Pharmacodynamics of voriconazole in a dynamic in vitro model of invasive pulmonary aspergillosis: implications for in vitro susceptibility breakpoints.
BACKGROUND
Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole.


METHODS
An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and 3 resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodologies.


RESULTS
Isolates with higher minimum inhibitory concentrations (MICs) required higher area under the concentration time curves (AUCs) to achieve suppression of galactomannan. Using CLSI and EUCAST methodologies, the AUC:MIC values that achieved suppression of galactomannan were 55 and 32.1, respectively. Using CLSI and EUCAST methodologies, the trough concentration:MIC values that achieved suppression of galactomannan were 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are ≤ 0.5 mg/L for susceptible and >1 mg/L for resistant. Potential EUCAST breakpoints for voriconazole are ≤1 mg/L for susceptible and >2 mg/L for resistant.


CONCLUSIONS
This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.
Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine,  University of Manchester, University Hospital of South Manchester National Health Service Foundation Trust,  United Kingdom.
Adam R
AR
Jeans
Susan J
SJ
Howard
Zaid
Z
Al-Nakeeb
Joanne
J
Goodwin
Lea
L
Gregson
Jayesh B
JB
Majithiya
Cornelia
C
Lass-Flörl
Manuel
M
Cuenca-Estrella
Maiken C
MC
Arendrup
Peter A
PA
Warn
William W
WW
Hope
D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000378:metabolism; D019149:Bioreactors; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D025141:Drug Resistance, Fungal; D042783:Endothelial Cells / Q000166:cytology / Q000382:microbiology; D004847:Epithelial Cells / Q000166:cytology; D005690:Galactose / Q000031:analogs & derivatives; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008351:Mannans / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011651:Pulmonary Artery / Q000166:cytology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000166:cytology; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole
D000935:Antifungal Agents; D008351:Mannans; D011743:Pyrimidines; D014230:Triazoles; C012990:galactomannan; D065819:Voriconazole; D005690:Galactose