European Journal of Pediatrics

, Volume 167, Issue 2, pp 141–148 | Cite as

Tuberculosis: drug resistance, fitness, and strategies for global control

Review

Abstract

Directly observed standardized short-course chemotherapy (DOTS) regimes are an effective treatment for drug susceptible tuberculosis disease. Surprisingly, DOTS has been reported to reduce the transmission of multi-drug resistant tuberculosis, and standardized short-course chemotherapy regimens with first-line agents have been found to be adequate treatments for some patients with drug resistant tuberculosis, including multi-drug resistance. These paradoxical observations and the apparent heterogeneity in treatment outcome of multi-drug resistant tuberculosis when using standard regimens may be due in part to limitations of in vitro drug susceptibility testing based on unique but mistakenly used techniques in diagnostic mycobacteriology. Experimental data and mathematical models indicate that the fitness cost conferred by a resistance determinant is the single most important parameter which determines the spread of drug resistance. Chromosomal alterations that result in resistance to first-line antituberculosis agents, e.g. isoniazid, rifampicin, streptomycin, may or may not be associated with a fitness cost. Based on work in experimental models and from observations in clinical drug resistant isolates a picture emerges in which, among the various resistance mutations that appear with similar rates, those associated with the least fitness cost are selected in the population.

Keywords

Tuberculosis Resistance Treatment Prevention Fitness Susceptibility testing 

References

  1. 1.
    Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin Microbiol 2:489–493PubMedCrossRefGoogle Scholar
  2. 2.
    Belanger AE, Besra GS, Ford ME, Mikosova K, Belsle JR, Brennan PJ, Inamine JM (1996) The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol. Proc Natl Acad Sci USA 93:11919–11924PubMedCrossRefGoogle Scholar
  3. 3.
    Bertrand T, Eady NA, Jones JN, Jesmin, Nagy JM, Jamart-Grégoire B, Raven EL, Brown KA (2004) Crystal structure of Mycobacterium tuberculosis catalase-peroxidase. J Biol Chem 279:38991–38999PubMedCrossRefGoogle Scholar
  4. 4.
    Billington OJ, McHugh TD, Gillespie SH (1999) Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob Agents Chemother 46:1866–1869Google Scholar
  5. 5.
    Bjorkman J, Nagaev I, Berg OG, Hughes D, Andersson DI (2000) Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science 287:1479–1482PubMedCrossRefGoogle Scholar
  6. 6.
    Böttger EC (2001) Drug resistant tuberculosis. Lancet 357:1288–1289PubMedCrossRefGoogle Scholar
  7. 7.
    Böttger EC, Pletschette M, Andersson D (2005) Drug resistance and fitness in Mycobacterium tuberculosis infection. J Infect Dis 191:823–824PubMedCrossRefGoogle Scholar
  8. 8.
    Böttger EC, Springer B, Pletschette M, Sander P (1998) Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nat Med 4:1343–1344PubMedCrossRefGoogle Scholar
  9. 9.
    British Thoracic Association (1982) A controlled trial of six month chemotherapy in pulmonary tuberculosis: second report results during the 24 months after the end of chemotherapy. Am Rev Respir Dis 126:460–462Google Scholar
  10. 10.
    Canetti G (1965) Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 92:687–703PubMedGoogle Scholar
  11. 11.
    Canetti G, Fox W, Khomenko A, Mahler HT, Menon NK, Mitchison DA, Rist N, Šmelev NA (1969) Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests in tuberculosis control programmes. Bull World Health Organ 41:21–43PubMedGoogle Scholar
  12. 12.
    Canetti G, Froman S, Grosset J, Hauduroy P, Langerová M, Mahler HT, Meissner G, Mitchison DH, Šula L (1963) Mycobacteria: laboratory methods for testing drug sensitivity and resistance. Bull World Health Organ 29:565–578PubMedGoogle Scholar
  13. 13.
    Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V (2000) Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407:340–348PubMedCrossRefGoogle Scholar
  14. 14.
    Cohn ML, Kovitz C, Oda U, Middlebrook G (1954) Studies on isoniazid and tubercle bacilli. II. The growth requirements, catalase activities, and pathogenic properties of isoniazid-resistant mutants. Am Rev Tuberc 70:641–664PubMedGoogle Scholar
  15. 15.
    Cynamon MH, Zhang Y, Harpster T, Cheng S, DeStefano MS (1999) High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection. Antimicrob Agents Chemother 43:2922–2924PubMedGoogle Scholar
  16. 16.
    Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C (2003)The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163:1009–1021PubMedCrossRefGoogle Scholar
  17. 17.
    DeRiemer K, García-García L, Bobadilla-del-Valle M, Palacios-Martínez M, Martínez-Gamboa A, Small PM, Sifuentes-Osornio J, Ponce-de-León A (2005) Does DOTS work in populations with drug-resistant tuberculosis? Lancet 365:1239–1245PubMedCrossRefGoogle Scholar
  18. 18.
    Dye C, Espinal MA, Watt CJ, Mbiaga C, William BG (2002) Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 185:1197–1202PubMedCrossRefGoogle Scholar
  19. 19.
    Espinal MA, Kim SI, Suarez PG, Kam KM, Khomenko AG, Migliori GB, Baez J, Kochi A, Dye C, Raviglione MC (2000) Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcome in 6 countries. JAMA 283:2537–2545PubMedCrossRefGoogle Scholar
  20. 20.
    Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJM (2006) The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–1946PubMedCrossRefGoogle Scholar
  21. 21.
    Hazbón MH, Bobadilla-del-Valle M, Guerrero MI, Varma-Basil M, Filliol IN, Cavatore M, Colangeli R, Safi H, Billman-Jacobe H, Lavender C, Fyfe J, García-García L, Davidow A, Brimacome M, León CI, Porras T, Bose M, Chaves F, Eisenach KD, Sifuentes-Osornio J, Ponce-de-León A, Cave MD, Alland D (2005) Role of embB codon 306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance. Antimicrob Agents Chemother 49:3794–3802PubMedCrossRefGoogle Scholar
  22. 22.
    Huitric E, Werngren J, Juréen P, Hoffner S (2006) Resistance levels and rpoB gene mutations among in vitro-selected rifampin-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother 50:2860–2862PubMedCrossRefGoogle Scholar
  23. 23.
    Inderlied CB, Salfinger M (1995) Antimicrobial agents and susceptibility tests: mycobacteria. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH (eds) Manual of clinical microbiology. American Society for Microbiology, Washington, DC, pp 1385–1404Google Scholar
  24. 24.
    Johnson R, Jordaan AM, Pretorius L, Engelke E, van der Spuy G, Bosman M, van Helden PD, Warren R, Victor TC (2006) Ethambutol resistance testing by mutation detection. Int J Tuberc Lung Dis 10:68–73PubMedGoogle Scholar
  25. 25.
    Kapetanaki SM, Chouchane S, Yu S, Zhao X, Magliozoo RS, Schelvis JP (2005) Mycobacterium tuberculosis KatG (S315T) catalase-peroxidase retains all active site properties for proper catalytic function. Biochemistry 44:243–252PubMedCrossRefGoogle Scholar
  26. 26.
    Kurland CG, Hughes D, Ehrenberg M (1996) Limitations of translational accuracy. In: Neidhardt FC (ed) Escherichia coli and Salmonella: cellular and molecular biology, 2nd edn. ASM Press, Washington, DC, pp 979–1004Google Scholar
  27. 27.
    Lawn SD, Bekker LG, Middelkoop K, Myer L, Wood R (2006) Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. Clin Infect Dis 42:1040–1047PubMedCrossRefGoogle Scholar
  28. 28.
    Madison B, Robinson-Dunn B, George I, Gross W, Lipman H, Metchuck B, Sloctsky A, Washabange G, Mazurek G, Riddershof J (2002) Multicenter evaluation of ethambutol susceptibility testing of Mycobacterium tuberculosis by agar proportion and radiometric methods. J Clin Microbiol 40:3976–3979PubMedCrossRefGoogle Scholar
  29. 29.
    Mariam DH, Mengistu Y, Hoffner SE, Andersson DI (2004) Effect of rpoB mutations conferring rifampin resistance on fitness of Mycobacterium tuberculosis. Antimicrob Agents Chemother 48:1289–1294PubMedCrossRefGoogle Scholar
  30. 30.
    Medical Research Council Investigation (1950) Treatment of pulmonary tuberculosis with streptomycin and para-amino salicylic acid. Br Med J 2:1073–1085Google Scholar
  31. 31.
    Meier A, Sander P, Schaper KJ, Scholz M, Böttger EC (1996) Correlation of molecular resistance mechanism and phenotypic resistance level in streptomycin-resistant M. tuberculosis. Antimicrob Agents Chemother 40:2452–2454PubMedGoogle Scholar
  32. 32.
    Mitchinson DA (1985) Mechanisms of the action of drugs in short-course chemotherapy. Bull Int Union Tuberc 60:36–40Google Scholar
  33. 33.
    Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcántara F, Sánchez E, Sarria M, Becerra M, Smith Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Yong Kim J, Farmer P (2003) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 348:119–128PubMedCrossRefGoogle Scholar
  34. 34.
    Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O (2002) Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing. J Clin Microbiol 40:3810–3813PubMedCrossRefGoogle Scholar
  35. 35.
    Pym AS, Saint-Joanis B, Cole ST (2002) Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect Immun 70:4955–4960PubMedCrossRefGoogle Scholar
  36. 36.
    Ramaswamy S, Musser JM (1998) Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79:3–29PubMedCrossRefGoogle Scholar
  37. 37.
    Sander P, Böttger EC (1999) Mycobacteria: genetics of resistance and implications for treatment. Chemotherapy 45:95–108PubMedCrossRefGoogle Scholar
  38. 38.
    Sander P, Springer B, Prammananan T, Sturnfels A, Kappler M, Pletschette M, Böttger EC (2002) Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob Agents Chemother 46:1204–1211PubMedCrossRefGoogle Scholar
  39. 39.
    Sherman DR, Mdluli K, Hickey MJ, Arain TM, Morris SL, Barry CE, Stover CK (1996) Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science 272:1641–1643PubMedCrossRefGoogle Scholar
  40. 40.
    Somoskovi A, Dormandy J, Mitsani D, Rivenburg J, Salfinger M (2006) Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin. J Clin Microbiol 44:4459–4463PubMedCrossRefGoogle Scholar
  41. 41.
    Styblo K (1980) Recent advances in epidemiological research in tuberculosis. Adv Tuberc Res 20:1–63PubMedGoogle Scholar
  42. 42.
    NCCLS (2003) Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes. Approved standard NCCLS document M24-A (ISBN-1-56238-500-3). NCCLS, Wayne, Pennsylvania, USAGoogle Scholar
  43. 43.
    Telenti A, Philipp WJ, Screevatsan S, Bernasconi C, Stockbauer KE, Wieles B, Musser JM, Jacobs WR Jr (1997) The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 3:567–570PubMedCrossRefGoogle Scholar
  44. 44.
    Uys PW, Warren RM, van Helden PD (2007) A threshold value for the time delay to TB diagnosis. PLoSONE 2(8):e757Google Scholar
  45. 45.
    van Helden PD, Donald PR, Victor TC, Schaaf HS, Hoal EG, Walzl G, Warren RM (2006) Antimicrobial resistance in tuberculosis: an international perspective. Expert Rev Anti-Infect Ther 4:759–766PubMedCrossRefGoogle Scholar
  46. 46.
    van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA, Beyers N, van Helden PD (1999) Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341:1174–1179PubMedCrossRefGoogle Scholar
  47. 47.
    van Rie A, Warren R, Richardson M, Gie RP, Enarson DA, Beyers N, van Helden PD (2000) Classification of drug-resistant tuberculosis in an epidemic area. Lancet 356:22–25PubMedCrossRefGoogle Scholar
  48. 48.
    van Soolingen D, Borgdorff MW, de Haas PE, Sebek MM, Veen J, Dessens M, Kremer K, van Embden JD (1999) Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997. J Infect Dis 180:726–736PubMedCrossRefGoogle Scholar
  49. 49.
    van Soolingen D, de Haas PE, van Doorn HR, Kuijper E, Rinder H, Borgdorff MW (2000) Mutations at amino acid position 315 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance, and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 182:1788–1790PubMedCrossRefGoogle Scholar
  50. 50.
    Verver S, Warren RM, Beyers N, Richardson M, van der Spuy GD, Borgdorff MW, Enarson DA, Behr MA, van Helden PD (2005) Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 171:1430–1435PubMedCrossRefGoogle Scholar
  51. 51.
    Victor TC, Warren R, Butt JL, Jordaan AM, Felix JV, Venter A, Sirgel FA, Schaaf HS, Donald PR, Richardson M, Cynamon MH, van Helden PD (1997) Genome and MIC stability in Mycobacterium tuberculosis and indications for continuation of use of isoniazid in multidrug-resistant tuberculosis. J Med Microbiol 46:847–857PubMedCrossRefGoogle Scholar
  52. 52.
    Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Jr, Sacchettini JC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204:73–78PubMedCrossRefGoogle Scholar
  53. 53.
    Whalen CC (2006) Failure of directly observed treatment for tuberculosis in Africa: a call for new approaches. Clin Infect Dis 42:1048–1050PubMedCrossRefGoogle Scholar
  54. 54.
    WHO Global Tuberculosis Programme (2002) An expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/2002.297. World Health Organization, GenevaGoogle Scholar
  55. 55.
    WHO/IUATLO Global Project on Anti-Tuberculosis Drug Resistance Surveillance (2004) Anti-tuberculosis drug resistance in the world: third global report. WHO/HTM/TB/2004.343. World Health Organization, GenevaGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Nationales Zentrum für Mykobakterien, Institut für Medizinische MikrobiologieUniversität ZürichZürichSwitzerland
  2. 2.Institut für Medizinische Mikrobiologie und HygieneGrazAustria

Personalised recommendations