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Review
. 2014 Jan;27(1):68-88.
doi: 10.1128/CMR.00046-13.

Tissue penetration of antifungal agents

Affiliations
Review

Tissue penetration of antifungal agents

Timothy Felton et al. Clin Microbiol Rev. 2014 Jan.

Abstract

Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

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Figures

FIG 1
FIG 1
Potential differences in plasma and tissue concentrations. There may be discordance in concentrations between these two compartments. "Hysteresis" refers to discordance in the shapes of the concentration-time profiles.
FIG 2
FIG 2
Different stages of invasive pulmonary aspergillosis (IPA) and the potential therapeutic importance of different tissue subcompartments. (A) In the very earliest stages of disease, the relevant subcompartments include epithelial lining fluid, alveolar epithelial cells, pulmonary endothelial cells, and pulmonary alveolar macrophages (PAMs). (B) In the early stages of established disease, a halo sign may be seen that consists of a nodule (n) surrounded by a halo (h), which is caused by active infection and inflammation around the nodule. In this case, the relevant subcompartments are within the nodule and contiguous lung. (C) In late disease, an air crescent sign may be present, which represents an organizing sequestrum. (A pulmonary sequestrum [s] is surrounded by an air crescent [ac].) The therapeutic challenge in this case is the achievement of antifungal drug concentrations within a relatively avascular area. (Reprinted from reference with permission; imaging and details kindly provided by Reginald Greene.)
FIG 3
FIG 3
Fluconazole tissue and fluid concentrations in humans as multiples of the maximal or simultaneously measured concentration in plasma (μg/ml) after systemic administration. Tissue multiples are from μg/g tissue values. Fluid multiples are from μg/ml concentrations. Numbers in parentheses indicate relevant references.
FIG 4
FIG 4
Voriconazole tissue and fluid concentrations in humans as multiples of the maximal or simultaneously measured concentration in plasma (μg/ml) after systemic administration. Tissue multiples are from μg/g tissue values. Fluid multiples are from μg/ml concentrations. *, autopsy data; in these cases, the multiples are based on plasma Cmax values at the same dose in volunteers (188).
FIG 5
FIG 5
Itraconazole tissue and fluid concentrations in humans as multiples of the maximal or simultaneously measured concentration in plasma (μg/ml) after systemic administration. Tissue multiples are from μg/g tissue values. Fluid multiples are from μg/ml concentrations.
FIG 6
FIG 6
Cross section of the brain of a mouse with cryptococcal meningoencephalitis. The organism was stained with an antibody directed toward the cryptococcal capsule. The disease is multifocal. Attempts to use whole-brain homogenates to estimate drug concentrations at the site of infection may be misleading. (Reprinted from reference by permission of the Infectious Diseases Society of America [taken by Julie Schwartz, Charles River Laboratories].)
FIG 7
FIG 7
Concentrations in tissues and body fluids for each systemic antifungal agent relative to its concentration in plasma. X, human data; O, animal data. Colors illustrate differing ratios; multiple colors within a column give the range of published data. Red, from below level of detection to ≤0.5 times the plasma concentration; yellow, from>0.5 times to ≤5 times the plasma concentration; green,>5 times the plasma concentration; white, no data. ●くろまる, pleural fluid, buccal mucosa, or pancreatic pseudocyst; open diamond, based on autopsy data and human pharmacokinetics; Ω, wound fluid; o2, only detected in inflamed eyes; o3, bronchial secretions; x3, below level of detection in bronchial secretions; o4, pulmonary lymph; x5, bronchial biopsy specimen.
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