Skip to main content

Prevention of Drug Resistance by Combined Drug Treatment of Tuberculosis

  • Chapter
  • First Online:
Antibiotic Resistance

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 211))

Abstract

Treatment with a combination of anti-tuberculosis drugs is thought to work by the first drug killing mutants resistant to the second drug, while the second drug kills those resistant to the first drug. Combined treatment has been remarkably successful in preventing the emergence of resistance during the treatment of tuberculosis. This success has led to the introduction of multi-drug treatment for leprosy, HIV infections and cancer. Its success in tuberculosis depends on a number of conditions such as the chromosomal nature of drug resistance in Mycobacterium tuberculosis and the absence of plasmids carrying resistance factors as well as the manner in which the bacterial population in tuberculosis does not come into contact with other potentially resistant bacteria. For multi-drug treatment to be effective in preventing resistance, the drugs must be sufficiently active so that each can inhibit all the bacteria in lesions. There must also be effective post-antibiotic lags in growth restarting to prevent growth between doses. Special bacterial populations that are drug tolerant or survive drug action unusually successfully are also a potential source of resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andrews RH, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan CV, Velu S (1960) Prevalence of tuberculosis among close family contacts of tuberculous patients in South India, and influence of segregation of the patient on the early attack rate. Bull World Health Organ 23:463–510

    PubMed  CAS  Google Scholar 

  • Awaness AM, Mitchison DA (1973) Cumulative effects of pulsed exposures of Mycobacterium tuberculosis to isoniazid. Tubercle 54:153–158

    Article  PubMed  CAS  Google Scholar 

  • Cohen T, Wilson D, Wallengren K, Samuel EY, Murray M (2011) Mixed-strain Mycobacterium tuberculosis infections among patients dying in a hospital in KwaZulu-Natal, South Africa. J Clin Microbiol 49:385–388

    Article  PubMed  Google Scholar 

  • Crofton J (1958) Sputum conversion and the metabolism of isoniazid. Am Rev Tuberc 77:869–871

    PubMed  CAS  Google Scholar 

  • Dawson JJY, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan CV, Somasundaram PR, Stott H, Tripathy SP, Velu S (1966) A 5-year study of patients with pulmonary tuberculosis in a concurrent comparison of home and sanatorium treatment for one year with isoniazid plus PAS. Bull World Health Organ 34:533–551

    PubMed  CAS  Google Scholar 

  • Dickinson JM, Mitchison DA (1966) In vitro studies on the choice of drugs for intermittent chemotherapy of tuberculosis. Tubercle 47:370–380

    Article  Google Scholar 

  • Dickinson JM, Mitchison DA (1970) Suitability of rifampicin for intermittent administration in the treatment of tuberculosis. Tubercle 51:82–94

    Article  PubMed  CAS  Google Scholar 

  • Donald PR, Sirgel FA, Botha FJ, Seifart HI, Parkin DP, Vandenplas ML, Van de Wal BW, Maritz JS, Mitchison DA (1997) The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis. Am J Respir Crit Care Med 156:895–900

    PubMed  CAS  Google Scholar 

  • Donald PR, Sirgel FA, Venter A, Smit E, Parkin DP, Van de Wal BW, Dore CJ, Mitchison DA (2002) The early bactericidal activity of streptomycin. Int J Tuberc Lung Dis 6:693–698

    PubMed  CAS  Google Scholar 

  • East African/British Medical Research Council (1972) Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 299:1079–1085

    Article  Google Scholar 

  • East and Central African/British Medical Research Council (fifth Collaborative Study) (1986) Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis: final report. Tubercle 67:5–15

    Article  Google Scholar 

  • Elliott AM, Berning SE, Iseman MD, Peloquin CA (1995) Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema. Tuber Lung Dis 76:463–467

    Article  PubMed  CAS  Google Scholar 

  • Fox W (1953) The medical research council trials of isoniazid. Recent results of combined chemotherapy. Bull Int Union Tuberc Lung Dis 23:292–307

    Google Scholar 

  • Fox W, Ellard GA, Mitchison DA (1999) Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 3:S231–S279

    PubMed  CAS  Google Scholar 

  • Fox W, Sutherland I (1956) A five-year assessment of patients in a controlled trial of streptomycin, para-aminosalicylic acid, and streptomycin plus para-aminosalicylic acid, in pulmonary tuberculosis. Q J Med 25:221–243

    PubMed  CAS  Google Scholar 

  • Fox W, Sutherland I, Daniels M (1954) A five-year assessment of patients in a controlled trial of streptomycin in pulmonary tuberculosis. Q J Med 23:347–366

    PubMed  CAS  Google Scholar 

  • Fox W, Wiener A, Mitchison DA, Selkon JB, Sutherland I (1957) The prevalence of drug-resistant tubercle bacilli in untreated patients with pulmonary tuberculosis: A national survey, 1955–56. Tubercle 38:71–84

    Article  PubMed  CAS  Google Scholar 

  • Ginsburg AS, Lee J, Woolwine SC, Grosset JH, Hamzeh FM, Bishai WR (2005) Modeling in vivo pharmacokinetics and pharmacodynamics of moxifloxacin therapy for Mycobacterium tuberculosis infection by using a novel cartridge system. Antimicrob Agents Chemother 49:853–856

    Article  PubMed  CAS  Google Scholar 

  • Gumbo T, Dona CS, Meek C, Leff R (2009) Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs. Antimicrob Agents Chemother 53:3197–3204

    Article  PubMed  CAS  Google Scholar 

  • Hong Kong Tuberculosis Treatment Services and East African/British Medical Research Councils (1976) First-line chemotherapy in the retreatment of bacteriological relapses of pulmonary tuberculosis following a short-course regimen. Lancet 1:162–163

    Google Scholar 

  • Hong Kong Chest Service/British Medical Research Council (1991) Controlled trial of 2, 4 & 6 months of pyrazinamide in 6-month, 3× weekly regimens for smear- positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin and pyrazinamide. Am Rev Respir Dis 143:700–706

    Google Scholar 

  • Hu Y, Mangan JA, Dhillon J, Sole KM, Mitchison DA, Pd B, Coates ARM (2000) Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide. J Bacteriol 182:6358–6365

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Coates ARM, Mitchison DA (2003) Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 47:653–657

    Article  PubMed  CAS  Google Scholar 

  • Huang HY, Tsai YS, Lee JJ, Chiang MC, Chen YH, Chiang CY, Lin NT, Tsai PJ (2010) Mixed infection with Beijing and non-Beijing strains and drug resistance pattern of Mycobacterium tuberculosis. J Clin Microbiol 48:4474–4480

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim M, Andries K, Lounis N, Chauffour A, Truffot-Pernot C, Jarlier V, Veziris N (2007) Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother 51:1011–1015

    Article  PubMed  CAS  Google Scholar 

  • International Union against Tuberculosis (1964) An international investigation of the efficacy of chemotherapy in previously untreated patients with pulmonary tuberculosis. Bull Int Union Tuberc 34:80–191

    Google Scholar 

  • Ji BH (1985) Drug resistance in leprosy—a review. Lepr Rev 56:265–278

    PubMed  CAS  Google Scholar 

  • Jindani A, Aber VR, Edwards EA, Mitchison DA (1980) The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121:939–949

    PubMed  CAS  Google Scholar 

  • Jindani A, Doré CJ, Mitchison DA (2003) The bactericidal and sterilising activities of antituberculosis drugs during the first 14 days. Am J Respir Crit Care Med 167:1348–1354

    Article  PubMed  Google Scholar 

  • Jindani A, Griffin GE (2010) Challenges to the development of new drugs and regimens for tuberculosis. Tuberculosis (Edinb) 90:168–170

    Article  Google Scholar 

  • Lehmann J (1946) Para-aminosalicylic acid in the treatment of tuberculosis. Lancet 5(1):15

    Article  Google Scholar 

  • Mallard K, McNerney R, Crampin AC, Houben R, Ndlovu R, Munthali L, Warren RM, French N, Glynn JR (2010) Molecular detection of mixed infections of Mycobacterium tuberculosis strains in sputum samples from patients in Karonga District, Malawi. J Clin Microbiol 48:4512–4518

    Article  PubMed  Google Scholar 

  • Matsuoka M (2010) Drug resistance in leprosy. Jpn J Infect Dis 63:1–7

    PubMed  CAS  Google Scholar 

  • Medical Research Council (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2:769–782

    Article  Google Scholar 

  • Medical Research Council (1950) Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid. Br Med J 2:1073–1085

    Article  Google Scholar 

  • Medical Research Council (1953a) Isoniazid in the treatment of pulmonary tuberculosis. Second report. Br Med J 1:521–536

    Article  Google Scholar 

  • Medical Research Council (1953b) Emergence of bacterial resistance in pulmonary tuberculosis under treatment with isoniazid, streptomycin plus PAS, and streptomycin plus isoniazid. Lancet 262:217–223

    Article  Google Scholar 

  • Mitchison DA (1954) Problems of drug resistance. Br Med Bull 69:640–641

    CAS  Google Scholar 

  • Mitchison DA (1979) Basic mechanisms of chemotherapy. Chest 76S:771–781S

    Google Scholar 

  • Mitchison DA (1980) Treatment of tuberculosis. J R Coll Physicians Lond 14:91–99

    PubMed  CAS  Google Scholar 

  • Mitchison DA (1998) How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 2:10–15

    PubMed  CAS  Google Scholar 

  • Mitchison DA, Coates ARM (2004) Predictive in vitro models of the sterilizing activity of anti-tuberculosis drugs. Curr Pharm Des 10:3285–3295

    Article  PubMed  CAS  Google Scholar 

  • Mitchison DA, Dickinson JM (1971) Laboratory aspects of intermittent drug therapy. Postgrad Med J 47:737–741

    Article  PubMed  CAS  Google Scholar 

  • Mitchison DA, Selkon JB (1957) Bacteriological aspects of a survey of the incidence of drug-resistant tubercle bacilli among untreated patients. Tubercle 38:85–98

    Article  PubMed  CAS  Google Scholar 

  • Mukamolova GV, Turapov O, Malkin J, Woltmann G, Barer M (2010) Resuscitation-promoting factors reveal an occult population of tubercle bacilli in sputum. Am J Respir Crit Care Med 181:174–180

    Article  PubMed  CAS  Google Scholar 

  • Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, Reddy C, Sturm AW, Sirgel FA, Allen J, Coleman DJ, Fourie B, Mitchison DA, the Gatifloxacin for TB (OFLOTUB) study team (2008) A phase II study of the sterilizing activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 12:128–138

    PubMed  CAS  Google Scholar 

  • Shamputa IC, Jugheli L, Sadradze N, Willery E, Portaels F, Supply P, Rigouts L (2006) Mixed infection and clonal representativeness of a single sputum sample in tuberculosis patients from a penitentiary hospital in Georgia. Respir Res 7:99

    Article  PubMed  Google Scholar 

  • Sirgel FA, Botha FJH, Parkin DP, Van de Wal BW, Donald PR, Clark PK, Mitchison DA (1993) The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts. A new method of drug assessment. J Antimicrob Chemother 32:867–875

    Article  PubMed  CAS  Google Scholar 

  • Sirgel FA, Fourie PB, Donald PR, Padayatchi N, Rustomjee R, Levin J, Roscigno G, Norman J, McIllernon H, Mitchison DA, and the Rifapentine EBA Collaborative Study Group (2005) The early bactericidal activities of rifampicin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med 172:128–135

    Article  PubMed  Google Scholar 

  • Sulochana S, Mitchison DA, Kubendiren G, Venkatesan P, Paramasivan CN (2009) Bactericidal activity of moxifloxacin on exponential and stationary phase cultures of Mycobacterium tuberculosis. J Chemother 21:127–134

    PubMed  CAS  Google Scholar 

  • Tuberculosis Chemotherapy Centre, Madras (1959) A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 21:51–144

    Google Scholar 

  • Vandamme AM, Van Vaerenbergh K, De Clercq E (1998) Anti-human immunodeficiency virus drug combination strategies. Antivir Chem Chemother 9:187–203

    PubMed  CAS  Google Scholar 

  • Waters MF (1983) The treatment of leprosy. Tubercle 64:221–32

    Article  PubMed  CAS  Google Scholar 

  • WHO Study Group (1982) Chemotherapy of leprosy for control programs. WHO Tech rep Ser 675

    Google Scholar 

  • WHO Expert Committee on Leprosy (1998) Seventh Report. World Health Organ Tech Rep Ser 874:1–43

    Google Scholar 

  • World Health Organization Regional Office for South-East Asia New Delhi (2006) Global strategy for further reducing the leprosy burden and sustaining leprosy control activities 2006–2010. Operational guidelines. Lepr Rev 77:1–50

    Google Scholar 

  • Zhang M, Li SY, Rosenthal IM, Almeida DV, Ahmad Z, Converse PJ, Peloquin CA, Nuermberger EL, Grosset JH (2011) Treatment of tuberculosis with rifamycin-containing regimens in immune deficient mice. Am J Respir Crit Care Med 183:1254–1261

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Denis A. Mitchison .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Mitchison, D.A. (2012). Prevention of Drug Resistance by Combined Drug Treatment of Tuberculosis. In: Coates, A. (eds) Antibiotic Resistance. Handbook of Experimental Pharmacology, vol 211. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28951-4_6

Download citation

Publish with us

Policies and ethics