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Antimicrobial Agents and Chemotherapy, May 2009, p. 1858-1862, Vol. 53, No. 5
0066-4804/09/$08.00+0 doi:10.1128/AAC.01538-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Comparative Efficacies of Lipid-Complexed Amphotericin B and Liposomal Amphotericin B against Coccidioidal Meningitis in Rabbits
Karl V. Clemons,1,2,3*
Javier Capilla,1,2,3
Raymond A. Sobel,4,5
Marife Martinez,1
Ann-Jay Tong,1 and
David A. Stevens1,2,3
California Institute for Medical Research, San Jose, California,1 Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center, San Jose, California,2 Department of Medicine, Division of Infectious Diseases and Geographic Medicine,3 Department of Pathology, Stanford University, Stanford, California,4 Veterans Affairs Health Care System, Palo Alto, California5
Received 18 November 2008/ Returned for modification 29 December 2008/ Accepted 28 February 2009
In separate previous studies, we have shown that lipid-complexed amphotericin B (Abelcet [ABLC]) and liposomal amphotericin B (AmBisome [AmBi]) are efficacious against coccidioidal meningitis in rabbits. Here, we compared ABLC and AmBi directly in a coccidioidal meningitis model. Male New Zealand White rabbits were infected with 5 x 104 Coccidioides posadasii arthroconidia by direct cisternal puncture. Therapy with intravenous ABLC or AmBi at 7.5 or 15 mg/kg of body weight or sterile 5% dextrose water (D5W) began 5 days later. Clinical assessments were done daily; cerebrospinal fluid and blood samples were obtained on day 15 and upon euthanasia. Survivors to day 25 were euthanatized, the numbers of CFU in their tissues were determined, and histology analyses of the brains and spinal cords were done. Controls showed progressive disease, whereas animals treated with either dose of either drug showed few clinical signs of infection. All ABLC- or AmBi-treated rabbits survived, whereas eight of nine D5W-treated rabbits were euthanatized before day 25 (P < 0.0001). Numbers of CFU in the brains and spinal cords of ABLC- or AmBi-treated animals were 100- to 10,000-fold lower than those in the corresponding tissues of D5W-treated animals (P < 0.0006 to 0.0001). However, only two or fewer given a regimen of ABLC or AmBi were cured of infection in both tissues. Fewer ABLC-treated rabbits (four of eight treated with 7.5 mg/kg and five of eight treated with 15 mg/kg) than controls (nine of nine) had meningitis at any level of severity (P, 0.015 or 0.043 for animals treated with ABLC at 7.5 or 15 mg/kg, respectively). Although groups of rabbits treated with AmBi regimens did not have significantly fewer animals with meningitis than the control group (P > 0.05), ABLC and AmBi were not significantly different. In this model, intravenous ABLC and AmBi were similarly highly effective, with few clinical signs of infection, 100% survival, and significantly reduced fungal burdens among treated animals. There appeared to be little benefit in using the 15-mg/kg dosage of either formulation. There was no significant advantage of one drug over the other for this indication. Further studies are required to determine the lowest effective doses of these formulations.
* Corresponding author. Mailing address: Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, CA 95128. Phone: (408) 998-4557. Fax: (408) 998-2723. E-mail: clemons{at}cimr.org
Published ahead of print on 9 March 2009.
Antimicrobial Agents and Chemotherapy, May 2009, p. 1858-1862, Vol. 53, No. 5
0066-4804/09/$08.00+0 doi:10.1128/AAC.01538-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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