Efficacy of Microencapsulated Rifampin in Mycobacterium tuberculosis -Infected Mice

Abstract

Rifampin is a first-line drug useful in the treatment of tuberculosis. By using biocompatible polymeric excipients of lactide and glycolide copolymers, two microsphere formulations were developed for targeted and sustained delivery of rifampin, with minimal dosing. A small-microsphere formulation, with demonstrated ability to inhibit intracellularly replicating Mycobacterium tuberculosisH37Rv, was tested along with a large-microsphere formulation in an infected mouse model. Results revealed that by using a single treatment of the large-microsphere formulation, it was possible to achieve a significant reduction in M. tuberculosis H37Rv CFUs in the lungs of mice by 26 days postinfection. A combination of small (given as two injections on day 0 and day 7) and large (given as one injection at day 0) rifampin-loaded microsphere formulations resulted in significant reductions in CFUs in the lungs by 26 days, achieving a 1.23 log10 reduction in CFUs. By comparison, oral treatment with 5, 10, or 20 mg of rifampin/kg of body weight, administered every day, resulted in a reduction of 0.42, 1.7, or 1.8 log10units, respectively. Thus the microsphere formulations, administered in one or two doses, were able to achieve results in mice similar to those obtained with a daily drug regimen within the range of the highest clinically tolerated dosage in humans. These results demonstrate that microsphere formulations of antimycobacterial drugs such as rifampin can be used for therapy of tuberculosis with minimal dosing.

The Synergistic Effect of Exogenous Glutamine and Rifampicin Against Mycobacterium Persisters

“…Mechanistic insights into persistence can find better targets for novel drugs to shorten the tuberculosis treatment duration. In this study, we found that the glutamine can sensitize M. smegmatis to rifampicin-mediated killing ( Figures 1A,B ) ( di Mauro et al, 1969 ; Quenelle et al, 1999 ; Campbell et al, 2001 ), consistent with previous publications showing that high concentration arginine can synergize with gentamicin against E. coli ( Recht and Kolter, 2001 ; Lebeaux et al, 2014 ; Shan et al, 2015 ). Notably, prolonged starvation can enhance the tolerance to rifampicin though the addition of glutamine increased the activity of rifampicin (Supplementary Figure 2 ).…”

Induction of autophagy through CLEC4E in combination with TLR4: an innovative strategy to restrict the survival of Mycobacterium tuberculosis

“…More infiltration and accumulation of lymphocytes were observed in the non-immunized placebo control mice (Figure 3B,C). Next, we investigated whether treatment with C 4 .T 4 agonists potentiate the efficacy of anti-TB drugs even at a lower dose than the recommended concentration [50]. Interestingly, we observed that treatment of mice with C 4 .T 4 in combination with RIF considerably (p < 0.001) boosted the killing efficacy of the drug, when compared to the drug alone (Figure 3D).…”

Particulate and Vesicular Drug Carriers in the Management of Tuberculosis

“…doses of small microspheres with an oral dosing of INH for 25 days. While RIF loaded microspheres showed 1.23 log 10 reduction in CFU, combination with INH resulted in nearly complete elimination of CFU from the lungs and spleen [9,[56][57][58].…”