title: The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside.
abstract: Azole resistance is an emerging problem in Aspergillus fumigatus and is associated with a high probability of treatment failure. An azole resistance mechanism typically decreases the activity of multiple azole compounds, depending on the mutation. As alternative treatment options are limited and in some isolates the minimum inhibitory concentration (MIC) increases by only a few two-fold dilutions steps, we investigated if voriconazole and posaconazole have a role in treating azole-resistant Aspergillus disease. The relation between resistance genotype and phenotype, pharmacokinetic and pharmacodynamic properties, and (pre)clinical treatment efficacy were reviewed. The results were used to estimate the exposure needed to achieve the pharmacodynamic target for each MIC. For posaconazole adequate exposure can be achieved only for wild type isolates as dose escalation does not allow PD target attainment. However, the new intravenous formulation might result in sufficient exposure to treat isolates with a MIC of 0.5 mg/L. For voriconazole our analysis indicated that the exposure needed to treat infection due to isolates with a MIC of 2 mg/L is feasible and maybe isolates with a MIC of 4 mg/L. However, extreme caution and strict monitoring of drug levels would be required, as the probability of toxicity will also increase.
authors: Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, The Netherlands.
authors: Seyedmojtaba
authors: S
authors: Seyedmousavi
authors: Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands; Department of Medical Microbiology and Infectious Diseases, Erasmus MC, The Netherlands.
authors: Johan W
authors: JW
authors: Mouton
authors: Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands.
authors: Willem J G
authors: WJ
authors: Melchers
authors: Department of Pharmacy, Radboudumc, Nijmegen, The Netherlands.
authors: Roger J M
authors: RJ
authors: Brüggemann
authors: Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands. Electronic address: Paul.Verweij@Radboudumc.nl.
authors: Paul E
authors: PE
authors: Verweij
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001228:Aspergillosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D026141:Drug Resistance, Multiple, Fungal; D004359:Drug Therapy, Combination / Q000009:adverse effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation; D057170:Translational Research, Biomedical / Q000639:trends; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D065819:Voriconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D065819:Voriconazole
keywords: Aspergillus fumigatus; Azole-resistance; Invasive aspergillosis; Management; Posaconazole; Voriconazole