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Tissue Penetration of Antifungal Agents Tissue Penetration of Antifungal Agents Timothy Felton, Peter F. Troke and William W. Hope Clin. Microbiol. Rev. 2014, 27(1):68. DOI: 10.1128/CMR.00046-13. Downloaded from Updated information and services can be found at: http://cmr.asm.org/content/27/1/68 These include: http://cmr.asm.org/ REFERENCES This article cites 259 articles, 137 of which can be accessed free at: http://cmr.asm.org/content/27/1/68#ref-list-1 CONTENT ALERTS Receive: RSS Feeds, eTOCs, free email alerts (when new articles cite this article), more» on February 17, 2014 by University of Manchester Library Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/ Tissue Penetration of Antifungal Agents Timothy Felton,a,b Peter F. Troke,c William W. Hopeb The University of Manchester, Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdoma; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdomb; The Old Court, Kingsgate, Kent, United Kingdomc Downloaded from SUMMARY ...................................................................................................................................................68 INTRODUCTION..............................................................................................................................................68 PENETRATION OF ANTIFUNGAL AGENTS INTO TISSUES: CONCEPTS, IMPORTANCE, AND CURRENT GAPS IN KNOWLEDGE ...........................69 Importance of Tissue Concentrations for an Understanding of Antifungal Pharmacodynamics ..........................................................69 Determinants of Distribution of Antifungal Agents into Tissues ...........................................................................................69 Limitations of Current Understanding and Approaches ...................................................................................................72 ANTIFUNGAL DRUG CONCENTRATIONS IN ORGANS, TISSUES, AND BODY FLUIDS.......................................................................72 Brain and Cerebrospinal Fluid..............................................................................................................................73 http://cmr.asm.org/ Eye.........................................................................................................................................................74 Lung .......................................................................................................................................................75 Pulmonary Lymph Fluid ...................................................................................................................................76 Pleural Fluid................................................................................................................................................76 Bronchial Secretions .......................................................................................................................................76 Saliva, Sputum, Buccal Mucosa, and Esophagus ...........................................................................................................76 Heart .......................................................................................................................................................76 Liver........................................................................................................................................................77 Kidney .....................................................................................................................................................77 Spleen .....................................................................................................................................................77 on February 17, 2014 by University of Manchester Library Pancreas ...................................................................................................................................................78 Peritoneum ................................................................................................................................................78 Genital System.............................................................................................................................................78 Bone .......................................................................................................................................................78 Muscle .....................................................................................................................................................79 Skin and Nails ..............................................................................................................................................79 UNDERSTANDING TISSUE CONCENTRATIONS FOR OPTIMAL USE OF EXISTING AGENTS AND DEVELOPMENT OF NEWER ANTIFUNGAL AGENTS ....80 Current State of the Art ....................................................................................................................................80 Beyond State of the Art ....................................................................................................................................80 ACKNOWLEDGMENTS .......................................................................................................................................80 REFERENCES .................................................................................................................................................80 AUTHOR BIOS................................................................................................................................................88 SUMMARY However, a wide range of other fungi, often with limited suscep- Understanding the tissue penetration of systemically adminis- tibility to first-line antifungal agents, may also cause infection. tered antifungal agents is critical for a proper appreciation of their Mortality from IFI remains high (e.g., that from aspergillosis is antifungal efficacy in animals and humans. Both the time course Ϸ50% [3, 4], and that from candidemia is 10 to 49% [5, 6, 7]). An of an antifungal drug and its absolute concentrations within tis- understanding of the pharmacological properties of any antifun- sues may differ significantly from those observed in the blood- gal agent is crucial for optimizing patient outcomes for all these stream. In addition, tissue concentrations must also be interpreted infections (8). This may be especially true for an increasingly rec- within the context of the pathogenesis of the various invasive fun- ognized group of patients who have not previously been consid- gal infections, which differ significantly. There are major technical ered to be at high risk of IFI, such as critically ill patients and those obstacles to the estimation of concentrations of antifungal agents with chronic obstructive pulmonary disease (COPD), who may in various tissue subcompartments, yet these agents, even those demonstrate marked pharmacokinetic (PK) variability (9, 10). within the same class, may exhibit markedly different tissue dis- Penetration into the site of infection to achieve microbe-elim- tributions. This review explores these issues and provides a sum- inating concentrations is a key requirement for efficacy of all an- mary of tissue concentrations of 11 currently licensed systemic timicrobial agents (11, 12, 13, 14, 15). The importance of tissue antifungal agents. It also explores the therapeutic implications of concentrations for the various classes of antibacterial agents has their distribution at various sites of infection. been reviewed extensively, but relatively less attention has been INTRODUCTION espite recent advances in antifungal chemotherapy, invasive Address correspondence to William W. Hope, [email protected]. Dfungal infections (IFI) remain a significant cause of morbid- Copyright © 2014, American Society for Microbiology. All Rights Reserved. ity and mortality (1). Candida species, Aspergillus fumigatus, and doi:10.1128/CMR.00046-13 Cryptococcus neoformans are the most common pathogens (2). 68 cmr.asm.org Clinical Microbiology Reviews p. 68–88 January 2014 Volume 27 Number 1 Tissue Penetration of Systemic Antifungal Agents paid to the currently available antifungal agents (12, 16, 17, 18, 19). This review examines the tissue penetration of 11 commonly used systemic antifungal agents (amphotericin B deoxycholate [AmBd], amphotericin B lipid complex [ABLC], liposomal am- photericin B [L-AMB], fluconazole, itraconazole, posaconazole, voriconazole, 5-fluorocytosine [5FC], anidulafungin, caspofun- gin, and micafungin) into the clinically relevant compartments for human infection and disease. All human data, ranging from case studies through autopsies to small clinical studies in volunteers or Downloaded from patients, were included. We also considered key laboratory animal data, where relevant, especially if the respective information for humans is absent. Because only free drug is considered to be bio- logically active (20, 21, 22), tissue and fluid concentrations are placed in context with the key physicochemical properties of each agent. The major organ systems covered include the lungs, liver, kidney, spleen, and heart. Attention has also been given
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