Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy

The in vitro and in vivo anti-mycobacterial activities of a number of pheno thiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tube rculosis at concentrations that are significantly greater than those that c an safely be achieved in a patient harbouring these infections. Nevertheles s, one of these phenothiazines, chlorpromazine, is concentrated by human ma cro-phages to 10-100 times its concentration in plasma, and has activity ag ainst mycobacteria that have been phagocytosed by these cells. Phenothiazin es have significant in vitro activity against susceptible, polydrug- and mu ltidrug-resistant strains of M. tuberculosis, as well as enhancing the acti vity of some agents employed for first-line treatment. Because thioridazine , the very mild anti-psychotic agent whose most common side effect is drows iness, has equal anti-tuberculosis properties in vitro to chlorpromazine, w e recommend that thioridazine be studied as an adjuvant to the four- or fiv e-drug regimens employed for the management of a freshly diagnosed tubercul osis infection of unknown antibiotic susceptibility, at least during the pe riod required for the assessment of antibiotic susceptibility. Because it a lso enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of t hioridazine as an adjuvant may eventually allow a reduction In the dosages of these antibiotics and result in a decreased frequency of adverse effects . It is important to note that whereas the management of patients with thio ridazine for periods In excess of many months will result in the appearance of some undesirable side effects, its use for a limited period of 2-3 mont hs should not produce side effects that are more severe than simple drowsin ess. Nevertheless, further in vitro and in vivo studies are essential befor e thioridazine may be recommended for the management of select cases of pul monary tuberculosis.