Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis.
Isavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamic in vitro model of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates of Aspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Helen
H
Box
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Joanne
J
Livermore
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Adam
A
Johnson
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Laura
L
McEntee
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Timothy W
TW
Felton
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Sarah
S
Whalley
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Joanne
J
Goodwin
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
William W
WW
Hope
D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development; D019149:Bioreactors; D015194:Diffusion Chambers, Culture; D025141:Drug Resistance, Fungal; D005690:Galactose / Q000031:analogs & derivatives; D006801:Humans; D008351:Mannans / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D015233:Models, Statistical; D009570:Nitriles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology
D000935:Antifungal Agents; D008351:Mannans; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C012990:galactomannan; C508735:isavuconazole; D005690:Galactose