Effects of Antifungal Drugs on Cytokines and Matrix Metalloproteases in Experimental Cerebral Aspergillosis

Ref ID: 18644

Author:

. ULLMANN, A. AREGGER, S. L. LEIB, S. ZIMMERLI;

Author address:

Inst. for Infectious Diseases, Univ. of Bern, Bern, Switzerland.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The pathophysiology of cerebral aspergillosis is not well understood and therapeutic options are limited. Here we assessed the effects of currently used therapeutic agents on clinical and pathophysiologic parameters in an infant rat model of cerebral aspergillosis.
Methods: Eleven days (d) old Wistar rats were infected by intracisternal injection of 7.17 log10 colony-forming units of Aspergillus fumigatus conidia. Treatment started after 22h and was continued for 10d. Regimens were (i) caspofungin (CAS) 1mg/kg/d i.p. qd, (ii) liposomal amphotericin B (LAMB) 5mg/kg/d i.p. qd, (iii) both drugs combined at the same dose, and (iv) voriconazole (VCZ) starting at 15mg/kg bid. Infected controls were given NaCl 0.9% i.p. Animals were sacrificed 2, 3, 5, and 11d after infection (n=108). In survival studies, brains were harvested at the time of death (n=104). Brain homogenates were assessed for fungal burden, concentration of cytokines and matrix metalloproteases (MMPs) -2 & -9.
Results: Survival studies: Compared to controls (4.4 ± 2.7d), survival times were increased by treatment with CAS alone (10.3 ± 1.7d; p<0.0001) and CAS 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 LAMB treated animals (4.3 ± 3.1d) was not different from controls. Fungal culture: Cerebral fungal burden declined in all animals over time. There were no significant differences between controls and treated animals. Cytokines at 3d after infection: LAMB treated animals had higher ratios of TNF-a/IL-10 (p<0.05) and IFN-g/IL-10 (p<0.01) than those treated with CAS or VCZ. Controls had higher IFN-g levels (p<0.05) compared to VCZ. MMPs: At 2d after infection MMP-9/MMP-2 ratios were higher with LAMB (p<0.05) than with CAS. Conclusions: In this lethal model of cerebral aspergillosis mortality is unrelated to cerebral fungal burden but associated with a high ratio of pro-inflammatory over anti-inflammatory cytokines and MMP-9 over MMP-2.

Abstract Number: M-1818

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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