Antifungal drugs improve survival by immunomodulation rather than by reduction of fungal burden in experimental cerebral aspergillosis
Abstract number: O369
Ullmann I., Strahm R., Leib S.L., Zimmerli S.
Objectives: To evaluate the antifungal and immunomodulatory effects of antifungal drugs we used a lethal model of cerebral aspergillosis in non-immunosuppressed infant rats.
Methods: Eleven-day-old male Wistar rats were infected by intracisternal injection of 7.17 log10 colony-forming units of Aspergillus fumigatus conidia. Treatment started 22 h after infection and was given for 10d. Regimens were (i) caspofungin (CAS) 1 mg/kg/d i.p. qd, (ii) liposomal amphotericin B (L-AmB) 5 mg/kg/d i.p. qd, (iii) both drugs combined at the same dose, and (iv) voriconazole (VCZ) starting at 15 mg/kg bid and increasing the dose to compensate for auto induction of metabolism. In survival experiments censored at 11d brains were examined at the time of death. To monitor cerebral disease progression, animals were sacrificed 2, 3, 5, and 11d after infection. Brain homogenates were analyzed by quantitative fungal culture, a flow-cytometry based assay for cytokine quantification, and ELISA for galactomannan (GM) detection. Animals with symptoms of severe disease were sacrificed for ethical reasons.
1Survival experiments [Fig. A]: Compared to controls (4.4±2.7d), survival times were significantly increased by treatment with CAS alone (10.3±1.7d; p < 0.0001) and combined with L-AmB (9.3±2.8d; p < 0.0001) as well as VCZ (10.1±2.2d; p < 0.0001). In contrast, survival time of animals treated with L-AmB alone (4.3±3.1d) was not different from untreated controls.
2Fungal culture: The cerebral fungal burden declined over time in all animals including untreated ones. Interestingly, there was no significant difference between controls and treated animals.
3GM: GM peaked later than the CFU counts in all treatment groups except L-AmB. There were no significant differences in GM indices regarding treatment and time.
4Cytokines: At 2d after infection both IFN-g and TNF-a [Fig. B] levels were significantly higher in animals treated with L-AmB alone (135.8±93.9pg/mg and 25.8±22.2pg/mg) compared to CAS (24.1±20.8pg/mg and 6.3±8.4pg/mg; p < 0.001), and VCZ (13.8±8.0pg/mg and 2.0±1.9pg/mg; p < 0.001). No differences were found for IL-1a and IL-10. IL-6 was undetectable in most animals but elevated in severe disease.
Conclusion: In this lethal model of cerebral aspergillosis mortality is not determined by the antifungal drug's effect on cerebral fungal burden but by its modulation of the host's immune response.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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