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Efficacy and safety of tigecycline for Mycobacterium abscessus disease
Respiratory Medicine 158 (2019) 89–91
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed
Short communication
Efficacy and safety of tigecycline for Mycobacterium abscessus disease Yong-Soo Kwon a, b, *, Adrah Levin b, Shannon H. Kasperbauer b, c, Gwen A. Huitt b, c, Charles L. Daley b, c, ** a
Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO, USA c Department of Medicine, University of Colorado, Denver, CO, USA b
A R T I C L E I N F O
A B S T R A C T
Keywords: Nontuberculous mycobacteria Mycobacterium abscessus Tigecycline Efficacy Safety
Purpose: Mycobacterium abscessus disease is one of the most difficult mycobacterial infections to cure, as the bacterium is highly resistant to conventional antibiotics. The purpose of this study was to evaluate the efficacy and safety of tigecycline treatment of M. abscessus disease. Procedure: We performed retrospective chart reviews of patients with M. abscessus disease receiving tigecyclinecontaining regimens at National Jewish Health from January 2009 to December 2017. Main findings: Among the 35 patients, pulmonary disease was the most common presentation of M. abscessus disease (n ¼ 29, 82.9%). Of those receiving tigecycline treatment, 17.4% (4/23) showed microbiological improvement (�2 consecutive negative sputum cultures), while 86.2% (25/29) and 59.3% (16/27) showed symptomatic and radiological improvements, respectively. The rate of dose reduction or discontinuation of tigecycline owing to adverse drug reactions was 57.1% (20/35) at a median of 56.5 days (IQR 10.8–122.3). The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea. Conclusions: Tigecycline-containing regimens for M. abscessus disease have a high rate of symptomatic and radiological improvement. However, considering the poor microbiological response and the common adverse effects, selection of patients for tigecycline treatment and monitoring for adverse drug reactions should be performed carefully.
1. Introduction
2. Methods
Mycobacterium abscessus is resistant to many antibiotics [1–3]. Therefore, new, effective agents for M. abscessus disease are needed to improve the treatment success rate. Tigecycline is a parenteral glycylcycline, a semisynthetic tetracy cline, that was developed to overcome bacterial resistance to tetracy cline [4]. Interestingly, it also exhibits potent antibacterial activity against rapidly growing mycobacteria, with a minimum inhibitory concentration (MIC) as low as 0.06–0.25 μg/ml in clinical isolates, which are 4- to 11-fold more susceptible to this drug than to tetracycline [5]. Current guidelines recommend its use to treat M. abscessus disease in patients both with and without cystic fibrosis (CF) [6,7]. However, few studies have reported on the efficacy and safety of tigecycline in the treatment of M. abscessus and M. chelonae diseases [8–10].
We retrospectively reviewed all patients with M. abscessus disease who were treated with a tigecycline-containing regimen at National Jewish Health (NJH) from January 2009 to December 2017, examining data obtained from the NJH research database and a review of medical charts. The Institutional review board (IRB) at NJH approved the study protocols (IRB number: HS 3126). All patients, except for six with extrapulmonary M. abscessus disease, met the diagnostic criteria for NTM pulmonary disease [1]. The efficacy of tigecycline was evaluated in patients who received tigecycline treatment for more than one month. The symptomatic response to tigecycline treatment was measured by changes in the res piratory symptoms of patients with pulmonary disease and symptoms related to infection sites including infection site pain, swelling, and
* Corresponding author. Department of Internal Medicine, Chonnam National University Hospital, 42 Jebongro, Donggu, Gwangju, 61469, South Korea. ** Corresponding author. Division of Mycobacterial and Respiratory Infections, National Jewish Health, Room J204, 1400 Jackson Street, Denver, CO, 80206, USA. E-mail addresses: [email protected] (Y.-S. Kwon), [email protected] (C.L. Daley). https://doi.org/10.1016/j.rmed.2019.10.006 Received 15 April 2019; Received in revised form 23 September 2019; Accepted 7 October 2019 Available online 8 October 2019 0954-6111/© 2019 Published by Elsevier Ltd.
Y.-S. Kwon et al.
Respiratory Medicine 158 (2019) 89–91
discharge in patients with extrapulmonary disease. The radiological response was evaluated by measuring changes in lung lesions, including the extent of the nodules and/or the size of the cavity for pulmonary disease and inflammatory lesions for extrapulmonary disease between the start and end of the tigecycline treatment. The microbiological response was evaluated by the results of sputum culture in patients with pulmonary disease who received tigecycline treatment for more than one month. Culture conversion was defined as three consecutive nega tive sputum cultures in patients with pulmonary disease [11] and microbiological improvement was defined as two or more consecutive negative sputum cultures in patients with pulmonary disease. The safety of tigecycline was evaluated in all patients based on the descriptions of the patients’ symptoms from medical records during treatment with a tigecycline-containing regimen. Adverse drug re actions that prompted a reduction in dosage or discontinuation of tige cycline owing to side effects were recorded and analyzed.
starting daily dose was 25 mg in 5 patients, 50 mg in 15 patients, and 100 mg in 15 patients. The commonly co-administered drugs were amikacin (68.6%), azithromycin (60.0%), clofazimine (40.0%), and imipenem (45.7%). Surgical lung resection was performed in four of the 29 (13.8%) patients, all of whom were infected with a M. abscessus subspecies abscessus. The six patients with extrapulmonary diseases received surgical treatment including debridement, excision, and removal of prosthetic material. Among the 29 patients with M. abscessus pulmonary disease, the microbiological responses were evaluated in the 23 patients who received tigecycline treatment for >1 month and had a positive sputum culture at the start of tigecycline treatment. Of the 23 patients who were evaluated for microbiological responses, four showed microbiological improvement (17.4%) including one patient with culture conversion. Of these four patients, one patient with microbiological improvement received a surgical lung resection. In contrast to the low rate of micro biological improvement, the rates of symptomatic and radiological improvement were high (86.2% and 59.3%, respectively) (Table 1). There were no differences in the rates of microbiological response (4/21 [19.0%] vs. 0/2 [0%], p ¼ 1.000), symptomatic improvement (18/22 [82.8%] vs. 7/7 [100%], p ¼ 0.546), and radiological improvement (11/ 20 [55.0%] vs. 5/7 [71.4%], p ¼ 0.662) between in patients with and without a history of previous treatment for M. abscessus disease. Of the 35 patients, 20 (57.1%) experienced a dose reduction or discontinuation of tigecycline at a median of 56.5 days (IQR 10.8–122.253) of treatment. The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea despite the frequent use of antiemetic pre-medications with ondansetron. (77.1%) (Table 1).
3. Results Among the 35 patients, the median age was 58.0 years (interquartile range [IQR] 47.0–66.0 years), and 26 (74.3%) were women. The most common presenting disease was pulmonary disease (n ¼ 29, 82.9%) (Table 1). Among the 35 patients treated with tigecycline, 29 (82.9%) patients received tigecycline treatment for > 1 month. The median duration and daily dose of tigecycline for all 35 patients were 80.0 days (IQR 46.0–179.5 days) and 50 mg (IQR 50–100 mg), respectively. The Table 1 Baseline characteristics, treatment outcomes, and adverse drug reactions in 35 patients with Mycobacterium abscessus disease treated with regimens containing tigecycline. Characteristic
Median (IQR) or N (%)
Age, years Sex, female Body mass index, kg/m2 FEV1, % predicted Ever smoker Mycobacterium abscessus subspecies Mycobacterium abscessus subspecies abscessus Mycobacterium abscessus subspecies bolletii Mycobacterium abscessus subspecies massiliense Previous treatment for nontuberculous mycobacterial disease Number of drugs previously used (more than one month) Indication for tigecycline treatment First line Failed previous treatments Substitute drug due to adverse drug reactions of other drugs Cystic fibrosis Extrapulmonary disease Cavitary disease Positive sputum AFB smear Outcomes Culture conversion (>3 negative sputum cultures) Microbiological improvement (>2 negative sputum cultures) Symptomatic improvement Radiological improvement Adverse drug reactions causing a dose reduction or discontinuation of tigecycline Dose reduction of tigecycline Discontinuation of tigecycline Causes of dose reduction or discontinuation GI adverse drug reactions including nausea, vomiting, and diarrhea Hepatotoxicity Anemia Rash Antiemetic premedication
58.0 (47.0–66.0) 26 (74.3%) 21.6 (19.7–25.1) 69.0 (56.3–80.8) 9 (25.7%)
4. Discussion Data on the efficacy and safety of tigecycline treatment for M. abscessus disease are very limited. In a study of 52 patients with M. abscessus or M. chelonae disease who received tigecycline-containing regimens as salvage treatment, 25 patients (48.1%) showed clinical improvements [8]. This is consistent with our study, which also found rates of high symptomatic and radiological improvement. In contrast to the high rates of clinical and radiological improve ment, the microbiological response in this study (17.4%) was lower than that in a meta-analysis of M. abscessus pulmonary disease, which showed 54% (95% confidence interval 40%–68%) overall sustained culture conversion [12]. Even in patients who received surgical lung resection, only one patient showed microbiological improvement (two consecutive negative sputum cultures). There might be several reasons why culture conversion in our cohort was low despite the very favorable in vitro MICs of tigecycline. First, the efficacy of tigecycline might be attenuated because of high rates of cavitary disease (65.5%) and refractory disease (60%) in our cohort. However, further studies are needed to determine whether culture conversion rates could be improved if the drug administration is started in an early disease. Second, the low clinical efficacy of tigecycline might be because of the high rates of dose reduction and discontinuation. Third, there might be an inconsistency between the in vitro and in vivo activity of this drug against M. abscessus. There was no significant difference in the median tigecycline dose of patients with and without microbiological improvement in our study (50.0 mg/day [IQR 37.5–75.0] vs. 50.0 mg/day [IQR 36.3–100.0], p ¼ 0.745). However, the median starting dose was higher in patients who later had a dose reduction or discontinued tigecycline, although this difference was not statistically significant (100 mg/day [IQR 50100] vs 50 mg/day [IQR 50-100], p ¼ 0.691). Since dose-related gastrointestinal side effects of this drug have also been reported in previous studies [13,14], starting with a low dose and increasing it might be better than the standard starting dose. Gastrointestinal symptoms including nausea, vomiting, and diar rhea, are the most commonly reported side effects of tigecycline in
19/21 (90.5%) 1/21 (4.8%) 1/21 (4.8%) 25 (71.4%) 4 (3–5) 6 (17.1%) 21 (60.0%) 8 (22.9%) 9 (25.7%) 6 (17.1%) 19/29 (65.5%) 12/29 (41.4%) 1/23 (4.3%) 4/23 (17.4%) 25/29 (86.2%) 16/27 (59.3%) 20 (57.1%) 4 (11.4%) 16 (45.7%) 17 (85.0%) 1 (5.0%) 1 (5.0%) 1 (5.0%) 27 (77.1%)
AFB ¼ acid-fast bacilli; FEV1 ¼ forced expiratory volume in 1 s; GI ¼ gastroin testinal; IQR ¼ interquartile range. 90
Y.-S. Kwon et al.
Respiratory Medicine 158 (2019) 89–91
References
clinical trials [13,14]. Similar findings have also been reported in studies of tigecycline treatment for M. abscessus disease [8–10]. In a study of 52 patients with M. abscessus or M. chelonae disease, a high rate of adverse events (94.2%) was observed, and gastrointestinal side effects were most common [8]. These are consistent with the findings in our study. Although earlier phase 1 studies and a clinical study of M. abscessus or M. chelonae disease showed that ondansetron improved tolerability of tigecycline [8,14], our study showed a high rate of gastrointestinal adverse drug reactions despite the frequent use of antiemetic premed ication (77.1%). As the gastrointestinal side effects of tigecycline could be a major hurdle for the long-term use of this drug, further studies are needed to determine the optimal tigecycline dose and optimal use of antiemetic premedication to decrease adverse drug reactions and possibly increase the effectiveness of the treatment. This study has some limitations owing to its retrospective design. First, decisions about tigecycline treatment, including when during the course of M. abscessus disease tigecycline treatment was started, the duration of the treatment, the daily dose of tigecycline, and the treat ment regimens including the drugs used, were made by individual attending physicians. Second, symptomatic and radiological responses could not be accurately evaluated. Third, not all patients with M. abscessus pulmonary disease were evaluated for their microbiological response owing to the lack of sputum culture results.
[1] 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 (4) (2007) 367–416. [2] S.H. Kasperbauer, M.A. De Groote, The treatment of rapidly growing mycobacterial infections, Clin. Chest Med. 36 (1) (2015) 67–78. [3] R. Nessar, E. Cambau, J.M. Reyrat, A. Murray, B. Gicquel, Mycobacterium abscessus: a new antibiotic nightmare, J. Antimicrob. Chemother. 67 (4) (2012) 810–818. [4] G.A. Pankey, Tigecycline, J. Antimicrob. Chemother. 56 (3) (2005) 470–480. [5] R.J. Wallace Jr., B.A. Brown-Elliott, C.J. Crist, L. Mann, R.W. Wilson, Comparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria, Antimicrob. Agents Chemother. 46 (10) (2002) 3164–3167. [6] R.A. Floto, K.N. Olivier, L. Saiman, C.L. Daley, J.L. Herrmann, J.A. Nick, P. G. Noone, D. Bilton, P. Corris, R.L. Gibson, S.E. Hempstead, K. Koetz, K. A. Sabadosa, I. Sermet-Gaudelus, A.R. Smyth, J. van Ingen, R.J. Wallace, K. L. Winthrop, B.C. Marshall, C.S. Haworth, U.S.C.F. Foundation, S. European cystic fibrosis, US cystic fibrosis foundation and european cystic fibrosis society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis, Thorax 71 (Suppl 1) (2016) i1–22. [7] C.S. Haworth, J. Banks, T. Capstick, A.J. Fisher, T. Gorsuch, I.F. Laurenson, A. Leitch, M.R. Loebinger, H.J. Milburn, M. Nightingale, P. Ormerod, D. Shingadia, D. Smith, N. Whitehead, R. Wilson, R.A. Floto, British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTMPD), Thorax 72 (Suppl 2) (2017) ii1–ii64. [8] R.J. Wallace Jr., G. Dukart, B.A. Brown-Elliott, D.E. Griffith, E.G. Scerpella, B. Marshall, Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of Mycobacterium abscessus and Mycobacterium chelonae infections, J. Antimicrob. Chemother. 69 (7) (2014) 1945–1953. [9] S. Regnier, E. Cambau, J.P. Meningaud, A. Guihot, L. Deforges, A. Carbonne, F. Bricaire, E. Caumes, Clinical management of rapidly growing mycobacterial cutaneous infections in patients after mesotherapy, Clin. Infect. Dis. 49 (9) (2009) 1358–1364. [10] M. Sfeir, M. Walsh, R. Rosa, L. Aragon, S.Y. Liu, T. Cleary, M. Worley, C. Frederick, L.M. Abbo, Mycobacterium abscessus complex infections: a retrospective cohort study, Open Forum Infect. Dis. 5 (2) (2018) ofy022. [11] J. van Ingen, T. Aksamit, C. Andrejak, E.C. Bottger, E. Cambau, C.L. Daley, D. E. Griffith, L. Guglielmetti, S.M. Holland, G.A. Huitt, W.J. Koh, C. Lange, P. Leitman, T.K. Marras, K. Morimoto, K.N. Olivier, M. Santin, J.E. Stout, R. Thomson, E. Tortoli, R.J. Wallace Jr., K.L. Winthrop, D. Wagner, N.-N. for, Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement, Eur. Respir. J. 51 (3) (2018) 1800170. [12] J.G. Pasipanodya, D. Ogbonna, B.E. Ferro, G. Magombedze, S. Srivastava, D. Deshpande, T. Gumbo, Systematic review and meta-analyses of the effect of chemotherapy on pulmonary Mycobacterium abscessus outcomes and disease recurrence, Antimicrob. Agents Chemother. 61 (11) (2017) e01206–e01217. [13] Q. Kaewpoowat, L. Ostrosky-Zeichner, Tigecycline : a critical safety review, Expert Opin. Drug Saf. 14 (2) (2015) 335–342. [14] G. Muralidharan, M. Micalizzi, J. Speth, D. Raible, S. Troy, Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects, Antimicrob. Agents Chemother. 49 (1) (2005) 220–229.
5. Conclusions In conclusion, a treatment regimen including tigecycline is associ ated with symptomatic and radiological improvement in patients with M. abscessus disease. However, considering the low microbiological response rate and the prevalence of adverse effects, it is important to carefully select patients for tigecycline treatment and monitor them closely for adverse drug reactions. Role of funding source This study was supported by the National Research Foundation of Korea funded by the Korean Government (Grant 2016R1D1A1B03931132) and generous support from Eileen Polinger. Declaration of competing interest None. Acknowledgements None.
91
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed
Short communication
Efficacy and safety of tigecycline for Mycobacterium abscessus disease Yong-Soo Kwon a, b, *, Adrah Levin b, Shannon H. Kasperbauer b, c, Gwen A. Huitt b, c, Charles L. Daley b, c, ** a
Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, CO, USA c Department of Medicine, University of Colorado, Denver, CO, USA b
A R T I C L E I N F O
A B S T R A C T
Keywords: Nontuberculous mycobacteria Mycobacterium abscessus Tigecycline Efficacy Safety
Purpose: Mycobacterium abscessus disease is one of the most difficult mycobacterial infections to cure, as the bacterium is highly resistant to conventional antibiotics. The purpose of this study was to evaluate the efficacy and safety of tigecycline treatment of M. abscessus disease. Procedure: We performed retrospective chart reviews of patients with M. abscessus disease receiving tigecyclinecontaining regimens at National Jewish Health from January 2009 to December 2017. Main findings: Among the 35 patients, pulmonary disease was the most common presentation of M. abscessus disease (n ¼ 29, 82.9%). Of those receiving tigecycline treatment, 17.4% (4/23) showed microbiological improvement (�2 consecutive negative sputum cultures), while 86.2% (25/29) and 59.3% (16/27) showed symptomatic and radiological improvements, respectively. The rate of dose reduction or discontinuation of tigecycline owing to adverse drug reactions was 57.1% (20/35) at a median of 56.5 days (IQR 10.8–122.3). The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea. Conclusions: Tigecycline-containing regimens for M. abscessus disease have a high rate of symptomatic and radiological improvement. However, considering the poor microbiological response and the common adverse effects, selection of patients for tigecycline treatment and monitoring for adverse drug reactions should be performed carefully.
1. Introduction
2. Methods
Mycobacterium abscessus is resistant to many antibiotics [1–3]. Therefore, new, effective agents for M. abscessus disease are needed to improve the treatment success rate. Tigecycline is a parenteral glycylcycline, a semisynthetic tetracy cline, that was developed to overcome bacterial resistance to tetracy cline [4]. Interestingly, it also exhibits potent antibacterial activity against rapidly growing mycobacteria, with a minimum inhibitory concentration (MIC) as low as 0.06–0.25 μg/ml in clinical isolates, which are 4- to 11-fold more susceptible to this drug than to tetracycline [5]. Current guidelines recommend its use to treat M. abscessus disease in patients both with and without cystic fibrosis (CF) [6,7]. However, few studies have reported on the efficacy and safety of tigecycline in the treatment of M. abscessus and M. chelonae diseases [8–10].
We retrospectively reviewed all patients with M. abscessus disease who were treated with a tigecycline-containing regimen at National Jewish Health (NJH) from January 2009 to December 2017, examining data obtained from the NJH research database and a review of medical charts. The Institutional review board (IRB) at NJH approved the study protocols (IRB number: HS 3126). All patients, except for six with extrapulmonary M. abscessus disease, met the diagnostic criteria for NTM pulmonary disease [1]. The efficacy of tigecycline was evaluated in patients who received tigecycline treatment for more than one month. The symptomatic response to tigecycline treatment was measured by changes in the res piratory symptoms of patients with pulmonary disease and symptoms related to infection sites including infection site pain, swelling, and
* Corresponding author. Department of Internal Medicine, Chonnam National University Hospital, 42 Jebongro, Donggu, Gwangju, 61469, South Korea. ** Corresponding author. Division of Mycobacterial and Respiratory Infections, National Jewish Health, Room J204, 1400 Jackson Street, Denver, CO, 80206, USA. E-mail addresses: [email protected] (Y.-S. Kwon), [email protected] (C.L. Daley). https://doi.org/10.1016/j.rmed.2019.10.006 Received 15 April 2019; Received in revised form 23 September 2019; Accepted 7 October 2019 Available online 8 October 2019 0954-6111/© 2019 Published by Elsevier Ltd.
Y.-S. Kwon et al.
Respiratory Medicine 158 (2019) 89–91
discharge in patients with extrapulmonary disease. The radiological response was evaluated by measuring changes in lung lesions, including the extent of the nodules and/or the size of the cavity for pulmonary disease and inflammatory lesions for extrapulmonary disease between the start and end of the tigecycline treatment. The microbiological response was evaluated by the results of sputum culture in patients with pulmonary disease who received tigecycline treatment for more than one month. Culture conversion was defined as three consecutive nega tive sputum cultures in patients with pulmonary disease [11] and microbiological improvement was defined as two or more consecutive negative sputum cultures in patients with pulmonary disease. The safety of tigecycline was evaluated in all patients based on the descriptions of the patients’ symptoms from medical records during treatment with a tigecycline-containing regimen. Adverse drug re actions that prompted a reduction in dosage or discontinuation of tige cycline owing to side effects were recorded and analyzed.
starting daily dose was 25 mg in 5 patients, 50 mg in 15 patients, and 100 mg in 15 patients. The commonly co-administered drugs were amikacin (68.6%), azithromycin (60.0%), clofazimine (40.0%), and imipenem (45.7%). Surgical lung resection was performed in four of the 29 (13.8%) patients, all of whom were infected with a M. abscessus subspecies abscessus. The six patients with extrapulmonary diseases received surgical treatment including debridement, excision, and removal of prosthetic material. Among the 29 patients with M. abscessus pulmonary disease, the microbiological responses were evaluated in the 23 patients who received tigecycline treatment for >1 month and had a positive sputum culture at the start of tigecycline treatment. Of the 23 patients who were evaluated for microbiological responses, four showed microbiological improvement (17.4%) including one patient with culture conversion. Of these four patients, one patient with microbiological improvement received a surgical lung resection. In contrast to the low rate of micro biological improvement, the rates of symptomatic and radiological improvement were high (86.2% and 59.3%, respectively) (Table 1). There were no differences in the rates of microbiological response (4/21 [19.0%] vs. 0/2 [0%], p ¼ 1.000), symptomatic improvement (18/22 [82.8%] vs. 7/7 [100%], p ¼ 0.546), and radiological improvement (11/ 20 [55.0%] vs. 5/7 [71.4%], p ¼ 0.662) between in patients with and without a history of previous treatment for M. abscessus disease. Of the 35 patients, 20 (57.1%) experienced a dose reduction or discontinuation of tigecycline at a median of 56.5 days (IQR 10.8–122.253) of treatment. The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea despite the frequent use of antiemetic pre-medications with ondansetron. (77.1%) (Table 1).
3. Results Among the 35 patients, the median age was 58.0 years (interquartile range [IQR] 47.0–66.0 years), and 26 (74.3%) were women. The most common presenting disease was pulmonary disease (n ¼ 29, 82.9%) (Table 1). Among the 35 patients treated with tigecycline, 29 (82.9%) patients received tigecycline treatment for > 1 month. The median duration and daily dose of tigecycline for all 35 patients were 80.0 days (IQR 46.0–179.5 days) and 50 mg (IQR 50–100 mg), respectively. The Table 1 Baseline characteristics, treatment outcomes, and adverse drug reactions in 35 patients with Mycobacterium abscessus disease treated with regimens containing tigecycline. Characteristic
Median (IQR) or N (%)
Age, years Sex, female Body mass index, kg/m2 FEV1, % predicted Ever smoker Mycobacterium abscessus subspecies Mycobacterium abscessus subspecies abscessus Mycobacterium abscessus subspecies bolletii Mycobacterium abscessus subspecies massiliense Previous treatment for nontuberculous mycobacterial disease Number of drugs previously used (more than one month) Indication for tigecycline treatment First line Failed previous treatments Substitute drug due to adverse drug reactions of other drugs Cystic fibrosis Extrapulmonary disease Cavitary disease Positive sputum AFB smear Outcomes Culture conversion (>3 negative sputum cultures) Microbiological improvement (>2 negative sputum cultures) Symptomatic improvement Radiological improvement Adverse drug reactions causing a dose reduction or discontinuation of tigecycline Dose reduction of tigecycline Discontinuation of tigecycline Causes of dose reduction or discontinuation GI adverse drug reactions including nausea, vomiting, and diarrhea Hepatotoxicity Anemia Rash Antiemetic premedication
58.0 (47.0–66.0) 26 (74.3%) 21.6 (19.7–25.1) 69.0 (56.3–80.8) 9 (25.7%)
4. Discussion Data on the efficacy and safety of tigecycline treatment for M. abscessus disease are very limited. In a study of 52 patients with M. abscessus or M. chelonae disease who received tigecycline-containing regimens as salvage treatment, 25 patients (48.1%) showed clinical improvements [8]. This is consistent with our study, which also found rates of high symptomatic and radiological improvement. In contrast to the high rates of clinical and radiological improve ment, the microbiological response in this study (17.4%) was lower than that in a meta-analysis of M. abscessus pulmonary disease, which showed 54% (95% confidence interval 40%–68%) overall sustained culture conversion [12]. Even in patients who received surgical lung resection, only one patient showed microbiological improvement (two consecutive negative sputum cultures). There might be several reasons why culture conversion in our cohort was low despite the very favorable in vitro MICs of tigecycline. First, the efficacy of tigecycline might be attenuated because of high rates of cavitary disease (65.5%) and refractory disease (60%) in our cohort. However, further studies are needed to determine whether culture conversion rates could be improved if the drug administration is started in an early disease. Second, the low clinical efficacy of tigecycline might be because of the high rates of dose reduction and discontinuation. Third, there might be an inconsistency between the in vitro and in vivo activity of this drug against M. abscessus. There was no significant difference in the median tigecycline dose of patients with and without microbiological improvement in our study (50.0 mg/day [IQR 37.5–75.0] vs. 50.0 mg/day [IQR 36.3–100.0], p ¼ 0.745). However, the median starting dose was higher in patients who later had a dose reduction or discontinued tigecycline, although this difference was not statistically significant (100 mg/day [IQR 50100] vs 50 mg/day [IQR 50-100], p ¼ 0.691). Since dose-related gastrointestinal side effects of this drug have also been reported in previous studies [13,14], starting with a low dose and increasing it might be better than the standard starting dose. Gastrointestinal symptoms including nausea, vomiting, and diar rhea, are the most commonly reported side effects of tigecycline in
19/21 (90.5%) 1/21 (4.8%) 1/21 (4.8%) 25 (71.4%) 4 (3–5) 6 (17.1%) 21 (60.0%) 8 (22.9%) 9 (25.7%) 6 (17.1%) 19/29 (65.5%) 12/29 (41.4%) 1/23 (4.3%) 4/23 (17.4%) 25/29 (86.2%) 16/27 (59.3%) 20 (57.1%) 4 (11.4%) 16 (45.7%) 17 (85.0%) 1 (5.0%) 1 (5.0%) 1 (5.0%) 27 (77.1%)
AFB ¼ acid-fast bacilli; FEV1 ¼ forced expiratory volume in 1 s; GI ¼ gastroin testinal; IQR ¼ interquartile range. 90
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Respiratory Medicine 158 (2019) 89–91
References
clinical trials [13,14]. Similar findings have also been reported in studies of tigecycline treatment for M. abscessus disease [8–10]. In a study of 52 patients with M. abscessus or M. chelonae disease, a high rate of adverse events (94.2%) was observed, and gastrointestinal side effects were most common [8]. These are consistent with the findings in our study. Although earlier phase 1 studies and a clinical study of M. abscessus or M. chelonae disease showed that ondansetron improved tolerability of tigecycline [8,14], our study showed a high rate of gastrointestinal adverse drug reactions despite the frequent use of antiemetic premed ication (77.1%). As the gastrointestinal side effects of tigecycline could be a major hurdle for the long-term use of this drug, further studies are needed to determine the optimal tigecycline dose and optimal use of antiemetic premedication to decrease adverse drug reactions and possibly increase the effectiveness of the treatment. This study has some limitations owing to its retrospective design. First, decisions about tigecycline treatment, including when during the course of M. abscessus disease tigecycline treatment was started, the duration of the treatment, the daily dose of tigecycline, and the treat ment regimens including the drugs used, were made by individual attending physicians. Second, symptomatic and radiological responses could not be accurately evaluated. Third, not all patients with M. abscessus pulmonary disease were evaluated for their microbiological response owing to the lack of sputum culture results.
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5. Conclusions In conclusion, a treatment regimen including tigecycline is associ ated with symptomatic and radiological improvement in patients with M. abscessus disease. However, considering the low microbiological response rate and the prevalence of adverse effects, it is important to carefully select patients for tigecycline treatment and monitor them closely for adverse drug reactions. Role of funding source This study was supported by the National Research Foundation of Korea funded by the Korean Government (Grant 2016R1D1A1B03931132) and generous support from Eileen Polinger. Declaration of competing interest None. Acknowledgements None.
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