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Antimicrobial Agents and Chemotherapy, June 2000, p. 1512-1517, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Comparison of Fluconazole and Itraconazole in a Rabbit Model of Coccidioidal Meningitis

Kevin N. Sorensen,1,2,3,dagger Raymond A. Sobel,4,5 Karl V. Clemons,1,2,3 Demosthenes Pappagianis,6 David A. Stevens,1,2,3,* and Paul L. Williams2,7

Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center,1 and California Institute for Medical Research,2 San Jose, California 95128; Department of Medicine, Division of Infectious Diseases and Geographic Medicine,3 and Department of Pathology,4 Stanford University, Stanford, California 94305; Veterans Affairs Health Care System, Palo Alto, California 943045; Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, California 956166; and Kaweah Delta District Hospital, Visalia, California 932917

Received 23 September 1999/Returned for modification 24 December 1999/Accepted 3 March 2000

Coccidioidal meningitis is a devastating disease that requires long-term therapy with little hope of cure. A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of fluconazole (FCZ) and itraconazole (ITZ). Hydrocortisone-treated male New Zealand white rabbits were infected intracisternally with 5.0 × 104 to 5.4 × 104 arthroconidia of Coccidioides immitis. Oral treatment with polyethylene glycol 200 (PEG) (n = 9), FCZ (n = 8; 80 mg/kg of body weight/day), or ITZ (n = 8; 80 mg/kg/day) began 5 days after infection and continued for 28 consecutive days. Both FCZ and ITZ reduced the number of CFU of C. immitis organisms in the spinal cord and brain compared with the number in PEG-treated animals (P <=  0.003), but the results for FCZ and ITZ were not different from each other. Histopathologic severity (semiquantitative scoring system by an observer blinded to treatment) was equally reduced in both FCZ and ITZ treatment groups compared with that in controls (P <=  0.0004). Both treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of C. immitis from CSF compared with the results for PEG-treated controls. Neither drug affected CSF glucose levels. Both compounds were effective at reducing neurological and systemic signs and extending survival (P <=  0.014). FCZ was more effective at reducing head and body shakes, posture changes, and incontinence; ITZ was more effective at reducing continuous fever. Mean levels of FCZ and ITZ in the serum and CSF were determined by bioassay; at 17 to 26 h postdosing, levels were 28.1 to 40.0 and 22.4 to 29.9 µg/ml, respectively, for FCZ and 0.77 to 2.51 and 0 µg/ml, respectively, for ITZ. The sera of most animals developed antibody to C. immitis, but azole treatment attenuated antibody development in CSF and its titer. In conclusion, both FCZ and ITZ were efficacious, but neither was curative in a rabbit model of coccidioidal meningitis.

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

dagger Present address: Microcide Pharmaceuticals, Inc., Mountain View, CA 94043.

Antimicrobial Agents and Chemotherapy, June 2000, p. 1512-1517, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Clemons, K. V., Capilla, J., Sobel, R. A., Martinez, M., Tong, A.-J., Stevens, D. A. (2009). Comparative Efficacies of Lipid-Complexed Amphotericin B and Liposomal Amphotericin B against Coccidioidal Meningitis in Rabbits. Antimicrob. Agents Chemother. 53: 1858-1862 [Abstract] [Full Text]  
  • Capilla, J., Clemons, K. V., Sobel, R. A., Stevens, D. A. (2007). Efficacy of amphotericin B lipid complex in a rabbit model of coccidioidal meningitis. J Antimicrob Chemother 60: 673-676 [Abstract] [Full Text]  
  • Kamberi, P., Sobel, R. A., Clemons, K. V., Waldvogel, A., Striebel, J. M., Williams, P. L., Stevens, D. A. (2007). Comparison of Itraconazole and Fluconazole Treatments in a Murine Model of Coccidioidal Meningitis. Antimicrob. Agents Chemother. 51: 998-1003 [Abstract] [Full Text]  
  • Clemons, K. V., Sobel, R. A., Williams, P. L., Pappagianis, D., Stevens, D. A. (2002). Efficacy of Intravenous Liposomal Amphotericin B (AmBisome) against Coccidioidal Meningitis in Rabbits. Antimicrob. Agents Chemother. 46: 2420-2426 [Abstract] [Full Text]  
  • Sorensen, K. N., Sobel, R. A., Clemons, K. V., Calderon, L., Howell, K. J., Irani, P. R., Pappagianis, D., Williams, P. L., Stevens, D. A. (2000). Comparative Efficacies of Terbinafine and Fluconazole in Treatment of Experimental Coccidioidal Meningitis in a Rabbit Model. Antimicrob. Agents Chemother. 44: 3087-3091 [Abstract] [Full Text]  


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