title: Impact of the order of initiation of fluconazole and amphotericin B in sequential or combination therapy on killing of Candida albicans in vitro and in a rabbit model of endocarditis and pyelonephritis.
abstract: In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC-->AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of > or =1 microg/ml; antagonism was seen using an AMB concentration of 0.5 microg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB-->AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC-->AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC-->AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB-->FLC regimen. However, FLC-->AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Albany Medical College, Albany Medical College and Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12208, USA. LouieA@mail.amc.edu
authors.forename: A
authors.initials: A
authors.lastname: Louie
authors.forename: P
authors.initials: P
authors.lastname: Kaw
authors.forename: P
authors.initials: P
authors.lastname: Banerjee
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: M H
authors.initials: MH
authors.lastname: Miller
mesh_terms: D000666:Amphotericin B / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects*; D004696:Endocarditis / Q000382:microbiology*; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000382:microbiology; D007668:Kidney / Q000382:microbiology; D007677:Kidney Function Tests; D008297:Male; D008826:Microbial Sensitivity Tests; D011704:Pyelonephritis / Q000382:microbiology*; D011817:Rabbits; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole