Surface response modeling to examine the combination of amphotericin B deoxycholate and 5-fluorocytosine for treatment of invasive candidiasis.
The strategy of combining antifungal drugs in a treatment regimen may improve the outcome of invasive candidiasis. Using a well-validated pharmacodynamic murine model of invasive candidiasis, we defined the effect of the combination of amphotericin B deoxycholate (AmB) and 5-fluorocytosine (5FC) by use of the Greco model of drug interaction. The combination was additive, meaning that the experimental effect did not deviate in a statistically significant manner from the null reference model (or additive surface) of the combined effect. From a clinical perspective, the addition of 5FC to a regimen of AmB may enable the near-maximum effect to be reached in circumstances in which the administration of a given dose of AmB alone produces a submaximum effect but an increase in the dose is not possible, because of dose-related toxicity. Our methods provide a way in which some of the complex issues surrounding antifungal combination treatment can be addressed.
Hope
William W
WW
Department of Medicine, University of Manchester, Manchester, UK. hopew@mail.nih.gov
Warn
Peter A
PA
Sharp
Andrew
A
Reed
Paul
P
Keevil
Brian
B
Louie
Arnold
A
Denning
David W
DW
Drusano
George L
GL
D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D002177:Candidiasis / Q000188:drug therapy*; D003840:Deoxycholic Acid / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005437:Flucytosine / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological
D000935:Antifungal Agents; D004338:Drug Combinations; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D005437:Flucytosine