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Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model

Purohit, Prashant J. MD1; Elkomy, Mohammed H. PhD2,3; Frymoyer, Adam MD4; Sutherland, Scott M. MD4; Drover, David R. MD5; Hammer, Gregory B. MD4,5; Su, Felice MD4

doi: 10.1097/CCM.0000000000003895
Online Clinical Investigations
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Objectives: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model.

Design: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole).

Setting: University research laboratory.

Patients: None.

Interventions: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug.

Measurements and Main Results: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates.

Conclusions: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

1Department of Pediatrics, Kapiolani Medical Center for Women and Children, Honolulu, HI.

2Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia.

3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.

4Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

5Department Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA.

Drs. Purohit and Elkomy shared equally in the first authorship. Drs. Purohit and Elkomy contributed equally to be the first author on this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by grant from the Child Health Research Institute, Lucile Packard Foundation for Children’s Health and the Stanford Clinical and Translational Science Award UL1 TR001085.

Dr. Purohit disclosed that this work was supported by the National Institutes of Health and the Child Health Research Institute, Lucile Packard Foundation for Children’s Health and the Stanford Clinical and Translational Science Award UL1 TR001085. Dr. Drover received funding from Masimo. The remaining authors have disclosed that they do not have any potential conflicts of interest.

This work was performed at Stanford University School of Medicine.

For information regarding this article, E-mail: drpurohit22@gmail.com

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