TY - JOUR
T1 - The role of azoles in the management of azole-resistant aspergillosis
T2 - From the bench to the bedside
AU - Seyedmousavi, Seyedmojtaba
AU - Mouton, Johan W.
AU - Melchers, Willem J.G.
AU - Brüggemann, Roger J.M.
AU - Verweij, Paul E.
N1 - Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Aspergillus fumigatus
KW - Azole-resistance
KW - Invasive aspergillosis
KW - Management
KW - Posaconazole
KW - Voriconazole
UR - http://www.scopus.com/inward/record.url?scp=84909639404&partnerID=8YFLogxK
U2 - 10.1016/j.drup.2014.06.001
DO - 10.1016/j.drup.2014.06.001
M3 - Article
C2 - 25066814
AN - SCOPUS:84909639404
SN - 1368-7646
VL - 17
SP - 37
EP - 50
JO - Drug Resistance Updates
JF - Drug Resistance Updates
IS - 3
ER -