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Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections

Dolton, Michael J.a,b; McLachlan, Andrew J.b,c

Current Opinion in Infectious Diseases: December 2014 - Volume 27 - Issue 6 - p 493–500
doi: 10.1097/QCO.0000000000000103
ANTIMICROBIALS: Edited by Monica A. Slavin and William Irving

Purpose of review Azole antifungals are widely used in the prophylaxis and treatment of fungal infections, but are associated with a range of pharmacokinetic challenges and safety issues that necessitate individualized therapy to achieve optimal clinical outcomes. Recent advances in our knowledge of azole exposure–response relationships, therapeutic drug monitoring and individualized dosing strategies are reviewed as follows.

Recent findings Recent studies have significantly improved the understanding of exposure–response relationships for efficacy and toxicity, increasing confidence in target exposure ranges for azole antifungal agents. Population pharmacokinetic modelling of voriconazole has led to studies demonstrating the feasibility of model-guided dose individualization strategies with the drug, which holds significant promise for optimizing therapy. The recent approval of a solid oral tablet formulation of posaconazole with improved bioavailability and once-daily dosing has significantly improved the clinical utility of this agent. Further clinical experience with the investigational azole isavuconazole is needed to determine the role of individualized therapy.

Summary The coordination of CYP2C19 pharmacogenomic testing with model-guided dose individualization holds significant promise for optimizing therapy with voriconazole. Pharmacokinetic challenges with itraconazole, voriconazole and posaconazole oral suspension continue to require therapeutic drug monitoring to individualize therapy and optimize treatment outcomes.

aBiomedical Simulations Resource, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA

bFaculty of Pharmacy, University of Sydney, Camperdown

cCentre For Education and Research on Ageing, Concord Repatriation General Hospital, Concord, New South Wales, Australia

Correspondence to Dr Michael J. Dolton, BPharm, PhD, Biomedical Simulations Resource, University of Southern California, 1042 Downey Way, DRB 367E, Los Angeles, CA 90089, USA. Tel: +1 213 740 0342; fax: +1 213 740 0343; e-mail: dolton@usc.edu

© 2014 Lippincott Williams & Wilkins, Inc.