Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model.

Yanan Zhao,Minh Hong Nguyen,Landry Blanc,Véronique Dartois,Cornelius J Clancy,Yoji Nagasaki,Brendan Prideaux,Min Hee Lee,David S Perlin,Hsinpin Ho,Pei-Yu Chen

doi:10.1128/aac.01009-17

Abstract

ABSTRACTIntra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents; however, their clinical effectiveness is highly variable, with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic doses. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC.

Highlights

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality
Nothing is known about penetration into tissue lesions, one population PK study reported that micafungin exposure in peritoneal fluid was significantly lower than that in plasma in IAC patients [14]
Echinocandin antifungal drugs were introduced and the spatial distribution of micafungin and CD101 was visualized by MALDI-MSI, delivering high-resolution heat maps of drug concentrations in liver and kidney tissues

Summary

Introduction

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC. Taking the specific histopathology of IAC into account, perhaps the most clinically important and informative data are how a drug distributes and penetrates into abscesses or other infected lesions within tissues rather than drug concentrations in serum or whole organs. We took the initiative to apply this technology as well as standard analytical techniques to investigate echinocandin drug penetration at the site of infection in a clinically relevant IAC mouse model involving C. albicans [22]

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