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Antimicrobial Agents and Chemotherapy, April 2005, p. 1369-1376, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1369-1376.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Efficacy of Caspofungin against Central Nervous System Aspergillus fumigatus Infection in Mice Determined by TaqMan PCR and CFU Methods

Gaurav Singh,1 Jackie Imai,1 Karl V. Clemons,1,2,3* and David A. Stevens1,2,3

California Institute for Medical Research,1 Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, San Jose,2 Stanford University School of Medicine, Stanford, California3

Received 4 December 2004/ Returned for modification 6 December 2004/ Accepted 18 December 2004

We have reported previously that prolonged caspofungin (CAS) dosing enhances survival in a murine model of central nervous system aspergillosis. In this study we determined by quantitative PCR (qPCR) and CFU enumeration whether CAS could reduce fungal burdens, prior to the deaths of untreated animals, and also assessed progressive infection in untreated mice. Mice were infected intracranially and treated for 4 days with CAS (1, 5, or 10 mg/kg of body weight/day) or amphotericin B (AMB) (3 mg/kg/day) starting 1 day postinfection. Fungal burdens in brains and kidneys of untreated controls were determined on days 1, 3, and 5 to assess progressive infection; burdens in treated animals were determined on day 5. qPCR showed higher burdens than CFU enumeration in all comparisons. In untreated animals, qPCR showed transiently increased burdens in brains, while CFU enumeration showed a decrease. qPCR showed increased burdens in kidneys, but CFU enumeration did not. Neither method indicated drug efficacy in the brain. Both methods showed AMB efficacy in the kidneys, and qPCR demonstrated CAS efficacy at all doses. Spearman correlations of qPCR and CFU determination results showed a significant correlation for most untreated groups; results correlated well for kidneys (P ≤ 0.03) but not for brains in treated mice. Regression analyses of qPCR and CFU groups indicated different slopes for progressive infection in untreated animals but the same slopes for CAS dose-response efficacy. qPCR appeared to better reflect the progression of untreated infection. The lack of demonstration of efficacy in the brain suggests that longer dosing is necessary to cause burden reduction. These results also suggest that, when there is drug efficacy in a therapeutic study, either method appears to be useful for determining Aspergillus fumigatus burdens.

* Corresponding author. Mailing address: Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128-2699. Phone: (408) 998-4557. Fax: (408) 998-2723. E-mail: clemons{at}cimr.org.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1369-1376, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1369-1376.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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