M-1550. Development of a Murine Model of Cryptococcus gattii Meningitis
Session: Poster Session: Experimental Mycology
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: CG is an emerging fungal infection and differs from meningitis caused by Cryptococcus neoformans (CN) in its ability to infect immunocompetent hosts and worse clinical severity in some patients. We developed a murine model capable of evaluating antifungal therapy in CG meningitis based our established Cryptococcus neoformans (CN) model. Methods: ICR mice received intracranial inoculation with CG or CN at two inocula: 500 & 2000 CFU/animal. Tissue burdens were obtained (days 7, 10, & 14), and serum collected (days 3, 5, & 7) for cryptococcal antigen determination. Treatment studies were performed with fluconazole (FLC) and posaconazole (PSC) (10 & 20 mg/kg PO BID) begun 1 day after CG inoculation (500 CFU/animal) and continued for 10 days. Mice were monitored over an 11 day period off therapy and survival assessed by Kaplan-Meier analysis. Results: Meningitis and dissemination to the liver, lung, spleen, and kidneys were observed by day 7 with CG and CN. In all groups cryptococcal antigen was detected earlier with CG. Median survival was significantly less with CG than CN at each inocula. Significant improvement in median survival was observed with FLC (10 & 20 mg/kg >21 days) and PSC (10 mg/kg 20 days, 20 mg/kg >21 days) versus controls (p < 0.001). Treatment resulted in a 2.5 - 6 log reduction in brain CFU/g but only FLC 20 mg/kg sterilized brain tissues.
Inocula (CFU/animal) & Median Antigen Titers (Range) in Untreated Animals
CG 500CN 500CG 2000CN 2000
Day 31:12
(0 - 1:15)
0
(0 - 1:11)
1:75
(1:58 - 1:158)
1:3
(0 - 1:8)
Day 51:423
(1:84 - 1:1340)
1:5
(0 - 1:189)
1:672
(1:610 - 1:4054)
1:238
(1:98 - 1:263)
Day 71:10738
(1:6400 - 1:11700)
1:56
(1:2 - 1:3435)
1:4478
(1:4099 - 1:6338)
1:1785
(1:677 - 1:1985)
Median
Survival (days)
p-value vs. CN
10
(p < 0.01)
>2110
(p < 0.01)
20

Conclusions: In this model of meningitis CG resulted in earlier cryptococcal antigenemia and worse survival versus CN. Responses to FLC and PSC were observed demonstrating the utility of this model in the evaluation of drug therapy.
Destiny Molina1, George Thompson, MD2, John Graybill, MD3, Laura Najvar, BS1, Marcos Olivo1, Nathan Wiederhold, PharmD4, Rosie Bocanegra1, Thomas Patterson, MD, FIDSA5 and  G. R. Thompson, None., (1)Univ. TX Hlth. Sci. Ctr., (2)UTHSCSA, San Antonio, TX, (3)University of Texas Health Science Center, San Antonio, TX, (4)Univ. TX, San Antonio, TX, (5)The University of Texas Health Science Center, San Antonio, TX


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