- Email: [email protected]
Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints
G Model
IJID 2824 1–3 International Journal of Infectious Diseases xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
1
Short Communication
2
Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints
3
4 Q1
Thomas Schöna,b,* , Erja Chryssanthouc,d
5 6 7 8
a
Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, 391 85 Kalmar, Sweden Department of Clinical and Experimental Medicine (IKE), Division of Medical Microbiology, Linköping University, Linköping, Sweden c Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden d Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden b
A R T I C L E I N F O
S U M M A R Y
Article history: Received 2 November 2016 Received in revised form 21 December 2016 Accepted 23 December 2016 Corresponding Editor: Eskild Petersen, Aarhus, Denmark
Background: Patients with clinical infections caused by the Mycobacterium avium complex (MAC) are treated for at least 1 year following sputum conversion with a regimen that suffers from a suboptimal cure rate. The correlation between clinical outcomes and drug susceptibility testing breakpoints other than for the macrolides is regarded to be poor. A systematic evaluation of clinical breakpoints for MAC has not been performed so far; thus, the aim of this study was to initiate the process by establishing minimum inhibitory concentration (MIC) distributions. Methods: The MICs of the major drugs used in the treatment of MAC infections were determined for 229 clinical MAC isolates in cation-adjusted Mueller–Hinton II broth. Results: The MIC50 and MIC ranges were established and compared to suggested susceptibility breakpoints for clarithromycin (2; 0.064–128 mg/l), rifabutin (0.25; 0.25–16 mg/l), ethambutol (8; 0.5– 32 mg/l), amikacin (16; 1–128 mg/l), moxifloxacin (2; 0.25–16 mg/l), linezolid (32; 1–128 mg/l), rifampicin (8; 0.125–16 mg/l), and trimethoprim–sulfamethoxazole (2/38; 0.125/2–16/304 mg/l). Conclusions: These results, together with those from available studies, indicate that MICs are high for drugs such as rifabutin, rifampicin, ethambutol, linezolid, and moxifloxacin used against MAC at levels unlikely to be associated with clinical efficacy at current dosing. This may partly explain the poor correlation between susceptibility testing and clinical outcomes for drugs other than clarithromycin. © 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Q2
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Introduction The recommended duration of treatment for Mycobacterium avium complex (MAC) infections of 12 months following sputum conversion has a cure rate of around 75%, indicating a suboptimal strategy.1,2 Macrolides remain the cornerstone of treatment, together with a rifamycin and ethambutol.1 In severe cases, amikacin, clofazimine, or fluoroquinolones can also be considered.2,3 The correlation between the clinical outcomes of MAC infections and antimicrobial susceptibility testing (AST) breakpoints other than for the macrolides is regarded to be poor, although very limited supporting data exist.1 For MAC, the epidemiological cut-off point (ECOFF) and MIC distributions of wild-type isolates are not well described, and these are essential in establishing AST breakpoints for other bacteria together with
* Corresponding author. Tel.: +46 480 81000. E-mail address: [email protected] (T. Schön).
clinical outcomes and pharmacokinetic/pharmacodynamic (PK/ PD) data.4 Thus, the aim of this study was to describe the wild-type Q3 MIC distributions of the drugs commonly used to treat MAC.
23
Methods
26
Following decontamination, specimens were inoculated into MGIT 960 tubes (BD, USA) and Löwenstein–Jensen slopes. Identification was performed by GenoType Mycobacterium CM test system (Hain Lifescience, Germany). A total of 229 MAC strains (157 Mycobacterium avium, 72 Mycobacterium intracellulare complex), isolated from 229 patients at the Karolinska University Laboratory between 2011 and 2015 were included. AST was performed by broth microdilution method using the SLOMYCO Sensititre panel (Trek Diagnostic Systems, USA). A 0.5-McFarland bacterial suspension was transferred to cation-adjusted Mueller– Hinton II broth (BD, USA) supplemented with 5% oleic albumin dextrose catalase (OADC). The MICs were read using the Sensititre Vizion System after an incubation period of 7–14 days at 37 C. The
27
http://dx.doi.org/10.1016/j.ijid.2016.12.027 1201-9712/© 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027
24 25
28 29 30 31 32 33 34 35 36 37 38 39
G Model
IJID 2824 1–3 2 40
T. Schön, E. Chryssanthou / International Journal of Infectious Diseases xxx (2016) xxx–xxx
45
MIC50 was defined as the MIC required to inhibit the growth of 50% of the organisms. The reference strain M. avium ATCC 700898 was included in each run as a quality control. The breakpoints for clarithromycin (S 8 mg/l), moxifloxacin (S 1 mg/l), and linezolid (S 8 mg/l) were those of the Clinical and Laboratory Standards Institute (CLSI).5
46
Results
41 42 43 44
47 48 49 50
For clarithromycin, the MIC distribution of susceptible isolates ranged from 0.25 to 8 mg/l, with a MIC50 of 2 mg/l. Six isolates showed resistance (MIC 32 mg/l) (Figure 1A ).5 The MIC ranges for rifabutin and rifampicin were 0.25–16 mg/l and 0.125–16 mg/
l, respectively, with MIC50 of 0.25 and 8 mg/l, respectively. The distribution for trimethoprim (TMP)–sulfamethoxazole (SMX) ranged from 0.125/2 mg/l to 16/304 mg/l, with a MIC50 of 2/ 38 mg/l (Table 1). Rifabutin was clearly truncated at the lower end of the MIC distribution (Figure 1B). For ethambutol the MIC50 was 8 mg/l and MIC range was 0.5–32 mg/l (Figure 1C), and for amikacin MIC50 was 16 mg/l and the MIC range was 1–128 mg/l. Applying the suggested PK/PD-derived breakpoints of van Ingen et al. (8 mg/l),6 93.5% of the isolates were susceptible to clarithromycin, whereas only 9.6% were susceptible to ethambutol (2 mg/l) and 3% to rifampicin (0.5 mg/l). For moxifloxacin, the MIC50 was 2 mg/l and the MIC range was 0.25–16 mg/l; for linezolid, the MIC50 was 16 mg/l and the MIC range was 1–128 mg/l
Figure 1. Minimum inhibitory concentration (MIC) distributions of drugs used against Mycobacterium avium complex (MAC) infection: (A) clarithromycin (CLA); (B) rifabutin (RIB); (C) ethambutol (EMB). The pharmacokinetic/pharmacodynamic (PK/PD) breakpoints (Bp) as suggested by van Ingen et al., based on BACTEC 460 MIC determinations in combination with pharmacokinetic analyses, are included,3 as well as the Clinical and Laboratory Standards Institute (CLSI) suggested breakpoint for broth microdilution where applicable.5
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027
51 52 53 54 55 56 57 58 59 60 61 62 63
G Model
IJID 2824 1–3 T. Schön, E. Chryssanthou / International Journal of Infectious Diseases xxx (2016) xxx–xxx
3
Table 1 MIC distributions for alternative drugs used against Mycobacterium avium complex (MAC); the two-fold dilutions are given in mg/l. mg/l
Rifampicin Amikacin Moxifloxacin Linezolid TMP–SMXc
Q7
64
0.016
0.032
0.064
0.125
0.25
0.5
1
2
4
8
16
32
64
128
256
512
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
2 0 0 0 2
1 0 1 0 1
4a 0 10a 0 9
12 3 24b 1 48
30 4a 82 6 109
60 11 85 4 41
43 52 18 25b 13
77 115 9 75 6
0 33 0 93 0
0 9 0 22 0
0 2 0 3 0
0 0 0 0 0
0 0 0 0 0
MIC, minimum inhibitory concentration; TMP, trimethoprim; SMX, sulfamethoxazole; PK/PD, pharmacokinetic/pharmacodynamic. a Previously suggested breakpoints for MAC from PK/PD analyses.3 b Clinical and Laboratory Standards Institute breakpoints for broth microdilution.5 c The TMP concentration is 1/19 of the trimethoprim concentration (TMP = 1 mg/l, SMX = 19 mg/l).
In summary, the MIC distributions for common drugs used against MAC have been presented, which indicate the potential clinical efficacy of clarithromycin and possibly sulfamethoxazole and amikacin.
101
69
(Table 1). Considering the tentative CLSI breakpoints for moxifloxacin (S 1 mg/l) and linezolid (S 8 mg/l), 15.3% and 15.7% of the isolates, respectively, would be susceptible. The quality control strain had a MIC variability of less than 1 MIC dilution (n = 87) for all drugs tested and was within the CLSI target for clarithromycin.5
Funding
105
70
Discussion
This work was funded by the Swedish Heart and Lung Q5 Foundation.
106
71
In this study, MIC distributions were established for drugs used against MAC. It was found that for clarithromycin and TMP–SMX, the majority of strains had low MIC levels within the breakpoints for MAC and other mycobacteria.1,3,5,7–9 Although no breakpoint has been established for amikacin, a similar rate of isolates below 16 mg/l (80.8%) was found, in agreement with a previous study (85.9%).7 For the remaining drugs, and in particular for rifampicin, ethambutol, linezolid, and moxifloxacin, most isolates had MICs beyond the reach of therapeutic doses based on what is suggested by PK/PD, clinical outcome, and MIC distribution data for MAC,5,6,8 even if synergy is taken into account. The evidence on which such drugs are recommended for the initial treatment of MAC is unclear and this has been based in part on clinical trials involving HIV patients in the pre-antiretroviral therapy era.1 It should be stressed that single MIC distributions should not be used to define clinical breakpoints for MAC. Rather, the present results illustrate the importance of such basic data to define clinical breakpoints along with PK/PD and clinical outcome studies.10 However, for some drugs with generally very high MICs against MAC isolates, it is highly unlikely that clinical efficacy will be achieved, as this would imply that MAC behaves in a very unique way compared to other bacteria, including Mycobacterium tuberculosis, in the definition of clinical breakpoints. This study has several limitations. Resistance genes were not sequenced and the treatment history of the patients was unknown. Additionally, there was a truncation in the rifabutin MIC distribution. It is clear that more MIC distributions from several laboratories need to be gathered before firm conclusions on ECOFFs can be drawn and clinical breakpoints defined together with PK/PD and clinical outcome data.
Conflict of interest
108
None to declare.
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72 73 74 75 76 77 78 79 80 81 82 83 84 Q4 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100
References
102 103 104
107
110
111 1. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. 112 An official ATS/IDSA statement: diagnosis, treatment, and prevention of 113 nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 114 2. van Ingen J. Treatment of pulmonary disease caused by non-tuberculous 115 mycobacteria. Lancet Respir Med 2015;3:179–80. 116 3. van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, et al. The 117 pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium 118 avium complex disease treatment. Am J Respir Crit Care Med 2012;186:559–65. 119 4. Kahlmeter G. The 2014 Garrod Lecture: EUCAST—are we heading towards 120 international agreement? J Antimicrob Chemother 2015;70:2427–39. 121 5. Clinical and Laboratory Standards Institute. Susceptibility testing of mycobac122 teria, nocardiae, and other aerobic actinomycetes; approved standard—second Q6 123 edition. CLSI document M24-A2 2011. Wayne, PA: CLSI. 124 6. van Ingen J, Boeree MJ, van Soolingen D, Mouton JW. Resistance mechanisms 125 and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist 126 Updat 2012;15:149–61. 127 7. Brown-Elliott BA, Iakhiaeva E, Griffith DE, Woods GL, Stout JE, Wolfe CR, et al. 128 In vitro activity of amikacin against isolates of Mycobacterium avium complex 129 with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in 130 treated isolates. J Clin Microbiol 2013;51:3389–94. 131 8. Davies Forsman L, Schon T, Simonsson US, Bruchfeld J, Larsson M, Jureen P, et al. Intra- and extracellular activities of trimethoprim–sulfamethoxazole 132 against susceptible and multidrug-resistant Mycobacterium tuberculosis. 133 Antimicrob Agents Chemother 2014;58:7557–9. 134 9. World Health Organization. Companion handbook to the WHO guidelines for the 135 programmatic management of drug-resistant tuberculosis. Geneva: WHO; 2014. 136 10. Angeby K, Jureen P, Kahlmeter G, Hoffner SE, Schon T. Challenging a dogma: 137 antimicrobial susceptibility testing breakpoints for Mycobacterium tuberculo138 sis. Bull World Health Organ 2012;90:693–8.
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027
IJID 2824 1–3 International Journal of Infectious Diseases xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
1
Short Communication
2
Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints
3
4 Q1
Thomas Schöna,b,* , Erja Chryssanthouc,d
5 6 7 8
a
Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, 391 85 Kalmar, Sweden Department of Clinical and Experimental Medicine (IKE), Division of Medical Microbiology, Linköping University, Linköping, Sweden c Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden d Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden b
A R T I C L E I N F O
S U M M A R Y
Article history: Received 2 November 2016 Received in revised form 21 December 2016 Accepted 23 December 2016 Corresponding Editor: Eskild Petersen, Aarhus, Denmark
Background: Patients with clinical infections caused by the Mycobacterium avium complex (MAC) are treated for at least 1 year following sputum conversion with a regimen that suffers from a suboptimal cure rate. The correlation between clinical outcomes and drug susceptibility testing breakpoints other than for the macrolides is regarded to be poor. A systematic evaluation of clinical breakpoints for MAC has not been performed so far; thus, the aim of this study was to initiate the process by establishing minimum inhibitory concentration (MIC) distributions. Methods: The MICs of the major drugs used in the treatment of MAC infections were determined for 229 clinical MAC isolates in cation-adjusted Mueller–Hinton II broth. Results: The MIC50 and MIC ranges were established and compared to suggested susceptibility breakpoints for clarithromycin (2; 0.064–128 mg/l), rifabutin (0.25; 0.25–16 mg/l), ethambutol (8; 0.5– 32 mg/l), amikacin (16; 1–128 mg/l), moxifloxacin (2; 0.25–16 mg/l), linezolid (32; 1–128 mg/l), rifampicin (8; 0.125–16 mg/l), and trimethoprim–sulfamethoxazole (2/38; 0.125/2–16/304 mg/l). Conclusions: These results, together with those from available studies, indicate that MICs are high for drugs such as rifabutin, rifampicin, ethambutol, linezolid, and moxifloxacin used against MAC at levels unlikely to be associated with clinical efficacy at current dosing. This may partly explain the poor correlation between susceptibility testing and clinical outcomes for drugs other than clarithromycin. © 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Q2
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Introduction The recommended duration of treatment for Mycobacterium avium complex (MAC) infections of 12 months following sputum conversion has a cure rate of around 75%, indicating a suboptimal strategy.1,2 Macrolides remain the cornerstone of treatment, together with a rifamycin and ethambutol.1 In severe cases, amikacin, clofazimine, or fluoroquinolones can also be considered.2,3 The correlation between the clinical outcomes of MAC infections and antimicrobial susceptibility testing (AST) breakpoints other than for the macrolides is regarded to be poor, although very limited supporting data exist.1 For MAC, the epidemiological cut-off point (ECOFF) and MIC distributions of wild-type isolates are not well described, and these are essential in establishing AST breakpoints for other bacteria together with
* Corresponding author. Tel.: +46 480 81000. E-mail address: [email protected] (T. Schön).
clinical outcomes and pharmacokinetic/pharmacodynamic (PK/ PD) data.4 Thus, the aim of this study was to describe the wild-type Q3 MIC distributions of the drugs commonly used to treat MAC.
23
Methods
26
Following decontamination, specimens were inoculated into MGIT 960 tubes (BD, USA) and Löwenstein–Jensen slopes. Identification was performed by GenoType Mycobacterium CM test system (Hain Lifescience, Germany). A total of 229 MAC strains (157 Mycobacterium avium, 72 Mycobacterium intracellulare complex), isolated from 229 patients at the Karolinska University Laboratory between 2011 and 2015 were included. AST was performed by broth microdilution method using the SLOMYCO Sensititre panel (Trek Diagnostic Systems, USA). A 0.5-McFarland bacterial suspension was transferred to cation-adjusted Mueller– Hinton II broth (BD, USA) supplemented with 5% oleic albumin dextrose catalase (OADC). The MICs were read using the Sensititre Vizion System after an incubation period of 7–14 days at 37 C. The
27
http://dx.doi.org/10.1016/j.ijid.2016.12.027 1201-9712/© 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027
24 25
28 29 30 31 32 33 34 35 36 37 38 39
G Model
IJID 2824 1–3 2 40
T. Schön, E. Chryssanthou / International Journal of Infectious Diseases xxx (2016) xxx–xxx
45
MIC50 was defined as the MIC required to inhibit the growth of 50% of the organisms. The reference strain M. avium ATCC 700898 was included in each run as a quality control. The breakpoints for clarithromycin (S 8 mg/l), moxifloxacin (S 1 mg/l), and linezolid (S 8 mg/l) were those of the Clinical and Laboratory Standards Institute (CLSI).5
46
Results
41 42 43 44
47 48 49 50
For clarithromycin, the MIC distribution of susceptible isolates ranged from 0.25 to 8 mg/l, with a MIC50 of 2 mg/l. Six isolates showed resistance (MIC 32 mg/l) (Figure 1A ).5 The MIC ranges for rifabutin and rifampicin were 0.25–16 mg/l and 0.125–16 mg/
l, respectively, with MIC50 of 0.25 and 8 mg/l, respectively. The distribution for trimethoprim (TMP)–sulfamethoxazole (SMX) ranged from 0.125/2 mg/l to 16/304 mg/l, with a MIC50 of 2/ 38 mg/l (Table 1). Rifabutin was clearly truncated at the lower end of the MIC distribution (Figure 1B). For ethambutol the MIC50 was 8 mg/l and MIC range was 0.5–32 mg/l (Figure 1C), and for amikacin MIC50 was 16 mg/l and the MIC range was 1–128 mg/l. Applying the suggested PK/PD-derived breakpoints of van Ingen et al. (8 mg/l),6 93.5% of the isolates were susceptible to clarithromycin, whereas only 9.6% were susceptible to ethambutol (2 mg/l) and 3% to rifampicin (0.5 mg/l). For moxifloxacin, the MIC50 was 2 mg/l and the MIC range was 0.25–16 mg/l; for linezolid, the MIC50 was 16 mg/l and the MIC range was 1–128 mg/l
Figure 1. Minimum inhibitory concentration (MIC) distributions of drugs used against Mycobacterium avium complex (MAC) infection: (A) clarithromycin (CLA); (B) rifabutin (RIB); (C) ethambutol (EMB). The pharmacokinetic/pharmacodynamic (PK/PD) breakpoints (Bp) as suggested by van Ingen et al., based on BACTEC 460 MIC determinations in combination with pharmacokinetic analyses, are included,3 as well as the Clinical and Laboratory Standards Institute (CLSI) suggested breakpoint for broth microdilution where applicable.5
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027
51 52 53 54 55 56 57 58 59 60 61 62 63
G Model
IJID 2824 1–3 T. Schön, E. Chryssanthou / International Journal of Infectious Diseases xxx (2016) xxx–xxx
3
Table 1 MIC distributions for alternative drugs used against Mycobacterium avium complex (MAC); the two-fold dilutions are given in mg/l. mg/l
Rifampicin Amikacin Moxifloxacin Linezolid TMP–SMXc
Q7
64
0.016
0.032
0.064
0.125
0.25
0.5
1
2
4
8
16
32
64
128
256
512
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
2 0 0 0 2
1 0 1 0 1
4a 0 10a 0 9
12 3 24b 1 48
30 4a 82 6 109
60 11 85 4 41
43 52 18 25b 13
77 115 9 75 6
0 33 0 93 0
0 9 0 22 0
0 2 0 3 0
0 0 0 0 0
0 0 0 0 0
MIC, minimum inhibitory concentration; TMP, trimethoprim; SMX, sulfamethoxazole; PK/PD, pharmacokinetic/pharmacodynamic. a Previously suggested breakpoints for MAC from PK/PD analyses.3 b Clinical and Laboratory Standards Institute breakpoints for broth microdilution.5 c The TMP concentration is 1/19 of the trimethoprim concentration (TMP = 1 mg/l, SMX = 19 mg/l).
In summary, the MIC distributions for common drugs used against MAC have been presented, which indicate the potential clinical efficacy of clarithromycin and possibly sulfamethoxazole and amikacin.
101
69
(Table 1). Considering the tentative CLSI breakpoints for moxifloxacin (S 1 mg/l) and linezolid (S 8 mg/l), 15.3% and 15.7% of the isolates, respectively, would be susceptible. The quality control strain had a MIC variability of less than 1 MIC dilution (n = 87) for all drugs tested and was within the CLSI target for clarithromycin.5
Funding
105
70
Discussion
This work was funded by the Swedish Heart and Lung Q5 Foundation.
106
71
In this study, MIC distributions were established for drugs used against MAC. It was found that for clarithromycin and TMP–SMX, the majority of strains had low MIC levels within the breakpoints for MAC and other mycobacteria.1,3,5,7–9 Although no breakpoint has been established for amikacin, a similar rate of isolates below 16 mg/l (80.8%) was found, in agreement with a previous study (85.9%).7 For the remaining drugs, and in particular for rifampicin, ethambutol, linezolid, and moxifloxacin, most isolates had MICs beyond the reach of therapeutic doses based on what is suggested by PK/PD, clinical outcome, and MIC distribution data for MAC,5,6,8 even if synergy is taken into account. The evidence on which such drugs are recommended for the initial treatment of MAC is unclear and this has been based in part on clinical trials involving HIV patients in the pre-antiretroviral therapy era.1 It should be stressed that single MIC distributions should not be used to define clinical breakpoints for MAC. Rather, the present results illustrate the importance of such basic data to define clinical breakpoints along with PK/PD and clinical outcome studies.10 However, for some drugs with generally very high MICs against MAC isolates, it is highly unlikely that clinical efficacy will be achieved, as this would imply that MAC behaves in a very unique way compared to other bacteria, including Mycobacterium tuberculosis, in the definition of clinical breakpoints. This study has several limitations. Resistance genes were not sequenced and the treatment history of the patients was unknown. Additionally, there was a truncation in the rifabutin MIC distribution. It is clear that more MIC distributions from several laboratories need to be gathered before firm conclusions on ECOFFs can be drawn and clinical breakpoints defined together with PK/PD and clinical outcome data.
Conflict of interest
108
None to declare.
109
65 66 67 68
72 73 74 75 76 77 78 79 80 81 82 83 84 Q4 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100
References
102 103 104
107
110
111 1. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. 112 An official ATS/IDSA statement: diagnosis, treatment, and prevention of 113 nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 114 2. van Ingen J. Treatment of pulmonary disease caused by non-tuberculous 115 mycobacteria. Lancet Respir Med 2015;3:179–80. 116 3. van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, et al. The 117 pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium 118 avium complex disease treatment. Am J Respir Crit Care Med 2012;186:559–65. 119 4. Kahlmeter G. The 2014 Garrod Lecture: EUCAST—are we heading towards 120 international agreement? J Antimicrob Chemother 2015;70:2427–39. 121 5. Clinical and Laboratory Standards Institute. Susceptibility testing of mycobac122 teria, nocardiae, and other aerobic actinomycetes; approved standard—second Q6 123 edition. CLSI document M24-A2 2011. Wayne, PA: CLSI. 124 6. van Ingen J, Boeree MJ, van Soolingen D, Mouton JW. Resistance mechanisms 125 and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist 126 Updat 2012;15:149–61. 127 7. Brown-Elliott BA, Iakhiaeva E, Griffith DE, Woods GL, Stout JE, Wolfe CR, et al. 128 In vitro activity of amikacin against isolates of Mycobacterium avium complex 129 with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in 130 treated isolates. J Clin Microbiol 2013;51:3389–94. 131 8. Davies Forsman L, Schon T, Simonsson US, Bruchfeld J, Larsson M, Jureen P, et al. Intra- and extracellular activities of trimethoprim–sulfamethoxazole 132 against susceptible and multidrug-resistant Mycobacterium tuberculosis. 133 Antimicrob Agents Chemother 2014;58:7557–9. 134 9. World Health Organization. Companion handbook to the WHO guidelines for the 135 programmatic management of drug-resistant tuberculosis. Geneva: WHO; 2014. 136 10. Angeby K, Jureen P, Kahlmeter G, Hoffner SE, Schon T. Challenging a dogma: 137 antimicrobial susceptibility testing breakpoints for Mycobacterium tuberculo138 sis. Bull World Health Organ 2012;90:693–8.
Please cite this article in press as: T. Schön, E. Chryssanthou, Minimum inhibitory concentration distributions for Mycobacterium avium complex—towards evidence-based susceptibility breakpoints, Int J Infect Dis (2017), http://dx.doi.org/10.1016/j.ijid.2016.12.027