Human Tissue Distribution of Anidulafungin and Micafungin

Marx, Jana; Welte, René; Gasperetti, Tiziana; Moser, Patrizia; Joannidis, Michael; Bellmann, Romuald

doi:10.1128/aac.00169-21

Cited by 5 publications

(3 citation statements)

References 26 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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“…In general, the burden was the highest in the spleen, followed by the kidney, and the liver had the least burden. In fact, this observation is in line with a previous study documenting liver and kidney containing the highest and the lowest micafungin concentrations from autopsy samples, respectively ( 25 ). Similarly, we previously showed that caspofungin, not micafungin, had a lower concentration in the spleen but still higher than the MIC, compared to kidney ( 18 ).…”

Section: Resultssupporting

confidence: 92%

Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus Candida glabrata

Arastehfar,

Daneshnia,

Floyd

et al. 2024

mBio

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Recent epidemiological studies documented an alarming increase in the prevalence of echinocandin-resistant (ECR) Candida glabrata blood isolates. ECR isolates are known to arise from a minor subpopulation of a clonal population, termed echinocandin persisters. Although it is believed that isolates with a higher echinocandin persistence (ECP) are more likely to develop ECR, the implication of ECP needs to be better understood. Moreover, replacing laborious and time-consuming traditional approaches to determine ECP levels with rapid, convenient, and reliable tools is imperative to advance our understanding of this emerging concept in clinical practice. Herein, using extensive ex vivo and in vivo systemic infection models, we showed that high ECP isolates are less effectively cleared by micafungin treatment and exclusively give rise to ECR colonies. Additionally, we developed a flow cytometry-based tool that takes advantage of a SYTOX-based assay for the stratification of ECP levels. Once challenged with various collections of echinocandin-susceptible blood isolates, our assay reliably differentiated ECP levels in vitro and predicted ECP levels in real time under ex vivo and in vivo conditions when compared to traditional methods relying on colony-forming unit counting. Given the high and low ECP predictive values of 92.3% and 82.3%, respectively, our assay showed a high agreement with traditional approach. Collectively, our study supports the concept of ECP level determination in clinical settings and provides a robust tool scalable for high-throughput settings. Application of this tool facilitates the interrogation of mutant and drug libraries to further our understanding of persister biology and designing anti-persister therapeutics. IMPORTANCE Candida glabrata is a prevalent fungal pathogen able to replicate inside macrophages and rapidly develop resistance against frontline antifungal echinocandins. Multiple studies have shown that echinocandin resistance is fueled by the survival of a small subpopulation of susceptible cells surviving lethal concentrations of echinocandins. Importantly, bacterial pathogens that exhibit high antibiotic persistence also impose a high burden and generate more antibiotic-resistant colonies. Nonetheless, the implications of echinocandin persistence (ECP) among the clinical isolates of C. glabrata have not been defined. Additionally, ECP level determination relies on a laborious and time-consuming method, which is prone to high variation. By exploiting in vivo systemic infection and ex vivo models, we showed that C. glabrata isolates with a higher ECP are associated with a higher burden and more likely develop echinocandin resistance upon micafungin treatment. Additionally, we developed an assay that reliably determines ECP levels in real time. Therefore, our study identified C. glabrata isolates displaying high ECP levels as important entities and provided a reliable and convenient tool for measuring echinocandin persistence, which is extendable to other fungal and bacterial pathogens.

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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)(39)(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: Micafungin Efficiently Penetrates Into Macrophages and Rapid...supporting

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.

show abstract

Human Tissue Distribution of Anidulafungin and Micafungin

Cited by 5 publications

References 26 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

Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus Candida glabrata

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

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