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Published on: February 14, 2018

Concentration of antifungal agents within host cell membranes: a new paradigm governing the efficacy of prophylaxis

P Campoli1, Q Al Abdallah, R Robitaille

  • 1Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.

Antimicrobial Agents and Chemotherapy
|September 21, 2011
PubMed

Insights

Posaconazole prophylaxis effectively prevents fungal infections by accumulating in host cells, not just blood. This intracellular drug concentration, particularly in cell membranes, explains its high efficacy.

Area of Science:

  • Mycology
  • Pharmacology
  • Cell Biology

Background:

  • Invasive fungal infections (IFIs) pose significant threats, especially in immunocompromised individuals.
  • Posaconazole prophylaxis is effective against IFIs, yet its efficacy appears disproportionate to low serum concentrations.
  • High tissue drug levels suggest intracellular accumulation may be key to posaconazole's prophylactic action.

Purpose of the Study:

  • To investigate the role of intracellular antifungal drug concentrations in preventing mold infections.
  • To determine if host cell-associated antifungals contribute to prophylaxis efficacy.
  • To explore the relationship between drug localization and antifungal activity.

Main Methods:

  • Loading epithelial cells with posaconazole and itraconazole, then removing extracellular drug.
  • Challenging drug-loaded cells with medically important molds.
  • Quantifying intracellular and extracellular drug levels and assessing fungal growth and cell damage.

Main Results:

  • Epithelial cells loaded with posaconazole and itraconazole inhibited fungal growth for at least 48 hours.
  • Cell-associated posaconazole levels were 40-50 times higher than extracellular levels, primarily in cell membranes.
  • Intracellular fungistatic posaconazole concentrations persisted for up to 48 hours, protecting cells from fungal damage.

Conclusions:

  • Host cell membrane concentration of posaconazole is critical for its prophylactic efficacy against IFIs.
  • Intracellular drug accumulation, rather than serum levels, likely explains posaconazole's effectiveness.
  • This finding redefines the understanding of antifungal drug action in prophylaxis.

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