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

Leonard Amarala,*, Jette E. Kristiansenb, Miguel Viveirosa and Jorge Atouguiac

a Unit of Mycobacteriology and c Unit of Clinics of Tropical Diseases, Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Lisbon, Portugal; b Department of Microbiology, Sonderborg Sygehus, Sonderborg, Denmark


    Abstract
 Top
 Abstract
 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
The in vitro and in vivo anti-mycobacterial activities of a number of phenothiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tuberculosis at concentrations that are significantly greater than those that can safely be achieved in a patient harbouring these infections. Nevertheless, one of these phenothiazines, chlorpromazine, is concentrated by human macrophages to 10–100 times its concentration in plasma, and has activity against mycobacteria that have been phagocytosed by these cells. Phenothiazines have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. Because thioridazine, the very mild anti-psychotic agent whose most common side effect is drowsiness, has equal anti-tuberculosis properties in vitro to chlorpromazine, we recommend that thioridazine be studied as an adjuvant to the four- or five-drug regimens employed for the management of a freshly diagnosed tuberculosis infection of unknown antibiotic susceptibility, at least during the period required for the assessment of antibiotic susceptibility. Because it also enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of thioridazine 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 thioridazine 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 months should not produce side effects that are more severe than simple drowsiness. Nevertheless, further in vitro and in vivo studies are essential before thioridazine may be recommended for the management of select cases of pulmonary tuberculosis.


    Introduction
 Top
 Abstract
 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
According to a WHO report in 19981 Mycobacterium tuberculosis currently infects over 2 billion people worldwide, with 30 million new cases reported each year. This intracellular infection accounts for at least 3 million deaths annually. The problem is further increased by the increase in antibiotic-resistant infections, among which are those that are polydrug resistant (resistance to two or more antibiotics) and multidrug resistant (resistance to at least rifampicin and isoniazid).1 The resurgence of tuberculosis and the increasing frequency of single, poly- and multidrug resistance of the causative organism are the result of human actions.1 They are man-made for three reasons: (i) conditions that promote the dissemination and development of active disease are the result of socio-economic problems, such as homelessness, poverty, over-crowded living accommodation and the poor or undeveloped delivery of medical care.2 (ii) The development of drug resistance is the result of selection of resistant strains by sub-optimal treatment regimens or poor patient compliance.3,4 (iii) In countries that are economically disadvantaged and where rapid laboratory procedures required for the delivery of antibiotic susceptibility data are not available, the management of the infection takes place blindly.5 Unless all of these conditions are corrected, the dissemination of this problematic infection will increase.1 It is beyond scientists and physicians alone to bring about improvement of economic conditions so as to provide rapid antibiotic susceptibility tests, or to support the provision of four or five costly antibiotics to patients with infections predictably responsive to these agents, or still more expensive antibiotics when first-line agents are predicted to be ineffective. Nevertheless, there is an alternative that has the potential to treat patients effectively regardless of the antibiotic susceptibility profile of the causative organism at a cost that is affordable by the most economically deprived country. This same alternative also has potential as an adjunct to conventional therapy during the lengthy period before antibiotic susceptibility data are available. It has the potential to serve as an adjunct that may reduce morbidity associated with the use of rifampicin and streptomycin by allowing their use in lower dosages. It is therefore our intent in this review to provide cogent and comprehensive evidence supporting the contention that phenothiazines, and specifically thioridazine, may eventually facilitate the successful and safe management of many infections caused by M. tuberculosis, regardless of susceptibility profile.


    The potential solution
 Top
 Abstract
 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
The phenothiazine group are tricyclic compounds (FigureGo). Methylene blue, the first phenothiazine, is an aniline dye. The biological properties of this aniline dye were studied by Ehrlich,6,7 who demonstrated that it had activity against Plasmodium falciparum, and when administered to patients would cause them to become lethargic.8 The narcotizing properties of methylene blue and subsequent phenothiazines were of greater interest to the biomedical community than its antimicrobial ones, eventually resulting in the development of the first neuroleptic compound, chlorpromazine, in the early 1950s.5,9,10 The wide acceptance and use of chlorpromazine in the ensuing years for the management of severe neuroses and psychoses yielded a few anecdotal reports suggesting that this agent had anti-tuberculosis properties.1114 Although these findings were preceded by studies that showed that this compound, as well as promethazine, had in vitro activity against M. tuberculosis,1517 interest in the development of these compounds as anti-mycobacterial agents did not materialize because of the by then well-known severe side effects produced by the chronic administration of chlorpromazine. Furthermore, the introduction of isoniazid in the 1950s for the management of infections by M. tuberculosis, later followed by other effective compounds (streptomycin and rifampicin), lessened any further interest in the use of chlorpromazine as an anti-tuberculosis drug.18 Nevertheless, during the next few decades a number of studies indicated that chlorpromazine and its derivatives had in vitro activity against M. tuberculosis and that the anti-histaminic phenothiazine methdilazine was similarly effective.1922 However, the lowest concentration required for significant in vitro inhibition of growth greatly exceeded that achievable in patients (i.e. about 0.5 mg/L) receiving a minimum dose of 600 mg/day. Nevertheless, concomitant studies also showed that M. tuberculosis phagocytosed within macrophages was susceptible to concentrations of chlorpromazine 10 times lower in the culture medium than those needed for a similar inhibition of unphagocytosed bacteria.18 These concentrations were within the range anticipated in patients treated with this phenothiazine.9 These results suggested that macrophages had the ability to concentrate the phenothiazine, an interpretation consistent with those studies showing that chlorpromazine was found in pulmonary tissue in concentrations in excess of 100 times those in plasma.23



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Figure. Molecular structures of phenothiazines

 
The ability of phenothiazines and their derivatives to inhibit the growth in vitro and in vivo of M. tuberculosis is not by itself of any major significance in light of the number of available antibiotics that have been successfully employed in the past for the management of tuberculosis. However, the worldwide resurgence of tuberculosis and the escalating frequency of resistant strains, as discussed in the Introduction, predicate an urgent need for more drugs. Ideally, these should be effective against all strains of M. tuberculosis regardless of antibiotic susceptibility,3,4 sufficiently inexpensive that their availability to the poorest patient is assured, of good tolerability and active against a multiplicity of targets so as to lessen the probability of selecting resistant mutants. If these parameters can be potentially satisfied by one single drug, then that possibility is worthy of consideration now.


    Thioridazine: the phenothiazine that has the potential to satisfy all current needs for the management of antibiotic-resistant pulmonary tuberculosis
 Top
 Abstract
 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
Chlorpromazine, the first commercially produced phenothiazine for the management of psychosis, was also one of the first of the phenothiazine series shown to have anti-tuberculosis properties in vitro and in vivo.14,16 Since that first in vitro demonstration, chlorpromazine and other phenothiazines have been shown to inhibit the growth in vitro of M. tuberculosis.5,1822,2432 The MICs of a number of phenothiazines for M. tuberculosis are given in Table IGo, as well as the system employed for the determination of anti-tubercular activity. The identification of the system employed is important inasmuch as assays differ with respect to the criteria employed for defining inhibition. The MICs of chlorpromazine, the phenothiazine that has received the most attention, range from 0.9 mg/L to as high as 32 mg/L. The lowest effective in vitro concentration against M. tuberculosis is seen after the organism has been phagocytosed by human macrophages.18 In the absence of macrophages the MIC is almost 10-fold higher, which is a consequence of the ability of macrophages to concentrate chlorpromazine many times over that in the medium.1824,33 It should be noted that chlorpromazine at concentrations comparable to in vitro MICs in the absence of macrophages inhibits the transport of calcium by binding to the calcium-binding protein calmodulin.3436 This inhibition affects the integrity of the phagocytic process and is thus the basis for the in vitro exposure of the macrophage to the drug after the completion of the phagocytic process.37,38 The in vitro activity of chlorpromazine against clinical isolates of M. tuberculosis in the absence of macrophages is similar regardless of the testing system employed (Table IGo). Moreover, all strains of M. tuberculosis tested so far, regardless of whether they are susceptible to all agents, or are multi- or polydrug resistant, or even resistant to all five primary antibiotics, are equally affected by chlorpromazine (Table IIGo).5,21,31 Of significance is the observation that the activity of thioridazine, a very mild phenothiazine neuroleptic, against these strains is identical to that of chlorpromazine (Table IIGo).


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Table I. Phenothiazines reported to have in vitro activity against M. tuberculosis
 

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Table II. The activity of chlorpromazine and thioridazine against antibiotic-susceptible, and multidrug- and polydrug-resistant clinical strains of M. tuberculosis
 
The extensive use of chlorpromazine for the management of psychosis during the past 40 years provided abundent evidence for this compound producing severe side effects when administered over long periods. The more serious side effects are liver injury (acute and chronic),39 cholestatic disease and agranulocytosis.40,41 Chronic use of thioridazine can result in transient mild retinopathy.42 Although chronic use of thioridazine in experimental animals produces mild to severe cardiotoxicity,43 with the exception of overdoses (suicide attempts) and co-administration with potentially cardiotoxic drugs,4446 chronic use of thioridazine alone has not been observed to produce similar effects. The published side effects noted with the chronic administration of either chlorpromazine or thioridazine are given in Table IIIGo. The severe side effects associated with chlorpromazine are totally absent with thioridazine. Indeed, drowsiness is the most common side effect noted.


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Table III. Side effects produced by chronic use of chlorpromazine and thioridazine in the human
 
As stated above, interest in the development of chlorpromazine for treating tuberculosis was previously minimal because management of this infection with conventional antibiotics was effective. The emergence of increasingly antibiotic-resistant strains in many parts of the world, including the main urban centres of Western Europe, is now causing great concern.1 In the United States, the resurgence of tuberculosis and the emergence of drug resistance noted in 1992, especially in the city of New York,47 resulted in the development and application of new therapeutic guidelines for the management of freshly diagnosed tuberculosis that consisted of a regimen of rifampicin, isoniazid, streptomycin and pyrazinamide or ethambutol.2 These guidelines were successful in that infection rates in 1999 were below those of the 1950s. Although this approach will undoubtedly succeed in many parts of the world, there is reason to believe that it will fail in certain parts of Western and Eastern Europe, Africa, Asia and South America, because large numbers of infections are resistant to four or more conventional antibiotics.48 The upward spiral of infection is therefore anticipated to continue.49 For these reasons, interest in phenothiazines as potential treatment of tuberculosis is increasing, as evidenced by the number of published studies in recent years showing that these compounds have potential value.5,18,21,24 Nevertheless, resistance to their use continues as a consequence of the well-known side effects associated with the chronic use of chlorpromazine, as well as the knowledge that the in vitro concentrations of phenothiazines required for inhibiting the growth of M. tuberculosis are beyond those that are clinically achievable.24 These two objections are now obviated by observations that clearly show that the very mild phenothiazine thioridazine is as active as chlorpromazine and that in all probability the effective concentrations noted in vitro are reproduced within the macrophage that has phagocytosed the organism.

The use of thioridazine as the phenothiazine of choice for the management of freshly diagnosed pulmonary tuberculosis is further reinforced by the observations that this compound enhances the in vitro activity of rifampicin and streptomycin against polydrug-resistant strains of M. tuberculosis.32 Chlorpromazine also enhances the in vitro and in vivo activity of these antibiotics against antibiotic susceptible and polydrug-resistant strains of M. tuberculosis.18,31 These observations suggest that the use of thioridazine may allow a reduction in the dosages of these antibiotics and the morbidity associated with these antibiotics may therefore be reduced.18,32

The use of thioridazine for the management of tuberculosis affords another potential advantage, namely that mutations resulting in resistance to the drug are not anticipated since calmodulin, the calcium transport protein of eukaryotic cells and to which the phenothiazine binds and renders inactive, is also a vital constituent of the cell wall envelope of mycobacteria.25,26,50,51 Deletions of this gene or mutations that affect the binding of calcium would most probably be lethal. In addition, the phenothiazine affects a large number of targets that are required for the survival of the organism,27,51 and thus, even if mutations were to take place, the probability that all of these mutations would occur in one single cell, is very remote.24


    Conclusions
 Top
 Abstract
 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
The review provides fairly strong evidence that the phenothiazine thioridazine may, in certain patients, prove useful for the management of tuberculosis infections. In the case of full-blown cavitary disease, where the organism is primarily extracellular, little or no activity is anticipated since the concentrations required are in excess of those clinically achievable. Nevertheless, for moderate cavitary disease, and in patients probably infected with multidrug-resistant strains, the use of thioridazine while awaiting antibiotic susceptibility results may provide effective treatment as well as contributing to a reduction in the dissemination of infection. However, this possibility presently remains conjectural since there is much that is still unknown. The questions of whether thioridazine is concentrated by macrophages that have phagocytosed M. tuberculosis and whether it is active in situ remain to be answered. Furthermore, even if they were to be answered affirmatively, the question of whether this compound will be similarly effective in patients must be resolved. To this extent we must await the results of further in vitro and in vivo (macrophage and animal) studies before thioridazine may start to find its place in the armamentarium of anti-tuberculosis drugs.


    Acknowledgments
 
We would like to thank Professor Dr J. D. Williams, Professor Dr J. V. Costa and Professor Dr Tommie Victor for their valuable suggestions and critical reviews of the manuscript.


    Notes
 
* Correspondence address. Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua Junqueira 96, 1349-008 Lisbon, Portugal. Tel: +351-21-365-26-53; Fax: +351-21-363-21-05; E-mail: lamaral{at}ihmt.unl.pt Back


    References
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 Introduction
 The potential solution
 Thioridazine: the phenothiazine...
 Conclusions
 References
 
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