Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlations of the Concentration- and Dose- Dependent Interactions between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis
- 1 June 2009
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 53 (6), 2382-2391
- https://doi.org/10.1128/aac.00329-09
Abstract
We studied the antifungal activity of anidulafungin (AFG) in combination with voriconazole (VRC) against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlations by using Bliss independence drug interaction analysis. Treatment groups consisted of those receiving AFG at 5 (AFG5 group) and 10 (AFG10 group) mg/kg of body weight/day, VRC at 10 mg/kg every 8 h (VRC group), AFG5 plus VRC (AFG5+VRC group), and AFG10 plus VRC (AFG10+VRC group) and untreated controls. Survival throughout the study was 60% for the AFG5+VRC group, 50% for the VRC group, 27% for the AFG10+VRC group, 22% for the AFG5 group, 18% for the AFG10 group, and 0% for control rabbits ( P < 0.001). There was a significant reduction of organism-mediated pulmonary injury, measured by infarct scores, lung weights, residual fungal burdens, and galactomannan indexes, in AFG5+VRC-treated rabbits versus those treated with AFG5 and VRC alone ( P < 0.05). In comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10-treated animals ( P < 0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24 to 30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between AFG and VRC in vitro. However, for AFG10+VRC, only independence and antagonism were observed among the outcome variables. We concluded that the combination of AFG with VRC in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5 mg/kg/day but independent to antagonistic at 10 mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.Keywords
This publication has 39 references indexed in Scilit:
- Prevention and Early Treatment of Invasive Fungal Infection in Patients with Cancer and Neutropenia and in Stem Cell Transplant Recipients in the Era of Newer Broad-Spectrum Antifungal Agents and Diagnostic AdjunctsClinical Infectious Diseases, 2007
- Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosisJournal of Antimicrobial Chemotherapy, 2006
- Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary AspergillosisAntimicrobial Agents and Chemotherapy, 2006
- Safety and Pharmacokinetics of Coadministered Voriconazole and AnidulafunginThe Journal of Clinical Pharmacology, 2005
- Invasive aspergillosis: current and future challenges in diagnosis and therapyClinical Microbiology & Infection, 2004
- Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: Synergistic Interaction between an Antifungal Triazole and an EchinocandinThe Journal of Infectious Diseases, 2003
- Differential activity of triazoles in two-drug combinations with the echinocandin caspofungin against Aspergillus fumigatusJournal of Antimicrobial Chemotherapy, 2003
- In Vitro Interaction of Caspofungin Acetate with Voriconazole against Clinical Isolates of Aspergillus sppAntimicrobial Agents and Chemotherapy, 2002
- Efficacy of Caspofungin Alone and in Combination with Voriconazole in a Guinea Pig Model of Invasive AspergillosisAntimicrobial Agents and Chemotherapy, 2002
- The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated AspergillosisThe Journal of Infectious Diseases, 1985