INTRODUCTION AND AIMS: The optimal antifungal drug should combine good in vitro activity with the capacity to act in concert with the immune system in a way that potentiates the host's defences. Since patients with chronic renal failure are highly susceptible to fungal opportunistic infections characterized by high morbidity and mortality, related to an impairment of the phagocytic response, the present study was designed to evaluate the potential effect of caspofungin on the functions of polymorphonuclear cells (PMNs) harvested from both healthy volunteers and renal transplant recipients against Candida albicans, often associated with serious fungal infections in immunocompromised patients. METHODS: PMNs were separated from lithium heparinized venous blood pooled from healthy donors (30) and renal transplant recipients (54), by using Ficoll-Paque. The effects of caspofungin on either the phagocytosis of radiolabelled C.albicans [3H-uracil (specific activity: 1.27 TBq/mmol; NEN Products, Milan, Italy)] or the intracellular fungal killing by PMNs were investigated by incubating yeasts and the phagocytes (yeast:PMN ratio was 1:1) at 37oC for various periods in the presence of drug MIC. Caspofungin-free controls were also included. The % of phagocytosis at a given sampling time was calculated: [(counts per minute in PMN pellet)/(counts per minute in total fungal pellet)] x 100. The PMN killing values were expressed as the survival index (SI), which was calculated by adding the number of surviving yeasts at T0 to the number of survivors at Tx, and dividing by the number of survivors at T0. According to this formula, if fungal killing was 100% effective, the SI would be 1. RESULTS: In vitro, PMNs from renal transplant recipients showed a diminished phagocytic efficiency with reduced both phagocytosis and fungicidal activity towards intracellular yeasts compared with that of PMNs from healthy subjects. The presence of caspofungin did not result in a significant increase in the fungal uptake by PMNs from renal transplant recipients compared with controls and with that observed in healthy subjects. Conversely, the addition of caspofungin to PMNs from renal transplant recipients potentiated the intracellular killing rate against C.albicans, achieving values quite similar to those observed with PMNs from healthy subjects. CONCLUSIONS: The findings of this study show that caspofungin, a new echinocandin, is able to reset the depressed intracellular killing of polymorphonuclear cells and suggest that caspofungin possesses interesting beneficial properties which make it suitable for the treatment of candidal infections in patients with impaired components of the immune system, highly susceptible to fungal infections.
Caspofungin resets the depressed killing activity of polymorphonuclear cells from renal transplant recipients against Candida albicans
ALLIZOND, VALERIA;TULLIO, Viviana Cristina;SCALAS, Daniela;ROANA, Janira;BANCHE, Giuliana;MANDRAS, Narcisa;MERLINO, Chiara;CUFFINI, Annamaria
2010-01-01
Abstract
INTRODUCTION AND AIMS: The optimal antifungal drug should combine good in vitro activity with the capacity to act in concert with the immune system in a way that potentiates the host's defences. Since patients with chronic renal failure are highly susceptible to fungal opportunistic infections characterized by high morbidity and mortality, related to an impairment of the phagocytic response, the present study was designed to evaluate the potential effect of caspofungin on the functions of polymorphonuclear cells (PMNs) harvested from both healthy volunteers and renal transplant recipients against Candida albicans, often associated with serious fungal infections in immunocompromised patients. METHODS: PMNs were separated from lithium heparinized venous blood pooled from healthy donors (30) and renal transplant recipients (54), by using Ficoll-Paque. The effects of caspofungin on either the phagocytosis of radiolabelled C.albicans [3H-uracil (specific activity: 1.27 TBq/mmol; NEN Products, Milan, Italy)] or the intracellular fungal killing by PMNs were investigated by incubating yeasts and the phagocytes (yeast:PMN ratio was 1:1) at 37oC for various periods in the presence of drug MIC. Caspofungin-free controls were also included. The % of phagocytosis at a given sampling time was calculated: [(counts per minute in PMN pellet)/(counts per minute in total fungal pellet)] x 100. The PMN killing values were expressed as the survival index (SI), which was calculated by adding the number of surviving yeasts at T0 to the number of survivors at Tx, and dividing by the number of survivors at T0. According to this formula, if fungal killing was 100% effective, the SI would be 1. RESULTS: In vitro, PMNs from renal transplant recipients showed a diminished phagocytic efficiency with reduced both phagocytosis and fungicidal activity towards intracellular yeasts compared with that of PMNs from healthy subjects. The presence of caspofungin did not result in a significant increase in the fungal uptake by PMNs from renal transplant recipients compared with controls and with that observed in healthy subjects. Conversely, the addition of caspofungin to PMNs from renal transplant recipients potentiated the intracellular killing rate against C.albicans, achieving values quite similar to those observed with PMNs from healthy subjects. CONCLUSIONS: The findings of this study show that caspofungin, a new echinocandin, is able to reset the depressed intracellular killing of polymorphonuclear cells and suggest that caspofungin possesses interesting beneficial properties which make it suitable for the treatment of candidal infections in patients with impaired components of the immune system, highly susceptible to fungal infections.
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