Human plasma protein levels alter the in vitro antifungal activity of caspofungin: An explanation to the effect in critically ill?

Background Recent studies have shown low caspofungin concentrations in critically ill patients. In some patients, the therapeutic target, area under the total plasma concentration curve in relation to the minimal inhibition concentration (AUC(tot)/MIC), seems not to be achieved and therapeutic drug monitoring (TDM) has been proposed. Caspofungin is highly protein-bound and the effect of reduced plasma protein levels on pharmacodynamics has not been investigated. Objectives Fungal killing activity of caspofungin in vitro was investigated under varying levels of human plasma protein. Methods Time-kill studies were performed with clinically relevant caspofungin concentrations of 1-9 mg/L on four blood isolates of C. glabrata, three susceptible and one strain with reduced susceptibility, in human plasma and plasma diluted to 50% and 25% using Ringer's acetate. Results Enhanced fungal killing of the three susceptible strains was observed in plasma with lower protein content (p < .001). AUC(tot)/MIC required for a 1 log(10) CFU/ml kill at 24 h in 50% and 25% plasma was reduced with 36 + 12 and 80 + 9%, respectively. The maximum effect was seen at total caspofungin concentrations of 4-9 x MIC. For the strain with reduced susceptibility, growth was significantly decreased at lower protein levels. Conclusions Reduced human plasma protein levels increase the antifungal activity of caspofungin in vitro, most likely by increasing the free concentration. Low plasma protein levels in critically ill patients with candidemia might explain a better response to caspofungin than expected from generally accepted target attainment and should be taken into consideration when assessing TDM based on total plasma concentrations.