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 (AUCtot/MIC), seems not to be achieved and therapeutic drug mo...
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Published in | Mycoses Vol. 65; no. 1; pp. 79 - 87 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
Wiley Subscription Services, Inc
01.01.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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 (AUCtot/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). AUCtot/MIC required for a 1 log10 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 × 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. |
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Bibliography: | Funding information This work was funded by the Olinder‐Nielsen Family Fund for Research in Infectious Diseases and R&D funds of the Uppsala County Council. Thomas Tängdén acknowledges financial support from the Swedish Research Council (grant nos. 2019‐05911 and 2020‐02320) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0933-7407 1439-0507 1439-0507 |
DOI: | 10.1111/myc.13386 |