Beyond tissue concentrations: antifungal penetration at the site of infection

Abstract

Despite advances in antifungal therapy, invasive fungal infections remain a significant cause of morbidity and mortality worldwide. One important factor contributing to the relative ineffectiveness of existing antifungal drugs is insufficient drug exposure at the site of infection. Despite the importance of this aspect of antifungal therapy, we generally lack a full appreciation of how antifungal drugs distribute, penetrate, and interact with their target organisms in different tissue subcompartments. A better understanding of drug distribution will be critical to guide appropriate use of currently available antifungal drugs, as well as to aid development of new agents. Herein we briefly review current perspectives of antifungal drug exposure at the site of infection and describe a new technique, matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging, which has the potential to greatly expand our understanding of drug penetration.

Keywords: MALDI imaging; antifungals; drug quantification; posaconazole; site of infection; tissue penetration.

Figure 1.

Workflow of tissue drug exposure analysis by integrating MALDI imaging with LCM directed LC-MS/MS. This Figure is reproduced in color in the online version of Medical Mycology.

Figure 2.

Close up examination of drug penetration for micafungin at 24 h, and CD101 at 6 and 48 h post single dosing. Enlarged view of drug distribution in a single lesion at pixel level. Matched GMS staining of adjacent sections was placed on the bottom. Signal intensity is fixed for CD101 and micafungin, respectively. Scale bars, 5 mm. Figure reprinted by permission: Zhao et al.Antimicrob Agents Chemother. 2017; 61: e01009-17. Copyright (2017) American Society for Microbiology (ASM). This Figure is reproduced in color in the online version of Medical Mycology.

Figure 3.

MALDI imaging analysis of posaconazole and phosphatidylcholine (32:1) distribution in mouse lung infected with A. fumigatus embedded agar beads and collected at 4 h post two doses of posaconazole at 20 mg/kg. Images from left to right were acquired from the same tissue section: optical scan, ion map of posaconazole (m/z 701.337), ion map of phosphatidylcholine 32:1 (PC) (m/z 732.552), and corresponding overlay. Signal intensity color bar is fixed for posaconazole (red) and PC (green), respectively, with gradually increased intensity from black (no signal) to red or green (max signal). Yellow Outlines highlight one typical lesion formed with the A. fumigatus agar beads. This Figure is reproduced in color in the online version of Medical Mycology.