High caspofungin levels in alveolar cells of a lung transplant patient with suspected pulmonary aspergillosis

Burkhardt, Olaf; Ellis, S.; Burhenne, Heike; Kaever, Volkhard; Hadem, Johannes; Kielstein, Jan T.; Welte, Tobias

doi:10.1016/j.ijantimicag.2009.04.002

Cited by 10 publications

(4 citation statements)

References 6 publications

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“…Micafungin showed comparable penetration into the macrophages to clofazimine despite being used at a lower concentration. This result was consistent with previously reported strong penetration and accumulation of echinocandins in macrophages in clinical settings [39][40][41] and indicated that ICG retain high viability even though the intracellular micafungin concentration reaches >100 µM, or 256X of the MIC, by 0.5 h pst (Fig. 1g).…”

Section: Micafungin Efficiently Penetrates Into Macrophages and Rapid...supporting

confidence: 93%

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

et al. 2023

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Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

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Section: Micafungin Efficiently Penetrates Into Macrophages and Rapid...supporting

confidence: 93%

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

et al. 2023

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“…Micafungin showed comparable penetration into the macrophages to clofazimine despite being used at a lower concentration. This result was consistent with previously reported strong penetration and accumulation of echinocandins in macrophages in clinical settings (38–40) and indicated that ICG retain high viability even though the intracellular micafungin concentration reaches >100 μM, or 256X of the MIC, by 0.5 hour pst (Figure 1g).…”

Section: Resultssupporting

confidence: 93%

Macrophage internalization creates a multidrug-tolerant fungal persister population, providing a permissive reservoir for the emergence of drug resistance

Arastehfar

Daneshnia

Cabrera

et al. 2022

Preprint

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Candida glabratais a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptibleC. glabratacells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance inC. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellularC. glabrataechinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophageC. glabratais a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

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“…However, the concentrations of caspofungin in alveolar macrophages were Ͼ5 times the corresponding concentrations in plasma in a single patient (149). Both anidulafungin and micafungin also accumulated in the alveolar macrophages of volunteers, attaining concentrations approximately 14 and 4 times higher than those in plasma, respectively (58,62).…”

Section: Lungmentioning

confidence: 92%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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SUMMARY 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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High caspofungin levels in alveolar cells of a lung transplant patient with suspected pulmonary aspergillosis

Cited by 10 publications

References 6 publications

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

Macrophage internalization creates a multidrug-tolerant fungal persister population, providing a permissive reservoir for the emergence of drug resistance

Tissue Penetration of Antifungal Agents

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