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Antimicrobial Agents and Chemotherapy, June 2002, p. 1953-1959, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1953-1959.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Efficacy of Antifungal Therapy in a Nonneutropenic Murine Model of Zygomycosis

Eric Dannaoui,1 Johan W. Mouton,2 Jacques F. G. M. Meis,2 Paul E. Verweij,1* and Eurofung Network{dagger}

Department of Medical Microbiology, University Medical Center St. Radboud, 6500 HB Nijmegen,1 Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, 6500 GS Nijmegen, The Netherlands2

Received 5 November 2001/ Returned for modification 4 January 2002/ Accepted 18 March 2002

Three isolates of zygomycetes belonging to three different genera (Rhizopus microsporus, Absidia corymbifera, and Apophysomyces elegans) were used to produce a disseminated infection in nonimmunocompromised mice. The therapeutic efficacy of amphotericin B, given intraperitoneally at doses ranging from 0.5 to 4.5 mg/kg of body weight/day, oral itraconazole at 100 mg/kg/day, and oral terbinafine at 150 mg/kg/day was evaluated in this model. The markers of antifungal efficacy were the median survival time, the mortality rate, and the percentage of infected organs. Organ culture was performed along with microscopic direct examinations of tissues to assess the presence of an active infection. An acute and lethal infection was obtained in untreated mice challenged with each of the three strains. The data obtained for direct examinations and qualitative cultures indicate that, due to the nonseptate nature of the hyphae, each technique gives different information and should be used together with the others. Against all three strains, amphotericin B yielded a 90 to 100% survival rate. Itraconazole was inactive against R. microsporus but significantly reduced mortality in mice infected with A. corymbifera or A. elegans. Terbinafine had no beneficial effects against R. microsporus and A. corymbifera despite documented absorption of the drug. Overall, only limited correlations were observed between MICs determined in vitro and in vivo efficacy of the drugs. The efficacy of itraconazole in these models of zygomycosis suggests that this drug, as well as the new azole compounds presently under development, warrants close evaluation.

* Corresponding author. Mailing address: Department of Medical Microbiology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: (31) 24 361 43 56. Fax: (31) 24 354 02 16. E-mail: p.verweij{at}mmb.azn.nl.

{dagger} Consists of Emmanuel Roilides, coordinator, and Nicos Maglaveras, Aristotle University, Thessaloniki, Greece; Tore Abrahamsen and Peter Gaustad, Rikshospitalet National Hospital, Oslo, Norway; David W. Denning, University of Manchester, Manchester, United Kingdom; Paul E. Verweij and Jacques F. G. M. Meis, University of Nijmegen, Nijmegen, The Netherlands; Juan L. Rodriguez-Tudela, Instituto de Salud Carlos III, Madrid, Spain; and George Petrikkos, Athens University, Athens, Greece.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1953-1959, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1953-1959.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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