title: Posaconazole pharmacodynamic target determination against wild-type and Cyp51 mutant isolates of Aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis.
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 explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A. fumigatus isolates, including 4 Cyp51 wild-type isolates and 6 isolates carrying Cyp51 mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight 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(10) Aspergillus conidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log(10) CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 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 to 0.5 mg/liter.
authors.affiliation: University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lepak
authors.forename: Karen
authors.initials: K
authors.lastname: Marchillo
authors.forename: Jaimie
authors.initials: J
authors.lastname: Vanhecker
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D016867:Immunocompromised Host; D055744:Invasive Pulmonary Aspergillosis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D058886:Sterol 14-Demethylase / Q000235:genetics*; D016019:Survival Analysis; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D014230:Triazoles; C101425:posaconazole; D058886:Sterol 14-Demethylase