Short communicationActivity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice
Introduction
Multidrug resistance among Mycobacterium tuberculosis in particular and mycobacteria in general is a global problem requiring surveillance and control. Failure to cure effectively multidrug-resistant tuberculosis (MDR-TB) and latent infections using existing antibiotics and chemotherapeutics necessitates a search for newer and potent drugs, which also accelerate current treatment by shortening the total duration of therapy. Studies aimed at discovering antimycobacterial ‘non-antibiotics’ have demonstrated in vitro and in vivo enhancement of antibiotic activity against MDR-TB [1]. The anti-inflammatory drug diclofenac sodium (DCL) possesses powerful biocidal activity towards Gram-positive and Gram-negative bacteria [2], [3] and mycobacteria [4]. It was synergistic with streptomycin (STM) against Mycobacterium smegmatis [5] and strains of Escherichia coli and Staphylococcus aureus, and also with a non-antibiotic trifluoperazine against some Gram-positive and Gram-negative bacteria [6], [7].
Prolonged and widespread use of STM as monotherapy in tuberculosis has resulted in an average of 1 in 108 tubercle bacilli being resistant to STM at 10–100 μg/mL. Previously, STM was used at high doses, but its toxicity, coupled with development of resistance, limited its usefulness. As a result, short-course therapy with STM was started (lower doses given over long periods). This delayed the appearance of resistance and reduced toxicity. Subsequently, with the discovery of more drugs, combination therapy was started. However, successful treatment requires several months of therapy. Therefore, new options need to be explored to shorten the duration of treatment.
Patients treated for tuberculosis are often administered non-steroidal anti-inflammatory drugs such as DCL for inflammation. With this in mind, this study was undertaken to examine the possible effects of DCL on treatment of tuberculosis with STM in a murine model.
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Drugs
DCL, rifampicin (RIF), STM, ethambutol (ETB) and isonicotinic acid hydrazide (INAH) were kindly donated by their respective manufacturers. Initial stock solutions (preserved at 4 °C) were made in distilled water or dimethyl sulphoxide (DMSO) at 10 μg/mL or 20 μg/mL, from which further dilutions were made in 7H9 broth (Difco Laboratories, Detroit, MI). The maximum concentration of DMSO was 0.5% to avoid interference.
Bacteria
Forty-five strains of mycobacteria were tested, of which 18 were Trudeau Memorial
MIC of DCL against mycobacteria
The MIC of DCL against the 45 strains of mycobacteria tested ranged from 10 μg/mL to 25 μg/mL (MIC for 50% of the organisms (MIC50) = 20 μg/mL). Of these, 18 were sensitive to conventional antimycobacterial drugs (STM, RIF, INAH and ETB), 8 were multidrug resistant and 19 were polydrug resistant. The MIC of DCL is five to six times higher than that of conventional drugs. Susceptible strains such as M. tuberculosis H37Rv 102 were inhibited at lower doses of the conventional agents (0.5–2 μg/mL); the
Discussion
Antimycobacterial non-antibiotics discovered so far mostly have in vitro MIC values ranging from 10 μg/mL to 25 μg/mL [1], [4], [5]. DCL is biocidal both to Gram-positive and Gram-negative bacteria [2], [3]. In the current study, the MIC (10 μg/mL) and MBC (40 μg/mL) of DCL against species of M. tuberculosis H37Rv 102 are in agreement with accounts from other workers. DCL has significant structural correlation with reported antimycobacterial non-antibiotics in the phenothiazine group.
This study
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These two authors contributed equally to this work.