Antagonistic Interaction between Liposomal Amphotericin B and Ravuconazole in Experimental Invasive Pulmonary Aspergillosis: Implications for Combination Therapy

J. MELETIADIS, V. PETRAITIS, R. PETRAITIENE, A. KELAHER, H. MURRAY, C. MAYA-SAN, T. SEIN, R. SCHAUFELE, T. J. WALSH

Author address: 

NCI, Bethesda, MD

Abstract: 

Background: The combination of amphotericin B and antifungal triazoles may be used for treating refractory invasive pulmonary aspergillosis (IPA) but with minimal data to support its efficacy. We therefore investigated the efficacy of liposomal amphotericin B (LAMB) in combination with the new triazole ravuconazole (RAV) in experimental IPA in a persistently neutropenic rabbit model. Methods: One day after inoculation, animals were assigned to one of 6 groups of 6 animals each and were treated with 5mg/kg of RAV (RAV5), 1.5 and 3 mg/kg of LAMB (LAMP1.5 and LAMB3) and a combination of RAV with either dose of LAMB (RAV5-LAMBV1.5 and RAV5-LAMB3). The treatment outcome was assessed based on survival rates (SR), residual fungal burden (RFB), lung weight, and pulmonary infract scores. The RAV-LAMP combination was assessed with the Bliss independence (BI) model where the expected effect Eexp calculated as ERAVxELAMB (where ERAV and ELAMB are the mean effects of monotherapies) was compared with the observed effects Eobs. The difference Eexp-Eobs was calculated for each animal receiving a combination and when this difference and its 95% CI among the animals in each group was positive or negative, synergy or antagonism, respectively was concluded. Results: Survival rates after 13 days of treatment were 0% for control group and LAMP3, 60% for RAV5, 50% for LAMP1.5, 20% for RAV5-LAMP1.5 and 17% for RAV5-LAMP3 (logrank p=0.005). Bliss antagonism (BA) was found for both combination groups RAV5-LAMB1.5 and RAV5-LAMB3 with a median BA 49% (range 34%-67%) and 35% (range 9%-45%), respectively among all outcome variables and was statistically significant (p
2004

abstract No: 

M-238-2004

Full conference title: 

44th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 44th