TY - JOUR
T1 - Pharmacodynamics of anidulafungin against clinical Aspergillus fumigatus isolates in a nonneutropenic murine model of disseminated aspergillosis
AU - Seyedmousavi, Seyedmojtaba
AU - Brüggemann, Roger J.M.
AU - Melchers, Willem J.G.
AU - Verweij, Paul E.
AU - Mouton, Johan W.
PY - 2013/1
Y1 - 2013/1
N2 - Azole resistance is an emerging increasing problem in Aspergillus fumigatus that results in treatment failure. Alternative treatments may improve the therapeutic outcome in patients with azole-resistant invasive aspergillosis (IA). Little is known about the in vivo efficacy of the echinocandin anidulafungin (AFG) in IA. The in vivo efficacy of 2.5, 5, 10, and 20 mg/kg of body weight AFG was assessed against two clinical Aspergillus fumigatus isolates with identical AFG minimum effective concentrations (MECs; 0.03 mg/liter) in a murine model of IA: a wild-type voriconazole (VCZ)-susceptible (VCZs) A. fumigatus isolate (AZN 8196) and a VCZ-resistant (VCZr) A. fumigatus isolate (V52-35) harboring the TR34/L98H resistance mechanism (substitution at codon L98 in combination with a 34-bp tandem repeat in the promoter region of the CYP51A gene). The pharmacokinetics of AFG were also assessed for each dose. Increasing doses increased survival for both isolates in a manner dependent on the AFG dose level (R2 = 0.99 and 0.95, respectively) up to a maximum of 72.7% and 45.45% for the VCZs and VCZr isolates, respectively. The area under the concentration-time curve (AUC) correlated significantly with the dose in a linear fashion over the entire dosing range (R2 = 0.86). The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (R2 = 0.87; P < 0.05). The 50% effective AUC/MEC for total AFG was 126.5 (95% confidence interval, 79.09 to 202.03). AFG treatment improved the survival of mice in a dose-dependent manner; however, a maximal response was not achieved with either isolate even in those treated with the highest AFG dose.
AB - Azole resistance is an emerging increasing problem in Aspergillus fumigatus that results in treatment failure. Alternative treatments may improve the therapeutic outcome in patients with azole-resistant invasive aspergillosis (IA). Little is known about the in vivo efficacy of the echinocandin anidulafungin (AFG) in IA. The in vivo efficacy of 2.5, 5, 10, and 20 mg/kg of body weight AFG was assessed against two clinical Aspergillus fumigatus isolates with identical AFG minimum effective concentrations (MECs; 0.03 mg/liter) in a murine model of IA: a wild-type voriconazole (VCZ)-susceptible (VCZs) A. fumigatus isolate (AZN 8196) and a VCZ-resistant (VCZr) A. fumigatus isolate (V52-35) harboring the TR34/L98H resistance mechanism (substitution at codon L98 in combination with a 34-bp tandem repeat in the promoter region of the CYP51A gene). The pharmacokinetics of AFG were also assessed for each dose. Increasing doses increased survival for both isolates in a manner dependent on the AFG dose level (R2 = 0.99 and 0.95, respectively) up to a maximum of 72.7% and 45.45% for the VCZs and VCZr isolates, respectively. The area under the concentration-time curve (AUC) correlated significantly with the dose in a linear fashion over the entire dosing range (R2 = 0.86). The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (R2 = 0.87; P < 0.05). The 50% effective AUC/MEC for total AFG was 126.5 (95% confidence interval, 79.09 to 202.03). AFG treatment improved the survival of mice in a dose-dependent manner; however, a maximal response was not achieved with either isolate even in those treated with the highest AFG dose.
UR - http://www.scopus.com/inward/record.url?scp=84872008618&partnerID=8YFLogxK
U2 - 10.1128/AAC.01430-12
DO - 10.1128/AAC.01430-12
M3 - Article
C2 - 23114773
AN - SCOPUS:84872008618
SN - 0066-4804
VL - 57
SP - 303
EP - 308
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 1
ER -