Therapeutic Efficacy of Liposomal Rifabutin in a Mycobacterium avium Model of Infection

Abstract

Liposomal formulations of rifabutin were developed, and the effects of some parameters on the incorporation efficiency were studied. The antimycobacterial activity of rifabutin incorporated into liposomes prepared with phosphatidylcholine and phosphatidylserine (molar ratio, 7:3) was evaluated in a murine model of infection with a virulent Mycobacterium avium strain (strain P1581) and was compared with that of free rifabutin. The influences of the size of the liposomal rifabutin formulation, the administered doses, and the treatment schedules on the evolution of infection were studied. Two types of treatment schedules were assayed: therapeutic and prophylactic. The therapeutic treatment started 2 weeks after infection, while the prophylactic treatment began 1 day before the experimental infection with mycobacteria. Incorporation of rifabutin in liposomes resulted in a significant enhancement of activity against M. avium infection compared to that of rifabutin in the free form in both schedules. These results demonstrate that liposomal formulations of antibiotics such as rifabutin may be effective for the treatment or prophylaxis of infectious diseases.

Interaction of rifabutin with model membranes

“…The percentage of bound RB increased with increasing the ratio of cardiolipin in liposomes. These data are consistent with the results of a comparative study on binding of RB to liposomes of PC and phosphatidylglycerol [7]. It was shown that the interaction of model membranes with RB is associated with electrostatic forces.…”

“…Introduction of cholesterol into liposomes significantly decreased binding of RB, which is consistent with published data [7]. It can be hypothesized that RB is adsorbed on the membrane surface and then migrates into the hydrophobic membrane region, while cholesterol makes the structure of phospholipid molecules more compact and inhibits this process [8].…”

“…Only one study was performed to evaluate the effect of liposomal RB on mice infected with Mycobacterium avium complex. It was shown that liposomal RB is less effective compared to free RB [7].…”

In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium

“…Furthermore, rifampicin and rifabutin induce levels of hepatic microsomal enzymes that cause altered metabolism of clarithromycin, zidovudine and methadone. Reduction of the side effects and the interference with metabolism of other drugs by rifamycins could be achieved by increasing the therapeutic activity via encapsulation in liposomes [9], by using sustained-release microspheres obtained with lactide and glycolide co-polymers [10], or by reduction of therapeutic doses of rifamycins using synergistic drug combinations [11,12].…”

Evaluation of the Structure–Activity Relationship of Rifabutin and Analogs: A Drug–Membrane Study

“…[4,5] Rifabutin (RFB, Figure 1), one of the most efficient antibiotics used in TB/HIV co-infection, was chosen in this study as the lead compound for new analogues showing promise against TB. [6,7] In this context, N'-acetyl-rifabutin (RFB2, Figure 1) was obtained from RFB by selective acylation of the secondary amino group, as previously described. [8] In addition, N'-butanoyl-rifabutin (RFB3, Figure 1) was obtained from RFB as described in the Experimental Section.…”