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OBJECTIVES This study aimed to determine the oxygenator impact on alterations of remdesivir (RDV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i oxygenator. METHODS One-quarter--inch and a 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A 1-time dose of RDV was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 0 to 5 minutes, and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-hour time points. The RDV was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS For the 1/4-inch circuits with an oxygenator, there was a 35% to 60% RDV loss during the study period. For the 1/4-inch circuits without an oxygenator, there was a 5% to 20% RDV loss during the study period. For the 3/8-inch circuit with and without an oxygenator, there was a 60% to 70% RDV loss during the study period. CONCLUSIONS There was RDV loss within the circuit during the study period and the RDV loss was more pronounced with the larger 3/8-inch circuit when compared with the 1/4-inch circuit. The impact of the oxygenator on RDV loss appears to be variable and possibly dependent on the size of the circuit and oxygenator. These preliminary data suggest RDV dosing may need to be adjusted for concern of drug loss via the ECMO circuit. Additional single- and multiple-dose studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to determine the oxygenator impact on alterations of peramivir (PRV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra-corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of PRV was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5-min and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-h time points. PRV was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. Results: For the 1/4-in. circuit with an oxygenator, there was < 15% PRV loss, and for the 1/4-in. circuit without an oxygenator, there was < 3% PRV loss during the study period. For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss, and for the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. Conclusion: There was no significant PRV loss over the 24-h study period in either the 1/4-in. or 3/8-in circuit, regardless of the presence of the oxygenator. The concentrations obtained pre- and post-oxygenator appeared to approximate each other, suggesting there may be no drug loss via the oxygenator. This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Introduction: To determine the oxygenator impact on alterations of meropenem (MEM)/vaborbactam (VBR) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of MEM/VBR was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour time points. MEM/VBR was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. Results: For the 1/4-inch circuit, there was an approximate mean 55% MEM loss with the oxygenator in series and a mean 33%–40% MEM loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean 70% MEM loss with the oxygenator in series and a mean 30%–38% MEM loss without an oxygenator in series at 24 hours. For both the 1/4-inch circuit and 3/8-inch circuits with and without an oxygenator, there was <10% VBR loss for the duration of the experiment. Conclusions: This ex-vivo investigation demonstrated substantial MEM loss within an ECMO circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant VBR loss. Further evaluations with multiple dose in-vitro and in-vivo investigations are needed before specific MEM/VBR dosing recommendations can be made for clinical application with ECMO. [ABSTRACT FROM AUTHOR]

Introduction: To determine the oxygenator impact on alterations of voriconazole in a contemporary neonatal/pediatric (1/4 inch) and adolescent/adult (3/8 inch) extracorporeal membrane oxygenation circuit including the Quadrox-i® oxygenator. Methods: Simulated closed-loop extracorporeal membrane oxygenation circuits (1/4 and 3/8 inch) were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. In addition, 1/4- and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of voriconazole was administered into the circuits, and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24 hour time points. Voriconazole was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For the 1/4-inch circuit, there was an approximate mean of 64-67% voriconazole loss with the oxygenator in series and mean of 15-20% voriconazole loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean of 44-51% voriconazole loss with the oxygenator in series and a mean of 8-12% voriconazole loss without an oxygenator in series at 24 hours. The reference voriconazole concentrations remained relatively constant during the entire study period demonstrating that the drug loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation. Conclusion: This ex vivo investigation demonstrated substantial voriconazole loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant voriconazole loss in the absence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific voriconazole dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation. [ABSTRACT FROM AUTHOR]

Pharmacokinetic data regarding ceftaroline fosamil (CPT) penetration into cerebrospinal fluid (CSF) are limited to a rabbit model (15% inflamed) and adult case reports. We describe serum and CSF CPT concentrations in a 21-year-old, 34.8 kg female, medically complex patient presented with a 4-day history of fevers (Tmax 39.2°C), tachypnea, tachycardia, fatigue, and a 1-week history of pus and blood draining from the ventriculopleural (VPL) shunt. A head CT and an ultrasound of the neck revealed septated complex fluid collection surrounding the shunt. Therapy was initiated with vancomycin and ceftriaxone. Blood and CSF cultures from hospital day (HD) 1 were positive for methicillin-resistant Staphylococcus aureus with a CPT MIC of 0.5 mg/L and a vancomycin MIC range of 0.5 to 1 mg/L. On HD 3, CPT was added. On HD 7, simultaneous serum (69.4, 44, and 30.2 mg/L) and CSF (1.7, 2.3, and 2.3 mg/L) concentrations were obtained at 0.25, 1.5, and 4.75 hours from the end of an infusion. Based on these concentrations, CPT CSF penetration ratio ranged from 2.4% to 7.6%. After addition of CPT, the blood and CSF cultures remained negative on a regimen of vancomycin plus CPT. On HD 14, a new left-sided VPL shunt was placed. The patient continued on CPT for a period of 7 days after the new VPL shunt placement. This case demonstrated CPT CSF penetration in a range of 2.4% to 7.6%, approximately half of the rabbit model. This allowed for CSF concentrations at least 50% free time > 4 to 6× MIC of the dosing interval with a dosing regimen of 600 mg IV every 8 hours in a 34.8 kg chronic patient and resulted in a successful clinical outcome with no identified adverse outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVES To describe the pharmacokinetics of levofloxacin in an obese adolescent patient in the pediatric intensive care unit. METHODS A single-patient medical record review was conducted. RESULTS A 168-kg, 15-year-old female with past medical history of Prader-Willi syndrome and asthma initially presented with respiratory distress secondary to asthma exacerbation. She failed non-invasive ventilation and was subsequently intubated for respiratory failure and progressed to high-frequency oscillatory ventilation. On hospital day 1 (HD 1) an infectious workup was begun because of a fever, worsening clinical status, and initiation of vasopressors and an empiric antimicrobial regimen of cefepime and clindamycin. The urine culture subsequently grew Escherichia coli and the respiratory culture grew Pseudomonas aeruginosa. She continued to be febrile, which was thought to be due to an intra-abdominal abscess. On HD 14, the antimicrobial regimen was changed to levofloxacin because of continued fevers and no significant clinical improvement. Levofloxacin was initiated at 1000 mg IV every 24 hours. Levofloxacin serum levels were obtained at 0.5, 3.5, and 11.5 hours after infusion, which were 8.61, 5.76, and 2.7 mg/L, respectively. These concentrations translated into a peak level of 8.79 mg/L, a half-life of 6.4 hours, and an AUC of 80 mg·hr/L, which are discordant from the expected peak of 16 mg/L, a half-life of 8 hours, and an AUC of 120 mg·hr/L. Based on these values, the levofloxacin regimen was adjusted to 1000 mg IV every 12 hours, and repeat levels 0.5, 3.5, and 11.5 hours after infusion were 9.91, 6.56, and 3.27 mg/L, respectively, corresponding to a peak of 10.5 mg/L, a half-life of 5.18 hours, and an AUC of 200 mg·hr/L. After the adjustment in levofloxacin regimen, she became afebrile, WBC resolution and improvement in her overall clinical status, and she received a total duration for levofloxacin of 21 days. CONCLUSION A levofloxacin regimen of 1000 mg IV every 12 hours was successful in providing for an appropriate AUC exposure and was associated with a successful clinical outcome in this morbidly obese adolescent. ABBREVIATIONS AUC, area under the concentration-time curve; CL, clearance; Cmax, maximum concentrations; Ct, concentration at specified time; ke, elimination rate constant; HD, hospital day; MIC, minimum inhibitory concentration; PICU, pediatric intensive care unit; t1/2, half-life; Vd, volume of distribution; WBC, white blood cell. [ABSTRACT FROM AUTHOR]

Objective: To describe the peramivir (PRV) pharmacokinetics in critically ill children treated for influenza A or B viral infections. Design: Retrospective electronic medical record review of prospectively collected data from critically ill children receiving peramivir for influenza A or B viral infections in the pediatric intensive care unit (PICU). Setting: A 189‐bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. Patients: Critically ill children admitted to the PICU who were infected with influenza between January 1, 2016 and March 31, 2018. Interventions: None. Results: Eleven patients, two females (18%) and nine males (82%), accounted for 24 peramivir samples for therapeutic drug management. The median age was 5 years (interquartile range 1.5–6.5 yrs) with a median weight of 16.4 kg (interquartile range 14–24 kg). Ten (91%) patients demonstrated a larger volume of distribution, 11 (100%) patients demonstrated an increase in clearance, and 11 (100%) patients demonstrated a shorter half‐life estimate as compared with the package insert and previous pediatric trial data for peramivir. Eight (73%) patients tested positive for a strain of influenza A and 3 (27%) patients tested positive for influenza B; 4 of 11 (36%) patients tested positive for multiple viruses. All patients had adjustments made to their dosing interval to a more frequent interval. Ten (91%) patients were adjusted to an every‐12‐hour regimen and 1 (9%) patient was adjusted to an every‐8‐hour regimen. No adverse events were associated with peramivir treatment. Conclusion: The pharmacokinetics of PRV demonstrated in this PICU cohort differs in comparison to healthy pediatric and adult patients, and alterations to dosing regimens may be needed in PICU patients to achieve pharmacodynamic exposures. Additional investigations in the PICU population are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to describe the pharmacokinetics of cefazolin in paediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) who received cefazolin for peri-operative surgical prophylaxis in addition to having cefazolin added to the CPB circuit priming solution. Secondary aims were to determine the pharmacodynamic exposure associated with the addition of cefazolin to the CPB priming solution and to assess whether a target cefazolin concentration range for the CPB priming solution could be identified.Methods: A multicentre, prospective, open-label pharmacokinetic study was carried out in children from birth to 16 years of age undergoing cardiac surgery.Results: Forty-one patients met the inclusion criteria and accounted for 492 samples for analysis. Cefazolin concentrations were best described by a one-compartment model with weight as a covariate on the volume of distribution (Vd) with allometric scaling. The mean ± standard deviation (SD) total body CL for the birth-6 month cohort was 0.009 ± 0.006 mL/min/kg with a mean ± SD Vd of 0.59 ± 0.26 L/kg, the mean ± SD total body CL for the 7 month-3 year cohort was 0.01 ± 0.005 mL/min/kg with a mean ± SD Vd of 0.79 ± 0.15 L/kg, and the mean ± SD total body CL for the 4-16 year cohort was 0.007 ± 0.004 mL/min/kg with a mean ± SD Vd of 3.4 ± 0.94 L/kg. The median cefazolin loss in the CPB circuit ranged from 78% to 95% and the median patient cefazolin concentration after CPB circuit detachment ranged from 92 to 197 mg/L.Conclusions: These data demonstrate that mixing cefazolin in the CPB circuit priming solution was effective in maintaining cefazolin serum concentrations during surgery. If this practice is utilized, re-dosing of cefazolin during the CPB run and upon CPB circuit detachment is most probably not needed. Larger pharmacokinetic studies are warranted. [ABSTRACT FROM AUTHOR]

Meropenem‐vaborbactam is a new β‐lactam/β‐lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)‐producing Enterobacteriaceae. Meropenem‐vaborbactam was United States Food and Drug Administration–approved for complicated urinary tract infections in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem‐vaborbactam. In addition, the safety and efficacy of meropenem‐vaborbactam in a pediatric patient have yet to be described in the literature. The authors conducted a retrospective single‐patient chart review for a 4‐year‐old male patient with short bowel syndrome, colostomy and gastrojejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition and hydration management, complicated with multiple central line–associated bloodstream infections (BSIs). The patient was brought to our medical center with fever concerning for a BSI. On day 2, the patient was started on meropenem‐vaborbactam at a dosage of 40 mg/kg every 6 hours infused over 3 hours for KPC‐producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem‐vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 μg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem‐vaborbactam was continued for a total of 14 days. A meropenem‐vaborbactam regimen of 40 mg/kg every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient. [ABSTRACT FROM AUTHOR]

Background: The objective was to determine the alterations of daptomycin (DAP) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: Quarter-inch and 3/8-inch, simulated, closed-loop, ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. A one-time dose of DAP was administered into the circuit and serial pre- and post-oxygenator concentrations were obtained at 0-5 minutes and 1, 2, 3, 4, 5, 6 and 24-hour time points. DAP was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For both the 1/4-inch and 3/8-inch circuits, there was no significant DAP loss at 24 hours. Additionally, the reference DAP concentrations remained relatively constant during the entire 24-hour study period. Conclusion: This ex-vivo investigation demonstrated no significant DAP loss within an ECMO circuit with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of DAP in the setting of ECMO may be anticipated with current recommended doses, depending on the amount of extracorporeal volume needed for circuit maintenance in comparison to the patient’s apparent volume of distribution. Additional studies with a larger sample size are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Neither guidelines nor best practices for the treatment of external ventricular drain (EVD) and ventriculoperitoneal shunt infections exist. An antimicrobial regimen with a broad spectrum of activity and adequate cerebrospinal fluid ( CSF) penetration is vital in the management of both EVD and ventriculoperitoneal infections. In this case report, we describe the pharmacokinetics of continuous-infusion meropenem for a 2-year-old girl with Serratia marcescens ventriculitis. A right frontal EVD was placed for the management of a posterior fossa mass with hydrocephalus and intraventricular hemorrhage. On hospital day 6, CSF specimens were cultured, which identified a pan-sensitive Serratia marcescens with an initial cefotaxime minimum inhibitory concentration of 1 μg/ml or less. The patient was treated with cefotaxime monotherapy from hospital days 6 to 17, during which her CSF cultures and Gram's stain remained positive. On hospital day 26, Serratia marcescens was noted to be resistant to cefotaxime (minimum inhibitory concentration > 16 μg/ml), and the antimicrobial regimen was ultimately changed to meropenem and amikacin. Meropenem was dosed at 40 mg/kg/dose intravenously every 6 hours, infused over 30 minutes, during which, simultaneous serum and CSF meropenem levels were measured. Meropenem serum and CSF levels were measured at 2 and 4 hours from the end of the infusion with the intent to perform a pharmacokinetic/pharmacodynamic analysis. The resulting serum meropenem levels were 12 μg/ml at 2 hours and 'undetectable' at 4 hours, with CSF levels of 1 and 0.5 μg/ml at 2 and 4 hours, respectively. On hospital day 27, the meropenem regimen was changed to a continuous infusion of 200 mg/kg/day, with repeat serum and CSF meropenem levels measured on hospital day 33. The serum and CSF levels were noted to be 13 and 0.5 μg/ml, respectively. The serum level of 13 μg/ml corresponds to an estimated meropenem clearance from the serum of 10.2 ml/kg/minute. Repeat meropenem levels from the serum and CSF on hospital day 37 were 15 and 0.5 μg/ml, respectively. After instituting the continuous-infusion meropenem regimen, only three positive CSF Gram's stains were noted, with the CSF cultures remaining negative. The continuous-infusion dosing regimen allowed for 100% probability of target attainment in the serum and CSF and a successful clinical outcome. [ABSTRACT FROM AUTHOR]

Meropenem, a broad-spectrum carbapenem, is commonly used for empirical and definitive therapy in the pediatric intensive care unit ( ICU). Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or patients who are not in the ICU. Adult data demonstrate that pharmacokinetic parameters such as the volume of distribution and clearance can be significantly altered in individuals receiving extracorporeal membrane oxygenation ( ECMO). Alterations in the volume of distribution and clearance of antimicrobials in patients with sepsis and septic shock have also been documented, and these patients have demonstrated lower than expected antimicrobial serum concentrations based on standard dosing regimens. Therefore, an understanding of the pharmacokinetic changes in critically ill children receiving ECMO is crucial to determining the most appropriate dose and dosing interval selection for any antimicrobial therapy. In this case report, we describe the pharmacokinetics of a continuous infusion of meropenem in a pediatric cardiac ICU patient who was receiving concurrent extracorporeal life support. The patient was an 8-month-old male infant who underwent a Glenn procedure and pulmonary artery reconstruction. Postoperatively, he required ECMO with a total run of 21 days. On day 11 of ECMO, a bronchoalveolar lavage was performed, and blood cultures from days 11 and 12 of ECMO grew Pseudomonas aeruginosa, with a meropenem minimum inhibitory concentration ( MIC) of 0.5 μg/ml. On ECMO day 13, meropenem was initiated with a loading dose of 40 mg/kg and infused over 30 minutes, followed by a continuous infusion of 200 mg/kg/day. A meropenem serum concentration measured 8 hours after the start of the infusion was 46 μg/ml. Repeat levels were measured on days 3 and 9 of meropenem therapy and were 39 and 42 μg/ml, respectively. Repeat blood and respiratory cultures remained negative. This meropenem regimen (40-mg/kg bolus followed by a continuous infusion of 200 mg/kg/day) was successful in providing a target attainment of 100% for serum and lung concentrations above the MIC for at least 40% of the dosing interval and was associated with a successful clinical outcome. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether contemporary β-lactam anti-infective dosing recommendations in critically ill children achieve concentrations associated with maximal anti-infective activity. The secondary objective was to describe the microbiological and clinical outcomes associated with β-lactam therapeutic drug management.Design: Electronic Medical Record Review.Setting: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA.Patients: Patients admitted to the PICU from September 1, 2014, to May 31, 2017, with sepsis and those receiving extracorporal therapy with either extracorporeal membrane oxygenation or continuous renal replacement therapy that had routine β-lactam therapeutic drug management.Interventions: None.Measurements and Main Results: Eighty-two patients were in the total cohort and 23 patients in the infected cohort accounting for 248 samples for therapeutic drug management analysis. The median age was 1 year (range, 4 d to 18 yr) with a mean weight of 19.7 ± 22.3 kg (range, 2.7-116 kg). Twenty-three patients (28%) had growth of an identified pathogen from a normally sterile site. Seventy-eight of 82 patients (95%) had subtherapeutic anti-infective concentrations and did not attain the primary pharmacodynamic endpoint. All patients in the infected cohort achieved a microbiological response, and 22 of 23 (95.7%) had a positive clinical response.Conclusions: Overall, 95% of patients had subtherapeutic anti-infective concentrations and did not achieve the requisite pharmacodynamic exposure with current pediatric dosing recommendations. All patients achieved a microbiological response, and 95.7% achieved clinical response with active β-lactam therapeutic drug management. These data suggest β-lactam therapeutic drug management is a potentially valuable intervention to optimize anti-infective pharmacokinetics and the pharmacodynamic exposure. Further, these data also suggest the need for additional research in specific pediatric populations and assessing clinical outcomes associated with β-lactam therapeutic drug management in a larger cohort of pediatric patients. [ABSTRACT FROM AUTHOR]

B Learning Objectives: b Cefepime(FEP) is a frequently prescribed antibiotic in pediatric intensive care units(PICU) but pharmacokinetic(PK) data to justify the optimal dosing regimen are sparse in critically ill children. A 5000 patient Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) for the following FEP dosing regimens (50mg/kg q6-8h as 0.5 and 3-4-hour (h) infusions). A 2-compartment model best fit the FEP concentration data with weight as a covariate on volume of distribution (Vd) with allometric scaling. [Extracted from the article]