Efficacy of moxifloxacin & econazole against multidrug resistant (MDR) Mycobacterium tuberculosis in murine model

Background & objectives: Studies have shown the bactericidal potential of econazole and clotrimazole against Mycobacterium tuberculosis under in vitro and ex vivo conditions along with their synergism with conventional antituberculosis drugs. These molecules were also found to be effective against different multidrug resistant (MDR) M. tuberculosis isolates in vitro. Hence the present study was designed to evaluate the in vivo antimycobacterial potential of moxifloxacin and econazole alone and in combination against multidrug resistant tuberculosis (MDR-TB) in a mice model. Methods: Mice were infected with 2.5×107 bacilli of MDR strain of M. tuberculosis by aerosol route of infection. After four weeks of infection, chemotherapy was started orally by moxifloxacin 8.0 mg/kg body wt and econazole 3.3 mg/kg alone and in combination, as well as with four first line anti-tuberculosis drugs as a positive control. The animals were sacrificed and the lungs and spleen were excised under aspetic conditions. The tissues were homogenized with sterile normal saline, an aliquot of the homogenate was plated on Middlebrook 7H11 agar supplemented with oleate albumin dextrose catalase (OADC) and incubated at 37°C for four weeks. The number of visible and individual colonies were counted. Results: The first line anti-tuberculosis drugs (RIF+INH+EMB+PZA) after eight weeks of therapy had no impact as the bacillary load in lungs and spleens remained unchanged. However, econazole, moxifloxacin alone as well as in combination significantly reduced the bacillary load in lungs as well as in spleens of MDR-TB bacilli infected mice. Interpretation & conclusions: Co-administration of the two drugs (econazole and moxifloxacin) to MDR-TB strain JAL-7782 infected mice exhibited additive effect, the efficacy of the drugs in combination being higher as compared with ECZ or MOX alone. These results were substantiated by histopathological studies. This study suggests the utility of econazole for the treatment of MDR tuberculosis and warrants further work in this direction.

[1]  Jason C. Gallagher,et al.  Moxifloxacin as an Alternative or Additive Therapy for Treatment of Pulmonary Tuberculosis , 2011, The Annals of pharmacotherapy.

[2]  K. Kliiman,et al.  Predictors of Extensively Drug-Resistant Pulmonary Tuberculosis , 2009, Annals of Internal Medicine.

[3]  D. Menzies,et al.  Influence of multidrug resistance on tuberculosis treatment outcomes with standardized regimens. , 2008, American journal of respiratory and critical care medicine.

[4]  R. Pandey,et al.  Novel chemotherapy for tuberculosis: chemotherapeutic potential of econazole- and moxifloxacin-loaded PLG nanoparticles. , 2008, International journal of antimicrobial agents.

[5]  V. Nandi,et al.  Moxifloxacin, Ofloxacin, Sparfloxacin, and Ciprofloxacin against Mycobacterium tuberculosis: Evaluation of In Vitro and Pharmacodynamic Indices That Best Predict In Vivo Efficacy , 2006, Antimicrobial Agents and Chemotherapy.

[6]  V. M. Katoch,et al.  Antimycobacterial activity of econazole against multidrug-resistant strains of Mycobacterium tuberculosis. , 2006, International journal of antimicrobial agents.

[7]  Z. Ahmad,et al.  Azole antifungals as novel chemotherapeutic agents against murine tuberculosis. , 2006, FEMS microbiology letters.

[8]  Z. Ahmad,et al.  The potential of azole antifungals against latent/persistent tuberculosis. , 2006, FEMS microbiology letters.

[9]  Z. Ahmad,et al.  In vitro and ex vivo antimycobacterial potential of azole drugs against Mycobacterium tuberculosis H37Rv. , 2005, FEMS microbiology letters.

[10]  G. Besra,et al.  Altered expression profile of mycobacterial surface glycopeptidolipids following treatment with the antifungal azole inhibitors econazole and clotrimazole. , 2005, Microbiology.

[11]  R. Chaisson,et al.  Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. , 2004, American journal of respiratory and critical care medicine.

[12]  Max Salfinger,et al.  Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. , 2004, The Journal of infectious diseases.

[13]  J. Flynn,et al.  Immunology of tuberculosis. , 2003, Annual review of immunology.

[14]  V. Jarlier,et al.  Fluoroquinolone-Containing Third-Line Regimen against Mycobacterium tuberculosis In Vivo , 2003, Antimicrobial Agents and Chemotherapy.

[15]  W. Bishai,et al.  Fluoroquinolones, tuberculosis, and resistance. , 2003, The Lancet. Infectious diseases.

[16]  Malcolm D. Walkinshaw,et al.  Atomic Structure of Mycobacterium tuberculosis CYP121 to 1.06 Å Reveals Novel Features of Cytochrome P450* , 2003, The Journal of Biological Chemistry.

[17]  D. Mitchison,et al.  Sterilizing Activities of Fluoroquinolones against Rifampin-Tolerant Populations of Mycobacterium tuberculosis , 2003, Antimicrobial Agents and Chemotherapy.

[18]  M. T. Ruiz,et al.  In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. , 2002, International journal of antimicrobial agents.

[19]  R. Chaisson,et al.  Bactericidal Activity of Increasing Daily and Weekly Doses of Moxifloxacin in Murine Tuberculosis , 2002, Antimicrobial Agents and Chemotherapy.

[20]  A. Vaz,et al.  Azole-antifungal binding to a novel cytochrome P450 from Mycobacterium tuberculosis: implications for treatment of tuberculosis. , 2001, Biochemical pharmacology.