Antimicrobial Therapy of Tuberculosis: Justification for Currently Recommended Treatment Regimens

Prevention of drug resistance became the most important aim following the first clinical trial on streptomycin with a randomized intake in 1948. The occurrence of resistance was reduced by combined therapy with streptomycin and p-aminosalicylic acid and prevented by an initial phase with three drugs. Following the Madras comparison of domiciliary and sanatorium therapy, chemotherapy for the whole world became available, but there remained the problem of compliance during 1 year of treatment. Solutions were sought by the use of intermittently supervised drug administration, and in 1970, by the inclusion of the two major sterilizing drugs rifampicin and pyrazinamide, in regimens lasting only 6 months. The next 15 years were devoted to defining modern regimens, the first with a four-drug initial phase and rifampicin throughout (2EHRZ/4RH), and the second with a continuation phase of ethambutol and isoniazid (2EHRZ/6EH). Considering individual drugs, rifampicin and pyrazinamide provide almost all of the bactericidal activity, whereas isoniazid is bactericidal only during the first 2 days and thereafter prevents the emergence of drug resistance. Although models in vitro and in the mouse suggest that drug efficacy is related to area under the concentration-time curve/minimal inhibitory concentration (AUC/MIC), clinical trials with intermittent regimens indicate that this relationship is not present during human therapy.

KEYWORDS

History - PKPD - isoniazid - rifampicin - pyrazinamide

REFERENCES

• 1 Fox W, Ellard G A, Mitchison D A. 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. 1999;  2 S231-S279
• 2 Cohn M L, Middlebrook G, Russell Jr W F. Combined drug treatment of tuberculosis, I: Prevention of emergence of mutant populations of tubercle bacilli resistant to both streptomycin and isoniazid in vitro.  J Clin Invest. 1959;  38 1349-1355
• 3 Crofton J. Chemotherapy of pulmonary tuberculosis.  Brit Med J. 1959;  37 1610-1614
• 4 Mitchison D A. Treatment of tuberculosis.  J R Coll Physicians Lond. 1980;  14 91-99
• 5 Russell Jr W F, Kass I, Heaton A D, Dressler S H, Middlebrook G. Combined drug treatment of tuberculosis, III: Clinical application of the principles of appropriate and adequate chemotherapy to the treatment of pulmonary tuberculosis.  J Clin Invest. 1959;  38 1366-1375
• 6 International Union Against Tuberculosis . An international investigation of the efficacy of chemotherapy in previously untreated patients with pulmonary tuberculosis.  Bull Int Un Tuberc. 1964;  34(2) 79-191
• 7 Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis.  Tubercle. 1958;  39 269-274
• 8 Awaness A M, Mitchison D A. Cumulative effects of pulsed exposures of Mycobacterium tuberculosis to isoniazid.  Tubercle. 1973;  54 153-158
• 9 McCune Jr R M, Tompsett R. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique, I: The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy.  J Exp Med. 1956;  104 763-803
• 10 Grosset J. The sterilizing value of rifampicin and pyrazinamide in experimental short course chemotherapy.  Tubercle. 1978;  59 287-297
• 11 East African Medical Research Council . Controlled clinical trial of four short-course (6 month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third Report.  Lancet. 1974;  ii 237-240
• 12 Mitchison D A. Modern methods for assessing the drugs used in the chemotherapy of mycobacterial disease.  J Appl Bacteriol Symposium Supplement. 1996;  81 72S-80S
• 13 World Health Organization .Treatment of Tuberculosis: Guidelines for National Programmes. 3rd ed. Geneva; WHO 2003
• 14 Jindani A, Nunn A J, Enarson D. An evaluation of two eight-month regimens of chemotherapy for the treatment of newly diagnosed pulmonary tuberculosis (Study A): an international multicentre randomised trial.  Lancet. 2004;  , In press
• 15 Fox W. Whither short-course chemotherapy?.  Br J Dis Chest. 1981;  75 331-357
• 16 Jindani A, Doré C J, Mitchison D A. The bactericidal and sterilising activities of antituberculosis drugs during the first 14 days.  Am J Respir Crit Care Med. 2003;  167 1348-1354
• 17 Brindle R, Odhiambo J, Mitchison D. Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis.  BMC Pulmonary Medicine. 2001;  1 2
• 18 Mitchison D A. Role of individual drugs in the chemotherapy of tuberculosis.  Int J Tuberc Lung Dis. 2000;  4 796-806
• 19 Zhang Y, Telenti A. Genetics of drug resistance in Mycobacterium tuberculosis . In: Hatfull GF, Jacobs WR Molecular Genetics of Mycobacteria. Washington, DC; ASM 2000: 235-254
• 20 Donald P R, Sirgel F A, Botha F J et al.. The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis.  Am J Respir Crit Care Med. 1997;  156 895-900
• 21 Dickinson J M, Mitchison D A. Experimental models to explain the high sterilizing activity of rifampin in the chemotherapy of tuberculosis.  Am Rev Resp Dis. 1981;  123 367-371
• 22 Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review.  Int J Tuberc Lung Dis. 2003;  7 6-21
• 23 Mitchison D A. The action of anti-tuberculosis drugs in short course chemotherapy.  Tubercle. 1985;  66 219-225
• 24 Heifets L, Higgins M, Simon B. Pyrazinamide is not active against Mycobacterium tuberculosis residing in cultured human monocyte-derived macrophages.  Int J Tuberc Lung Dis. 2000;  4 491-495
• 25 Tuberculosis Research Centre, Madras . Ethambutol plus isoniazid for the treatment of pulmonary tuberculosis - a controlled trial of four regimens.  Tubercle. 1982;  61 13-29
• 26 Donald P R, Sirgel F A, Venter A et al.. The early bactericidal activity of streptomycin.  Int J Tuberc Lung Dis. 2002;  6 693-698
• 27 Mitchison D A. Plasma concentrations of isoniazid in the treatment of tuberculosis. In: Davies DS, Prichard BNC Biological Effects of Drugs in Relation to Their Plasma Concentrations. London; Macmillan 1973: 169-182
• 28 Jayaram R, Gaonkar S, Kaur P et al.. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis.  Antimicrob Agents Chemother. 2003;  47 2118-2124
• 29 Hu Y, Mangan J A, Dhillon J et al.. Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide.  J Bacteriol. 2000;  182 6358-6365