subsequent sub-standard treatment to the end of the observation period. Category A-1. The median duration of the standard treatment was 248 days (IQR 56–540). While 59% of the patients were treated for more than six months, fewer patients were treated more than one year (41%) and even fewer for more than 18 months (25%). During this period, 14 patients (7.6%) were administered aminoglycosides. Category A-2. A total of 53 patients (28.8%) underwent initial substandard treatment before the initiation of standard treatment (A-1). Among them, 28 patients (52.8%) were administered CLR þ EMB, 15 patients (28.3%) were administered CLR, and 3 patients (5.7%) were administered CLR þ RIF. Category A-3. Among the patients who initiated standard treatment, 49 (26.6%) changed regimens, and 31 (63.3%) used regimens that may induce macrolide resistance. Category A1-A3. Throughout the entire observation period, 23 pa tients (12.5%) used fluoroquinolone together with their standard or substandard treatment regimen for a median of 300 days (IQR 161–524), and 23 patients (21.1%) sporadically used FQ for a median of five days (IQR 5–28.5). Category B. The median duration of the period from January 2010
Fig. 2. Treatment course for standard treatment for pulmonary nontuberculous mycobacteriosis from 2010 to 2014. CLR, clarithromycin; AZM, azithromycin; EMB, ethambutol; RIF, rifamycin; FQs, fluoroquinolones.
to the initiation of standard or initial sub-standard treatment was 213 days (IQR 61–488). There was no case that had already on treatment in 2010. Macrolide was prescribed for 50 patients (27.2%). CLA was pre scribed for 40 patients for a total of 20 days (IQR 6–67), and azi thromycin was prescribed for 10 patients for three days (IQR 3–6). FQs were prescribed for 33 patients (17.9%) for a total of 19 days. Category C. After excluding 33 patients who continued their first treatment regimens through the period, 151 patients were evaluated for the period from the end of the standard or subsequent sub-standard treatment to the end of the observation period. Macrolide mono therapy was provided to 41 patients (27.2%), including duplication. Among them, CLR was prescribed for 39 patients (95.1%) for a median of 23 days (IQR 8–107) and azithromycin for less than 10 patients for a median of three days (IQR 3–3.8). FQs were prescribed for 26 patients (17.2%) for a total of 73 days. A second treatment regimen was initiated for 29 patients during this period, and 24 patients started the standard treatment. Among the seven patients (24.1%) who changed regimens, six changed to regimens that had a risk of macrolide resistance. Overall, 76 cases (42%) received at leaset one prescription that has the risk of macrolide resistance during the observation period. 4. Discussion A previous survey reported that 40% of NTM-PD cases continued standard treatment for more than 6 months in Japan [8]. Although our study showed a higher proportion of 58.9%, many MAC-PD cases did not receive standard treatment for the duration recommended by the guideline, a minimum of 12 months culture negativity, possibly causing relapse of the disease [9]. Intermittent treatment has been globally recommended for patients with the nodular-bronchiectatic form, which is characterized by an indolent clinical course, while daily treatment has been recommended in Japan [10–12]. Consequently, adverse events caused by EMB constitute a significant issue for MAC-PD treatment. In this study, we found that 26.6% (49) of the patients deviated from the standard
Fig. 1. Flow diagram of the study. 68
K. Morimoto et al.
Respiratory Medicine 158 (2019) 67–69
treatment, among whom 31 (63.3%) received treatment without EMB, associated with a risk of developing macrolide resistance. The sporadic and insufficient duration of CLR administration was commonly observed before and after the standard regimen. This might be because many patients seek care for acute respiratory infection (common cold, etc.) in local clinics where physicians may casually prescribe a single macrolide drug instead of visiting their regular doctor for MAC-PD even after diagnosis of NTM. To change this patient behaviour and prevent the development of resistant cases, education needs to be provided to both patients and health care providers. Twenty-seven percent of the patients in this study were prescribed FQ in combination with standard or sub-standard treatment; this pro portion was higher than that of aminoglycoside (7.6%). Although these prescriptions could have been given to patients with moderate to severe disease or substitution of any standard drugs, aminoglycosides should have been selected instead of FQ because they are strongly recom mended according to previous studies of the minimum inhibitory con centration (MIC) and clinical responses [13]. The present study has some limitations. Because we included only two percent of the cases who initially received the standard treatment when we performed the detailed analysis, the amount of random vari ation was relatively high. Second, the dataset did not include the data on the treatment regimens for other species, such as Mycobacterium abscessus complex.
Japan Agency for Medical Research and Development, AMED, under grant number JP18fk0108043. References [1] K. Morimoto, H. Namkoong, N. Hasegawa, T. Nakagawa, E. Morino, Y. Shiraishi, K. Ogawa, K. Izumi, J. Takasaki, T. Yoshiyama, Y. Hoshino, S. Matsuda, Y. Hayashi, Y. Sasaki, M. Ishii, A. Kurashima, T. Nishimura, T. Betsuyaku, H. Goto, Macrolideresistant Mycobacterium avium complex lung disease: analysis of 102 consecutive cases, Ann. Am. Thorac. Soc. 13 (2016) 1904–1911. [2] D.E. Griffith, B.A. Brown-Elliott, B. Langsjoen, Y. Zhang, X. Pan, W. Girard, K. Nelson, J. Caccitolo, J. Alvarez, S. Shepherd, R. Wilson, E.A. Graviss, R. J. Wallace Jr., Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease, Am. J. Respir. Crit. Care Med. 174 (2006) 928–934. [3] T. Kadota, H. Matsui, T. Hirose, J. Suzuki, M. Saito, T. Akaba, K. Kobayashi, S. Akashi, M. Kawashima, A. Tamura, H. Nagai, S. Akagawa, N. Kobayashi, K. Ohta, Analysis of drug treatment outcome in clarithromycin-resistant Mycobacterium avium complex lung disease, BMC Infect. Dis. 16 (2016) 31. [4] S.M. Moon, H.Y. Park, S.Y. Kim, B.W. Jhun, H. Lee, K. Jeon, D.H. Kim, H.J. Huh, C. S. Ki, N.Y. Lee, H.K. Kim, Y.S. Choi, J. Kim, S.H. Lee, C.K. Kim, S.J. Shin, C.L. Daley, W.J. Koh, Clinical characteristics, treatment outcomes, and resistance mutations associated with macrolide-resistant Mycobacterium avium complex lung disease, Antimicrob. Agents Chemother. 60 (2016) 6758–6765. [5] J. Adjemian, D.R. Prevots, J. Gallagher, K. Heap, R. Gupta, D. Griffith, Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease, Ann. Am. Thorac. Soc. 11 (2014) 9–16. [6] K. Morimoto, K. Iwai, K. Uchimura, M. Okumura, T. Yoshiyama, K. Yoshimori, H. Ogata, A. Kurashima, A. Gemma, S. Kudoh, A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan, Ann. Am. Thorac. Soc. 11 (2014) 1–8. [7] K. Morimoto, N. Hasegawa, K. Izumi, H. Namkoong, K. Uchimura, T. Yoshiyama, Y. Hoshino, A. Kurashima, J. Sokunaga, S. Shibuya, M. Shimojima, M. Ato, S. Mitarai, A laboratory-based analysis of nontuberculous mycobacterial lung disease in Japan from 2012 to 2013, Ann. Am. Thorac. Soc. 14 (2017) 49–56. [8] J. van Ingen, D. Wagner, J. Gallagher, K. Morimoto, C. Lange, C.S. Haworth, R. A. Floto, J. Adjemian, D.R. Prevots, D.E. Griffith, NTM-NET., Poor adherence to management guidelines in nontuberculous mycobacterial pulmonary diseases. Eur. Respir. J. 49 (2017). [9] D.E. Griffith, T. Aksamit, B.A. Brown-Elliott, A. Catanzaro, C. Daley, F. Gordin, S. M. Holland, R. Horsburgh, G. Huitt, M.F. Iademarco, M. Iseman, K. Olivier, S. Ruoss, C.F. von Reyn, R.J. Wallace Jr., K. Winthrop, An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Am. J. Respir. Crit. Care Med. 175 (2007) 367–416. [10] R.J. Wallace Jr., B.A. Brown-Elliott, S. McNulty, J.V. Philley, J. Killingley, R. W. Wilson, D.S. York, S. Shepherd, D.E. Griffith, Macrolide/Azalide therapy for nodular/bronchiectatic mycobacterium avium complex lung disease, Chest 146 (2014) 276–282. [11] B.H. Jeong, K. Jeon, H.Y. Park, S.Y. Kim, K.S. Lee, H.J. Huh, C.S. Ki, N.Y. Lee, S. J. Shin, C.L. Daley, W.J. Koh, Intermittent antibiotic therapy for nodular bronchiectatic Mycobacterium avium complex lung disease, Am. J. Respir. Crit. Care Med. 191 (2015) 96–103. [12] D.E. Griffith, B.A. Brown, P. Cegielski, D.T. Murphy, R.J. Wallace Jr., Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex, Clin. Infect. Dis.: Infect. Dis. Soc. Am. 30 (2000) 288–292. [13] Y. Kobashi, T. Matsushima, M. Oka, A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease, Respir. Med. 101 (2007) 130–138.
5. Conclusions In summary, this study revealed that the actual treatment practices for NTM-PD cases were vastly different from the guidelinerecommended standard. These deviations from the standard treatment may increase the number of problematic cases, increase the incidence of relapse after treatment completion, and induce macrolide resistance. To decrease these issues, the development of a patient-friendly standard regimen with new antimicrobial agents with lower toxicity and the implementation of countermeasures, including educational efforts and local guidelines, are essential. Declaration of competing interest The authors have no potential conflicts of interest that influence on the content of this study. Acknowledgement Funding: We would like to thank BIO Communications Inc. for pre paring the dataset. This work was supported by the Research Pro gramme on Emerging and Re-emerging Infectious Diseases from the
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