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Antimicrobial Agents and Chemotherapy, February 2001, p. 485-494, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.485-494.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Arnold Louie,1,2,3,* Pamela Kaw,1 Partha Banerjee,3 Weiguo Liu,1,2 George Chen,1 and Michael H. Miller1,2

Division of Infectious Diseases, Department of Medicine,1 and the Center for Immunology and Microbial Disease,2 Albany Medical College, and the Clinical Research Institute,3 Albany Medical College and Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12208

Received 6 July 2000/Returned for modification 3 August 2000/Accepted 20 November 2000

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 (FLCright-arrowAMB+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 >= 1 µg/ml; antagonism was seen using an AMB concentration of 0.5 µg/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 (AMBright-arrowAMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLCright-arrowAMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLCright-arrowAMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMBright-arrowFLC regimen. However, FLCright-arrowAMB 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.

* Corresponding author. Mailing address: Division of Infectious Diseases, Mail Code-49, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. Phone: (518) 262-6548. Fax: (518) 262-6727. E-mail: LouieA{at}mail.amc.edu.

Antimicrobial Agents and Chemotherapy, February 2001, p. 485-494, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.485-494.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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