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Antimicrobial Agents and Chemotherapy, September 2004, p. 3407-3411, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3407-3411.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Paradoxical Effect of Caspofungin: Reduced Activity against Candida albicans at High Drug Concentrations

David A. Stevens,1,2,3* Marife Espiritu,3 and Rachana Parmar3

Department of Medicine, Santa Clara Valley Medical Center, San Jose,1 Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford,2 California Institute for Medical Research, San Jose, California3

Received 16 January 2004/ Returned for modification 21 February 2004/ Accepted 25 May 2004

Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 µg/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 µg/ml, an additional 53% showed a "mini-paradoxical effect": no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.

* Corresponding author. Mailing address: Department of Medicine, Santa Clara Valley Medical Center, 751 S. Bascom Ave., San Jose, CA 95128-2699. Phone: (408) 885-4313. Fax: (408) 885-4306. E-mail: stevens{at}stanford.edu.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3407-3411, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3407-3411.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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