Effects of ex vivo Extracorporeal Membrane Oxygenation Circuits on Sequestration of Antimicrobial Agents

Abstract

Objectives: Our ex vivo study was designed to determine the sequestration of teicoplanin, tigecycline, micafungin, meropenem, polymyxin B, caspofungin, cefoperazone sulbactam, and voriconazole in extracorporeal membrane oxygenation (ECMO) circuits.Methods: Simulated closed-loop ECMO circuits were prepared using 2 types of blood-primed ECMO. After the circulation was stabilized, the study drugs were injected into the circuit. Blood samples were collected at 2, 5, 15, 30 min, 1, 3, 6, 12, and 24 h after injection. Drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Control groups were stored at 4°C after 3, 6, 12, and 24 h immersing in a water bath at 37°C to observe spontaneous drug degradation.Results: Twenty-six samples were analyzed. The average drug recoveries from the ECMO circuits and control groups at 24 h relative to baseline were 67 and 89% for teicoplanin, 100 and 145% for tigecycline, 67 and 99% for micafungin, 45 and 75% for meropenem, 62 and 60% for polymyxin B, 83 and 85% for caspofungin, 79 and 98% for cefoperazone, 75 and 87% for sulbactam, and 60 and 101% for voriconazole, respectively. Simple linear regression showed no significant correlation between lipophilicity (r2 = 0.008, P = 0.225) or the protein binding rate (r2 = 0.168, P = 0.479) of drugs and the extent of drug loss in the ECMO circuits.Conclusions: In the two ECMO circuits, meropenem and voriconazole were significantly lost, cefoperazone was slightly lost, while tigecycline and caspofungin were not lost. Drugs with high lipophilicity were lost more in the Maquet circuit than in the Sorin circuit. This study needs more in vivo studies with larger samples for further confirmation, and it suggests that therapeutic drug concentration monitoring should be strongly considered during ECMO.

Antibiotics and ECMO in the Adult Population—Persistent Challenges and Practical Guides

“…Protein binding is low [47]. Several studies have demonstrated significant sequestration of the drug by circuit in vitro [110]. While increases in both volumes of distribution and clearance are likely, several trials failed to show a significant difference in pharmacodynamics in ECMO patients [47,75,80].…”

“…One study comparing 26 ECMO patients with 51 matched controls, wherein peak meropenem concentrations were drawn at 2 h after infusion and immediately prior to a subsequent dose, found no differences in distribution volume, half-life, or clearance [73]. Another study comparing 11 ECMO patients to historical controls sampled meropenem at 15, 30, 45, 60, 120, 360 and 480 min, finding a slight decrease in clearance and increase in volume of distribution [110]. Recommended dosing in this population involves a 1 g load followed by 1 g q8h [43], or 2 g q8h [110].…”

“…Another study comparing 11 ECMO patients to historical controls sampled meropenem at 15, 30, 45, 60, 120, 360 and 480 min, finding a slight decrease in clearance and increase in volume of distribution [110]. Recommended dosing in this population involves a 1 g load followed by 1 g q8h [43], or 2 g q8h [110]. Higher doses of meropenem may be employed, and a regimen totaling 6g/d showed to be slightly superior in achieving MIC to standard dosing.…”

“…Higher doses of meropenem may be employed, and a regimen totaling 6g/d showed to be slightly superior in achieving MIC to standard dosing. Continuous infusion of 3-6/g has been recommended in patients with increased clearance or resistant organisms [110]. Notably, 6.1% of patients did not achieve target MIC compared to 0% of those receiving a higher-dose regimen [80].…”

“…For teicoplanin, 89% of the drug can be sequestered, according to an in vitro study of the primed circuit [110]. Two in vivo studies agreed that the drug's loading has to be increased to 12 mg/kg to achieve therapeutic concentrations [113,114].…”