Combination antifungal therapy involving amphotericin B, rapamycin and 5-fluorocytosine using PEG-phospholipid micelles

Pharm Res. 2008 Sep;25(9):2056-64. doi: 10.1007/s11095-008-9588-1. Epub 2008 Apr 16.


Purpose: Rapamycin and 5-fluorocytosine (5-FC) are antifungal agents with unique mechanisms of activity, with potential for cooperative interaction with AmB. Combination antifungal therapy involving conventional AmB has been restricted by poor physical stability and compatibility with antifungal drugs and vehicles.

Methods: AmB and rapamycin were encapsulated in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy poly(ethylene glycol) (PEG-DSPE) micelles using a solvent evaporation method. The physical stability of micelle encapsulated AmB and rapamycin with 5-FC and saline was evaluated using dynamic light scattering (DLS). In vitro susceptibility of Candida albicans isolates to 5-FC and PEG-DSPE micelle solubilized AmB and rapamycin has been evaluated. Interactive effects have been quantified using a checkerboard layout.

Results: In contrast with conventional AmB, PEG-DSPE micelles encapsulating AmB and rapamycin are compatible with saline and 5-FC over 12 h. The solubilized drugs retain high level of potency in vitro. The combination of solubilized AmB and rapamycin was indifferent, as fractional inhibitory concentration (FIC) index and combination index (CI) values were approximately 1. Combinations of solubilized AmB or rapamycin with 5-FC, and the three-drug combination were moderately synergistic since the FIC index and CI values were consistent less than 1.

Conclusions: These results indicate that AmB solubilized in PEG-DSPE micelles is compatible with solubilized rapamycin and 5-FC. The indifferent or moderately synergistic activity of combinations is encouraging and warrants further investigation in appropriate rodent models.

MeSH terms

  • Amphotericin B / chemistry
  • Amphotericin B / pharmacology*
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects
  • Candida albicans / growth & development
  • Chemistry, Pharmaceutical
  • Drug Carriers*
  • Drug Combinations
  • Drug Stability
  • Drug Synergism
  • Flucytosine / chemistry
  • Flucytosine / pharmacology*
  • Micelles*
  • Microbial Sensitivity Tests
  • Phosphatidylethanolamines / chemistry*
  • Polyethylene Glycols / chemistry*
  • Sirolimus / chemistry
  • Sirolimus / pharmacology*
  • Solubility
  • Technology, Pharmaceutical / methods


  • Antifungal Agents
  • Drug Carriers
  • Drug Combinations
  • Micelles
  • Phosphatidylethanolamines
  • 1,2-distearoylphosphatidylethanolamine
  • Polyethylene Glycols
  • Amphotericin B
  • monomethoxypolyethylene glycol
  • Flucytosine
  • Sirolimus