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

Abstract

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.

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade

“…The existence of a homologous gene of a fungal enzyme (lanosterol 14 α-demethylase) in M.tb , is the basis behind repurposing Econazole and Clotrimazole against M.tb. The azole drugs cause inhibition of this fungal enzyme and have anti-TB effects both in vitro and in vivo , including drug-resistant clinical isolates . However, due to their poor oral bioavailability, the use of Azoles as oral drugs has been limited.…”

Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

“…Through their antibacterial property, they have been identified as a beneficial candidate to treat TB. In a study conducted by Gupta et al, [ 43 ] first‐line anti‐TB drugs after 8 weeks of treatment had no effect on bacillary load in lungs and spleens of MDR‐TB infected mice. However, the bacillary load in the lungs and spleens of the infected mice was significantly lower with moxifloxacin.…”

“…A combination of moxifloxacin and econazole was found to be much more effective than either of the drugs alone. [ 43 ] These studies suggest that moxifloxacin may serve as the lead candidate to treat MDR‐TB. Phase III clinical trials are currently underway to determine the stability of moxifloxacin.…”

“…This regime has already reached the animal evaluation stage, for the development of possible oral drugs to treat MDR and XDR‐TB. [ 81 ] In another study done by Gupta et al, [ 43 ] it was shown that after 8 weeks of treatment, the first‐line anti‐TB drugs had no effect on MDR‐TB bacilli‐infected mice. However, both econazole and moxifloxacin, separately and in combination, significantly decreased the bacillary load in both the lungs and the spleens of the infected mice.…”

Analytical Methods for Determining Third and Fourth Generation Fluoroquinolones: A Review

“…LEVO is used in CAP and in multidrug resistant tuberculosis (MDR-TB) treatment [ 62 ]. The killing effect on slow replicating bacilli in the tissues is an important factor that shortens MDR-TB treatment and, therefore, MOXI is often added to standard therapy [ 63 – 66 ]. TROVA exhibits a broad activity spectrum against Gram-positive and Gram-negative bacteria.…”