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Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation

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... Despite the wide use of antimicrobial agents during ECMO (23), PK data related to newer systems are limited and heterogeneous, resulting in a poor level of evidence-based pharmacotherapy (22,24). Previous pharmacological knowledge (25)(26)(27) needs to be updated according to the recent advances of extracorporeal technology to prevent altered antimicrobial exposure during ECMO. Furthermore, the optimization of pharmacotherapy is required to limit the burden of microbial resistance (28,29). ...
... Vancomycin is a hydrophilic and moderately protein-bound agent and, given the narrow therapeutic window and the risk of nephrotoxicity, its PK profile has been extensively evaluated both in in vitro and in vivo settings (25)(26)(27). Indeed, targeting the ratio of the area under the vancomycin concentration-time curve over a 24-h period to the minimum inhibitory concentration of the bacteria is crucial, especially among critically ill patients (1,38). ...
... Indeed, targeting the ratio of the area under the vancomycin concentration-time curve over a 24-h period to the minimum inhibitory concentration of the bacteria is crucial, especially among critically ill patients (1,38). Based on previous neonatal studies, vancomycin has shown an increased volume of distribution (Vd) and a decreased clearance (Cl) during ECMO, resulting in prolonged half-life (25)(26)(27). However, these findings were related to older roller pump-based systems, whereas data on centrifugal pump-based circuits are limited. ...
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Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung® petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.
... 11 12 Several studies have been conducted on the effects of ECMO on the pharmacokinetics of vancomycin in neonates and infants. [13][14][15] Since poor understanding of vancomycin pharmacokinetics led to an increase in medical costs, 16 17 study of the pharmacokinetic characteristics of vancomycin in patients with ECMO could be of practical importance. However, most studies had small sample sizes and lacked adequate control groups. ...
... In that study, a historical control was employed as the comparison group and neonates whose SCr exceeded 1.5 mg/dL were excluded. 13 ...
Article
Objective This study aimed to characterise vancomycin pharmacokinetics in critically ill neonates undergoing extracorporeal membrane oxygenation. Methods In a retrospective analysis, the pharmacokinetics of vancomycin were determined in 25 full-term neonates receiving extracorporeal membrane oxygenation and compared with those of matched controls (n = 25) not receiving extracorporeal membrane oxygenation. Results The half-life of vancomycin in the neonates undergoing extracorporeal membrane oxygenation was significantly prolonged compared with that in the controls (17.45 ± 11.01 hour vs 5.92 ± 2.70 hour, P<0.001). Clearance decreased significantly in the extracorporeal membrane oxygenation group relative to the control group (0.03 ± 0.02 L/kg/hr vs 0.08 ± 0.05 L/kg/hr, P<0.001). No significant difference was found in the volume of distribution between the two groups (0.63 ± 0.30 L/kg in the extracorporeal membrane oxygenation group vs 0.57 ± 0.14 L/kg/hr in control, P=0.596). Clearance values were significantly correlated with serum creatinine (r = - 0.528, P<0.001). In the subgroup analysis using patients with serum creatinine < 0.5 mg/dL, similar results were obtained including significantly prolonged half-life (11.52 ± 6.31 hour vs 5.44 ± 2.36 hour, P<0.001) and decreased clearance (0.05 ± 0.02 L/kg/hr vs 0.09 ± 0.05 L/kg/hr, P<0.001) in the extracorporeal membrane oxygenation group relative to the control group. Conclusions Vancomycin clearance decreased significantly in the neonates undergoing extracorporeal membrane oxygenation compared with the controls. Dosing adjustments of vancomycin and close therapeutic drug monitoring are required for the safe and effective management of neonates during extracorporeal membrane oxygenation.
... 8 So far few PK studies in neonates treated with vancomycin on ECMO were conducted showing an increased volume of distribution (Vd) and decreased or variable clearance (CL) of vancomycin in comparison with non-ECMO patients. [9][10][11] Perfusion 00(0) PK simulation was performed in a one-compartmental PK model with first-order elimination kinetics using MWPharm ++ software (MediWare, Prague, Czech Republic). 12 The vancomycin population PK model was then individualised to maximise fitting of the simulated PK profile curve with observed concentration points. ...
Article
Introduction Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. Pharmacological consequences of ECMO-induced haemolysis in neonates are not well understood. Case report We report a case report of a full-term neonate treated for congenital diaphragmatic hernia and sepsis with ECMO and with vancomycin. While the population elimination half-life of 7 h was estimated, fitting of the simulated population pharmacokinetic profile to truly observed drug concentration points resulted in the personalized value of 41 h. Discussion The neonate developed ECMO-induced haemolysis with subsequent acute kidney injury resulting in prolonged drug elimination. Whole blood/serum ratio of 0.79 excluded possibility of direct increase of vancomycin serum concentration during haemolysis. Conclusion Vancomycin elimination may be severely prolonged due to ECMO-induced haemolysis and acute kidney injury, while hypothesis of direct increase of vancomycin levels by releasing the drug from blood cells during haemolysis has been disproved.
... Reports in the literature on the impact of ECMO on vancomycin pharmacokinetics are mixed. Several studies suggest alterations in vancomycin serum concentrations [10][11][12], whereas other studies have not found significant differences between critically ill patients with ECMO support compared to patients without ECMO support [13][14][15]. We sought to create a mechanistically relevant model to understand the pharmacokinetic behavior of vancomycin within an ECMO circuit and assess if ECMO flow rates impacted clearance. ...
Article
Background Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary life support frequently utilized in catastrophic lung and or cardiac failure. Patients on ECMO often receive vancomycin therapy for treatment or prophylaxis against Gram-positive organisms. It is unclear if ECMO affects vancomycin pharmacokinetics, thus we modeled the pharmacokinetic behavior of vancomycin according to ECMO-specific variables.Methods Adult patients receiving vancomycin and Veno-Arterial-ECMO between 12/1/2016 and 10/1/2017 were prospectively enrolled. Extracorporeal membrane oxygenation settings and four sets of pre- and post-oxygenator vancomycin concentrations were collected for each patient. Compartmental models were built and assessed ECMO flow rates on vancomycin clearance and potential circuit sequestration. Bayesian posterior concentrations of the pre- and post-oxygenator concentrations were obtained for each patient, and summary pharmacokinetic parameters were calculated. Simulations were performed from the final model for efficacy and toxicity predictions.ResultsEight patients contributed 64 serum concentrations. Patients were a median (interquartile range) age of 58.5 years (50.8–62.3) with a calculated creatinine clearance of 39 mL/min (29.5–62.5) and ECMO flow rates of 3980 mL/min (interquartile range = 3493.75–4132.5). A three-compartment model best fit the data (Bayesian: plasma pre-oxygenation R2 = 0.99, post-oxygenation R2 = 0.99). Vancomycin clearance was not impacted by ECMO flow rate (p = 0.7). Simulations demonstrated that vancomycin 1 g twice daily was rarely sufficient for minimum inhibitory concentrations > 0.5 mg/L. Doses ≥ 1.5 g twice daily often exceeded toxicity thresholds for exposure.Conclusions Extracorporeal membrane oxygenation flow rates did not influence vancomycin clearance between flow rates of 3500 and 5000 mL/min and vancomycin was not sequestered in ECMO. Common vancomycin regimens resulted in suboptimal efficacy and/or excessive toxicity. Individual therapeutic drug monitoring is recommended for patients on ECMO.
... Vancomycin is the most common drug studied for PK/PD variations in ECMO [48]. Various studies show an increased volume of distribution and decreased clearance for vancomycin for neonates and infants on ECMO [49]. However, no variations have been seen in the PK/PD parameters of drugs like piperacillin-tazobactam, meropenem, and amikacin. ...
Article
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Sepsis is being recognized as an important complication of extracorporeal membrane oxygenation (ECMO) and its presence is a poor prognostic marker and increases the overall mortality. The survival rate differs in the various types of cannulation techniques. Adult patients with prolonged duration of ECMO constitute the major risk population. Ventilator-associated pneumonia and bloodstream infections form the main sources of sepsis in these patients. It is important to know the most common etiological agents for sepsis in ECMO, which varies partly with the local epidemiology of the hospitals. A high index of suspicion, drawing adequate volumes for blood culture and early and timely administration of appropriate empirical antimicrobials can substantially decrease the morbidity and mortality in this high-risk population. The dosing of antimicrobials is influenced by the pharmacological variations on ECMO machine and is an important consideration. Infection control practices are of paramount importance and need to be followed meticulously to prevent sepsis in ECMO.
... Vancomycin is a hydrophilic time-dependent antimicrobial, largely used in the NICUs for treatment of Gram-positive infections (118,153). Given the narrow therapeutic window and the risk of nephrotoxicity, the PK profile of vancomycin has been extensively evaluated both in vitro and in vivo neonatal settings since the 90's (154)(155)(156). Vancomycin Cl is strictly related to renal function (155,157) and the drug half-life was found to be prolonged in ECMO patients (156). ...
Article
Full-text available
Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.
... Vd is either increased or unaffected by ECMO. Cl was decreased, but primarily correlated to renal function (31,(66)(67)(68). A decrease in renal perfusion likely results in a decreased vancomycin Cl. ...
Article
Data evaluating pharmacokinetic/pharmacodynamic (PK/PD) aspect in the pediatric population are scarce especially regarding the pediatric intensive care unit. Dosing of frequently used drugs (sedatives, analgesics, antibiotics and cardiovascular drugs) are mainly based on non "pediatric intensive care unit (PICU)" patients, and sometimes are translated from adult patients. Among PICU patients, the most complex patients are the ones who are critically ill and are receiving mechanical circulatory/respiratory support for cardiac and/or respiratory failure. The use of extracorporeal membrane oxygenation is associated with major PK and PD changes, especially in neonates and children. The objective of this review is to assess the current literature for pediatric PK data in patients receiving extracorporeal membrane oxygenation (ECMO).
... 2 In many cases, broadspectrum antibiotics are used to treat these infections. Vancomycin is often chosen for its efficacy in treating Gram-positive infections including methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus infections. 4 By adding volume to patients as well as introducing opportunities for drug sequestration, ECMO can change the pharmacokinetics of many drugs, including vancomycin. 5 Several earlier studies [6][7][8][9] have investigated the pharmacokinetics of vancomycin in pediatric ECMO patients. These early pharmacokinetic studies revealed that vancomycin has a greater volume of distribution, clearance, and half-life. ...
Article
Objectives: The objective of the current study was to evaluate the doses of vancomycin used to obtain therapeutic drug concentrations in pediatric patients on extracorporeal membrane oxygenation (ECMO), using new ECMO technologies. Methods: This was a single-center, retrospective study of patients treated with vancomycin while receiving ECMO using low-volume circuit technology. Results: A total of 28 patients were included in the analysis of the primary endpoint. Patients had a median age of 6 weeks (0-11 years) and a median weight of 3.45 kg (2.44-37.2 kg). Ultrafiltration was used in 89.3% of patients at initiation of ECMO regardless of baseline renal function, resulting in a median urine output of 2 mL/kg/hr at the time of the final vancomycin dose. Most patients started vancomycin at the same time as ECMO. The median total daily dose was 30 mg/kg/day. The median total daily dose in a subset of patients less than one year of age was 20 mg/kg/day. Nearly all patients had at least 1 therapeutic trough serum vancomycin concentration. A total of 16 patients completed their vancomycin course using an interval of every 12 hours or shorter. Half-life was calculated in a subset of 11 patients and the mean was found to be 12.3 ± 2.8 hours. Conclusions: An initial dosing interval of every 12 hours to provide a total daily dose of 30 mg/kg/day is a possible option in pediatric patients on ECMO provided that renal function is normal at baseline. Monitoring of serum vancomycin concentrations for adjustment of dosing is required throughout therapy and is still warranted.
Article
The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000 mg dose of vancomycin, samples were collected 9 times per patient prospectively. A population PK model was developed using a nonlinear mixed effect model. The probability of target attainment (PTA) of vancomycin was evaluated for various dosing strategies using Monte Carlo simulation. The ratio of the area under the vancomycin concentration-time curve at steady-state over 24 h to the minimum inhibitory concentration (AUC/MIC) was investigated by applying the vancomycin break point distribution of MICs for methicillin-resistant Staphylococcus aureus . A total of 22 adult patients with 194 concentration measurements were included. The population PK was best described by a three-compartment model with a proportional residual error model. Vancomycin clearance and steady state volume of distribution were 0.0542 L/h/kg (4.01 L/h) and 29.6 L (0.400 L/kg), respectively. If the treatment target was only AUC/MIC ≥400, a total daily dose of 3 to 4 g would be optimal (PTA ≥90%) for patients with normal renal function (estimated glomerular filtration rate [eGFR] = 60–120 mL/min/1.73 m ² ) when MIC was presumed to be 1 mg/L. However, AUC/MIC 400 to 600 was difficult to attain with any dosing strategy regardless of MIC and eGFR. Thus, it is hard to achieve efficacy and safety targets in patients on ECMO using the population dosing approach with Monte Carol simulations, and therapeutic drug monitoring should be implemented in these patients.
Article
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Optimal pharmacological management during extracorporeal membrane oxygenation (ECMO) involves more than administering drugs to reverse underlying disease. ECMO is a complex therapy that should be administered in a goal-directed manner to achieve therapeutic endpoints that allow reversal of disease and ECMO wean, minimisation of complications (treatment of complications when they do occur), early interruption of sedation and rehabilitation, maximising patient comfort and minimising risks of delirium. ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs and our understanding of these alterations is still evolving. Based on available data it appears that modern ECMO circuitry probably has a less significant impact on PK when compared with critical illness itself. However, these findings need further confirmation in clinical population PK studies and such studies are underway. The altered PD associated with ECMO is less understood and more research is indicated. Until robust dosing guidelines become available, clinicians will have to rely on the principles of drug dosing in critically ill and known PK alterations induced by ECMO itself. This article summarises the PK alterations and makes preliminary recommendations on possible dosing approaches.
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