Impact of Extracorporeal Membrane Oxygenation Circuitry on Remdesivir.

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.

Oxygenator impact on peramivir in extra-corporeal membrane oxygenation circuits.

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.

Oxygenator impact on meropenem/vaborbactam in extracorporeal membrane oxygenation circuits.

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.

Oxygenator impact on voriconazole in extracorporeal membrane oxygenation circuits.

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.

Ceftaroline Cerebrospinal Fluid Penetration in the Treatment of a Ventriculopleural Shunt Infection: A Case Report.

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.

Oxygenator Impact on Ceftolozane and Tazobactam in Extracorporeal Membrane Oxygenation Circuits.

OBJECTIVES: 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: 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: None. INTERVENTIONS: 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: 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.

Peramivir for Influenza A and B Viral Infections: A Pharmacokinetic Case Series.

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.

Pharmacokinetics of cefazolin delivery via the cardiopulmonary bypass circuit priming solution in infants and children.

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.

Pharmacokinetics of the Meropenem Component of Meropenem-Vaborbactam in the Treatment of KPC-Producing Klebsiella pneumoniae Bloodstream Infection in a Pediatric Patient.

Meropenem-vaborbactam is a new ß-lactam/ß-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.

Impact of ex-vivo extracorporeal membrane oxygenation circuitry on daptomycin.

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.

Oxygenator Impact on Ceftaroline in Extracorporeal Membrane Oxygenation Circuits.

OBJECTIVES: To determine the oxygenator impact on alterations of ceftaroline 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: Quarter-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. An one-time dose of ceftaroline was administered into the circuits, and serial pre- and postoxygenator concentrations were obtained at 5 minutes, 1-, 2-, 3-, 4-, 5-, 6-, and 24-hour time points. Ceftaroline 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: None. INTERVENTION: Single dose administration of ceftaroline 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: For the 1/4-inch circuit with an oxygenator, there was 79.8% drug loss preoxygenator and 82.5% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 1/4-inch circuit. For the 1/4-inch circuit without an oxygenator, there was no significant drug loss at any study time point. For the 3/8-inch circuit with an oxygenator, there was 76.2% drug loss preoxygenator and 77.6% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 3/8-inch circuit. For the 3/8-inch circuit without an oxygenator, there was no significant drug loss at any study time point. The reference ceftaroline concentrations remained relatively constant during the entire study period demonstrating the ceftaroline loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation and primarily the result of the oxygenator. CONCLUSIONS: This ex vivo investigation demonstrated significant ceftaroline loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of ceftaroline in the setting of extracorporeal membrane oxygenation may not be achieved with current U.S. Food and Drug Administration-recommended doses, and further evaluation is needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.

Ceftaroline for Suspected or Confirmed Invasive Methicillin-Resistant Staphylococcus aureus: A Pharmacokinetic Case Series.

OBJECTIVES: To describe the ceftaroline pharmacokinetics in critically ill children treated for suspected or confirmed methicillin-resistant Staphylococcus aureus infections, including blood stream infection and describe the microbiological and clinical outcomes. DESIGN: Retrospective electronic medical record review. SETTINGS: Free-standing tertiary/quaternary pediatric children's hospital. PATIENTS: Critically ill children receiving ceftaroline monotherapy or combination therapy for suspected or confirmed methicillin-resistant S. aureus infections in the PICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Seven patients, three females (43%), and four males (57%), accounted for 33 ceftaroline samples for therapeutic drug management. A median of four samples for therapeutic drug management was collected per patient (range, 2-9 samples). The median age was 7 years (range, 1-13 yr) with a median weight of 25.5 kg (range, 12.6-40.1 kg). Six of seven patients (86%) demonstrated an increase in volume of distribution, five of seven patients (71%) demonstrated an increase in clearance, and 100% of patients demonstrated a shorter half-life estimate as compared with the package insert estimate. Six of seven patients (85.7%) had documented methicillin-resistant S. aureus growth from a normally sterile site with five of six (83.3%) having documented BSI, allowing six total patients to be evaluated for the secondary objective of microbiological and clinical response. All six patients achieved a positive microbiological and clinical response for a response rate of 100%. CONCLUSIONS: These data suggest the pharmacokinetics of ceftaroline in PICU patients is different than healthy pediatric and adult patients, most notably a faster clearance and larger volume of distribution. A higher mg/kg dose and a more frequent dosing interval for ceftaroline may be needed in PICU patients to provide appropriate pharmacodynamic exposures. Larger pharmacokinetic, pharmacodynamic, and interventional treatment trials in the PICU population are warranted.

ß-lactam Therapeutic Drug Management in the PICU.

OBJECTIVES: To determine whether contemporary ß-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 ß-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 ß-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 ß-lactam therapeutic drug management. These data suggest ß-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 ß-lactam therapeutic drug management in a larger cohort of pediatric patients.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children.

OBJECTIVE: This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children. METHODS: The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring. RESULTS: There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R2 and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R2, bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and Vc was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L. CONCLUSION: These data suggest the reference dosage regimens for meropenem (20-40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.

Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy.

An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring.