Drug Susceptibility Testing of Nontuberculous Mycobacteria

  • Jakko van Ingen
Part of the Respiratory Medicine book series (RM)


Drug susceptibility testing of nontuberculous mycobacteria is an important tool to guide and optimize treatment of these severe infections. Its role has long been controversial, owing to perceived discrepancies between in vitro susceptibility of mainly Mycobacterium avium complex isolates and the in vivo outcome of treatment. These discrepancies related to classic antituberculosis drugs (rifampicin, ethambutol, isoniazid); the role of these drugs in the treatment regimens is merely to prevent macrolide resistance, and their antimycobacterial activity is thus less important to treatment success. Results of tests for macrolide, aminoglycoside, fluoroquinolone, tetracycline, and oxazolidinone antibiotic susceptibility are known to predict outcomes of treatment with combination regimens containing these agents. This chapter provides a summary of known resistance mechanisms and a historical overview of susceptibility test methods and achievements, focused on in vitro-in vivo correlations derived from clinical studies.


Antibiotic resistance Nontuberculous mycobacteria Mycobacterium Antimicrobial susceptibility testing Drug susceptibility testing Macrolides Treatment outcome 


  1. 1.
    Griffith DE, Aksamit T, Brown-Elliot BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367–416.PubMedGoogle Scholar
  2. 2.
    van Ingen J, Boeree M, van Soolingen D, Mouton J. Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat. 2012;15:149–61.PubMedGoogle Scholar
  3. 3.
    Lambert PA. Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria. J Appl Microbiol. 2002;92(Suppl):46S–54S.PubMedGoogle Scholar
  4. 4.
    Cangelosi GA, Do JS, Freeman R, Bennett JG, Semret M, Behr MA. The two-component regulatory system mtrAB is required for morphotypic multidrug resistance in Mycobacterium avium. Antimicrob Agents Chemother. 2006;50:461–8.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Gao LY, Laval F, Lawson EH, Groger RK, Woodruff A, Morisaki JH, Cox JS, Daffe M, Brown EJ. Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. Mol Microbiol. 2003;49:1547–63.PubMedGoogle Scholar
  6. 6.
    Nguyen L, Chinnapapagari S, Thompson CJ. FbpA-Dependent biosynthesis of trehalose dimycolate is required for the intrinsic multidrug resistance, cell wall structure, and colonial morphology of Mycobacterium smegmatis. J Bacteriol. 2005;187:6603–11.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Nguyen HT, Wolff KA, Cartabuke RH, Ogwang S, Nguyen L. A lipoprotein modulates activity of the MtrAB two-component system to provide intrinsic multidrug resistance, cytokinetic control and cell wall homeostasis in Mycobacterium. Mol Microbiol. 2010;76:348–64.PubMedGoogle Scholar
  8. 8.
    Philalay JS, Palermo CO, Hauge KA, Rustad TR, Cangelosi GA. Genes required for intrinsic multidrug resistance in Mycobacterium avium. Antimicrob Agents Chemother. 2004;48:3412–8.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Ren H, Liu J. AsnB is involved in natural resistance of Mycobacterium smegmatis to multiple drugs. Antimicrob Agents Chemother. 2006;50:250–5.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L. Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother. 2009;53:3515–9.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Howard ST, Rhoades E, Recht J, Pang X, Alsup A, Kolter R, Lyons CR, Byrd TF. Spontaneous reversion of Mycobacterium abscessus from a smooth to a rough morphotype is associated with reduced expression of glycopeptidolipid and reacquisition of an invasive phenotype. Microbiology. 2006;152:1581–90.PubMedGoogle Scholar
  12. 12.
    Schorey JS, Sweet L. The mycobacterial glycopeptidolipids: structure, function, and their role in pathogenesis. Glycobiology. 2008;18:832–41.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Cangelosi GA, Palermo CO, Laurent JP, Hamlin AM, Brabant WH. Colony morphotypes on Congo red agar segregate along species and drug susceptibility lines in the Mycobacterium avium-intracellulare complex. Microbiology. 1999;145(Pt 6):1317–24.PubMedGoogle Scholar
  14. 14.
    Falkinham JO 3rd. Growth in catheter biofilms and antibiotic resistance of Mycobacterium avium. J Med Microbiol. 2007;56:250–4.PubMedGoogle Scholar
  15. 15.
    Nguyen L, Thompson CJ. Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends Microbiol. 2006;14:304–12.PubMedGoogle Scholar
  16. 16.
    Stephan J, Mailaender C, Etienne G, Daffe M, Niederweis M. Multidrug resistance of a porin deletion mutant of Mycobacterium smegmatis. Antimicrob Agents Chemother. 2004;48:4163–70.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Danilchanka O, Pavlenok M, Niederweis M. Role of porins for uptake of antibiotics by Mycobacterium smegmatis. Antimicrob Agents Chemother. 2008;52:3127–34.PubMedPubMedCentralGoogle Scholar
  18. 18.
    van Ingen J, Ferro BE, Hoefsloot W, Boeree MJ, van Soolingen D. Drug treatment of pulmonary nontuberculous mycobacterial disease in HIV-negative patients: the evidence. Expert Rev Anti Infect Ther. 2013;11(10):1065–77.PubMedGoogle Scholar
  19. 19.
    Schmalstieg AM, Srivastava S, Belkaya S, Deshpande D, Meek C, Leff R, van Oers NSC, Gumbo T. The antibiotic resistance arrow of time: Efflux pump induction is a general first step in the evolution of mycobacterial drug resistance. Antimicrob Agents Chemother. 2012;56:4806–15.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Silva PE, Bigi F, Santangelo MP, Romano MI, Martin C, Cataldi A, Ainsa JA. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2001;45:800–4.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Ramon-Garcia S, Martin C, Ainsa JA, De Rossi E. Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J Antimicrob Chemother. 2006;57:252–9.PubMedGoogle Scholar
  22. 22.
    De Rossi E, Blokpoel MC, Cantoni R, Branzoni M, Riccardi G, Young DB, De Smet KA, Ciferri O. Molecular cloning and functional analysis of a novel tetracycline resistance determinant, tet(V), from Mycobacterium smegmatis. Antimicrob Agents Chemother. 1998;42:1931–7.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Sander P, De Rossi E, Boddinghaus B, Cantoni R, Branzoni M, Bottger EC, Takiff H, Rodriquez R, Lopez G, Riccardi G. Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance. FEMS Microbiol Lett. 2000;193:19–23.PubMedGoogle Scholar
  24. 24.
    Li XZ, Zhang L, Nikaido H. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother. 2004;48:2415–23.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Briffotaux J, Huang W, Wang X, Gicquel B. MmpS5/MmpL5 as an efflux pump in Mycobacterium species. Tuberculosis. 2017;107:13–9.PubMedGoogle Scholar
  26. 26.
    Alexander DC, Vasireddy R, Vasireddy S, et al. The emergence of mmpT5 variants during bedaquiline treatment of Mycobacterium intracellulare Lung Disease. J Clin Microbiol. 2017;55:574–84.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Bhatt K, Banerjee SK, Chakraborti PK. Evidence that phosphate specific transporter is amplified in a fluoroquinolone resistant Mycobacterium smegmatis. Eur J Biochem. 2000;267:4028–32.PubMedGoogle Scholar
  28. 28.
    Morris RP, Nguyen L, Gatfield J, Visconti K, Nguyen K, Schnappinger D, Ehrt S, Liu Y, Heifets L, Pieters J, Schoolnik G, Thompson CJ. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2005;102:12200–5.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Flores AR, Parsons LM, Pavelka MS Jr. Genetic analysis of the beta-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to beta-lactam antibiotics. Microbiology. 2005;151:521–32.PubMedGoogle Scholar
  30. 30.
    Nash DR, Wallace RJ Jr, Steingrube VA, Udou T, Steele LC, Forrester GD. Characterization of beta-lactamases in Mycobacterium fortuitum including a role in beta-lactam resistance and evidence of partial inducibility. Am Rev Respir Dis. 1986;134:1276–82.PubMedGoogle Scholar
  31. 31.
    Lefebvre AL, Le Moigne V, Bernut A, Veckerlé C, Compain F, Herrmann JL, Kremer L, Arthur M, Mainardi JL. Inhibition of the β-Lactamase BlaMab by avibactam improves the in vitro and in vivo efficacy of imipenem against Mycobacterium abscessus. Antimicrob Agents Chemother. 2017;61.
  32. 32.
    Adjei MD, Heinze TM, Deck J, Freeman JP, Williams AJ, Sutherland JB. Acetylation and nitrosation of ciprofloxacin by environmental strains of mycobacteria. Can J Microbiol. 2007;53:144–7.PubMedGoogle Scholar
  33. 33.
    Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat. 2010;13:151–71.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ripoll F, Pasek S, Schenowitz C, Dossat C, Barbe V, Rottman M, Macheras E, Heym B, Herrmann JL, Daffe M, Brosch R, Risler JL, Gaillard JL. Non mycobacterial virulence genes in the genome of the emerging pathogen Mycobacterium abscessus. PLoS One. 2009;4:–e5660.Google Scholar
  35. 35.
    Ho II, Chan CY, Cheng AF. Aminoglycoside resistance in Mycobacterium kansasii, Mycobacterium avium-M. intracellulare, and Mycobacterium fortuitum: are aminoglycoside-modifying enzymes responsible? Antimicrob Agents Chemother. 2000;44:39–42.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Baysarowich J, Koteva K, Hughes DW, Ejim L, Griffiths E, Zhang K, Junop M, Wright GD. Rifamycin antibiotic resistance by ADP-ribosylation: structure and diversity of Arr. Proc Natl Acad Sci U S A. 2008;105:4886–91.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Nash KA, Brown-Elliott BA, Wallace RJ Jr. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009;53:1367–76.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Brown-Elliott BA, Hanson K, Vasireddy S, Iakhiaeva E, Nash KA, Vasireddy R, Parodi N, Smith T, Gee M, Strong A, Barker A, Cohen S, Muir H, Slechta ES, Wallace RJ Jr. Absence of a functional erm gene in isolates of Mycobacterium immunogenum and the Mycobacterium mucogenicum group, based on in vitro clarithromycin susceptibility. J Clin Microbiol. 2015;53:875–8.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Dey A, Verma AK, Chatterji D. Role of an RNA polymerase interacting protein, MsRbpA, from Mycobacterium smegmatis in phenotypic tolerance to rifampicin. Microbiology. 2010;156:873–83.PubMedGoogle Scholar
  40. 40.
    Griffith DE, Brown-Elliott BA, Langsjoen B, Zhang Y, Pan X, Girard W, Nelson K, Caccitolo J, Alvarez J, Shepherd S, Wilson R, Graviss EA, Wallace RJ Jr. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006;174:928–34.PubMedGoogle Scholar
  41. 41.
    Meier A, Heifets L, Wallace RJ Jr, Zhang Y, Brown BA, Sander P, Bottger EC. Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: observation of multiple 23S rDNA mutations in a clonal population. J Infect Dis. 1996;174:354–60.PubMedGoogle Scholar
  42. 42.
    Bastian S, Veziris N, Roux AL, Brossier F, Gaillard JL, Jarlier V, Cambau E. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother. 2011;55:775–81.PubMedGoogle Scholar
  43. 43.
    Long KS, Munck C, Andersen TM, Schaub MA, Hobbie SN, Bottger EC, Vester B. Mutations in 23S rRNA at the peptidyl transferase center and their relationship to linezolid binding and cross-resistance. Antimicrob Agents Chemother. 2010;54:4705–13.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Brown-Elliott BA, Iakhiaeva E, Griffith DE, Woods GL, Stout JE, Wolfe CR, Turenne CY, Wallace RJ Jr. In vitro activity of amikacin against isolates of Mycobacterium avium complex with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in treated isolates. J Clin Microbiol. 2013;51:3389–94.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Olivier KN, Griffith DE, Eagle G, et al. Randomized trial of liposomal amikacin for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med. 2017;195(6):814–23.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Prammananan T, Sander P, Brown BA, Frischkorn K, Onyi GO, Zhang Y, Bottger EC, Wallace RJ Jr. A single 16S ribosomal RNA substitution is responsible for resistance to amikacin and other 2-deoxystreptamine aminoglycosides in Mycobacterium abscessus and Mycobacterium chelonae. J Infect Dis. 1998;177:1573–81.PubMedGoogle Scholar
  47. 47.
    Klein JL, Brown TJ, French GL. Rifampin resistance in Mycobacterium kansasii is associated with rpoB mutations. Antimicrob Agents Chemother. 2001;45:3056–8.PubMedPubMedCentralGoogle Scholar
  48. 48.
    van Ingen J, Kohl TA, Kranzer K, Hasse B, Keller PM, Katarzyna Szafrańska A, Hillemann D, Chand M, Schreiber PW, Sommerstein R, Berger C, Genoni M, Rüegg C, Troillet N, Widmer AF, Becker SL, Herrmann M, Eckmanns T, Haller S, Höller C, Debast SB, Wolfhagen MJ, Hopman J, Kluytmans J, Langelaar M, Notermans DW, Ten Oever J, van den Barselaar P, Vonk ABA, Vos MC, Ahmed N, Brown T, Crook D, Lamagni T, Phin N, Smith EG, Zambon M, Serr A, Götting T, Ebner W, Thürmer A, Utpatel C, Spröer C, Bunk B, Nübel U, Bloemberg GV, Böttger EC, Niemann S, Wagner D, Sax H. Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study. Lancet Infect Dis. 2017;17:1033–41.PubMedGoogle Scholar
  49. 49.
    Stinear TP, Seemann T, Harrison PF, Jenkin GA, Davies JK, Johnson PD, Abdellah Z, Arrowsmith C, Chillingworth T, Churcher C, Clarke K, Cronin A, Davis P, Goodhead I, Holroyd N, Jagels K, Lord A, Moule S, Mungall K, Norbertczak H, Quail MA, Rabbinowitsch E, Walker D, White B, Whitehead S, Small PL, Brosch R, Ramakrishnan L, Fischbach MA, Parkhill J, Cole ST. Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res. 2008;18(5):729–41.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Matsumoto CK, Bispo PJ, Santin K, Nogueira CL, Leão SC. Demonstration of plasmid-mediated drug resistance in Mycobacterium abscessus. J Clin Microbiol. 2014;52:1727–9 [Epub ahead of print]Google Scholar
  51. 51.
    Canetti G, Froman S, Grosset J, Hauduroy P, Langerova M, Mahler HT, Meissner G, Mitchison DA, Sula L. Mycobacteria: laboratory methods for testing drug sensitivity and resistance. Bull World Health Organ. 1963;29:565–78.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am. 1959;43:273–90.PubMedGoogle Scholar
  53. 53.
    Middlebrook G, Cohn ML. Bacteriology of tuberculosis: laboratory methods. Am J Public Health Nations Health. 1958;48:844–53.PubMedPubMedCentralGoogle Scholar
  54. 54.
    van Ingen J, van der Laan T, Dekhuijzen PNR, Boeree MJ, van Soolingen D. In vitro drug susceptibility of 2275 clinical nontuberculous Mycobacterium isolates of 49 species in the Netherlands. Int J Antimicrob Agents. 2010;35:169–73.PubMedGoogle Scholar
  55. 55.
    Research Committee of the British Thoracic Society. First randomised trial of treatments for pulmonary disease caused by M. avium intracellulare, M. malmoense, and M. xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax. 2001;56:167–72.Google Scholar
  56. 56.
    Wallace RJ Jr, Dalovisio JR, Pankey GA. Disk diffusion testing of susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to antibacterial agents. Antimicrob Agents Chemother. 1979;16:611–4.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Stone MS, Wallace RJ Jr, Swenson JM, Thornsberry C, Christensen LA. Agar disk elution method for susceptibility testing of Mycobacterium marinum and Mycobacterium fortuitum complex to sulfonamides and antibiotics. Antimicrob Agents Chemother. 1983;24:486–93.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Snider DE Jr, Good RC, Kilburn JO, Laskowski LF Jr, Lusk RH, Marr JJ, Reggiardo Z, Middlebrook G. Rapid drug-susceptibility testing of Mycobacterium tuberculosis. Am Rev Respir Dis. 1981;123:402–6.PubMedGoogle Scholar
  59. 59.
    Heifets LB, Iseman MD, Lindholm-Levy PJ. Determination of MICs of conventional and experimental drugs in liquid medium by the radiometric method against Mycobacterium avium complex. Drugs Exp Clin Res. 1987;13:529–38.PubMedGoogle Scholar
  60. 60.
    Hoffner SE, Svenson SB, Kallenius G. Synergistic effects of antimycobacterial drug combinations on Mycobacterium avium complex determined radiometrically in liquid medium. Eur J Clin Microbiol. 1987;6:530–5.PubMedGoogle Scholar
  61. 61.
    Hansen KT, Clark RB, Sanders WE. Effects of different test conditions on the susceptibility of Mycobacterium fortuitum and Mycobacterium chelonae to amikacin. J Antimicrob Chemother. 1994;33:483–94.PubMedGoogle Scholar
  62. 62.
    Yew WW, Piddock LJ, Li MS, Lyon D, Chan CY, Cheng AF. In-vitro activity of quinolones and macrolides against mycobacteria. J Antimicrob Chemother. 1994;34:343–51.PubMedGoogle Scholar
  63. 63.
    Clinical Laboratory Standards Institute. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes – approved standard. 2nd ed. Wayne, PA: Clinical Standards Institute. CLSI document M24-A2; 2011.Google Scholar
  64. 64.
    Drobniewski F, Rusch-Gerdes S, Hoffner S. Antimicrobial susceptibility testing of Mycobacterium tuberculosis (EUCAST document E.DEF 8.1)--report of the Subcommittee on Antimicrobial Susceptibility Testing of Mycobacterium tuberculosis of the European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Clin Microbiol Infect. 2007;13:1144–56.PubMedGoogle Scholar
  65. 65.
    Piersimoni C, Nista D, Bornigia S, De Sio G. Evaluation of a new method for rapid drug susceptibility testing of Mycobacterium avium complex isolates by using the mycobacteria growth indicator tube. J Clin Microbiol. 1998;36:64–7.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Hombach M, Somoskövi A, Hömke R, Ritter C, Böttger EC. Drug susceptibility distributions in slowly growing non-tuberculous mycobacteria using MGIT 960 TB eXiST. Int J Med Microbiol. 2013;303:270–6.PubMedGoogle Scholar
  67. 67.
    Ericsson HM, Sherris JC. Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathol Microbiol Scand B Microbiol Immunol. 1971;217(Suppl):211.Google Scholar
  68. 68.
    Swenson JM, Thornsberry C, Silcox VA. Rapidly growing mycobacteria: testing of susceptibility to 34 antimicrobial agents by broth microdilution. Antimicrob Agents Chemother. 1982;22:186–92.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Swenson JM, Wallace RJ Jr, Silcox VA, Thornsberry C. Antimicrobial susceptibility of five subgroups of Mycobacterium fortuitum and Mycobacterium chelonae. Antimicrob Agents Chemother. 1985;28:807–11.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Wallace RJ Jr, Nash DR, Steele LC, Steingrube V. Susceptibility testing of slowly growing mycobacteria by a microdilution MIC method with 7H9 broth. J Clin Microbiol. 1986;24:976–81.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Woods GL, Williams-Bouyer N, Wallace RJ Jr, Brown-Elliott BA, Witebsky FG, Conville PS, Plaunt M, Hall G, Aralar P, Inderlied C. Multisite reproducibility of results obtained by two broth dilution methods for susceptibility testing of Mycobacterium avium complex. J Clin Microbiol. 2003;41:627–31.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Flynn CM, Kelley CM, Barrett MS, Jones RN. Application of the Etest to the antimicrobial susceptibility testing of Mycobacterium marinum clinical isolates. J Clin Microbiol. 1997;35:2083–6.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Fabry W, Schmid EN, Ansorg R. Comparison of the E test and a proportion dilution method for susceptibility testing of Mycobacterium kansasii. Chemotherapy. 1995;41:247–52.PubMedGoogle Scholar
  74. 74.
    Fabry W, Schmid EN, Ansorg R. Comparison of the E test and a proportion dilution method for susceptibility testing of Mycobacterium avium complex. J Med Microbiol. 1996;44:227–30.PubMedGoogle Scholar
  75. 75.
    Hoffner SE, Klintz L, Olsson-Liljequist B, Bolmstrom A. Evaluation of Etest for rapid susceptibility testing of Mycobacterium chelonae and M. fortuitum. J Clin Microbiol. 1994;32:1846–9.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Werngren J, Olsson-Liljequist B, Gezelius L, Hoffner SE. Antimicrobial susceptibility of Mycobacterium marinum determined by E-test and agar dilution. Scand J Infect Dis. 2001;33:585–8.PubMedGoogle Scholar
  77. 77.
    Woods GL, Bergmann JS, Witebsky FG, Fahle GA, Boulet B, Plaunt M, Brown BA, Wallace RJ Jr, Wanger A. Multisite reproducibility of Etest for susceptibility testing of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum. J Clin Microbiol. 2000;38:656–61.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Mougari F, Loiseau J, Veziris N, Bernard C, Bercot B, Sougakoff W, Jarlier V, Raskine L, Cambau E. French National Reference Center for Mycobacteria. Evaluation of the new GenoType NTM-DR kit for the molecular detection of antimicrobial resistance in non-tuberculous mycobacteria. J Antimicrob Chemother. 2017;72:1669–77.PubMedGoogle Scholar
  79. 79.
    Truffot-Pernot C, Ji B, Grosset J. Effect of pH on the in vitro potency of clarithromycin against Mycobacterium avium complex. Antimicrob Agents Chemother. 1991;35:1677–8.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Heginbothom ML, Lindholm-Levy PJ, Heifets LB. Susceptibilities of Mycobacterium malmoense determined at the growth optimum pH (pH 6.0). Int J Tuberc Lung Dis. 1998;2:430–4.PubMedGoogle Scholar
  81. 81.
    Lounis N, Vranckx L, Gevers T, Kaniga K, Andries K. In vitro culture conditions affecting minimal inhibitory concentration of bedaquiline against M. tuberculosis. Med Mal Infect. 2016;46:220–5.PubMedGoogle Scholar
  82. 82.
    Veenemans J, Mouton JW, Kluytmans JA, Donnely R, Verhulst C, van Keulen PH. Effect of manganese in test media on in vitro susceptibility of Enterobacteriaceae and Acinetobacter baumannii to tigecycline. J Clin Microbiol. 2012;50(9):3077–9.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Wallace RJ Jr, Wiss K, Bushby MB, Hollowell DC. In vitro activity of trimethoprim and sulfamethoxazole against the nontuberculous mycobacteria. Rev Infect Dis. 1982;4:326–31.PubMedGoogle Scholar
  84. 84.
    Tison F, Tacquet A, Guillaume J, Devulder B. Unsuitability of the basic coletsos medium for the measurement of sensitivity to cycloserine. Inactivation of cycloserine by sodium pyruvate. Ann Inst Pasteur Lille. 1963;14:117–24.PubMedGoogle Scholar
  85. 85.
    Wallace RJ Jr, Wiss K. Susceptibility of Mycobacterium marinum to tetracyclines and aminoglycosides. Antimicrob Agents Chemother. 1981;20:610–2.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Davis CE Jr, Carpenter JL, Trevino S, Koch J, Ognibene AJ. In vitro susceptibility of Mycobacterium avium complex to antibacterial agents. Diagn Microbiol Infect Dis. 1987;8:149–55.PubMedGoogle Scholar
  87. 87.
    Rynearson TK, Shronts JS, Wolinsky E. Rifampin: in vitro effect on atypical mycobacteria. Am Rev Respir Dis. 1971;104:272–4.PubMedGoogle Scholar
  88. 88.
    Watt B, Edwards JR, Rayner A, Grindey AJ, Harris G. In vitro activity of meropenem and imipenem against mycobacteria: development of a daily antibiotic dosing schedule. Tuber Lung Dis. 1992;73:134–6.PubMedGoogle Scholar
  89. 89.
    Woods GL, Bergmann JS, Witebsky FG, Fahle GA, Wanger A, Boulet B, Plaunt M, Brown BA, Wallace RJ Jr. Multisite reproducibility of results obtained by the broth microdilution method for susceptibility testing of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum. J Clin Microbiol. 1999;37:1676–82.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Schon T, Chryssanthou E. Minimum inhibitory concentration distributions for Mycobacterium avium complex – towards evidence-based susceptibility breakpoints. Int J Infect Dis. 2017;55:122–4.PubMedGoogle Scholar
  91. 91.
    Goldman KP. Treatment of unclassified mycobacterial infection of the lungs. Thorax. 1968;23:94–9.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Research Committee of the British Thoracic Society. Pulmonary disease caused by Mycobacterium avium-intracellulare in HIV-negative patients: five-year follow-up of patients receiving standardised treatment. Int J Tuberc Lung Dis. 2002;6:628–34.Google Scholar
  93. 93.
    Hoffner SE, Heurlin N, Petrini B, Svenson SB, Kallenius G. Mycobacterium avium complex develop resistance to synergistically active drug combinations during infection. Eur Respir J. 1994;7:247–50.PubMedGoogle Scholar
  94. 94.
    Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Ann Intern Med. 1994;121:905–11.PubMedGoogle Scholar
  95. 95.
    Sison JP, Yao Y, Kemper CA, Hamilton JR, Brummer E, Stevens DA, Deresinski SC. Treatment of Mycobacterium avium complex infection: do the results of in vitro susceptibility tests predict therapeutic outcome in humans? J Infect Dis. 1996;173:677–83.PubMedGoogle Scholar
  96. 96.
    Wallace RJ Jr, Brown BA, Griffith DE, Girard WM, Murphy DT. Clarithromycin regimens for pulmonary Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med. 1996;153:1766–72.PubMedGoogle Scholar
  97. 97.
    Tanaka E, Kimoto T, Tsuyuguchi K, et al. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med. 1999;160:866–72.PubMedGoogle Scholar
  98. 98.
    Ahn CH, Lowell JR, Ahn SS, Ahn SI, Hurst GA. Short-course chemotherapy for pulmonary disease caused by Mycobacterium kansasii. Am Rev Respir Dis. 1983;128:1048–50.PubMedGoogle Scholar
  99. 99.
    Ahn CH, Wallace RJ Jr, Steele LC, Murphy DT. Sulfonamide-containing regimens for disease caused by rifampin-resistant Mycobacterium kansasii. Am Rev Respir Dis. 1987;135:10–6.PubMedGoogle Scholar
  100. 100.
    Wallace RJ Jr, Dunbar D, Brown BA, Onyi G, Dunlap R, Ahn CH, Murphy DT. Rifampin-resistant Mycobacterium kansasii. Clin Infect Dis. 1994;18:736–43.PubMedGoogle Scholar
  101. 101.
    Shitrit D, Baum GL, Priess R, et al. Pulmonary Mycobacterium kansasii infection in Israel, 1999–2004: clinical features, drug susceptibility, and outcome. Chest. 2006;129:771–6.PubMedGoogle Scholar
  102. 102.
    van Ingen J, Totten SE, Heifets LB, Boeree MJ, Daley CL. Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. Int J Antimicrob Agents. 2012;39:173–6.PubMedGoogle Scholar
  103. 103.
    van Ingen J, Hoefsloot W, Mouton JW, Boeree MJ, van Soolingen D. Synergistic activity of rifampicin and ethambutol against slow growing nontuberculous mycobacteria is currently of questionable clinical significance. Int J Antimicrob Agents. 2013;42:80–2.PubMedGoogle Scholar
  104. 104.
    Aubry A, Chosidow O, Caumes E, Robert J, Cambau E. Sixty-three cases of Mycobacterium marinum infection: clinical features, treatment, and antibiotic susceptibility of causative isolates. Arch Intern Med. 2002;162:1746–52.PubMedGoogle Scholar
  105. 105.
    Ljungberg B, Christensson B, Grubb R. Failure of doxycycline treatment in aquarium-associated Mycobacterium marinum infections. Scand J Infect Dis. 1987;19:539–43.PubMedGoogle Scholar
  106. 106.
    Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann J-L, Nick JA, Noone PG, Bilton D, Corris P, Gibson RL, Hempstead SE, Koetz K, Sabadosa KA, Sermet-Gaudelus I, Smyth AR, van Ingen J, Wallace RJ, Winthrop KL, Marshall BC, Haworth CSUS. Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 2016;71(Suppl 1):1–22.Google Scholar
  107. 107.
    Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis. 2011;52:565–71.PubMedGoogle Scholar
  108. 108.
    Jeon K, Kwon OJ, Lee NY, Kim BJ, Kook YH, Lee SH, Park YK, Kim CK, Koh WJ. Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients. Am J Respir Crit Care Med. 2009;180:896–902.PubMedGoogle Scholar
  109. 109.
    Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, Park YK, Kim CK, Shin SJ, Huitt GA, Daley CL, Kwon OJ. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med. 2011;183:405–10.PubMedGoogle Scholar
  110. 110.
    Harada T, Akiyama Y, Kurashima A, et al. Clinical and Microbiological Differences between Mycobacterium abscessus and Mycobacterium massiliense Lung Diseases. J Clin Microbiol. 2012;50:3556–61.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Wallace RJ, Swenson JM, Silcox VA, Bulen MG. Treatment of nonpulmonary infections due to Mycobacterium fortuitum and Mycobacterium chelonei on the basis of in vitro susceptibilities. J Infect Dis. 1985;152:500–14.PubMedGoogle Scholar
  112. 112.
    Mouton JW, Brown DF, Apfalter P, Canton R, Giske CG, Ivanova M, Macgowan AP, Rodloff A, Soussy CJ, Steinbakk M, Kahlmeter G. The role of pharmacokinetics/ pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect. 2011;18:E37–45.Google Scholar
  113. 113.
    van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, Aarnoutse R, Heifets LB, Peloquin CA, Daley CL. The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment. Am J Respir Crit Care Med. 2012;186:559–65.PubMedGoogle Scholar
  114. 114.
    Koh WJ, Jeong BH, Jeon K, Lee SY, Shin SJ. Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2012;186:797–802.PubMedGoogle Scholar
  115. 115.
    Magis-Escurra C, Alffenaar JW, Hoefnagels I, Dekhuijzen PN, Boeree MJ, van Ingen J, Aarnoutse RE. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections. Int J Antimicrob Agents. 2013;42:256–61.PubMedGoogle Scholar
  116. 116.
    Ferro BE, van Ingen J, Wattenberg M, van Soolingen D, Mouton JW. Time-kill kinetics of slowly growing mycobacteria common in pulmonary disease. J Antimicrob Chemother. 2015;70(10):2838–43.PubMedGoogle Scholar
  117. 117.
    Ferro BE, Srivastava S, Deshpande D, Sherman CM, Pasipanodya JG, van Soolingen D, Mouton JW, van Ingen J, Gumbo T. Amikacin pharmacokinetics/pharmacodynamics in a novel hollow fiber Mycobacterium abscessus disease model. Antimicrob Agents Chemother. 2016;60(3):1242–8.PubMedCentralGoogle Scholar
  118. 118.
    Ferro BE, Srivastava S, Deshpande D, Pasipanodya JG, van Soolingen D, Mouton JW, van Ingen J, Gumbo T. Moxifloxacin’s limited efficacy in the Hollow-Fiber Model of Mycobacterium abscessus disease. Antimicrob Agents Chemother. 2016;60:3779–85. Scholar
  119. 119.
    Ferro BE, Srivastava S, Deshpande D, Pasipanodya JG, van Soolingen D, Mouton JW, van Ingen J, Gumbo T. Tigecycline is highly efficacious against mycobacterium abscessus pulmonary disease. Antimicrob Agents Chemother. 2016;60:2895–900. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jakko van Ingen
    • 1
  1. 1.Department of Medical MicrobiologyRadboud University Medical CenterNijmegenThe Netherlands

Personalised recommendations