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Susceptibility to thrombin-induced platelet microbicidal protein is associated with increased fluconazole efficacy

Michael R Yeaman1, Darwin Cheng, Bhavesh Desai

  • 1Division of Infectious Diseases, St. John's Cardiovascular Research Center, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA. mryeaman@ucla.edu

Antimicrobial Agents and Chemotherapy
|July 27, 2004
PubMed

Insights

Susceptibility to platelet microbicidal protein 1 (tPMP-1) enhances fluconazole (FLU) efficacy against Candida albicans infective endocarditis (IE). This suggests tPMP-1 plays a key role in host defense and antifungal therapy success.

Area of Science:

  • Infectious Diseases
  • Microbiology
  • Pharmacology

Background:

  • Platelet microbicidal proteins (PMPs) are crucial for host defense against endovascular infections.
  • Previous studies linked susceptibility to thrombin-induced PMP 1 (tPMP-1) to reduced Candida albicans virulence.
  • The role of tPMP-1 susceptibility in antifungal therapy efficacy remained unclear.

Purpose of the Study:

  • To investigate the relationship between tPMP-1 susceptibility or resistance and the effectiveness of fluconazole (FLU) therapy in a rabbit model of Candida albicans infective endocarditis (IE).

Main Methods:

  • Established Candida IE in rabbits using either tPMP-1 susceptible (tPMP-1s) or resistant (tPMP-1r) strains.
  • Treated infected rabbits with FLU (100 mg/kg/day) for 7 or 14 days, with untreated controls.
  • Quantitatively cultured cardiac vegetations, kidneys, and spleens to assess fungal burden at treatment endpoints.
  • Evaluated in vitro fungicidal effects of FLU alone and in combination with tPMP-1 against both susceptible and resistant strains.

Main Results:

  • Fluconazole therapy achieved greater fungal clearance in animals infected with the tPMP-1s strain compared to the tPMP-1r strain across all tissues examined.
  • Statistically significant differences in fungal clearance were observed in the spleen and kidney.
  • In vitro, tPMP-1 combined with FLU demonstrated enhanced fungicidal activity, most pronounced against the tPMP-1s C. albicans strain.

Conclusions:

  • tPMP-1 susceptibility is a significant factor contributing to the overall efficacy of fluconazole treatment for Candida albicans IE in vivo.
  • These findings highlight the importance of tPMP-1 in host defense mechanisms and its potential to influence antifungal treatment outcomes, particularly in platelet-rich environments.

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