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Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis

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Abstract

The comparative activity of five phenothiazines against multidrug-resistant strains of Mycobacterium tuberculosis (MDRTB) was studied using the Bactec 460 system. The order of antimycobacterial activity of the phenothiazines was: chlorpromazine=thioridazine>promethazine>promazine=desipramine. However, the levels required for an MIC 50 exceeded 1 mg/l and are beyond those that are clinically achievable. As phenothiazines are concentrated by macrophages that phagocytose and have in situ activity against mycobacteria, these agents may be considered for use as adjuvants for the management of freshly diagnosed tuberculosis in patients from populations with a high prevalence of MDRTB.

Introduction

Since the development of chlorpromazine by Charpentier et al. [1] in 1952 the in vitro antimicrobial activity of this neuroleptic as well as that of others of the phenothiazine series has been frequently demonstrated [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Recently, chlorpromazine and thioridazine have been shown to have activity against multidrug-resistant strains of Mycobacterium tuberculosis [2]. The in vitro activity of phenothiazines takes place at concentrations that exceed those that are clinically achievable. Because phenothiazines are concentrated by macrophages that have phagocytosed mycobacteria and have intracellular activity against mycobacteria [5] we have recommended that the mild phenothiazine, thioridazine, should be employed as an adjuvant for the management of freshly diagnosed infections of M. tuberculosis in patients from areas associated with a high prevalence of MDRTB, at least for the interval during which the antibiotic susceptibility of the isolate is being determined [13]. As this period would be only a few months, side effects associated with the use of neuroleptics are not anticipated. The antimycobacterial activities against MDRTB of commonly employed phenothiazines have not been previously compared in one study.

Section snippets

Phenothiazines

Chlorpromazine (CPZ), thioridazine (THZ), promethazine (PMZ), promazine (PZ) and desipramine (DSP) were purchased from Sigma. Stock solutions and dilutions of each phenothiazine with Bactec 12B medium as the diluent were freshly prepared prior to use in brown flasks and protected from light.

MDRTB strains

The 11 MDRTB strains used in this study came from routine specimens from hospitals in the Lisbon area. The methods used for the isolation, culture, identification and antibiotic susceptibility have been

Results and discussion

The average activity of chlorpromazine, thioridazine, promethazine, promazine and desipramine against 11 MDRTB strains is shown in Fig. 1. Chlorpromazine, a neuroleptic that produces severe and frequent side effects, had the same average activity as the very mild neuroleptic thioridazine. The lowest significant concentration of these two phenothiazines was 1 mg/l and produced an average inhibition of 26% in the amount of 14CO2 produced. At a concentration of 3 mg/l inhibition was 60%. Complete

Acknowledgements

We wish to thank Josefina Almeida and Rosario Bettencourt for their excellent technical assistance during the course of this study.

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