Susceptibility to thrombin-induced platelet microbicidal protein is associated with increased fluconazole efficacy against experimental endocarditis due to Candida albicans.
Platelet microbicidal proteins (PMPs) are believed to be integral to host defense against endovascular infection. We previously demonstrated that susceptibility to thrombin-induced PMP 1 (tPMP-1) in vitro negatively influences Candida albicans virulence in the rabbit model of infective endocarditis (IE). This study evaluated the relationship between in vitro tPMP-1 susceptibility (tPMP-1s) or resistance (tPMP-1r) and efficacy of fluconazole (FLU) therapy of IE due to C. albicans. Candida IE was established in rabbits with either tPMP-1s or tPMP-1r strains. Treatment groups received FLU (100 mg/kg/day) intraperitoneally for 7 or 14 days; control animals received no therapy. At these time points, cardiac vegetations, kidneys, and spleens were quantitatively cultured to assess fungal burden. At both 7 and 14 days and in all target tissues, the extent of candidal clearance by FLU was greater in animals infected with the tPMP-1s strain than in those infected with the tPMP-1r strain. These differences were statistically significant in the spleen and kidney. Corroborating these in vivo data, FLU (a candidastatic agent), in combination with tPMP-1, exerted an enhanced fungicidal effect in vitro against tPMP-1s and tPMP-1r C. albicans, with the extent of this effect greatest against the tPMP-1s strain. Collectively, these results support the concept that tPMP-1 susceptibility contributes to the net efficacy of FLU against C. albicans IE in vivo, particularly in tissues in which platelets and tPMP-1 likely play significant roles in host defense.
Division of Infectious Diseases, St. John's Cardiovascular Research Center, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA. mryeaman@ucla.edu
Michael R
MR
Yeaman
Darwin
D
Cheng
Bhavesh
B
Desai
Leon I
LI
Kupferwasser
Yan-Qiong
YQ
Xiong
Kimberly D
KD
Gank
John E
JE
Edwards
Arnold S
AS
Bayer
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001798:Blood Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004696:Endocarditis / Q000188:drug therapy* / Q000382:microbiology; D015725:Fluconazole / Q000627:therapeutic use*; D006321:Heart / Q000382:microbiology; D007668:Kidney / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009928:Organ Specificity; D011817:Rabbits; D013045:Species Specificity; D013154:Spleen / Q000382:microbiology
D000935:Antifungal Agents; D001798:Blood Proteins; C077150:platelet microbicidal protein, Oryctolagus cuniculus; D015725:Fluconazole