Review article: Biomedical intelligence
Vol. 142 No. 3334 (2012)
From Magic Mountain to Table Mountain
- Andreas Diacon
- Florian von Groote-Bidlingmaier
- Peter R. Donald
Summary
Prior to the introduction of chemotherapy, tuberculosis management relied upon aerotherapy, heliotherapy and good nutrition. This “treatment”, exemplified by the regimen applied in Swiss and other European mountain resorts, is described by Thomas Mann in the book “The Magic Mountain”. Tuberculosis chemotherapy began in 1944 with the introduction of streptomycin and para-amino-salicylic acid, later augmented by isoniazid. Early experience taught physicians that treatment must be given with multiple drugs to prevent emergence of resistance and that prolonged treatment adherence for 18–24 months was needed for a permanent cure of tuberculosis. Between 1970 and 1980 rifampicin was introduced and with pyrazinamide it made “short-course” treatment possible. For 30 years, a 6-month directly observed treatment short-course (DOTS) based on the three compounds isoniazid, rifampicin and pyrazinamide was the foundation of tuberculosis control strategies world-wide, and in recent years this was supplemented with ethambutol in view of increasing rates of isoniazid resistance. However, even 6 months of treatment is too long to easily ensure the compliance necessary to permanently cure tuberculosis. The recent spread of the HIV/AIDS epidemic has placed tuberculosis programmes under severe pressure and is accompanied by an increase in drug-resistance making tuberculosis virtually untreatable in some instances. In 2004 the first of a new generation of anti-tuberculosis drugs entered clinical evaluation. A series of clinical trials, often conducted at sites in Cape Town, South Africa, has shown them to be efficacious and hold promise of being able to shorten tuberculosis treatment and treat drug-resistant tuberculosis. Development and assessment of these drugs is ongoing but there is renewed hope that these new drugs and regimens will assist in finally conquering tuberculosis, preventing a return to Magic Mountain where sunshine and fresh air was all that could be offered to patients.
References
- Amberson J, McMahon B, Pinner M. A clinical trial of sanocrysin in pulmonary tuberculosis. Am Rev Tuberculosis. 1931;24:401–35.
- Mann T. Der Zauberberg. Berlin: S Fischer Verlag; 1924.
- McMurray DN. Impact of nutritional deficiencies on resistance to experimental pulmonary tuberculosis. Nutr Rev. 1998;56(1 Pt 2):S147–52.
- Green M. Cod liver oil and tuberculosis. BMJ. 2011;343:d7505.
- Chocano-Bedoya P, Ronnenberg AG. Vitamin D and tuberculosis. Nutr Rev. 2009;67(5):289–93.
- McMurray DN. Hematogenous reseeding of the lung in low-dose, aerosol-infected guinea pigs: unique features of the host-pathogen interface in secondary tubercles. Tuberculosis (Edinb). 2003;83(1–3):131–4.
- Murray JF. Bill Dock and the location of pulmonary tuberculosis: how bed rest might have helped consumption. Am J Respir Crit Care Med. 2003;168(9):1029–33.
- Balasubramanian V, Wiegeshaus EH, Taylor BT, Smith DW. Pathogenesis of tuberculosis: pathway to apical localization. Tuber Lung Dis. 1994;75(3):168–78.
- Domagk G. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Deutsche Medizinische Wochenschrift. 1935;61:250.
- Feldman WH, Hinshaw HC, Mann FC. Promizole in tuberculosis. Am Rev Tuberculosis. 1944;50:418–40.
- Lincoln EM, Stone S, Hoffman OR. The treatment of miliary tuberculosis with promizole. Bull Johns Hopkins Hosp. 1948;82(1):56–75.
- Ryan F. Tuberculosis: The greatest story never told. Bromsgrove, Worcestershire, UK: Swift Publishers; 1992.
- Bernheim F. The effect of salicylate on the oxygen uptake of the tubercle bacillus. Science. 1940;92(2383):204.
- Dubovsky H. Correspondence with a pioneer, Jurgen Lehmann (1898–1989), producer of the first effective antituberculosis specific. S Afr Med J. 1991;79(1):48–50.
- Lehmann J. Twenty years afterward: Historical notes on the discovery of the antituberculosis effect of paraaminosalicylic acid (PAS) and the first clinical trials. Am Rev Respir Dis. 1994;90:953–6.
- The Therapeutic Trials Committee of the Swedish National Association against Tuberculosis. Para-aminosalicylic acid treatment in pulmonary tuberculosis. Am Rev Tuberc. 1950;61(5):597–612.
- Schatz A, Bugie E, Waksman SA. Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc Soc Exp Biol Med. 1944;55:66–9.
- Feldman WH, Hinshaw HC. Effects of streptomycin on experimental tuberculosis in guinea pigs: a preliminary report. Proc Staff Meet Mayo Clin. 1944;19:593–9.
- Medical Research Council. Streptomcyin treatment of pulmonary tuberculosis. Br Med J. 1948;2(4582):769–82.
- Fox W, Sutherland I, Daniels M. A five-year assessment of patients in a controlled trial of streptomycin in pulmonary tuberculosis; report to the Tuberculosis Chemotherapy Trials Committee of the Medical Research Council. Q J Med. 1954;23(91):347–66.
- Fox W, Sutherland I. 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. 1956;25(98):221–43.
- Domagk G. Die experimentellen Grundlagen einer Chemotherapie der Tuberkulose. Beitr Klin Tuberk Spezif Tuberkuloseforsch. 1948;101(4):365–94.
- Heilmeyer L. Die Chemotherapie der Tuberkulose. Dtsch Med Wochenschr. 1949;74(6):161–7.
- Fox HH. The chemical attack on tuberculosis. Trans N Y Acad Sci. 1953;15(7):234–42.
- McDermott W. The story of INH. J Infect Dis. 1969;119(6):678–83.
- Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med. 2005;171(7):699–706.
- Medical Research Council. Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation: a report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Tubercle. 1962;43:201–67.
- McDermott W. Antimicrobial therapy of pulmonary tuberculosis. Bull World Health Organ. 1960;23(4–5):427–61.
- Shepherd RG, Wilkinson RG. Antituberculous agents II. N,N'-diisopropylethylenediamine and analogs. J Med Pharm Chem. 1962;91:823–35.
- Carr RE, Henkind P. Ocular manifestations of ethambutol, toxic amblyopia after administration of an experimental antituberculous drug. Arch Ophthalmol. 1962;67:566–71.
- Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000;4(9):796–806.
- Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet. 2004;364(9441):1244–51.
- Sensi P, Margalith P, Timbal MT. Rifomycin, a new antibiotic; preliminary report. Farmaco Sci. 1959;14(2):146–7.
- van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis. 2011;52(9):e194–9.
- Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. Chemotherapy. 1966;11(5):285–92.
- Grumbach F, Canetti G, Le Lirzin M. Rifampicin in daily and intermittent treatment of experimental murine tuberculosis, with emphasis on late results. Tubercle. 1969;50(3):280–93.
- Sirgel FA, Fourie PB, Donald PR, Padayatchi N, Rustomjee R, Levin J, et al. The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med. 2005;172(1):128–35.
- Verbist L, Gyselen A. Antituberculous activity of rifampin in vitro and in vivo and the concentrations attained in human blood. Am Rev Respir Dis. 1968;98(6):923–32.
- Fox W, Ellard GA, Mitchison DA. 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;3(10 Suppl 2):S231–79.
- McDermott W, McCune RM, Jr., Tompsett R. Dynamics of antituberculous chemotherapy. Am Rev Tuberc. 1956;74(2 Part 2):100–8.
- Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis. 1987;136(6):1339–42.
- Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Results at 30 months. Am Rev Respir Dis. 1991;143(4 Pt 1):700–6.
- Iseman MD, Sbarbaro JA. Short-course chemotherapy of tuberculosis. Hail Britannia (and friends)! Am Rev Respir Dis. 1991;143(4 Pt 1):697–8.
- Chretien J. Tuberculosis and HIV. The cursed duet. Bull Int Union Tuberc Lung Dis. 1990;65(1):25–8.
- Tsukamura M, Nakamura E, Yoshii S, Amano H. Therapeutic effect of a new antibacterial substance ofloxacin (DL8280) on pulmonary tuberculosis. Am Rev Respir Dis. 1985;131(3):352–6.
- Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605–12.
- Sirgel FA, Donald PR, Odhiambo J, Githui W, Umapathy KC, Paramasivan CN, et al. A multicentre study of the early bactericidal activity of anti-tuberculosis drugs. J Antimicrob Chemother. 2000;45(6):859–70.
- Tuberculosis Research Centre (Indian Council of Medical Research). Shortening short course chemotherapy: A randomised clinical trial for treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Ind J Tub. 2002;49:27–38.
- Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev. 2008(1):CD004795.
- Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307(5707):223–7.
- Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet. 2010;375(9731):2100–9.
- Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011;55(12):5485–92.
- Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831–5.
- Diacon AH, Dawson R, Hanekom M, Narunsky K, Venter A, Hittel N, et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int J Tuberc Lung Dis. 2011;15(7):949–54.
- Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother. 2010;54(8):3402–7.
- Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 2012;56(6):3027–31.
- Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009;360(23):2397–405.
- Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366(23):2151–60.
- Diacon AH, Dawson R, Von Groote-Bidlingmaier FT, et al. A randomized trial of the 14-day bactericidal activity of combinations of PA-824, bedaquiline, pyrazinamide and moxifloxacin. Lancet. 2012; in press.
- Dheda K, Migliori GB. The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Lancet. 2012;379(9817):773–5.