Efficacy of voriconazole versus anidulafungin alone and in combination in a guinea pig model of invasive pulmonary aspergillosis
Abstract number: 1733_1281
Kirkpatrick W.R., Najvar L.K., Bocanegra R., Vallor A.C., Olivo M.C., Molina D., Graybill J.R., Patterson T.F.
Objectives: Combination therapy for invasive aspergillosis with an echinocandin and a triazole antifungal is attractive due to distinct mechanisms of action. Possible antagonism of some drug combinations and the potential paradoxical ``eagle'' effect of higher doses of echinocandins have been suggested; thus, combination therapy remains controversial. The antifungal activities of voriconazole (VRC) and anidulafungin (ANID) alone or in combination were evaluated in a guinea pig model of invasive pulmonary aspergillosis (IPA).
Methods: Guinea pigs were immunosuppressed with cortisone acetate and made temporarily neutropenic with cyclophosphamide 2 days prior to, and 3 days following aerosolised challenge with 12 ml 109 CFU/mL Aspergillus fumigatus AF293 in an acrylic chamber. Therapy with oral VRC at 2.5 or 10 mg/kg/bid, ip ANID at 1, 6 or 12 mg/kg/d, or combinations of VRC 2.5+ANID 1 or VRC10+ANID6 or 12 was begun 24 hr after challenge and continued for 8 d.
Results: Both doses of VRC and the low dose combination of VRC2.5+ANID1 showed significantly increased survival vs controls. Decreased mortality, expressed as mean day of death, was also shown in a dose dependent manner with all 3 doses of ANID with longer survival seen with higher doses of ANID. Semi-quantitative assessment of lung tissue burden by colony forming units (CFU) revealed that therapy with VRC10 and both VRC10/ANID combinations yielded significant reductions in counts as compared to controls. Similarly, therapy with VRC10 or VRC10+ANID12 yielded significant reductions in counts as compared to either ANID6 or 12. Assessment of lung tissue burden by Q-PCR (Conidial equivalents ''CE'') revealed that VRC10 and both VRC10/ANID combinations yielded significant reductions in counts as compared to controls. Similarly, Q-PCR showed that therapy with VRC10 yielded significant reductions in counts as compared to ANID12 as did VRC10+ANID12 as compared to either ANID 1 or 12.
Conclusion: Therapy with VRC yielded greater survival than did ANID, and VRC10 or the combination of VRC10+ANID12 were superior in reducing tissue burden as assessed by either CFU or CE. In this model of IPA, VRC10 alone was superior to any dose of ANID tested alone. ANID combined with low dose VCR reduced lung CE. Combination therapy with the higher VRC doses demonstrated similar efficacy to VRC alone although no evidence of a paradoxical effect in tissue burden was seen.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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