Session: Poster Session: Experimental Mycology
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: We demonstrated in separate preclinical testing that i.v. ABLC and AmBi are efficacious against coccidioidal meningitis. This suggests that ABLC or AmBi may be effective clinically, whereas i.v. conventional amphotericin B is not. Here, we compared ABLC and AmBi directly in a coccidioidal meningitis model. Methods: Male NZW rabbits were infected with 5 x 104 arthroconidia of Coccidioides immitis by direct cisternal puncture. Therapy began 5 days later with i.v. ABLC or AmBi at 7.5 or 15 mg/kg or sterile 5% dextrose water (D5W). Clinical assessments were done daily; CSF and blood were sampled at day 15 and at euthanasia. Survivors to day 25 were euthanatized, CFU determined, and histology done on brain and spinal cord. Results: Controls showed progressive disease with both doses of each drug reducing clinical signs. All ABLC- or AmBi-treated rabbits survived, whereas 8 of 9 D5W-treated needed euthanasia before day 25 (P < 0.0001). CFU in brain and spinal cord were 100 to 10,000-fold lower in ABLC- or AmBi-treated than in D5W-treated animals (P < 0.0006 to 0.0001). Two or fewer in any regimen were cured of infection in both tissues. Fewer ABLC-treated rabbits had any severity of meningitis compared to controls (P = 0.015 or 0.043 for ABLC at 7.5 or 15 mg/kg, respectively); AmBi regimens did not have fewer animals with meningitis than controls (P > 0.05); ABLC and AmBi were not different. Conclusions: In this model, ABLC and AmBi were equally and highly effective given i.v., with few clinical signs, 100% survival, and significantly reduced fungal burdens. There appeared to be little benefit in using the 15 mg/kg dosage of either formulation. Neither ABLC nor AmBi showed significant advantage for treatment of coccidioidal meningitis. Further studies are required to determine the lowest effective dose of these formulations.