M-1552. Comparative Efficacy of Lipid-Complexed (ABLC) and Liposomal (AmBi) Amphotericin B against Coccidioidal Meningitis in Rabbits
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.
Ann-Jay Tong, BA1, David Stevens, MD2, Javier Capilla, PhD3, Karl Clemons, PhD1, Marife Martinez, BS1, Raymond Sobel, MD4 and  K. V. Clemons,
Enzon Pharmaceuticals Role(s): Grant Investigator, Received: Research Support., (1)Calif. Inst. Med. Res. and Santa Clara Vly. Med. Ctr, San Jose, CA, (2)Santa Clara Valley Medical Center, Saratoga, CA, (3)Stanford Univ., San Jose, CA, (4)Dept of Pathol, Stanford Univ Med Sch, Stanford, CA, San Jose, CA


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