Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
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Posaconazole Pharmacodynamic Target Determination against Wild-type and Cyp51 Mutant Isolates of Aspergillus fumigatus in an in vivo Model of Invasive Pulmonary Aspergillosis
Alexander J. Lepak a, Karen Marchillo a, Jaimie VanHecker a and David R. Andes a,#
Author Affiliations; <SUP>a</SUP>University of Wisconsin, Madison, Wisconsin, USA
ABSTRACT
Invasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explores the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A. fumigatus isolates including 4 Cyp51 wild-type and 6 Cyp51 mutants conferring azole resistance. The posaconazole MIC range was 0.25 ? 8 mg/L. Following infection, mice were given 0.156 ? 160 mg/kg of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy mice had 5.59 ? 0.19 log<SUB>10</SUB> Aspergillus conidial equivalents (C.E.)/ml of lung homogenate and increased to 7.11 ? 0.29 log<SUB>10</SUB> C.E./ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug AUC/MIC and qPCR lung burden. The static dose range was 1.09 ? 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ? 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ? 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 - 0.5 mg/L.
FOOTNOTES
# Corresponding Author: David Andes, MD, Department of Medicine, Department of Medical Microbiology and Immunology, University of Wisconsin, 1685 Highland Ave, MFCB, Room 5211, Madison, WI 53705-2281, dra@medicine.wisc.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations; <SUP>a</SUP>University of Wisconsin, Madison, Wisconsin, USA
ABSTRACT
Invasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explores the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A. fumigatus isolates including 4 Cyp51 wild-type and 6 Cyp51 mutants conferring azole resistance. The posaconazole MIC range was 0.25 ? 8 mg/L. Following infection, mice were given 0.156 ? 160 mg/kg of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy mice had 5.59 ? 0.19 log<SUB>10</SUB> Aspergillus conidial equivalents (C.E.)/ml of lung homogenate and increased to 7.11 ? 0.29 log<SUB>10</SUB> C.E./ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug AUC/MIC and qPCR lung burden. The static dose range was 1.09 ? 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ? 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ? 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 - 0.5 mg/L.
FOOTNOTES
# Corresponding Author: David Andes, MD, Department of Medicine, Department of Medical Microbiology and Immunology, University of Wisconsin, 1685 Highland Ave, MFCB, Room 5211, Madison, WI 53705-2281, dra@medicine.wisc.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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