Phenothiazines: an alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies

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Abstract

Increased frequency of multidrug resistant strains of Mycobacterium tuberculosis results from inappropriate treatment and lack of patient compliance. The Center for Disease Control/American Thoracic Society (CDC/ATS) guidelines issued for the management of newly diagnosed cases of tuberculosis (TB) will not be totally effective regardless of adherence to the guidelines and patient cooperation. The long interim period between the diagnosis of TB and confirmation of antibiotic susceptibility contributes to the infection rate. Consequently, the use of an adjuvant that is known to inhibit all encountered multidrug resistant strains of M. tuberculosis may be helpful until antibiotic susceptibility is known. Phenothiazines such as chlorpromazine, methdilazine and thioridazine are effective against strains of M. tuberculosis in vitro and in vivo. It is recommended that studies be designed and conducted for the purpose of managing new cases of TB that emanate from areas known to harbour multidrug resistant strains of M. tuberculosis, with phenothiazines as adjuvants to the regimen recommended by the CDC/ATS guidelines until antibiotic susceptibility is defined. Because the normal maximum period for obtaining conventional antibiotic susceptibility results is less than 7 or 8 weeks, the probability of serious side effects from the use of a phenothiazine is remote.

Introduction

In 1993, the Center for Disease Control (CDC) in conjunction with the American Thoracic Society (ATS) updated the previously issued guidelines for the management of newly diagnosed tuberculosis (TB) among children and adults that emanated from areas of the USA known to harbor strains of Mycobacterium tuberculosis resistant to two or more drugs that exceeded 4% of all clinical isolates [1]. The need for these new CDC/ATS guidelines arose because of the 18% increase of TB infections between 1983 and 1991, many of which were resistant to one or more of the conventional antibiotics employed for therapy. During this period, New York City for example, experienced a doubling of its case load of TB, with 33% of all reported cases caused by mycobacteria resistant to one drug, and 19% were resistant to two or more drugs (multidrug resistance tuberculosis — MDRTB) [2]. In response to these findings, the CDC/ATS guidelines recommended the use of a four-drug regimen: isoniazid (INH), rifampin (RF), pyrazinamide (PZA), and either streptomycin (ST) or ethambutol (EMB). If the recent report by Liu, Shilkret and Finelli [3] of the New Jersey Department of Health is to indicate adherence to these guidelines, at least for New Jersey, 33% of all new cases of TB that emanated from areas that had experienced at least 4% of its cases to be MDRTB were treated according to the guidelines. Failure to adhere to the guidelines is likely to increase the rate of multidrug resistance. However, even total adherence to the guidelines may not be sufficient inasmuch as Reichlin, Frei and Reusser of the Kantonhospital of Basel, Switzerland recently reported a case of TB that was resistant to four of the five drugs recommended by the CDC/ATS guidelines [4]. These physicians recommended a regimen of as many as six different drugs.

Resistance of M. tuberculosis to a given antibiotic is the result of a spontaneous and random mutation of one or more genes which are responsible for the target affected by the drug. The rate of resistance to EMB is one mutation per 10 000 replications, to INH or ST is one of a million, and for RF, one of 100 million. Resistance to two drugs is the product of the individual mutation rate of the two drugs. Because the anticipated rate of mutation for both INH and RF (one out of 100 trillion) exceeds the total number of organisms present even in the most advanced case of cavitating disease, and because resistance to these two drugs was reported to be 19% in New York City, it is concluded by the CDC that MDRTB is due to the consecutive passage of mycobacteria that is resistant to one drug to another patient in which the second mutation occurs [1]. M. tuberculosis resistant to all four drugs would seem to require three or more such consecutive passages. Although theoretically sound, this argument is not supported by the Basel patient who was found to be initially resistant to INH and RF and when treated with two other ‘front line antibiotics’ developed resistance to the latter as well [4].

The problem associated with MDRTB is of course, one that transcends the patient infected, and threatens individuals in the surroundings whenever the treatment rendered is ineffective. Although rapid methods for the assessment of drug resistance have been developed and show promise for such assessment within one or 2 days [5], [6], [7], such methods are still in trial. Only the expensive Bactec TB system is readily available for securing reliable susceptibility data, and it requires at least 7 days. Therefore, even under the best of circumstances, TB patients whose origins may be from areas of the world that are known to have a high rate of TB, whose original treatment was limited at best, to two drugs, and whose causative organisms are quite probably of a MDRTB type, will, if treatment occurs under the CDC/ATS guidelines experience some clinical failures. The assessment of each failure by conventional or available rapid methods will take time, during which the infection may be passed on to others, and they in turn, when managed in like-fashion, become new epicenters of infections that would become almost impossible to manage. The question of whether there is an alternative form of managing patients who are suspected of harboring strains of MDRTB is thus of importance and is the subject of this paper.

Section snippets

The antimycobacterial activity of phenothiazines

In the late 19th century, Paul Ehrlich reported that methylene blue rendered bacteria immobile [8]. However, because the dye also caused animals to respond slowly to stimuli, the effects of methylene blue on the central nervous system overshadowed its antimicrobial potential, even though the need for an antibiotic was far greater than that for the management of psychoses. Thus, derivatives of methylene blue, termed phenothiazines, eventually found their place in the management of psychosis via

The potential role of phenothiazines for the management of suspect MDRTB: a call for studies

The significant increase in cases of TB in affluent western European cities is to a major extent due to the immigration of people from third world countries where treatment of the infection may be inappropriate [21], [22], [23], [24], [25]. The increase in TB in the USA between 1983 and 1993 is due to the HIV epidemic, deterioration in the health care infrastructure, increase in the homeless population and increased number of immigrants from third world countries [1]. The accompanying increase

Acknowledgements

We wish to thank Dr Leopold Reiner, Professor J. David Williams and Professor Dr D. A. Mitchison for their valuable advice, keen comments and editorial assistance.

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