TY - JOUR
T1 - Antifungal extraction by the extracorporeal membrane oxygenation circuit
AU - Watt, Kevin M.
AU - Cohen-Wolkowiez, Michael
AU - Williams, Duane C.
AU - Bonadonna, Desiree K.
AU - Cheifetz, Ira M.
AU - Thakker, Dhiren
AU - Benjamin, Daniel K.
AU - Brouwer, Kim L.R.
N1 - Funding Information:
We gratefully acknowledge the assistance of Jen Turi, Duke University, for providing much of the ECMO equipment used in these studies; Mike Gentile, Mike Lowe, and Lainie Parker for technical support; and Mary Lee Campbell and Leury Laureano, Duke Transfusion Services, for obtaining the blood products for these experiments. None of the authors has any conflict of interest to report for the present study. This work was supported by the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1K23HD075891, 2K24HD058735), the Duke-University of North Carolina Collaborative T32 Clinical Pharmacology Fellowship (1T32GM086330), and the Thrasher Research Fund. Kevin M. Watt, MD, PhD, receives support from the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1K23HD075891, 2K24HD058735), the Duke-University of North Carolina Collaborative T32 Fellowship (1T32GM086330), and the Thrasher Research Fund (www.thrasherresearch.org) for his work in pediatric clinical pharmacology. Michael Cohen-Wolkowiez, MD, PhD receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute for Child Health and Human Development of the NIH (HHSN275201000003I), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (BARDA) (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), and from industry (CardioDx and Durata Therapeutics) for drug development in adults and children (www.dcri.duke.edu/research/coi. jsp). Duane C. Williams, MD, has no conflicts of interest related to this study. Desiree K. Bonadonna, BSE, CCP, LP has no conflicts of interest related to this study. Ira M. Cheifetz, MD has no conflicts of interest related to this study. Dhiren Thakker, PhD has no conflicts of interest related to this study. Daniel K. Benjamin, Jr., MD, PhD, MPH receives support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, and NICHD contract HHSN2752010000031) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Kim L.R. Brouwer, PharmD, PhD, receives support from the National Institutes of Health, National Institute of General Medical Sciences through award number R01 GM041935.
Publisher Copyright:
© 2018 AmSECT.
PY - 2017
Y1 - 2017
N2 - Invasive candidiasis is common and often fatal in patients supported with extracorporeal membrane oxygenation (ECMO), and treatment relies on optimal antifungal dosing. The ECMO circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. This ex vivo study determined the extraction of antifungal drugs by the ECMO circuit. Fluconazole and micafungin were studied separately in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction. Each circuit was primed with human blood, and flow was set to 1 L/min. Drug was dosed to achieve therapeutic concentrations. Each antifungal was added to a separate tube of blood to serve as a control. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point: (Ct/Ci)*100, with Ct and Ci the concentrations at time 5 t and 1 minute, respectively. After 24 hours of recirculation, mean recovery of fluconazole in the ECMO circuit (95-98%) and controls (101%) was high. In contrast, mean recovery of micafungin was dependent on the time and circuit configuration. Recovery at 4 hours was only 46% when a hemofilter was in-line but was much higher when the hemofilter was removed (91%). By 24 hours, however, micafungin recovery was low in all circuit configurations (26-43%), regardless of the presence of a hemofilter, as well as in the controls (57%). In conclusion, these results suggest that micafungin is extracted by the ECMO circuit, which may result in decreased drug exposure in vivo.
AB - Invasive candidiasis is common and often fatal in patients supported with extracorporeal membrane oxygenation (ECMO), and treatment relies on optimal antifungal dosing. The ECMO circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. This ex vivo study determined the extraction of antifungal drugs by the ECMO circuit. Fluconazole and micafungin were studied separately in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction. Each circuit was primed with human blood, and flow was set to 1 L/min. Drug was dosed to achieve therapeutic concentrations. Each antifungal was added to a separate tube of blood to serve as a control. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point: (Ct/Ci)*100, with Ct and Ci the concentrations at time 5 t and 1 minute, respectively. After 24 hours of recirculation, mean recovery of fluconazole in the ECMO circuit (95-98%) and controls (101%) was high. In contrast, mean recovery of micafungin was dependent on the time and circuit configuration. Recovery at 4 hours was only 46% when a hemofilter was in-line but was much higher when the hemofilter was removed (91%). By 24 hours, however, micafungin recovery was low in all circuit configurations (26-43%), regardless of the presence of a hemofilter, as well as in the controls (57%). In conclusion, these results suggest that micafungin is extracted by the ECMO circuit, which may result in decreased drug exposure in vivo.
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M3 - Article
C2 - 28979038
AN - SCOPUS:85042375681
VL - 49
SP - 150
EP - 159
JO - Journal of Extra-Corporeal Technology
JF - Journal of Extra-Corporeal Technology
SN - 0022-1058
IS - 3
ER -