The Dioctadecyldimethylammonium bromide (DODAB), a bilayer-forming synthetic lipid previously shown to solubilize amphotericin B (AMB), inspired this evaluation of in vivo activity of the DOD/AMB formulation in a mouse model of systemic candidiasis from survival and tissue burden experiments. AMB was solubilized in DODAB bilayer fragments obtained by sonication with tip at concentrations £ 0.1 and 10 mg/mL, respectively, organic solvent free. The AMB aggregation state was evaluated with UV-visible light absorption and dynamic light scattering for aggregate sizing. Groups of Swiss Webster mice were infected intavenously (IV) with 106 CFU/mouse of Candida albicans. Groups of 10 mice were treated intraperitoneally (IP) for 10 days post infection with saline, empty DODAB, DOD/AMB or deoxycholate/AMB (DOC/AMB) - AMB ranging from 0.2 to 0.4 mg/kg/day IP. Mice were followed for survival through day 35 post infection. For kidney and spleen burden assays, groups of 7 mice were treated daily for 7 days (AMB ranging from 0.2 to 4.0 mg/kg/day) and sacrificed on day 8. AMB was stabilized by the DODAB bilayer fragments in its monomeric form. From survival experiments, effective AMB doses in DOD/AMB formulation were very similar to those in DOC/AMB (100% and 70% survival at 0.4 mg/kg/day IP respectively, P>0.05). From tissue burden study, DOD/AMB efficacy was equivalent to the one exhibited by DOC/AMB (P>0.05). In summary, DOD/AMB is a monomeric AMB as effective as DOC/AMB, requiring much lower AMB doses than other lipid-based AMB formulations, employing a synthetic, inexpensive cationic lipid.
Full conference title:
43rd Interscience Conference on Antimicrobial Agents
- ICAAC 43rd