Faculty Bibliography

INTRODUCTION: Remdesivir (RDV) is an antiviral agent with in-vitro activity against SARS-CoV-2 that has been used during the COVID-19 pandemic. Dosing strategies for pediatric and adolescent patients have primarily been extrapolated from adult dosing recommendations and, to date, there is a lack of pharmacokinetic (PK) data of RDV in this patient population.
METHOD(S): Electronic medical record review of patients receiving RDV with concurrent therapeutic drug monitoring (TDM). RDV and GS-441524 concentrations were determined by LC-MS/MS methodology.
RESULT(S): 3 patients (2 female:1 male) met inclusion criteria and contributed 74 samples for determination of RDV and the active GS-441524 metabolite. The median age was 16 yrs (IQR 15.5-16 yrs) with a median weight of 76.4 kg (IQR 74.9-94.3kg). Patient #1 received ECMO support for the duration of RDV therapy. Patients #1 and 2 received RDV for 10 days with levels obtained daily. Patient #3 received RDV for 5 days with levels obtained daily. For all patients, mean RDV exposures, range 272-893 ng/mL were below the mean exposures reported in the RDV investigators brochure, 2900-7800 ng/mL. Patient #1 received ECMO and RDV exposures did not appear impacted by ECMO when compared with patients #2 and #3 that did not receive ECMO. For all patients, mean GS-441524 exposures, range 109-258 ng/mL, were similar to the mean exposures reported in the RDV investigators brochure, range 69-184 ng/mL. Similarly, the GS-441524 exposure did not appear to be affected by ECMO. Patients #1 and #2 did not appear to have any observable adverse events as a result of receiving RDV. Patient #3 experienced and increase in ALT >5x ULN which resulted in having RDV discontinued. All 3 patients experienced clinical resolution.
CONCLUSION(S): These are the first PK data of RDV in critically ill adolescent patients. These preliminary data suggest using adult dosing recommendations in adolescent patients result in RDV exposures below mean values demonstrated in adults with similar exposures of GS-441524 which could be a result of rapid conversion of RDV to GS- 441524 with delayed elimination in the setting of critical illness. Additional PK data of RDV in the critically ill pediatric population is warranted

INTRODUCTION/UNASSIGNED:oxygenator. METHODS/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

BACKGROUND:To determine if receiving targeted antimicrobial (AM) prophylaxis has an effect on the rate of postoperative infections in patient's colonized with a multidrug resistant organism (MDRO) undergoing cardiothoracic surgery (CTS). METHODS:Single-center, retrospective medical record review of pediatric patients from birth to 18 years of age undergoing CTS from January 2013 to September 2018. Demographic data collected included age, specific MDRO, site of MDRO colonization, type of surgery, perioperative AM agent and type of infection. Patients were stratified into 2 groups, MDRO+ and MDRO-. Demographic and clinical characteristics were compared between groups with a Student's t test for continuous variables and a χ2, Fisher exact test or Mann-Whitney U test for noncontinuous variables. A 2-sided significance level of α = 0.05 was used to determine statistical significance. All analyses were performed using IBM SPSS Version 24 (SPSS Inc., Chicago, IL). RESULTS:Fifty patients (26 males/24 females) were included in the MDRO (+) group and 295 patients (168 males/127 females) in the MDRO (-) group. The median age was 0.48 years (interquartile range 0.24-1 year) and 0.9 years (interquartile range 0.19-8 years) in the MDRO (+) and MDRO (-) groups, P = 0.003. 2 of 50 (4%) MDRO (+) patients and 15 of 295 (5.1 %) MDRO (-) patients developed an infection, P = 1. 10 of 50 (20%) MDRO (+) patients received targeted AM toward the MDRO and none developed an infection. Of the 2 MDRO (+) patients with infection, 1 was infected with the MDRO. For MDRO (+) patients, there was no difference in the rate of infection whether targeted AM therapy was received, P = 1. CONCLUSIONS:There was no difference in the rate of postoperative infection between MDRO (+) and MDRO (-) patients. Additionally, these preliminary pediatric data suggest targeting AM agents to a specific MDRO does not impact the rate of postoperative infection in children undergoing CTS. Larger studies are warranted to confirm these findings.

OBJECTIVES/OBJECTIVE:To determine the oxygenator impact on alterations of ceftolozane/tazobactam in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ). DESIGN/METHODS:A 1/4-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation 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 ceftolozane/tazobactam was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24-hour time points. Ceftolozane/tazobactam 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 SETTING:: A free-standing extracorporeal membrane oxygenation circuit. PATIENTS/METHODS:None. INTERVENTIONS/METHODS:Single-dose administration of ceftolozane/tazobactam into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period. MEASUREMENTS AND MAIN RESULTS/RESULTS:For the 1/4-inch circuit, there was approximately 92% ceftolozane and 22-25% tazobactam loss with the oxygenator in series and 19-30% ceftolozane and 31-34% tazobactam loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was approximately 85% ceftolozane and 29% tazobactam loss with the oxygenator in series and 25-27% ceftolozane and 23-26% tazobactam loss without an oxygenator in series at 24 hours. The reference ceftolozane and tazobactam concentrations remained relatively constant during the entire study period demonstrating 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. CONCLUSIONS:This ex vivo investigation demonstrated substantial ceftolozane loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and significant ceftolozane loss in the absence of an oxygenator. Tazobactam loss was similar regardless of the presence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.

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.

OBJECTIVES/OBJECTIVE: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/CONCLUSIONS: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.

OBJECTIVE:To describe the peramivir (PRV) pharmacokinetics in critically ill children treated for influenza A or B viral infections. DESIGN/METHODS: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/METHODS:A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS/METHODS:Critically ill children admitted to the PICU who were infected with influenza between January 1, 2016 and March 31, 2018. INTERVENTIONS/METHODS:None. RESULTS:), 11 (100%) patients demonstrated an increase in clearance (CL), 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/CONCLUSIONS: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. This article is protected by copyright. All rights reserved.

OBJECTIVES/OBJECTIVE:Influenza is an environmental pathogen and infection presents as a range from asymptomatic to fulminant illness. Though treatment is supportive, antiviral agents have a role in the management of infection. Pediatric use of peramivir is largely based on reports and extrapolations of pharmacokinetic data. We seek to describe efficacy and safety of peramivir in critically ill pediatric patients. METHODS:This is a retrospective, institutional review board-approved chart review of all patients under 21 years of age, admitted to the PICU, and treated with peramivir for influenza H1N1 infection between January 1, 2016, and March 31, 2016, at a single-center, 12-bed PICU. The primary outcome was time to sustained resolution of fever; secondary outcomes included dose, duration, and adverse effects of peramivir therapy. RESULTS:Seven patients were included with median age of 3.7 years. Median time to sustained resolution of fever was 49.3 hours, median duration of mechanical ventilation was 14.2 days, median ICU LOS was 18.7 days, and hospital LOS was 24.7 days. No patients suffered mortality. Three patients experienced leukopenia, one of which experienced a concurrent neutropenia. Three patients experienced hyperglycemia, 2 experienced hypertension, 1 experienced increased aspartate aminotransferase and increased alanine aminotransferase, and 1 experienced diarrhea. All adverse events assessed were classified as possible using published adverse event causality assessments. CONCLUSIONS:Peramivir has been shown to be an effective therapy for the treatment of influenza H1N1 in critically ill pediatric patients. In our experience with 7 pediatric patients, peramivir was well tolerated at typical durations of therapy; however, increased vigilance is warranted during prolonged courses or in patients with reasons for altered pharmacokinetics and pharmacodynamics.

Infants with meconium aspiration syndrome (MAS) and/or persistent pulmonary hypertension of newborn (PPHN) have the most favorable outcomes among infants requiring extracorporeal membrane oxygenation (ECMO). Early term (ET) infants have been shown to have higher morbidities when compared with term infants. It is not known if ET infants requiring ECMO for MAS and/or PPHN have higher morbidities and mortality than term infants. Objective of our study was to compare morbidity and mortality in ET infants with MAS and/or PPHN requiring ECMO in comparison to their term counterparts. A total of 3831 neonatal ECMO runs for MAS and/or PPHN were reviewed from the de-identified ELSO registry patient dataset from 2007- 2017. Neonates born at ET (37+0/7 - 38+6/7 weeks) and term (39+0/7 - 40+6/7 weeks) were further classified as two study groups. Both groups were compared using chi-square test. Of 2529 infants who were included in the study, there were 799 ET and 1730 term infants. ET infants when compared with term infants had higher mortality (9.6% vs 6%, P=0.002), lower survival to discharge (80.4% vs 87.7%, P<0.001), higher neurologic complications (14.8% vs 11.5%, P=0.024), and increased need for hemofiltration (32.9% vs 28.7%, P=0.033). There were no statistically significant differences between both groups in hemorrhagic, infectious, metabolic and cardiovascular complications. ET infants with MAS and/or PPHN have higher morbidities and mortality than term infants on ECMO. Caregivers should be informed of higher risks associated with use of ECMO in ET infants when compared to full term newborns