The chemotherapy of tuberculosis: past, present and future

Abstract

The history of the development of modern chemotherapy for tuberculosis (TB), largely due to the British Medical Research Council, is first described. There is a current need to shorten the duration of treatment and to prevent and cure drug-resistant disease. These aims will only be achieved if the way in which multidrug treatment prevents resistance from emerging and the reasons for the very slow response to chemotherapy are understood. Consideration of mutation rates to resistance and the size of bacterial populations in lesions makes it very unlikely that resistance would emerge spontaneously, leaving irregularity in drug taking and inadequate dosage as the main reasons for its occurrence. Slow response to treatment seems due to the presence of persister populations whose natural history is only partly known. In the future, we need to explore the persister state in patients and in experimental murine TB, and to take it into account in the design of future mouse experiments. The activity of rifamycins and pyrazinamide is being increased by a rise in rifamycin dosage and the inhalation of pyrazinoic acid. New drugs are gradually being brought into use, initially TMC207 and the nitroimadazoles, PA824 and OPC67683. They will need to be tested in new combination regimens for drug-susceptible and multi- and extensively drug-resistant disease.

Figure 1

EBA during the first 2 days of treatment with a range of dose sizes of INH, RMP or SM chosen to include low doses that produced no EBA. EBA = early bactericidal activity; INH = isoniazid; RMP = rifampicin; SM = streptomycin.

Figure 2

The efficacy, peak concentrations and AUCs obtained in rapid and slow acetylators of isoniazid in a series of small trials of treatment with isoniazid alone. AUC = area under curve; MIC = minimum inhibitory concentration; R = rapid; S = slow.

Figure 3

The cfu count of viable M. tuberculosis in sputum in patients receiving treatment with isoniazid-containing regimens. Data from Brindle et al. cfu = colony-forming unit.