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Antimicrobial Agents and Chemotherapy, October 2005, p. 4220-4226, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4220-4226.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

D. T. A. te Dorsthorst,1,2,3 P. E. Verweij,2,3 J. F. G. M. Meis,1 and J. W. Mouton1*

Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital Nijmegen, Nijmegen,1 Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen,2 Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands3

Received 31 March 2005/ Returned for modification 19 April 2005/ Accepted 1 July 2005

The therapeutic efficacy of flucytosine (5FC) monotherapy and the pharmacodynamic index predictive of efficacy were evaluated in a nonneutropenic mouse model of acute invasive aspergillosis. Mice were infected intravenously with an Aspergillus fumigatus isolate (the median MICs of 5FC were 128 µg/ml under the standard condition, 0.5 µg/ml at pH 6.0, and 0.031 µg/ml at pH 5.0) 2 h prior to the start of therapy and were treated for 7 days with different 5FC dosing regimens. The total doses ranged from 50 to 800 mg/kg of body weight/day and were administered at 6-, 12-, and 24-h intervals. The efficacy was assessed by means of survival. The survival rates of the treatment groups ranged from 40 to 90%, while the survival rate of the control group was 20%. The efficacy found depended primarily on the total daily dose. However, the power of our sample size may have been too low to exclude an effect of dose fractionation. The pharmacodynamic index that most strongly correlated with the efficacy was the area under the serum concentration-time curve and MIC ratio (R2 = 0.86). We conclude that 5FC monotherapy is efficacious in a murine Aspergillus fumigatus infection model.

* Corresponding author. Mailing address: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands. Phone: 31-(0)24-3657514. Fax: 31-(0)24-3657516. E-mail: mouton{at}cwz.nl.

Antimicrobial Agents and Chemotherapy, October 2005, p. 4220-4226, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4220-4226.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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