The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside.

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.