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Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis
K N Sorensen1, R A Sobel, K V Clemons
1Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center, San Jose, California 95128-2699, USA.
Abstract:
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 5.0x10(4) to 5.4x10(4) 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< or =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< or =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< or =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 microg/ml, respectively, for FCZ and 0.77 to 2.51 and 0 microg/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.
Insights
This study compared fluconazole (FCZ) and itraconazole (ITZ) for treating coccidioidal meningitis in rabbits. Both antifungals effectively reduced fungal load and disease severity, though neither achieved a cure.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Coccidioidal meningitis is a severe fungal infection requiring prolonged treatment with limited curative options.
- The rabbit model is crucial for evaluating therapeutic strategies against Coccidioides immitis infections in the central nervous system.
Purpose of the Study:
- To compare the therapeutic efficacy of fluconazole (FCZ) and itraconazole (ITZ) in a rabbit model of coccidioidal meningitis.
- To assess the impact of FCZ and ITZ on fungal burden, histopathology, cerebrospinal fluid parameters, and survival.
Main Methods:
- New Zealand white rabbits with hydrocortisone treatment were intracisternally infected with Coccidioides immitis.
- Animals received oral treatment with polyethylene glycol 200 (PEG), FCZ, or ITZ daily for 28 days.
- Fungal load (CFU), histopathologic severity, CSF analysis, and survival rates were evaluated.
Main Results:
- Both FCZ and ITZ significantly reduced C. immitis in the brain and spinal cord compared to PEG controls.
- Histopathologic severity, CSF protein, and leukocyte counts were equally reduced by FCZ and ITZ.
- Both drugs extended survival and reduced neurological signs, with FCZ showing better control of certain symptoms and ITZ of fever.
Conclusions:
- Fluconazole and itraconazole demonstrate comparable efficacy in treating experimental coccidioidal meningitis in rabbits.
- While effective in reducing disease burden and improving outcomes, neither FCZ nor ITZ provided a complete cure.
- Azole treatment modulated the immune response, reducing antibody development in the cerebrospinal fluid.
