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Antimicrobial Agents and Chemotherapy, June 2000, p. 1598-1603, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mild Heating of Amphotericin B-Desoxycholate: Effects on Ultrastructure, In Vitro Activity and Toxicity, and Therapeutic Efficacy in Severe Candidiasis in Leukopenic Mice

Els W. M. van Etten,1,* Wim van Vianen,1 Patty Roovers,1 and Peter Frederik2

Department of Medical Microbiology and Infectious Diseases, Erasmus University of Rotterdam, 3000 DR Rotterdam,1 and EM Unit, University of Maastricht, 6200 MD Maastricht,2 The Netherlands

Received 23 December 1999/Returned for modification 14 February 2000/Accepted 21 March 2000

Heated (20 min at 70°C) amphotericin B-desoxycholate (hAMB-DOC) was further characterized, as was another formulation obtained after centrifugation (60 min, 3000 × g), hcAMB-DOC. Conventional AMB-DOC consisted of individual micelles (approximately 4 nm in diameter) and threadlike aggregated micelles, as revealed by cryo-transmission electron microscopy. For both hAMB-DOC and hcAMB-DOC, pleiomorphic cobweb structures were observed with a mean particle size of approximately 300 nm as determined by laser diffraction. The potent antifungal activity of AMB-DOC against Candida albicans is not reduced by heating. Effective killing of C. albicans (>99.9% within 6 h) was obtained at 0.1 mg/liter with each of the AMB formulations. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, cation release (86Rb+) from C. albicans of >= 50% was observed at 0.8, 0.4, and 0.4 mg/liter, respectively. After heating of AMB-DOC, toxicity was reduced 16-fold as determined by red blood cell (RBC) lysis. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, hemolysis of >= 50% was observed at 6.4, 102.4, and 102.4 mg/liter, respectively. In contrast, AMB-DOC and its derivates showed similar toxicities in terms of cation release from RBC. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, cation release (86Rb+) of >= 50% was observed at 1.6, 0.8, and 0.8 mg/liter, respectively. In persistently leukopenic mice with severe invasive candidiasis, higher dosages of both hAMB-DOC and hcAMB-DOC were tolerated than those of conventional AMB-DOC (3 versus 0.8 mg/kg of body weight, respectively), resulting in significantly improved therapeutic efficacy. In conclusion, this new approach of heating AMB-DOC may be of great value for further optimizing the treatment of severe fungal infections.

* Corresponding author. Mailing address: Department of Medical Microbiology and Infectious Diseases, Erasmus University of Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31-10-4087664. Fax: 31-10-4089454. E-mail: vanetten{at}kmic.fgg.eur.nl.

Antimicrobial Agents and Chemotherapy, June 2000, p. 1598-1603, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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