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Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature

      Abstract

      Purpose

      Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that is used to temporarily support the most critically ill of patients with respiratory and/or cardiac failure. Infection and its sequelae may be an indication for ECMO or infections may be acquired while on ECMO and are associated with a mortality >50%. Effective therapy requires optimal dosing. However, optimal dosing can be different in patients on ECMO because the ECMO circuit can alter drug pharmacokinetics. This review assessed the current literature for pharmacokinetic data and subsequent dosing recommendations for anti-infective drugs in patients on ECMO.

      Methods

      We searched the PubMed and Embase databases (1965 to February 2016) and included case reports, case series, or studies that provided pharmacokinetic data for anti-infective drugs including antibiotics, antifungals, and antivirals being used to treat patients of all age groups on ECMO. Pharmacokinetic parameters and dosing recommendations based on these data are presented.

      Findings

      The majority of data on this topic comes from neonatal studies of antibiotics from the 1980s and 1990s. These studies generally demonstrate a larger volume of distribution due to ECMO and therefore higher doses are needed initially. More adult data are now emerging, but with a predominance of case reports and case series without comparison with critically ill controls. The available pharmacokinetic analyses do suggest that volume of distribution and clearance are unchanged in the adult population, and therefore dosing recommendations largely remain unchanged. There is a lack of data on children older than 1 year of age. The data support the importance of therapeutic drug monitoring when available in this population of patients.

      Implications

      This review found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infectives. In order to better determine optimal dosing for patients on ECMO, a systematic approach is needed. Approaches that combine ex vivo ECMO experiments, animal studies, specialized pharmacokinetic modeling, and human clinical trials are being developed.

      Key words

      Introduction

      Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that supports patients with respiratory and/or cardiac failure. Mechanically, blood is drained from the venous system, pumped through an artificial lung membrane, and then returned to either the venous or arterial circulation. ECMO support comes in 2 forms: venovenous (VV) and venoarterial (VA). VV ECMO provides pulmonary support and VA ECMO provides both pulmonary and cardiac support. Regardless of whether the ECMO circuit is configured for VV or VA ECMO, the components are the same: tubing, pump, and oxygenator (Figure 1).
      Figure 1
      Figure 1Basic extracorporeal membrane oxygenation (ECMO) diagram.
      Although ECMO is lifesaving in a very critically ill subset of patients, it also presents new challenges related to their management. One of these challenges is understanding and appropriately compensating for the effect of ECMO on drug pharmacokinetics. This topic has been studied since the late 1980s in neonates and isolated ex vivo ECMO circuits and more recently in older children and adults. In general, ECMO has been shown to affect pharmacokinetics in 3 primary ways, as discussed in the following.

      Direct Extraction by the Circuit

      Drug extraction by the ECMO circuit is a well-recognized contributor to pharmacokinetic (PK) alterations across all patient populations that depends on both the circuit component materials and the drug physicochemical properties. The interaction between the drug and the ECMO circuit has been studied primarily in ex vivo experiments in which drug is administered to isolated ECMO circuits.
      • Bhatt-Mehta V
      • Johnson CE
      • Schumacher RE2
      Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.
      • Dagan O.
      • Klein J.
      • Gruenwald C.
      • et al.
      Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs.
      • Harthan A.A.
      • Buckley K.W.
      • Heger M.L.
      • et al.
      Medication adsorption into contemporary extracorporeal membrane oxygenator circuits.
      • Koren G.
      • Crean P.
      • Klein J.
      • et al.
      Sequestration of fentanyl by the cardiopulmonary bypass (CPBP).
      • Lemaitre F.
      • Hasni N.
      • Leprince P.
      • et al.
      Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood.
      • Mehta N.M.
      • Halwick D.R.
      • Dodson B.L.
      • et al.
      Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.
      • Mulla H.
      • Lawson G.
      • von Anrep C.
      • et al.
      In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
      • Wildschut E.D.
      • Ahsman M.J.
      • Allegaert K.
      • et al.
      Determinants of drug absorption in different ECMO circuits.
      Because there is no human attached to the circuit, any change in concentration over time is due to extraction by the circuit or drug degradation. In general, ex vivo studies have demonstrated increased extraction of highly lipophilic and protein-bound drugs.
      • Harthan A.A.
      • Buckley K.W.
      • Heger M.L.
      • et al.
      Medication adsorption into contemporary extracorporeal membrane oxygenator circuits.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
      However, the degree of extraction, even for the same drug, can be markedly affected by circuit materials. A study of fentanyl (LogP 4, protein binding 80%) in an ECMO circuit using a silicone membrane oxygenator showed >99% fentanyl loss in 180 minutes.
      • Wildschut E.D.
      • Ahsman M.J.
      • Allegaert K.
      • et al.
      Determinants of drug absorption in different ECMO circuits.
      When the same experiment was repeated in a circuit with a microporous, hollow-fiber polypropylene oxygenator, fentanyl loss was only 66% at 180 minutes.
      • Wildschut E.D.
      • Ahsman M.J.
      • Allegaert K.
      • et al.
      Determinants of drug absorption in different ECMO circuits.
      Another study compared the effect of 6 different coatings on drug extraction by the polyvinyl chloride tubing by administering fentanyl to circuits constructed with only a pump and tubing (no oxygenator).
      • Preston T.J.
      • Hodge A.B.
      • Riley J.B.
      • et al.
      In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit.
      • Preston T.J.
      • Ratliff T.M.
      • Gomez D.
      • et al.
      Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit.
      In the uncoated circuit, fentanyl loss at 120 minutes was 80%.
      • Preston T.J.
      • Hodge A.B.
      • Riley J.B.
      • et al.
      In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit.
      In the coated tubing, fentanyl loss at 120 minutes ranged from 40% to 75%.
      • Preston T.J.
      • Ratliff T.M.
      • Gomez D.
      • et al.
      Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit.
      Drug extraction by the circuit is likely due to nonspecific adsorption.
      • Harthan A.A.
      • Buckley K.W.
      • Heger M.L.
      • et al.
      Medication adsorption into contemporary extracorporeal membrane oxygenator circuits.
      • Preston T.J.
      • Hodge A.B.
      • Riley J.B.
      • et al.
      In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit.
      • Preston T.J.
      • Ratliff T.M.
      • Gomez D.
      • et al.
      Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit.
      • Palmgren J.J.
      • Monkkonen J.
      • Korjamo T.
      • et al.
      Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.
      • Unger J.K.
      • Kuehlein G.
      • Schroers A.
      • et al.
      Adsorption of xenobiotics to plastic tubing incorporated into dynamic in vitro systems used in pharmacological research--limits and progress.
      Adsorption is a function of (1) interactions between the drug and the material surface, (2) the maximal amount of binding per unit of surface area, and (3) the affinity of the drug for the surface. The process of adsorption is driven primarily by electrostatic and hydrophobic interactions. Interactions with polymers such as those used in ECMO circuit equipment tend to be due to hydrophobic interactions (ie, hydrophobic drugs adhere to hydrophobic alkyl groups on polymers). Electrostatic interactions tend to dominate when surface coatings are applied to ECMO circuit components. Surface coatings are increasingly applied to ECMO circuit components to minimize the inflammatory response triggered when blood comes into contact with a foreign material,
      • De Somer F.
      • Francois K.
      • van Oeveren W.
      • et al.
      Phosphorylcholine coating of extracorporeal circuits provides natural protection against blood activation by the material surface.
      • Palatianos G.M.
      • Foroulis C.N.
      • Vassili M.I.
      • et al.
      A prospective, double-blind study on the efficacy of the bioline surface-heparinized extracorporeal perfusion circuit.
      • Tayama E.
      • Hayashida N.
      • Akasu K.
      • et al.
      Biocompatibility of heparin-coated extracorporeal bypass circuits: new heparin bonded bioline system.
      but coatings also can change the nature of interaction between the drug and material surface. When the drug and surface are oppositely charged, the degree of ionization driven by blood pH and drug pKa can influence the degree of adsorption. The extent and irreversibility of adsorption depend on the number of binding sites on the material surface and the affinity of the drug for the surface. In the ECMO system, data are conflicting as to whether binding is saturable.
      • Dagan O.
      • Klein J.
      • Gruenwald C.
      • et al.
      Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs.
      • Wildschut E.D.
      • Ahsman M.J.
      • Allegaert K.
      • et al.
      Determinants of drug absorption in different ECMO circuits.

      Increased Volume of Distribution

      ECMO support can increase volume of distribution (V) via multiple mechanisms: (1) drug extraction via direct interaction with the circuit as mentioned previously, (2) hemodilution, and (3) physiologic changes related to ECMO support and critical illness. Hemodilution occurs due to the large volume of exogenous blood required to prime the circuit, frequent transfusions of blood products, and administration of crystalloid to maintain circuit flows. Hemodilution has the greatest effect on drugs whose distribution is limited to the plasma compartment (ie, low V drugs). Drugs that distribute widely to tissues (ie, high V drugs) may be less affected because drug extracted by the circuit may be replaced by drug stored in the tissue. The impact of hemodilution is likely inversely related to age. For a 3-kg infant, the circuit prime volume (250–400 mL) might exceed the infant’s native blood volume (~250 mL), whereas in a 30-kg child, the prime volume is ~20% of the child’s blood volume (~2.1 L) and therefore represents ~40% of the child’s total circulating blood volume while on ECMO (Figure 2). In addition, ongoing hemolysis and the need to maintain hemostasis result in frequent transfusions of blood products, sometimes totaling 6 to 8 L over the course of an ECMO run.
      • Buck M.L.
      Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates.
      Figure 2
      Figure 2Age-dependent impact of extracorporeal membrane oxygenation (ECMO) prime volume on native blood volume for neonates, children, and adults on ECMO.
      The disease state can also affect V. Exposure to the ECMO circuit results in an inflammatory response.
      • Butler J.
      • Pathi V.L.
      • Paton R.D.
      • et al.
      Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms.
      • Kozik D.J.
      • Tweddell J.S.
      Characterizing the inflammatory response to cardiopulmonary bypass in children.
      • McIlwain R.B.
      • Timpa J.G.
      • Kurundkar A.R.
      • et al.
      Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine.
      Inflammation often results in capillary leak and edema, which can increase V.
      • Butler J.
      • Pathi V.L.
      • Paton R.D.
      • et al.
      Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms.
      • Seghaye M.C.
      • Grabitz R.G.
      • Duchateau J.
      • et al.
      Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations.
      • Anderson 3rd, H.L.
      • AACoran A.G.
      • Drongowski R.A.
      • et al.
      Extracellular fluid and total body water changes in neonates undergoing extracorporeal membrane oxygenation.
      In addition, patients on ECMO can have an altered blood pH, which can affect a drug’s ionization and distribution into tissues. Finally, the renin-angiotensin system in the kidney can be upregulated, possibly related to nonpulsatile blood flow seen in VA EMCO.
      • Many M.
      • Soroff H.S.
      • Birtwell W.C.
      • et al.
      The physiologic role of pulsatile and nonpulsatile blood flow. II. Effects on renal function.
      Upregulation of the renin-angiotensin system alters handling of fluids and can change the ratio of fluids in the body fluid compartments.
      Our understanding of the impact of ECMO on V is limited by the fact that most studies were done in infants or an ex vivo system. Although ex vivo studies are useful in understanding how drugs interact with an ECMO circuit in isolation, direct translation of those results to humans is challenging. Translating results from infant studies is challenging because infants differ from older children and adults in important ways. In addition to the different ratio of exogenous to native blood volume described previously, infants have a higher proportion of body water and lower protein binding, both of which can affect V.
      • Ehrnebo M.
      • Agurell S.
      • Jalling B.
      • et al.
      Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults.
      • Friis-Hansen B.
      Water distribution in the foetus and newborn infant.
      • McNamara P.J.
      • Alcorn J.
      Protein binding predictions in infants.
      For these reasons, extrapolation of infant ECMO data to older children and adults must be done with caution.

      Altered Clearance

      ECMO alters the PK of certain drugs by the effect it has on various organ systems. Renal dysfunction is common in patients on ECMO, occurring in >30% of ECMO patients.

      Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. 2016; https://www.elso.org/Registry/Statistics/InternationalSummary.aspx.

      Reasons for the renal dysfunction are not entirely clear but appear to be multifactorial. Hypoxia and poor organ perfusion before ECMO support likely contributes. Nonpulsatile blood flow seen with VA ECMO is associated with a decreased glomerular filtration rate.
      • Many M.
      • Soroff H.S.
      • Birtwell W.C.
      • et al.
      The physiologic role of pulsatile and nonpulsatile blood flow. II. Effects on renal function.
      Of note, in VV ECMO where blood flow is pulsatile, the incidence of renal dysfunction (32%) is almost as high as that observed in VA ECMO (47%).

      Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. 2016; https://www.elso.org/Registry/Statistics/InternationalSummary.aspx.

      Altered renal function can substantially increase exposure of renally cleared drugs and can place patients at risk of toxicity. The effect is complicated if hemofiltration or dialysis is combined with ECMO support. Some drugs are cleared by hemodialysis (compensating for decreased renal function), whereas others are not.
      The impact of ECMO on metabolic capacity is not well described. It is postulated that decreased regional flow to the liver could result in decreased metabolism of hepatically cleared drugs, especially those where extraction is blood-flow dependent.
      • Mulla H.
      • Lawson G.
      • Firmin R.
      • et al.
      Drug Disposition During Extracorporeal Membrane Oxygenation (ECMO).
      Further, we know that ECMO causes inflammation and that inflammation tends to decrease the expression and function of drug-metabolizing enzymes.
      • McIlwain R.B.
      • Timpa J.G.
      • Kurundkar A.R.
      • et al.
      Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine.
      • Morgan E.T.
      Regulation of cytochromes P450 during inflammation and infection.
      • Abdel-Razzak Z.
      • Loyer P.
      • Fautrel A.
      • et al.
      Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture.
      • Rivory L.P.
      • Slaviero K.A.
      • Clarke S.J.
      Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response.
      • Siewert E.
      • Bort R.
      • Kluge R.
      • et al.
      Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent.
      • Richardson T.A.
      • Sherman M.
      • Kalman D.
      • et al.
      Expression of UDP-glucuronosyl transferase isoform mRNAs during inflammation and infection in mouse liver and kidney.
      There are no data describing the impact of ECMO on drug transporters.
      Patients on ECMO are critically ill and receive multiple drugs; therefore, understanding the PK alterations that occur on ECMO is crucial. Anti-infective drugs are frequently used in patients on ECMO. Optimal dosing is important because infections are common in patients on ECMO and result in substantial morbidity and mortality. According to the Extracorporeal Life Support Organization, infection rates among all age groups on ECMO are as high as 15 per 1000 ECMO days.
      • Bizzarro M.J.
      • Conrad S.A.
      • Kaufman D.A.
      • et al.
      Extracorporeal Life Support Organization Task Force on Infections EMO. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults.
      The mortality of patients on ECMO with reported infections ranges from 56% to 68%.

      Extracorporeal Life Support Organization Registry Report: International Summary. January 2016. https://www.elso.org/. Accessed February 29, 2016

      The objective of this paper is to review the current literature and provide dosing recommendations for antimicrobial drugs in patients on ECMO.

      Methods

      We performed a literature review by searching PubMed (1965 to February 2016) and Embase (1965 to February 2016). Search terms included “pharmacokinetics OR dosing,” “Extracorporeal Membrane Oxygenation OR ECMO,” and “anti-infectives.” The search terms were developed in conjunction with a Duke University Medical Center librarian. Animal studies, ex vivo studies, and studies in languages other than English were excluded. Studies were included if they contained PK data on anti-infective drugs for study populations including neonates (0–28 days of age), infants (29 days to 2 years of age), children (2 to younger than 12 years of age), adolescents (12 to younger than 18 years of age), and adults (18 years of age and older) on ECMO. References from searched articles were also considered and cited if they met the aforementioned criteria.

      Results

      Dosing recommendations based on the available data are presented by age in Tables I through III. In many cases, limited data existed for a given drug. In these instances, we provide a dosing recommendation but note the limitations of those recommendations.
      Table IAnti-infective pharmacokinetics and dosing in neonates/infants
      Neonates are children <30 days of age; infants are 1 month to 2 years of age.
      on ECMO.
      DrugVolume of Distribution Compared With Non-ECMO PatientsClearance Compared With Non-ECMO PatientsStandard Dosing in Critically Ill Patients
      All doses are intravenous.
      ,
      Unless otherwise noted, all dosing recommendations for standard of care dosing were obtained from Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      Dosing Recommendations for Patients on ECMO
      All doses are intravenous.
      Antibiotics
       CefotaximeIncreasedUnchangedGeneral: ≤7 days: 50 mg/kg every 12 hStandard dosing
      7–28 days: 50 mg/kg every 8 h
      >28 days: 150 mg/kg/d divided every 6–8 h
       GentamicinUnchanged or increasedDecreased<3 mo: 4–5 mg/kg every 24 h<3 months: 4–5 mg/kg once, then check 2- and 8- to 12-h concentrations
      3 mo to 2 y: 9.5 mg/kg every 24 h
      McDade EJ, Wagner JL, Moffett BS, Palazzi DL. Once-daily gentamicin dosing in pediatric patients without cystic fibrosis. Pharmacotherapy. 2010;30:248–253.
      3 mo to 2 y: 9.5 mg/kg once, then check 2- and 8- to 12-h concentrations
       MeropenemNot reportedIncreasedGeneral Correct: 20 mg/kg every 8 h40 mg/kg loading dose, then 200 mg/kg/d continuous infusion
      Case report of an 8-month-old infant.
      or 33.3 mg/kg over 3 h every 4 h
      Meningitis: 40 mg/kg every 8 h
       VancomycinIncreasedDecreased<7 days: 30 mg/kg/d divided every 8–12 h20 mg/kg once, then check 2- and 8- to 12-h
      ≥7–28 days: 40–45 mg/kg/d divided every 6–8 hconcentrations
      >28 days: 45–60 mg/kg/d divided every 6–8 h
      Antifungals
       CaspofunginIncreasedIncreased<3 mo: 25 mg/m2/d>78 mg/m2/d
      Case report of an 11-month-old infant; dose still resulted in subtherapeutic levels.
      >3 mo: 70 mg/m2 on day 1, then 50 mg/m2/d
      Enzyme inducers
      Enzyme-inducing medications include rifampin, phenytoin, carbamazepine, dexamethasone, etc.
      : 70 mg/m2/d
       FluconazoleIncreasedAffected by renal function, not ECMOProphylaxis: ≤28 d: 3 mg/kg/d or 6 mg/kg every 48 hProphylaxis: 12 mg/kg loading dose then 6 mg/kg every 24 h
      Doses for infants 0 to 2 years of age.
      >28 days: 6 mg/kg every 24 hTreatment: 35-mg/kg loading dose, then 12 mg/kg every 24 h
      Doses for infants 0 to 2 years of age.
      Treatment: 25-mg/kg loading dose, then 12 mg/kg every 24 h
       MicafunginIncreasedDecreasedProphylaxis: ≥4 mo: 1–3 mg/kg every 24 hProphylaxis: 3 mg/kg every 24 h
      Doses for infants 0 to 2 years of age.
      Treatment: <4 mo: 7–10 mg/kg every 24 hTreatment: 5 mg/kg q24h
      Doses for infants 0 to 2 years of age.
      ≥4 mo: 3–7 mg/kg every 24 h
      Antivirals
       GanciclovirNot reportedNot reportedProphylaxis: 5 mg/kg every 24 h6 mg/kg every 12 h
      Case report of a neonate with congenital CMV.
      Treatment: 5 mg/kg every 24 h
      Congenital CMV: 6 mg/kg every 12 h
       RibavirinDecreasedUnchangedNot established for patients <3 y of age5 mg/kg every 6 h
      Case report of a neonate with disseminated adenovirus.
      CMV = cytomegalovirus; ECMO = extracorporeal membrane oxygenation.
      * Neonates are children <30 days of age; infants are 1 month to 2 years of age.
      All doses are intravenous.
      Unless otherwise noted, all dosing recommendations for standard of care dosing were obtained from Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      § McDade EJ, Wagner JL, Moffett BS, Palazzi DL. Once-daily gentamicin dosing in pediatric patients without cystic fibrosis. Pharmacotherapy. 2010;30:248–253.
      Case report of an 8-month-old infant.
      Enzyme-inducing medications include rifampin, phenytoin, carbamazepine, dexamethasone, etc.
      # Case report of an 11-month-old infant; dose still resulted in subtherapeutic levels.
      ** Doses for infants 0 to 2 years of age.
      †† Case report of a neonate with congenital CMV.
      ‡‡ Case report of a neonate with disseminated adenovirus.
      Table IIAnti-infective pharmacokinetics and dosing in children
      Children younger than 2 years of age through 18 years of age.
      on ECMO.
      DrugVolume of Distribution Compared With Non-ECMO PatientsClearance Compared With Non-ECMO PatientsStandard Dosing in Critically Ill Patients
      All doses intravenous except oseltamivir (enteral).
      ,
      Unless otherwise noted, all recommendations for standard of care dosing were obtained from Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      Dosing Recommendations for Patients on ECMO
      All doses intravenous except oseltamivir (enteral).
      Antibiotics
       VancomycinIncreasedDecreased60-mg/kg dose divided every 6–8 h20 mg/kg once, then check 2- and 8- to 12-h concentrations
      Antifungals
       Amphotericin B (conventional)UnchangedUnchanged1 mg/kg every 24 hStandard dosing
      Case report of an adult-size 15-year-old patient with pulmonary blastomycosis.
       VoriconazoleNot reportedDecreased10–12 mg/kg every 12 h × 2 doses, then 8–9 mg/kg every 12 h14 mg/kg every 12 h
      Case report of a 5-year-old patient with Aspergillus fumigates.
      Antivirals
       OseltamivirUnchangedUnchanged<15 kg: 30 mg BIDStandard dosing with caution in
      15–23 kg: 45 mg BIDpatients with decreased gastric
      23–40 kg: 60 mg BIDmobility or other gastrointestinal
      >40 kg: 75 mg BIDcomorbidities
       PeramivirNot reportedNot reported180 days–5 y: 12 mg/kg every 24 h5.4 mg/kg every 24 h
      Case report of a 10-year-old renal transplant recipient with H1N1; patient required Continuous Renal Replacement Therapy for renal failure.
      >5 y: 10 mg/kg every 24 h
      ECMO = extracorporeal membrane oxygenation.
      * Children younger than 2 years of age through 18 years of age.
      All doses intravenous except oseltamivir (enteral).
      Unless otherwise noted, all recommendations for standard of care dosing were obtained from Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      § Case report of an adult-size 15-year-old patient with pulmonary blastomycosis.
      Case report of a 5-year-old patient with Aspergillus fumigates.
      Case report of a 10-year-old renal transplant recipient with H1N1; patient required Continuous Renal Replacement Therapy for renal failure.
      Table IIIAnti-infective pharmacokinetics and dosing in adults on ECMO (many of the recommendations are based on a single case study or case series and must be used acknowledging this limitation).
      DrugVolume of Distribution Compared With Non-ECMO PatientsClearance Compared With Non-ECMO PatientsStandard Dosing in Critically Ill Patients
      All doses intravenous except oseltamivir (enteral).
      ,
      Unless otherwise noted, all recommendations for standard of care dosing were obtained from Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      Dosing Recommendations for Patients on ECMO
      All doses intravenous except oseltamivir (enteral).
      Antibiotics
       AzithromycinDecreasedUnchanged500 mg every 24 h or 500 mg × 1, then 250 mg every 24 hStandard dosing
      Case series of 3 patients with acute respiratory distress syndrome.
       EthambutolNot reportedNot reportedWeight 40–55 kg: 800 mg every 24 h50% increase over standard dosing
      Dose required to achieve target serum levels in a case report of a patient with miliary tuberculosis.
      Weight 56–75 kg: 1200 mg every 24 h
      Weight 76–90 kg: 1600 mg every 24 h
       ImipenemNot reportedNot reported500–1000 mg every 6–8 hStandard dosing unless treating resistant organism
      Case series of 2 lung transplant recipients with refractory acute respiratory distress syndrome.
       LevofloxacinNot reportedNot reported500–1000 mg every 24 hStandard dosing
      Dose required to achieve target serum levels in a case report of a patient with miliary tuberculosis.
       LinezolidUnchangedNot reported600 mg IV every 12 hStandard dosing unless MRSA MIC is >1 mg/L
      Case series of 3 patients with Methicillin-resistant Staphylococcus aureus pneumonia
       MeropenemUnchangedUnchangedGeneral: 500 mg every 6 h or 1 g every 8 h1 g every 8 h for susceptible organisms (MIC ≤2)
      Meningitis/cystic fibrosis: 2 g every 8 h2 g every 8 h for resistant organisms (MIC >2–8)
       Piperacillin/tazobactamUnchangedUnchanged3.375 g every 6 h, 4.5 g every 6–8 hStandard dosing may be adequate for susceptible organisms
       PyrazinamideWeight 40–55 kg: 1000 mg every 24 h50% increase over standard dosing
      Dose required to achieve target serum levels in a case report of a patient with miliary tuberculosis.
      Weight 56–75 kg: 1500 mg every 24 h
      Weight 76–90 kg: 2000 mg every 24 h
       RifampinNot reportedNot reportedTuberculosis treatment: 10 mg/kg every 24 h20 mg/kg every 24 h
      Case series of 2 lung transplant recipients with refractory acute respiratory distress syndrome.
       TigecyclineUnchangedUnchanged100 mg once, then 50 mg every 12 hStandard dosing
      case report of a patient with vancomycin-resistant Staphylococcus epidermidis pneumonia.
       VancomycinUnchangedUnchanged15- to 20-mg/kg dose every 8–12 hStandard dosing
      Antifungals
       Liposomal amphotericin BNot reportedNot reported3–5 mg/kg every 24–hStandard dosing
      Case report of a patient with Aspergillus fumigatus pneumonia.
       CaspofunginNot reportedNot reported70 mg on day 1, then 50 mg every 24 hDefinitive dosing recommendations cannot be made
      Enzyme inducers
      Enzyme-inducing medications include rifampin, phenytoin, carbamazepine, dexamethasone, etc.
      : 70 mg every 24 h
       VoriconazoleNot reportedNot reported6 mg/kg every 12 h × 2 doses, then 4 mg/kg every 2 hDefinitive dosing recommendations cannot be made
      Antivirals
       OseltamivirUnchangedUnchanged75 or 150 mg enterally BID for severe illnessStandard dosing unless impaired renal function or enteral absorption
       GanciclovirNot reportedNot reported6 mg/kg every 12 hStandard dosing
      Case series of 2 patients with Candida albicans and Aspergillus.
      ECMO = extracorporeal membrane oxygenation; MRSA = methicillin-resistant Staphylococcus aureus.
      * All doses intravenous except oseltamivir (enteral).
      Unless otherwise noted, all recommendations for standard of care dosing were obtained from Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc: April 2016.
      Case series of 3 patients with acute respiratory distress syndrome.
      § Dose required to achieve target serum levels in a case report of a patient with miliary tuberculosis.
      Case series of 2 lung transplant recipients with refractory acute respiratory distress syndrome.
      Case series of 3 patients with Methicillin-resistant Staphylococcus aureus pneumonia
      # case report of a patient with vancomycin-resistant Staphylococcus epidermidis pneumonia.
      ** Case report of a patient with Aspergillus fumigatus pneumonia.
      †† Enzyme-inducing medications include rifampin, phenytoin, carbamazepine, dexamethasone, etc.
      ‡‡ Case series of 2 patients with Candida albicans and Aspergillus.

      Antibiotics

      Vancomycin

      As mentioned previously, the majority of the PK data on anti-infectives used on ECMO come from neonatal studies, with vancomycin being the most commonly studied drug.
      • Amaker R.D.
      • DiPiro J.T.
      • Bhatia J.
      Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.
      • Buck M.L.
      Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation.
      • Mulla H.
      • Pooboni S.
      Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
      • Hoie E.B.
      • Swigart S.A.
      • Leuschen M.P.
      • et al.
      Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation.
      Understanding of vancomycin pharmacokinetics on ECMO is of particular importance as Staphylococcus spp are some of the most common organisms cultured from ECMO patients.
      • Bizzarro M.J.
      • Conrad S.A.
      • Kaufman D.A.
      • et al.
      Extracorporeal Life Support Organization Task Force on Infections EMO. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults.
      Four PK studies including 49 neonates and infants showed an increased V and decreased CL compared with infants not on ECMO.
      • Amaker R.D.
      • DiPiro J.T.
      • Bhatia J.
      Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.
      • Buck M.L.
      Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation.
      • Mulla H.
      • Pooboni S.
      Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
      • Hoie E.B.
      • Swigart S.A.
      • Leuschen M.P.
      • et al.
      Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation.
      To account for the increased V and decreased CL, the authors recommended increasing the dose and decreasing dosing frequency, respectively. The absolute dose recommendations from these studies, with the exception of Mulla et al,
      • Mulla H.
      • Pooboni S.
      Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
      are not relevant as these studies were performed in the 1990s when dosing recommendations were different from those today. However, based on the PK changes, we recommend an initial 20-mg/kg dose in neonates and infants. Given the variability in circuit configurations, we would also recommend therapeutic drug monitoring (TDM) at 2 and 8 to 12 hours after the end of the infusion. Per Infectious Diseases Society of America guidelines, the goal trough is 15 to 20 µg/mL, and using first-dose kinetics, V and CL can be estimated from these early levels and subsequent doses adjusted accordingly. Using early levels rather than waiting for a true trough level is important to avoid significant time spent below therapeutic targets.
      The PK data for vancomycin in children older than 2 years of age are limited to a single study by Mulla et al.
      • Mulla H.
      • Pooboni S.
      Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
      Compared with critically ill children not on ECMO, children supported with ECMO demonstrated increased V and decreased CL. CL was found to be strongly associated with renal function, so dosing recommendations were made based on serum creatinine values. For children on ECMO, we recommend a 20-mg/kg initial dose followed by TDM at 2 and 8 to 12 hours post-infusion.
      Adult data have largely shown that ECMO does not significantly affect vancomycin V and CL.
      • Donadello K.
      • Roberts J.A.
      • Cristallini S.
      • et al.
      Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study.
      • Park S.J.
      • Yang J.H.
      • Park H.J.
      • et al.
      Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation.
      • Wu C.C.
      • Shen L.J.
      • Hsu L.F.
      • et al.
      Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.
      Both intermittent
      • Mulla H.
      • Pooboni S.
      Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
      • Park S.J.
      • Yang J.H.
      • Park H.J.
      • et al.
      Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation.
      • Wu C.C.
      • Shen L.J.
      • Hsu L.F.
      • et al.
      Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.
      and continuous
      • Donadello K.
      • Roberts J.A.
      • Cristallini S.
      • et al.
      Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study.
      infusions were evaluated, and these studies provided a variety of dosing recommendations. Even though the PK differences between ECMO and non-ECMO patients were not statistically significant, there were clinically and, in some cases, statistically significant differences in dosing regimens between the 2 cohorts.
      • Park S.J.
      • Yang J.H.
      • Park H.J.
      • et al.
      Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation.
      Patients on ECMO required a higher dose to reach adequate trough concentrations after the first dose. Differences in ECMO’s impact on vancomycin pharmacokinetics in adults versus children are not clear, but may be due to age-related effects on V discussed earlier. Variability in CL likely reflects the small sample sizes and critically ill nature of the population. Based on the results from all of the adult studies, standard vancomycin dosing is likely adequate in adults on ECMO, but we would start with a loading dose of 30 mg/kg with TDM at 2 and 8 to 12 hours after the infusion to guide additional dosing. The necessity of a loading dose is highlighted by 1 particular study in which vancomycin levels in 95% of patients on ECMO remained subtherapeutic for >3 days with conventional dosing.
      • Park S.J.
      • Yang J.H.
      • Park H.J.
      • et al.
      Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation.

      Gentamicin

      Gentamicin pharmacokinetics are also well described in infants on ECMO because the drug is commonly prescribed in this population, and TDM is routine. However, results are variable. When compared with infants not on ECMO, 1 study reported that infants on ECMO had increased V and decreased CL,
      • Cohen P.
      • Collart L.
      • Prober C.G.
      • et al.
      Gentamicin pharmacokinetics in neonates undergoing extracorporal membrane oxygenation.
      2 others reported similar V with decreased CL,
      • Bhatt-Mehta V
      • Johnson CE
      • Schumacher RE2
      Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.
      • Southgate W.M.
      • DiPiro J.T.
      • Robertson A.F.
      Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation.
      and a fourth reported no difference in V or CL.
      • Munzenberger P.J.
      • Massoud N.
      Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation.
      Decreased CL is not surprising given that gentamicin is cleared primarily by the kidneys, and ECMO is associated with decreased renal function. Although V is higher in infants than children,
      • Kelman A.W.
      • Thomson A.H.
      • Whiting B.
      • et al.
      Estimation of gentamicin clearance and volume of distribution in neonates and young children.
      gentamicin is still a low V drug, and we would expect that ECMO-related hemodilution would result in a larger V in infants on ECMO.
      Although the data do not present a solid consensus, the studies tended to recommend standard dosing with a longer dosing interval to account for decreased CL seen in infants on ECMO. Similar to vancomycin, the studies of gentamicin were performed in the late 1980s and early 1990s when standard dosing for critically ill neonates was 2.5 mg/kg every 12 hours. Current dosing recommendations are 4 to 5 mg/kg every 24 hours for infants younger than 3 months of age and 9.5 mg/kg every 24 hours for infants from 3 months to 2 years of age.
      • McDade E.J.
      • Wagner J.L.
      • Moffett B.S.
      • et al.
      Once-daily gentamicin dosing in pediatric patients without cystic fibrosis.
      We recommend using these updated doses as initial doses in infants on ECMO, followed by TDM at 2 and 8 to 12 hours after the infusion to guide further dosing. A decreased initial dose may be considered for neonates who weigh <3.5 kg. There are no studies describing gentamicin pharmacokinetics for children or adults on ECMO at this time.

      Cefotaxime

      The PK of cefotaxime and its active metabolite, desacetylcefotaxime, were recently evaluated in a group of 37 neonates and infants on ECMO.
      • Ahsman M.J.
      • Wildschut E.D.
      • Tibboel D.
      • et al.
      Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation.
      Increased V was noted, but there was no significant alteration in CL compared with neonates not on ECMO. Despite the increased V, standard age-based dosing of 50 mg/kg every 12 hours for patients 7 days of age or younger, 50 mg/kg every 8 hours daily for patients 7 to 28 days of age, and 37.5 mg/kg every 6 hours for patients older than 28 days of age
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs.
      were sufficient to maintain therapeutic drug concentrations (time above the minimum inhibitory concentration [t>MIC] of at least 50% of the dosing interval, assuming a MIC of 8 mg/L) in 36 of 37 patients. This led the authors to posit that non-ECMO patients may be receiving higher than necessary doses of the drug. Given these results, we agree with the authors’ recommendations in neonates and infants. There are no studies describing cefotaxime pharmacokinetics in children or adults on ECMO.

      Meropenem

      Both intermittent dosing and continuous-infusion meropenem pharmacokinetics on ECMO have been studied.
      • Cies J.J.
      • Moore 2nd, W.S.
      • Dickerman M.J.
      • et al.
      Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support.
      • Donadello K.
      • Antonucci E.
      • Cristallini S.
      • et al.
      beta-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study.
      • Shekar K.
      • Fraser J.F.
      • Taccone F.S.
      • et al.
      The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
      The pediatric data are limited to a case report describing an 8-month-old infant on ECMO receiving continuous-infusion meropenem for a Pseudomonas pneumonia.
      • Cies J.J.
      • Moore 2nd, W.S.
      • Dickerman M.J.
      • et al.
      Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support.
      This infant’s CL (4.5 mL/min/kg) was more than double that of 2 cohorts of critically ill term and preterm infants younger than 91 days of age and 2 months of age, respectively, who were not on ECMO.
      • Bradley J.S.
      • Sauberan J.B.
      • Ambrose P.G.
      • et al.
      Meropenem pharmacokinetics, pharmacodynamics, and Monte Carlo simulation in the neonate.
      • Smith P.B.
      • Cohen-Wolkowiez M.
      • Castro L.M.
      • et al.
      Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections.
      Other PK data that include older infants is from cohorts with patients up to 13 years of age, making a direct comparison difficult. Two studies with median ages of ~3 years both showed greater CL (7.13 and 6.9 mL/min/kg) than the 8-month-old infant on ECMO.
      • Du X.
      • Li C.
      • Kuti J.L.
      • et al.
      Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients.
      • Ohata Y.
      • Tomita Y.
      • Nakayama M.
      • et al.
      Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations.
      A 40-mg/kg bolus followed by a 200-mg/kg/d continuous infusion achieved the target serum and lung drug concentrations (t>MIC for 40% of the dosing interval) given the MIC of the patient’s pathogen (0.25 µg/mL in blood and 0.5 µg/mL in bronchoalveolar lavage). It should be noted that the MICs observed for Pseudomonas in this patient are much lower than the MIC for susceptible Pseudomonas of 2 mg/L as determined by the European Committee of Antimicrobial Susceptibility Testing. Consequently, it is difficult to extrapolate this dosing regimen to other patients. As meropenem is stable at room temperature for <4 hours, the logistics of a continuous infusion would be challenging and require frequent introduction of new batches of drug. A simpler solution may be an extended infusion regimen of 33.3 mg/kg given over 3 hours every 4 hours.
      Adult data showed no alteration in meropenem pharmacokinetics for patients on ECMO.
      • Donadello K.
      • Antonucci E.
      • Cristallini S.
      • et al.
      beta-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study.
      • Shekar K.
      • Fraser J.F.
      • Taccone F.S.
      • et al.
      The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
      One study in 6 adults on ECMO with normal renal function showed that standard dosing of 1000 mg every 8 hours
      Lexicomp Online, Lexi-Drugs.
      achieved t>MIC for 100% of the dosing interval, assuming a MIC of 2 mg/L.
      • Shekar K.
      • Fraser J.F.
      • Taccone F.S.
      • et al.
      The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
      However, for more resistant organisms (eg, Pseudomonas aeruginosa, MIC of 8 mg/L), dosing simulations suggested that 2000 mg every 8 hours are necessary to maintain concentrations >8 mg/L for 100% of the dosing interval. A retrospective study of 26 adults on ECMO and 41 matched controls evaluated a different target (t>MIC for 40% of the dosing interval assuming a MIC of 8 mg/L) and found that with standard dosing, ~10% of patients were subtherapeutic. We agree with the more conservative approach by Shekar et al
      • Shekar K.
      • Fraser J.F.
      • Taccone F.S.
      • et al.
      The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
      and recommend 1000 mg every 8 hours for susceptible organisms and 2000 mg every 8 hours for organisms with a MIC of 8 mg/L. Meropenem is renally cleared, and dosing needs to be adjusted for patients with either decreased or augmented renal clearance.

      Imipenem

      Two patients on ECMO after lung transplantation were treated with imipenem, 1 g every 6 hours, for acute respiratory distress syndrome (ARDS).
      • Welsch C.
      • Augustin P.
      • Allyn J.
      • et al.
      Alveolar and serum concentrations of imipenem in two lung transplant recipients supported with extracorporeal membrane oxygenation.
      Patient 1 had Enterobacter cloacae with a MIC of 0.125 mg/L, and patient 2 had Klebsiella pneumoniae with a MIC of 0.25 mg/L. Although trough concentrations in the 2 patients were quite discordant, both resulted in a t>MIC of 100% for each patient’s isolated organism. Data have shown that if treating a more resistant organism such as P aeruginosa (MIC >2 mg/L), better outcomes are achieved in critically ill patients by maintaining a drug concentration of 4 times the MIC for 100% of the treatment period.
      • McKinnon P.S.
      • Paladino J.A.
      • Schentag J.J.
      Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.
      If this is the case, then the authors state that a higher dose should be considered.

      Piperacillin/Tazobactam

      In the previously mentioned study by Donadello et al,
      • Donadello K.
      • Antonucci E.
      • Cristallini S.
      • et al.
      beta-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study.
      piperacillin/tazobactam pharmacokinetics were also studied. Although PK parameters were similar between ECMO and non-ECMO patients, only 40% of adults achieved the target exposure for treatment of P aeruginosa when receiving a dose of 4 g every 6 hours. The target pharmacodynamic parameters were a concentration 4 to 8 times the clinical MIC breakpoint of 2 mg/L with 50% of time spent above the MIC. Based on these results, the authors concluded that meropenem is a better drug for adults on ECMO.

      Linezolid

      In the first report of linezolid pharmacokinetics in patients on ECMO, 3 adults received a standard dosing regimen of 600 mg every 12 hours.
      • De Rosa F.G.
      • Corcione S.
      • Baietto L.
      • et al.
      Pharmacokinetics of linezolid during extracorporeal membrane oxygenation.
      Despite interpatient variability, drug exposure was adequate (ie, AUC/MIC ratio ≥80) to treat methicillin-resistant Staphylococcus aureus with a MIC <1 mg/L. In more resistant organisms with a MIC of 2 mg/L, satisfactory PK parameters were achieved in 2 of 3 of the patients, and with a MIC of 4 mg/L, they were adequate in only 1 patient. This suggests that increased dosing should be considered for isolates with MICs >1 mg/L.

      Azithromycin

      Three adults with ARDS requiring ECMO were treated with standard doses of azithromycin (500 mg/d
      Lexicomp Online, Lexi-Drugs.
      ), and ECMO had no appreciable effect on plasma concentrations.
      • Turner R.B.
      • Rouse S.
      • Elbarbry F.
      • et al.
      Azithromycin Pharmacokinetics in Adults With Acute Respiratory Distress Syndrome Undergoing Treatment With Extracorporeal-Membrane Oxygenation.
      Maximum and minimum concentrations and AUC were similar compared with hospitalized non-ECMO patients. Compared with healthy volunteers, CL was similar, but V was lower. A decreased V on ECMO is unusual, and although the authors acknowledged this, they stated that the small sample size made it difficult to determine the cause. They did note that all patients were obese and receiving vasopressor therapy during sample collection, both of which could affect pharmacokinetics.

      Tigecycline

      A case report of an adult on ECMO treated with tigecycline suggested that ECMO has no effect on the drug’s pharmacokinetics.
      • Veinstein A.
      • Debouverie O.
      • Gregoire N.
      • et al.
      Lack of effect of extracorporeal membrane oxygenation on tigecycline pharmacokinetics.
      Plasma concentrations were not significantly different from those measured in critically ill patients not on ECMO.

      Rifampin, Pyrazinamide, Pthambutol

      Antituberculosis agents have been described in a case report of an adult with tuberculosis on ECMO.
      • Kim H.S.
      • Lee E.S.
      • Cho Y.J.
      Insufficient serum levels of antituberculosis agents during venovenous extracorporeal membrane oxygenation therapy for acute respiratory distress syndrome in a patient with miliary tuberculosis.
      TDM was used, and to achieve therapeutic concentrations, this patient required daily rifampicin 1200 mg, pyrazinamide 1500 mg, ethambutol 1200 mg, streptomycin 750 mg, and levofloxacin 750 mg. This patient required nearly 23 mg/kg/d of rifampin compared with the standard of 10 mg/kg/d
      Lexicomp Online, Lexi-Drugs.
      and 50% more pyrazinamide and ethambutol than recommended for her weight (52 kg). Levofloxacin concentrations were therapeutic using standard dosing.
      Another case report described the pharmacokinetics of rifampin and ethambutol in a patient on ECMO and renal replacement therapy (RRT).
      • Strunk A.K.
      • Ciesek S.
      • Schmidt J.J.
      • et al.
      Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.
      Because both of these drugs are cleared by RRT, it is difficult to assess the impact of ECMO.
      Given the higher doses required in the first patient, we recommend starting with a higher dose and using TDM to adjust dosing.

      Antifungals

      Although less studied than antibiotics, there are emerging PK data on antifungal drugs used on ECMO. Candida species represent the most commonly cultured organisms in infants, children, and adults on ECMO and are the second most common in neonates.

      Extracorporeal Life Support Organization Registry Report: International Summary. January 2016. https://www.elso.org/. Accessed February 29, 2016

      Candida infections cause substantial morbidity and mortality
      • Gardner A.H.
      • Prodhan P.
      • Stovall S.H.
      • et al.
      Fungal infections and antifungal prophylaxis in pediatric cardiac extracorporeal life support.
      and are difficult to eradicate due to the organism’s ability to adhere to indwelling catheters. For this reason, routine management for candidiasis consists not only of antifungal agents but also removal of catheters.
      • Eppes S.C.
      • Troutman J.L.
      • Gutman L.T.
      Outcome of treatment of candidemia in children whose central catheters were removed or retained.
      Catheter removal for patients on ECMO is often impossible because the ECMO cannulas connect the patient to the ECMO circuit. Therefore, therapy on ECMO relies on either prevention of invasive candidiasis or optimal therapeutic dosing in patients with infection.

      Fluconazole

      A pharmacokinetics trial of fluconazole in 10 infants on ECMO performed by our group demonstrated a significantly higher V but a similar CL compared with critically ill infants not on ECMO.
      • Watt K.M.
      • Benjamin Jr., D.K.
      • Cheifetz I.M.
      • et al.
      Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.
      This was followed by a population PK analysis that included 21 infants and children on ECMO and 19 critically ill infants not on ECMO.
      • Watt K.M.
      • Gonzalez D.
      • Benjamin Jr., D.K.
      • et al.
      Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.
      The final population PK model showed that children on ECMO had ~40% higher V than children not on ECMO but similar CL. Based on the final population pharmacokinetics model, simulations were done to evaluate multiple dosing regimens for children on ECMO. In infants on ECMO who received 12 mg/kg d, none reached the therapeutic target of the AUC for a 24-hour dosing interval (AUC24 >400 mg∙h/L) in the first 24 hours, and it took 10 days for 90% of these simulated infants to reach this target. A 25-mg/kg loading dose, which is adequate to achieve therapeutic targets in infants not on ECMO, followed by 12 mg/kg/d was similarly inadequate. However, with a 35-mg/kg load followed by 12 mg/kg/d, fluconazole exposure was therapeutic in 88% of children in the first 24 hours. We recommend this regimen with maintenance dosing adjusted according to the product label for renal dysfunction.
      For prophylaxis, children receiving the standard dosing of 6 mg/kg/d did not achieve therapeutic exposure (AUC0–24 >200 mg∙h/L) until day 7 of therapy. With a loading dose of 12 mg/kg followed by daily dosing of 6 mg/kg, 69% of children reached the therapeutic target by day 2 and 90% by day 5. We recommend a prophylactic dosing regimen of a 12-mg/kg loading dose followed by 6 mg/kg/d.
      There were not enough children or adults in the study to adequately describe the pharmacokinetics and determine dosing in older populations. However, given the safety of fluconazole and devastating consequences of a fungal infection on ECMO, a 35-mg/kg load with standard maintenance therapy could also be considered for younger children as well. Providers should adhere to the manufacturer’s recommendations for dose adjustment in patients with renal insufficiency.

      Micafungin

      Our group has also studied micafungin in infants on ECMO.
      • Autmizguine J.
      • Hornik C.P.
      • Benjamin Jr., D.K.
      • et al.
      Pharmacokinetics and Safety of Micafungin in Infants Supported with Extracorporeal Membrane Oxygenation.
      Micafungin’s activity against a broad spectrum of Candida species as well as its ability to treat biofilms makes it an appealing antifungal choice in this population. However, high protein binding (>99%) raised the concern that micafungin might be extracted by the ECMO circuit.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
      Twelve infants received either prophylactic (4 mg/kg/d) or treatment doses (8 mg/kg/d) of micafungin depending on whether they had known fungal disease. Increased V was observed in infants on ECMO compared with historical controls not on ECMO. CL in infants on ECMO was on the upper end of the range reported in historical controls not on ECMO. In order to match exposures observed in adults not on ECMO, we recommend dosing of 2.5 and 5 mg/kg/d for prophylaxis and treatment of invasive candidiasis in infants, respectively. Median (range) exposures (AUC0–24) were 74 mg∙h/L (53, 106) and 213 mg∙h/L for 4 mg/kg and 8 mg/kg, respectively. However, even higher doses may be appropriate for 2 reasons: (1) the target exposure used in this study was derived from a Phase III efficacy study in which >85% of adults had their central catheter removed during candidemia treatment, a procedure that is not possible on ECMO,
      • Kuse E.R.
      • Chetchotisakd P.
      • da Cunha C.A.
      • et al.
      Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.
      and (2) micafungin is well tolerated up to 15 mg/kg in neonates (AUC0–24, 437.5 µg∙h/mL).
      • Smith P.B.
      • Walsh T.J.
      • Hope W.
      • et al.
      Pharmacokinetics of an elevated dosage of micafungin in premature neonates.
      It should be noted that these recommendations exclude treatment of premature neonates at risk of Candida meningoencephalitis as the higher doses (eg, 10 mg/kg) usually recommended for this condition were not studied. Micafungin has not been studied in children or adults on ECMO.

      Caspofungin

      The pharmacokinetics of caspofungin on ECMO has been evaluated in three case reports, involving one infant and two adults, with varying results.
      • Koch B.C.
      • Wildschut E.D.
      • Goede A.L.
      • et al.
      Insufficient serum caspofungin levels in a paediatric patient on ECMO.
      • Ruiz S.
      • Papy E.
      • Da Silva D.
      • et al.
      Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
      • Spriet I.
      • Annaert P.
      • Meersseman P.
      • et al.
      Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.
      The pharmacokinetics in an 11-month-old infant demonstrated a lower AUC and increased CL compared with previously described caspofungin pharmacokinetics in infants not on ECMO.
      • Koch B.C.
      • Wildschut E.D.
      • Goede A.L.
      • et al.
      Insufficient serum caspofungin levels in a paediatric patient on ECMO.
      This patient received substantially higher doses (78 mg/m2/d) compared with standard dosing of 50 to 70 mg/m2/d.
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs.
      Even with the higher dosing, the AUC was subtherapeutic at 69 mg∙h/L, and the patient died before further dose adjustments were made. Caspofungin has low lipophilicity but is highly protein bound, so sequestration by the circuit is a possible explanation for these findings.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
      Additionally, increased V due to hemodilution or disease state may have decreased exposure. No specific dosing recommendations were made.
      In an adult on ECMO who received both caspofungin and voriconazole, normal caspofungin concentrations were achieved with standard dosing of 70 mg/d.
      Lexicomp Online, Lexi-Drugs.
      • Spriet I.
      • Annaert P.
      • Meersseman P.
      • et al.
      Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.
      However, in a second adult treated with the same antifungal combination, standard dosing of caspofungin resulted in undetectable concentrations.
      • Ruiz S.
      • Papy E.
      • Da Silva D.
      • et al.
      Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
      Given the incongruence of these case reports and the overall very small sample size, it is difficult to make specific dosing recommendations for this drug.

      Voriconazole

      A child treated with voriconazole required a dose of 14 mg/kg every 12 hours to achieve target plasma concentrations >1 mg/L.
      • Bruggemann R.J.
      • Antonius T.
      • Heijst A.
      • et al.
      Therapeutic drug monitoring of voriconazole in a child with invasive aspergillosis requiring extracorporeal membrane oxygenation.
      This is compared with the recommended standard dosing of a 10 to 12 mg/kg every 12 hours for 2 doses followed by 8 to 9 mg/kg every 12 hours.
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs.
      The authors thought that it was unclear whether ECMO contributed to the patient’s higher dosing requirement but hypothesized that an increased V may have played a role. They endorse a dose of at least 10 mg/kg BID in children with the use of TDM in severely ill patients.
      Varying PK effects have been seen in 2 adults on ECMO treated with voriconazole.
      • Ruiz S.
      • Papy E.
      • Da Silva D.
      • et al.
      Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
      • Spriet I.
      • Annaert P.
      • Meersseman P.
      • et al.
      Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.
      Spriet et al
      • Spriet I.
      • Annaert P.
      • Meersseman P.
      • et al.
      Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.
      administered higher than standard doses (400 mg vs 280 mg BID
      Lexicomp Online, Lexi-Drugs.
      ) of voriconazole to account for possible circuit extraction due to the drug’s lipophilicity. Concentrations were initially similar to those before initiation of ECMO in the same patient, but then began to increase on the same dose, eventually reaching toxic concentrations. The authors thought that this was due to saturation of binding sites in the ECMO circuit over time. An alternative explanation is that higher exposure was due to decreased CL combined with voriconazole’s nonlinear kinetics.
      In the aforementioned case report of caspofungin and voriconazole by Ruiz et al,
      • Ruiz S.
      • Papy E.
      • Da Silva D.
      • et al.
      Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
      the adult patient also received standard doses of voriconazole. As with caspofungin, serum concentrations were not achieved, leading the authors to recommend against using these 2 agents in patients on ECMO. Voriconazole, however, has the advantage of readily available TDM. If voriconazole is needed, close TDM is recommended.

      Amphotericin B Deoxycholate and Liposomal Amphotericin B

      Amphotericin B deoxycholate was used treat a 15-year-old male patient with ARDS secondary to pulmonary blastomycosis.
      • Hertzog JH B.E.
      • Sale M.
      • Hauser G.J.
      • et al.
      Amphotericin B Pharmacokinetics During Extracorporeal Membrane Oxygenation: A Case Report.
      He received standard doses of amphotericin B deoxycholate of 1 mg/kg every 24 hours,
      Lexicomp Online, Lexi-Drugs.
      and drug concentrations were maintained within a therapeutic range. The authors found no increase in V in this adult-sized adolescent, but did not comment on CL. Additionally, there were multiple exchanges of the ECMO membrane oxygenator as well as an entire circuit change, without any apparent effect on amphotericin concentrations.
      In the previously mentioned case report by Ruiz et al,
      • Ruiz S.
      • Papy E.
      • Da Silva D.
      • et al.
      Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
      liposomal amphotericin B at standard doses of 3 mg/kg every 24 hours
      Lexicomp Online, Lexi-Drugs.
      was used to treat an adult patient. This drug was initiated after they were unable to reach therapeutic concentrations of caspofungin and voriconazole. Although they did not report PK parameters, they did report that plasma concentrations of liposomal amphotericin B at this dose were therapeutic. Based on these limited data, we recommend standard dosing of these drugs for adult-sized adolescents and adults on ECMO.

      Antivirals

      Oseltamivir

      Although antiviral drugs have been the least studied class of anti-infective drugs on ECMO, their importance became clear during the H1N1 influenza pandemic of 2009 and 2010 when ECMO was required to support the sickest patients. Oseltamivir is unique among the drugs discussed thus far in that it exists only as an enteral formulation.
      In 3 children on ECMO (6–15 years of age), the standard weight-based dose was doubled in an effort to account for the potential PK alterations seen with other drugs on ECMO.
      • Wildschut E.D.
      • de Hoog M.
      • Ahsman M.J.
      • et al.
      Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support.
      However, in 2 of the 3 patients, nearly 2-fold higher plasma concentrations were achieved, suggesting that this preemptive increase was unnecessary. The third patient had significant gastrointestinal comorbidities, and therapeutic concentrations were not achieved. This led the authors to posit that ECMO does not affect oseltamivir pharmacokinetics but that dosing adjustment should be considered in patients with altered gastric motility or other issues affecting enteral absorption.
      Adult data are similar in demonstrating a lack of effect of ECMO itself on oseltamivir’s pharmacokinestics.
      • Eyler R.F.
      • Heung M.
      • Pleva M.
      • et al.
      Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation.
      • Lemaitre F.
      • Luyt C.E.
      • Roullet-Renoleau F.
      • et al.
      Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza.
      • Mulla H.
      • Peek G.J.
      • Harvey C.
      • et al.
      Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support.
      Fourteen patients received standard oseltamivir dosing of 75 mg BID.
      Lexicomp Online, Lexi-Drugs.
      • Mulla H.
      • Peek G.J.
      • Harvey C.
      • et al.
      Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support.
      The mean systemic exposures at this dose were well above the MIC for H1N1 and comparable to those seen in non-ECMO patients and healthy volunteers. However, there was significant variability of PK parameters between patients in this study, which the authors attributed to differences in enteral absorption and renal function.
      Data from 7 patients on ECMO, some of whom required RRT, also showed that ECMO does not have a significant effect on oseltamivir, but that renal function does affect pharmacokinestics.
      • Lemaitre F.
      • Luyt C.E.
      • Roullet-Renoleau F.
      • et al.
      Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza.
      Patients on ECMO with preserved renal function had concentrations similar to those in healthy and noncritically ill controls. Those patients on ECMO and RRT, however, had a significant accumulation of the drug, suggesting that in this cohort, oseltamivir was not cleared by dialysis.
      Overall, the adult data on this enteral medication support the use of standard dosing regimens for patients on ECMO with preserved renal function and normal gastric motility.

      Peramivir

      Peramivir has been used to treat oseltamivir-resistant H1N1 influenza. A case report of a 10-year-old immunosuppressed kidney transplant recipient on ECMO and RRT describes use of the drug through an Emergency Investigational New Drug Application.
      • Shetty A.K.
      • Ross G.A.
      • Pranikoff T.
      • et al.
      Oseltamivir-resistant 2009 H1N1 influenza pneumonia during therapy in a renal transplant recipient.
      The patient was initially given 2.2 mg/kg every 24 hours but required a dose increase to 5.4 mg/kg every 24 hours to achieve target trough concentrations >1500 ng/mL. Standard dosing for a child of this age with normal renal function is 10 mg/kg every 24 hours.
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs.
      There are dosing recommendations for children with renal impairment but not those on RRT. Definitive dosing recommendations cannot be made, but, based on this case, initial dosing should be adjusted for renal function rather than ECMO itself.

      Ribavirin

      Ribavirin was used to treat a neonate on ECMO with disseminated adenovirus.
      • Aebi C.
      • Headrick C.L.
      • McCracken G.H.
      • et al.
      Intravenous ribavirin therapy in a neonate with disseminated adenovirus infection undergoing extracorporeal membrane oxygenation: pharmacokinetics and clearance by hemofiltration.
      The patient received 20 mg/kg/d, and plasma concentrations were comparable to those previously reported after single 6- to 10-mg/kg doses in children. This patient was also undergoing hemofiltration, and the percentage eliminated via hemofiltration was similar to those with normal renal function. Although this is only 1 patient, a dose of 20 mg/kg/d may be considered in neonates on ECMO with normal renal function or those requiring dialysis.

      Ganciclovir

      There is a single case report of a neonate with congenital cytomegalovirus (CMV) pneumonia on ECMO, treated with ganciclovir.
      • Hocker J.R.
      • Cook L.N.
      • Adams G.
      • et al.
      Ganciclovir therapy of congenital cytomegalovirus pneumonia.
      This infant received 5 mg/kg every 12 hours, which is less than the currently recommended dose of 6 mg/kg every 12 hours but higher than the standard dose at the time (4 mg/kg every 12 hours). With the 5-mg/kg dose, peak plasma concentrations were considered therapeutic as they were consistently above the MIC of most clinical isolates of human CMV (2.75 µg/mL) at the time that this case report was published. Today’s higher standard dosing reflects improved viral response to the higher dose,
      • Whitley R.J.
      • Cloud G.
      • Gruber W.
      • et al.
      Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
      so we would recommend using at least 6 mg/kg every 12 hours in this patient population for treatment of CMV. Given the known toxicity of the drug, careful laboratory monitoring is recommended.

      Discussion

      This review evaluated the currently available literature on the PK of anti-infective drugs on ECMO and found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infective drugs. The dosing recommendations about which we have the most confidence are those generated using dedicated PK trials (eg, vancomycin, fluconazole). However, even with these trials, there are important limitations. First, the effect of ECMO on exposure is drug specific, necessitating a trial for each drug of interest.
      • Shekar K.
      • Roberts J.A.
      • McDonald C.I.
      • et al.
      Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
      Second, the impact of ECMO can vary by the age of the patient.
      • Watt K.M.
      • Gonzalez D.
      • Benjamin Jr., D.K.
      • et al.
      Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.
      Most ECMO PK trials were done in infants, and it is unclear whether the results can be extrapolated to older children and adults. Third, ECMO technology changes over time and with it, the impact on drug disposition.
      • Wildschut E.D.
      • Ahsman M.J.
      • Allegaert K.
      • et al.
      Determinants of drug absorption in different ECMO circuits.
      Given the differences reported in drug extraction between older components (eg, silicone membrane oxygenators) and newer technology (eg, polymethylepentane hollow-fiber oxygenators), it is unknown whether dosing recommendations derived from trials using the older technology can be extrapolated to patients supported with modern ECMO circuits.
      For these reasons, it is difficult to draw broad conclusions about dosing on ECMO. Most of the infant trials on ECMO showed increased V and decreased CL, whereas many of the adult studies showed no difference in PK parameters between ECMO and non-ECMO patients. Although it is reasonable to suggest that infants are more susceptible to hemodilution and increased V, there are many other factors that could contribute to the differences observed between infants and adults. In addition to the different ratio of exogenous to native blood volume described earlier, infants have a higher proportion of body water and lower protein binding, both of which can affect V.
      • Ehrnebo M.
      • Agurell S.
      • Jalling B.
      • et al.
      Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults.
      • Friis-Hansen B.
      Water distribution in the foetus and newborn infant.
      • McNamara P.J.
      • Alcorn J.
      Protein binding predictions in infants.
      Furthermore, many of the infant trials were performed in the 1990s with circuit components that are no longer used today.
      In order to better determine optimal dosing on ECMO, a systematic approach is needed. The ECMO PK Project is coordinated by the Critical Care Research Group at The Prince Charles Hospital in Brisbane, Australia.
      • Shekar K.
      • Roberts J.A.
      • Smith M.T.
      • et al.
      The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation.
      This approach combines (1) ex vivo studies in isolated ECMO circuits to determine the drug interaction with the circuit, (2) ECMO animal experiments to elucidate mechanisms of PK changes, and (3) human PK trials in adults to evaluate mechanisms and develop population PK models to provide dosing guidelines in patients on ECMO. This approach should provide robust dosing recommendations for commonly used drugs and elucidate the mechanisms responsible for PK changes on ECMO. This approach has some limitations. As ECMO technology evolves, it is impossible to know whether recommendations determined using current equipment will be able to be extrapolated as new equipment is introduced. Although ECMO ex vivo experiments quantify drug extraction by the ECMO circuit, direct translation of these results into dosing recommendations is challenging. Additionally, care must be taken when extrapolating population PK model results to populations that were not used in the model-building process. Because of the age-related differences in PK, dedicated trials will likely need to be performed in all age groups.
      Our group is using a complementary approach that translates ECMO ex vivo results to bedside dosing recommendations using physiologically based PK (PBPK) modeling. PBPK offers an alternative modeling platform with the flexibility, efficiency, and the ability to account for the complex physiology of critically ill patients. PBPK models expand on traditional compartmental models by incorporating the key physiologic, biochemical, and physicochemical determinants of drug disposition. The models are parameterized using a physiologic structure (eg, liver compartment, kidney compartment) with mathematical equations that describe drug disposition as the drugs transit the compartments. These models can account for the effect that physiologic changes have on organ function (eg, decreased renal perfusion) and provide a mechanistic understanding of drug disposition. By including information about organ ontogeny, the PBPK models can predict dosing in populations across the pediatric and adult age spectrum, including populations that were not studied in the trials. In patients on ECMO, an ECMO compartment can be added to the PBPK model to account for the effect of ECMO on drug disposition. Drug interaction (eg, adsorption) within the ECMO compartment is informed by ex vivo ECMO experiments. Although the model predictions will still need to be validated with PK data from children on ECMO, the number of children required will be lower and the trial design more efficient. Further, if ECMO technology changes, the ex vivo experiment can be repeated with the new circuit to understand whether the drug interaction is different. Based on the interaction with the new circuit, parameterization of the ECMO compartment can be updated in the PBPK model, and new predictions of drug disposition can be generated.

      Conclusions

      This review describes PK data and dosing recommendations for anti-infective drugs in patients on ECMO. We found that although the neonatal data are the most robust, they are the oldest, which raises concerns for its validity today as ECMO technology has continued to evolve over time. In addition, optimal therapeutic targets, and therefore standard dosing recommendations, have been updated. The most well-defined PK effect of ECMO seems to be an increase in V in neonates. This effect is lost in adults, as evidenced by very few recommendations for dose adjustments in this population. Data for pediatric patients who fit neither the neonatal or adult categories are lacking and require further investigation. There is also a need for expansion of the drugs studied and an improvement in methodology to assist in making more definitive dosing recommendations. There are multiple projects currently in process to fill this void.

      Conflicts of Interest

      The authors have no conflict of interest regarding the content of this article.

      Acknowledgments

      Drs. Sherwin and Watt are responsible for the writing and reviewing of this article. Dr. Heath provided guidance on drug dosing and administration and reviewed the article.
      Dr. Watt, MD receives support from Dr. Watt receives support from NICHD (1K23HD075891) and the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349) for his work in pediatric clinical pharmacology.

      References

        • Bhatt-Mehta V
        • Johnson CE
        • Schumacher RE2
        Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.
        Pharmacotherapy. 1992; 12: 28-32
        • Dagan O.
        • Klein J.
        • Gruenwald C.
        • et al.
        Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs.
        Ther Drug Monit. 1993; 15: 263-266
        • Harthan A.A.
        • Buckley K.W.
        • Heger M.L.
        • et al.
        Medication adsorption into contemporary extracorporeal membrane oxygenator circuits.
        J Pediatr Pharmacol Ther. 2014; 19: 288-295
        • Koren G.
        • Crean P.
        • Klein J.
        • et al.
        Sequestration of fentanyl by the cardiopulmonary bypass (CPBP).
        Eur J Clin Pharmacol. 1984; 27: 51-56
        • Lemaitre F.
        • Hasni N.
        • Leprince P.
        • et al.
        Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood.
        Crit Care. 2015; 19: 40
        • Mehta N.M.
        • Halwick D.R.
        • Dodson B.L.
        • et al.
        Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.
        Intensive Care Med. 2007; 33: 1018-1024
        • Mulla H.
        • Lawson G.
        • von Anrep C.
        • et al.
        In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation.
        Perfusion. 2000; 15: 21-26
        • Shekar K.
        • Roberts J.A.
        • McDonald C.I.
        • et al.
        Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation.
        Crit Care. 2012; 16: R194
        • Shekar K.
        • Roberts J.A.
        • McDonald C.I.
        • et al.
        Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.
        Crit Care. 2015; 19: 164
        • Wildschut E.D.
        • Ahsman M.J.
        • Allegaert K.
        • et al.
        Determinants of drug absorption in different ECMO circuits.
        Intensive Care Med. 2010; 36: 2109-2116
        • Preston T.J.
        • Hodge A.B.
        • Riley J.B.
        • et al.
        In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit.
        J Extra Corpor Technol. 2007; 39: 234-237
        • Preston T.J.
        • Ratliff T.M.
        • Gomez D.
        • et al.
        Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit.
        J Extra Corpor Technol. 2010; 42: 199-202
        • Palmgren J.J.
        • Monkkonen J.
        • Korjamo T.
        • et al.
        Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.
        Eur J Pharm Biopharm. 2006; 64: 369-378
        • Unger J.K.
        • Kuehlein G.
        • Schroers A.
        • et al.
        Adsorption of xenobiotics to plastic tubing incorporated into dynamic in vitro systems used in pharmacological research--limits and progress.
        Biomaterials. 2001; 22: 2031-2037
        • De Somer F.
        • Francois K.
        • van Oeveren W.
        • et al.
        Phosphorylcholine coating of extracorporeal circuits provides natural protection against blood activation by the material surface.
        Eur J Cardiothorac Surg. 2000; 18: 602-606
        • Palatianos G.M.
        • Foroulis C.N.
        • Vassili M.I.
        • et al.
        A prospective, double-blind study on the efficacy of the bioline surface-heparinized extracorporeal perfusion circuit.
        Ann Thorac Surg. 2003; 76: 129-135
        • Tayama E.
        • Hayashida N.
        • Akasu K.
        • et al.
        Biocompatibility of heparin-coated extracorporeal bypass circuits: new heparin bonded bioline system.
        Artif Organs. 2000; 24: 618-623
        • Buck M.L.
        Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates.
        Clin Pharmacokinet. 2003; 42: 403-417
        • Butler J.
        • Pathi V.L.
        • Paton R.D.
        • et al.
        Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms.
        Ann Thorac Surg. 1996; 62: 538-542
        • Kozik D.J.
        • Tweddell J.S.
        Characterizing the inflammatory response to cardiopulmonary bypass in children.
        Ann Thorac Surg. 2006; 81: S2347-S2354
        • McIlwain R.B.
        • Timpa J.G.
        • Kurundkar A.R.
        • et al.
        Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine.
        Lab Invest. 2010; 90: 128-139
        • Seghaye M.C.
        • Grabitz R.G.
        • Duchateau J.
        • et al.
        Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations.
        J Thorac Cardiovasc Surg. 1996; 112: 687-697
        • Anderson 3rd, H.L.
        • AACoran A.G.
        • Drongowski R.A.
        • et al.
        Extracellular fluid and total body water changes in neonates undergoing extracorporeal membrane oxygenation.
        J Pediatr Surg. 1992; 27 (discussion 1007-1008): 1003-1007
        • Many M.
        • Soroff H.S.
        • Birtwell W.C.
        • et al.
        The physiologic role of pulsatile and nonpulsatile blood flow. II. Effects on renal function.
        Arch Surg. 1967; 95: 762-767
        • Ehrnebo M.
        • Agurell S.
        • Jalling B.
        • et al.
        Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults.
        Eur J Clin Pharmacol. 1971; 3: 189-193
        • Friis-Hansen B.
        Water distribution in the foetus and newborn infant.
        Acta Paediatr Scand Suppl. 1983; 305: 7-11
        • McNamara P.J.
        • Alcorn J.
        Protein binding predictions in infants.
        AAPS PharmSci. 2002; 4: E4
      1. Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. 2016; https://www.elso.org/Registry/Statistics/InternationalSummary.aspx.

        • Mulla H.
        • Lawson G.
        • Firmin R.
        • et al.
        Drug Disposition During Extracorporeal Membrane Oxygenation (ECMO).
        Pediatric and Perinatal Drug Therapy. 2001; 4: 109-120
        • Morgan E.T.
        Regulation of cytochromes P450 during inflammation and infection.
        Drug Metab Rev. 1997; 29: 1129-1188
        • Abdel-Razzak Z.
        • Loyer P.
        • Fautrel A.
        • et al.
        Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture.
        Mol Pharmacol. 1993; 44: 707-715
        • Rivory L.P.
        • Slaviero K.A.
        • Clarke S.J.
        Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response.
        Br J Cancer. 2002; 87: 277-280
        • Siewert E.
        • Bort R.
        • Kluge R.
        • et al.
        Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent.
        Hepatology. 2000; 32: 49-55
        • Richardson T.A.
        • Sherman M.
        • Kalman D.
        • et al.
        Expression of UDP-glucuronosyl transferase isoform mRNAs during inflammation and infection in mouse liver and kidney.
        Drug Metab Dispos. 2006; 34: 351-353
        • Bizzarro M.J.
        • Conrad S.A.
        • Kaufman D.A.
        • et al.
        Extracorporeal Life Support Organization Task Force on Infections EMO. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults.
        Pediatr Crit Care Med. 2011; 12: 277-281
      2. Extracorporeal Life Support Organization Registry Report: International Summary. January 2016. https://www.elso.org/. Accessed February 29, 2016

        • Amaker R.D.
        • DiPiro J.T.
        • Bhatia J.
        Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.
        Antimicrob Agents Chemother. 1996; 40: 1139-1142
        • Buck M.L.
        Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation.
        Pharmacotherapy. 1998; 18: 1082-1086
        • Mulla H.
        • Pooboni S.
        Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation.
        Br J Clin Pharmacol. 2005; 60: 265-275
        • Hoie E.B.
        • Swigart S.A.
        • Leuschen M.P.
        • et al.
        Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation.
        Clin Pharm. 1990; 9: 711-715
        • Donadello K.
        • Roberts J.A.
        • Cristallini S.
        • et al.
        Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study.
        Crit Care. 2014; 18: 632
        • Park S.J.
        • Yang J.H.
        • Park H.J.
        • et al.
        Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation.
        PLoS One. 2015; 10: e0141016
        • Wu C.C.
        • Shen L.J.
        • Hsu L.F.
        • et al.
        Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.
        J Formos Med Assoc. 2016; 115: 560-570
        • Cohen P.
        • Collart L.
        • Prober C.G.
        • et al.
        Gentamicin pharmacokinetics in neonates undergoing extracorporal membrane oxygenation.
        Pediatr Infect Dis J. 1990; 9: 562-566
        • Southgate W.M.
        • DiPiro J.T.
        • Robertson A.F.
        Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation.
        Antimicrob Agents Chemother. 1989; 33: 817-819
        • Munzenberger P.J.
        • Massoud N.
        Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation.
        ASAIO Trans. 1991; 37: 16-18
        • Kelman A.W.
        • Thomson A.H.
        • Whiting B.
        • et al.
        Estimation of gentamicin clearance and volume of distribution in neonates and young children.
        Br J Clin Pharmacol. 1984; 18: 685-692
        • McDade E.J.
        • Wagner J.L.
        • Moffett B.S.
        • et al.
        Once-daily gentamicin dosing in pediatric patients without cystic fibrosis.
        Pharmacotherapy. 2010; 30: 248-253
        • Ahsman M.J.
        • Wildschut E.D.
        • Tibboel D.
        • et al.
        Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation.
        Antimicrob Agents Chemother. 2010; 54: 1734-1741
      3. Lexicomp Online, Pediatric and Neonatal Lexi-Drugs.
        Lexi-Comp, Inc, Hudson, OhioApril 2016
        • Cies J.J.
        • Moore 2nd, W.S.
        • Dickerman M.J.
        • et al.
        Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support.
        Pharmacotherapy. 2014; 34: e175-e179
        • Donadello K.
        • Antonucci E.
        • Cristallini S.
        • et al.
        beta-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study.
        Int J Antimicrob Agents. 2015; 45: 278-282
        • Shekar K.
        • Fraser J.F.
        • Taccone F.S.
        • et al.
        The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study.
        Crit Care. 2014; 18: 565
        • Bradley J.S.
        • Sauberan J.B.
        • Ambrose P.G.
        • et al.
        Meropenem pharmacokinetics, pharmacodynamics, and Monte Carlo simulation in the neonate.
        Pediatr Infect Dis J. 2008; 27: 794-799
        • Smith P.B.
        • Cohen-Wolkowiez M.
        • Castro L.M.
        • et al.
        Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections.
        Pediatr Infect Dis J. 2011; 30: 844-849
        • Du X.
        • Li C.
        • Kuti J.L.
        • et al.
        Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients.
        J Clin Pharmacol. 2006; 46: 69-75
        • Ohata Y.
        • Tomita Y.
        • Nakayama M.
        • et al.
        Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations.
        Drug Metab Pharmacokinet. 2011; 26: 523-531
      4. Lexicomp Online, Lexi-Drugs.
        LexiComp, Inc, Hudson, OhioApril 2016
        • Welsch C.
        • Augustin P.
        • Allyn J.
        • et al.
        Alveolar and serum concentrations of imipenem in two lung transplant recipients supported with extracorporeal membrane oxygenation.
        Transpl Infect Dis. 2015; 17: 103-105
        • McKinnon P.S.
        • Paladino J.A.
        • Schentag J.J.
        Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.
        Int J Antimicrob Agents. 2008; 31: 345-351
        • De Rosa F.G.
        • Corcione S.
        • Baietto L.
        • et al.
        Pharmacokinetics of linezolid during extracorporeal membrane oxygenation.
        Int J Antimicrob Agents. 2013; 41: 590-591
        • Turner R.B.
        • Rouse S.
        • Elbarbry F.
        • et al.
        Azithromycin Pharmacokinetics in Adults With Acute Respiratory Distress Syndrome Undergoing Treatment With Extracorporeal-Membrane Oxygenation.
        Ann Pharmacother. 2016; 50: 72-73
        • Veinstein A.
        • Debouverie O.
        • Gregoire N.
        • et al.
        Lack of effect of extracorporeal membrane oxygenation on tigecycline pharmacokinetics.
        J Antimicrob Chemother. 2012; 67: 1047-1048
        • Kim H.S.
        • Lee E.S.
        • Cho Y.J.
        Insufficient serum levels of antituberculosis agents during venovenous extracorporeal membrane oxygenation therapy for acute respiratory distress syndrome in a patient with miliary tuberculosis.
        ASAIO J. 2014; 60: 484-486
        • Strunk A.K.
        • Ciesek S.
        • Schmidt J.J.
        • et al.
        Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.
        Int J Infect Dis. 2016; 42: 1-3
        • Gardner A.H.
        • Prodhan P.
        • Stovall S.H.
        • et al.
        Fungal infections and antifungal prophylaxis in pediatric cardiac extracorporeal life support.
        J Thorac Cardiovasc Surg. 2012; 143: 689-695
        • Eppes S.C.
        • Troutman J.L.
        • Gutman L.T.
        Outcome of treatment of candidemia in children whose central catheters were removed or retained.
        Pediatr Infect Dis J. 1989; 8: 99-104
        • Watt K.M.
        • Benjamin Jr., D.K.
        • Cheifetz I.M.
        • et al.
        Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.
        Pediatr Infect Dis J. 2012; 31: 1042-1047
        • Watt K.M.
        • Gonzalez D.
        • Benjamin Jr., D.K.
        • et al.
        Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.
        Antimicrob Agents Chemother. 2015; 59: 3935-3943
        • Autmizguine J.
        • Hornik C.P.
        • Benjamin Jr., D.K.
        • et al.
        Pharmacokinetics and Safety of Micafungin in Infants Supported with Extracorporeal Membrane Oxygenation.
        Pediatr Infect Dis J. 2016 Jun 16; ([Epub ahead of print])
        • Kuse E.R.
        • Chetchotisakd P.
        • da Cunha C.A.
        • et al.
        Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.
        Lancet. 2007; 369: 1519-1527
        • Smith P.B.
        • Walsh T.J.
        • Hope W.
        • et al.
        Pharmacokinetics of an elevated dosage of micafungin in premature neonates.
        Pediatr Infect Dis J. 2009; 28: 412-415
        • Koch B.C.
        • Wildschut E.D.
        • Goede A.L.
        • et al.
        Insufficient serum caspofungin levels in a paediatric patient on ECMO.
        Med Mycol Case Rep. 2012; 2: 23-24
        • Ruiz S.
        • Papy E.
        • Da Silva D.
        • et al.
        Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation.
        Intensive Care Med. 2009; 35: 183-184
        • Spriet I.
        • Annaert P.
        • Meersseman P.
        • et al.
        Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.
        J Antimicrob Chemother. 2009; 63: 767-770
        • Bruggemann R.J.
        • Antonius T.
        • Heijst A.
        • et al.
        Therapeutic drug monitoring of voriconazole in a child with invasive aspergillosis requiring extracorporeal membrane oxygenation.
        Ther Drug Monit. 2008; 30: 643-646
        • Hertzog JH B.E.
        • Sale M.
        • Hauser G.J.
        • et al.
        Amphotericin B Pharmacokinetics During Extracorporeal Membrane Oxygenation: A Case Report.
        J Extra Corpor Technol. 1996; 28: 94-98
        • Wildschut E.D.
        • de Hoog M.
        • Ahsman M.J.
        • et al.
        Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support.
        PLoS One. 2010; 5: e10938
        • Eyler R.F.
        • Heung M.
        • Pleva M.
        • et al.
        Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation.
        Pharmacotherapy. 2012; 32: 1061-1069
        • Lemaitre F.
        • Luyt C.E.
        • Roullet-Renoleau F.
        • et al.
        Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza.
        Ther Drug Monit. 2012; 34: 171-175
        • Mulla H.
        • Peek G.J.
        • Harvey C.
        • et al.
        Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support.
        Anaesth Intensive Care. 2013; 41: 66-73
        • Shetty A.K.
        • Ross G.A.
        • Pranikoff T.
        • et al.
        Oseltamivir-resistant 2009 H1N1 influenza pneumonia during therapy in a renal transplant recipient.
        Pediatr Transplant. 2012; 16: E153-E157
        • Aebi C.
        • Headrick C.L.
        • McCracken G.H.
        • et al.
        Intravenous ribavirin therapy in a neonate with disseminated adenovirus infection undergoing extracorporeal membrane oxygenation: pharmacokinetics and clearance by hemofiltration.
        J Pediatr. 1997; 130: 612-615
        • Hocker J.R.
        • Cook L.N.
        • Adams G.
        • et al.
        Ganciclovir therapy of congenital cytomegalovirus pneumonia.
        Pediatr Infect Dis J. 1990; 9: 743-745
        • Whitley R.J.
        • Cloud G.
        • Gruber W.
        • et al.
        Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
        J Infect Dis. 1997; 175: 1080-1086
        • Shekar K.
        • Roberts J.A.
        • Smith M.T.
        • et al.
        The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation.
        BMC Anesthesiol. 2013; 13: 7