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Antimicrobial Agents and Chemotherapy, March 2007, p. 998-1003, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00332-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Comparison of Itraconazole and Fluconazole Treatments in a Murine Model of Coccidioidal Meningitis{triangledown}

Perparim Kamberi,1,2,3 Raymond A. Sobel,4,5 Karl V. Clemons,1,2,3 Andreas Waldvogel,6 Joan M. Striebel,1 Paul L. Williams,1,7 and David A. Stevens1,2,3*

California Institute for Medical Research, San Jose, California 95128,1 Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center, San Jose, California 95128-2699,2 Department of Medicine, Division of Infectious Diseases and Geographic Medicine,3 Department of Pathology, Stanford University Medical School, Stanford, California 94305,4 Laboratory Service, Palo Alto Veterans Affairs Health Care System, Palo Alto, California 94304,5 Institute of Pathology, University of Bern, Bern 3001, Switzerland,6 Department of Adult Medicine, Kaiser Permanente Medical Group, Selma, California 936627

Received 17 March 2006/ Returned for modification 5 July 2006/ Accepted 11 December 2006

Coccidioidal meningitis (CM) is a devastating disease that requires long-term therapy and for which there is little hope of a cure. A model was used to compare the efficacies of itraconazole and fluconazole. CD-1 mice were infected intrathecally with 30 to 36 viable arthroconidia of Coccidioides. Oral therapy with cyclodextrin (control) or itraconazole or fluconazole at 10, 25, or 50 mg/kg of body weight twice daily (BID) was given for 12 days, from day 3 of infection. Treatment with both antifungals at all doses prolonged survival compared with that of the control treatment (P < 0.01 to 0.0001). At 50 mg/kg, itraconazole and fluconazole were equivalent, whereas itraconazole at 10 or 25 mg/kg prolonged survival compared to that achieved with fluconazole at these dosages (P < 0.05 and 0.01, respectively). Early histologic analysis (10 days of treatment) with 50 mg/kg BID itraconazole or fluconazole showed suppression of CM in all five animals per group; in quantitative cultures, three of three animals from each group had no detectable infection in the brain, spinal cord, or a site of secondary infection, the lungs. In contrast, four of seven controls showed mild to severe meningitis, with arteritis detected in three animals. In a short-term organ clearance study, 5 days of treatment with 10 or 50 mg/kg BID itraconazole or fluconazole reduced the tissue burdens in the brain and spinal cord compared to the tissue burdens in the controls (P < 0.02 to 0.0003). Fluconazole at 10 mg/kg did not reduce the fungal burden in secondary sites, the lungs and kidneys, whereas this itraconazole dose was more effective in clearing the fungi from both organs (P < 0.05 and P < 0.001, respectively). At 50 mg/kg, itraconazole and fluconazole were equivalent in clearing the fungi from the brain and kidney, but itraconazole was superior to fluconazole in clearing the fungi from the spinal cord and lungs (P < 0.05). Thus, both itraconazole and fluconazole were effective at controlling CM, but neither eliminated Coccidioides from tissues. Overall, itraconazole was more efficacious on an mg/kg basis; at high doses they were similarly effective.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, 751 S. Bascom Ave., San Jose, CA 95128-2699. Phone: (408) 885-4303. Fax: (408) 885-4306. E-mail: stevens{at}stanford.edu.

{triangledown} Published ahead of print on 18 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 998-1003, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00332-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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