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Synergistic Fungistatic Effects of Lactoferrin in Combination with Antifungal Drugs against Clinical Candida Isolates

M. E. Kuipers,1,* H. G. de Vries,2 M. C. Eikelboom,1 D. K. F. Meijer,1 and P. J. Swart1,
Section of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Studies, University Centre for Pharmacy, 9713 AV Groningen,1 and Section of Medical Microbiology, University Hospital Groningen, 9713 GZ Groningen,2 The Netherlands

Received 9 November 1998/Returned for modification 7 January 1999/Accepted 3 August 1999

Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of Candida species.

Distinct antifungal activities of lactoferrin were observed against clinical isolates of Candida. The MICs generally were determined to be in the range of 0.5 to 100 mg · ml1. Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of Candida by using lactoferrin and the three antifungals tested.

Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml).

Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several Candida species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with Candida is an attractive therapeutic option.

Since fluconazole-resistant Candida species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated.

* Corresponding author. Present address: Yamanouchi Europe BV, Clinical Pharmacology Research Department, Elisabethhof 1, 2353 EW Leiderdorp, The Netherlands. Phone: 31-71-5455283. Fax: 31-71-5455276. E-mail: kuipers.nl@yamanouchi-eu.com.

Present address: Yamanouchi Europe BV, Bioanalysis and Drug Metabolism Section, 2353 EW Leiderdorp, The Netherlands.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2635-2641, Vol. 43, No. 11
Copyright © 1999, American Society for Microbiology. All rights reserved.