Population Pharmacokinetics of Cefoxitin Administered for Pediatric Cardiac Surgery Prophylaxis.

BACKGROUND: Available data about pharmacokinetics (PK) of antimicrobials administered as surgical prophylaxis to children undergoing cardiac surgery with cardiopulmonary bypass (CPB) showed that drug concentrations during CPB may be supra or subtherapeutic. The aim of this study was to determine the population PK and pharmacodynamic target attainment (PTA) of cefoxitin during pediatric CPB surgery. METHODS: A prospective interventional study was conducted. Cefoxitin (40 mg/kg, up to max 1000 mg) was administered before skin incision. Blood samples were obtained in the operatory room throughout surgery. Population PK, PTA, and safety of cefoxitin were evaluated in neonates, infants, children <10 and >10 years old. RESULTS: Forty patients were enrolled. Cefoxitin levels correlated with time from bolus administration (r = -0.6, P = 0.0001) and, after 240 minutes from bolus, drug values below the target (8 mg/L) were shown. Cefoxitin concentrations were best described by a one-compartment model with first order elimination. A significant relationship was identified between body weight, age, body mass index, and serum creatinine on drug clearance and age, body weight, and body mass index on cefoxitin volume of distribution. The PTA for free drug concentration being above the minimum inhibitory concentration of 8 mg/L for at least 240 minutes was >90% in all age groups except in patients >10 years of age (PTA = 62%). CONCLUSIONS: Cefoxitin PK appears to be significantly influenced by CPB with generally reduced drug clearance. The PTA was adequately achieved in the majority of patients except in patients >10 years old or longer surgeries.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic-Ischemic Encephalopathy Receiving Controlled Hypothermia.

OBJECTIVE: Identify population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). DESIGN: Prospective open-label pharmacokinetic study. Gentamicin concentrations were modeled and dosing regimens simulated for a 5000-patient neonatal population with HIE receiving CH using PMetrics, a nonparametric, pharmacometric modeling, and simulation package for R. SETTING: A 189-bed children's tertiary care teaching hospital. RESULTS: Twelve patients, 5 (42%) females and 7 (58%) males, met inclusion criteria with a median gestation age of 39.9 weeks (interquartile range [IQR] 38.5-40.2 wks) and a median birthweight (BW) of 3.3 kg (IQR 3.1-3.7 kg). Gentamicin concentrations were best described by a two-compartment model with first-order elimination with BW as a covariate on volume of distribution (Vd). The mean total body population clearance (CL) was 2.2 ± 0.7 ml/minute/kg, and the volume of the central compartment was 0.44 ± 0.06 L/kg. The R2 , bias, and precision for the observed versus population predicted model were 0.917, 1.15, and 10.9 µg/ml; the R2 , bias, and precision for the observed versus individual predicted model were 0.982, -0.132, and 0.932 µg/ml, respectively. The calculated mean population estimate for the total Vd was 0.96 ± 0.4 L/kg. The dosing regimen that most consistently produced a maximum concentration (Cmax ) in the range of 10-12 mg/L with a minimum concentration (Cmin ) level less than 2 mg/L was 5 mg/kg/dose given every 36 hours. CONCLUSION: These data suggest the population pharmacokinetics of gentamicin in neonates with HIE receiving CH have an increase in gentamicin CL and are different from previous reports in neonates with HIE not receiving CH and/or neonates without HIE. This analysis suggests a dosing regimen of 5 mg/kg/dose every 36 hours results in a gentamicin Cmax within the range of 10-12 mg/L with a Cmin lower than 2 mg/L, which is appropriate for treating susceptible gram-negative organisms with minimum inhibitory concentrations of 1 mg/L or lower.

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 Vancomycin in Neonates on Extracorporeal Life Support.

OBJECTIVES: To evaluate the population pharmacokinetics and pharmacodynamic target attainment of vancomycin in neonates with a contemporary »-inch extracorporeal life support circuit with a Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC, Wayne, NJ). DESIGN: Retrospective medical record review. SETTING: Two free-standing tertiary/quaternary pediatric children's hospitals. PATIENTS: Neonates receiving either veno-arterial or veno-venous extracorporeal life support and vancomycin for empiric or definitive therapy with resulting serum concentrations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve patients with a median gestations age of 39 weeks (range 36-41 wk) and a median postnatal age of 9.5 days (range 0-28 d) accounted for 14 courses of vancomycin therapy while on extracorporeal life support and were included in the analysis. The median weight was 3.1 kg (range 2.2-4.41 kg) with five of 12 patients (41.7%) being female. Vancomycin concentrations were best described by an one-compartment model incorporating allometric scaling of estimated glomerular filtration rate on clearance. The mean total body clearance (mL/min/kg) for the population was 3.48 ± 1.31 mL/min/kg, and the mean total volume of distribution (L/kg) for the population was 1.2 ± 0.4 L/kg. The intermittent and continuous infusion dosing regimens that provided for the highest percentage of trough concentrations in the range of 10-20 mg/L were the 10 mg/kg/dose IV q8h, 12.5 mg/kg/dose IV q8-12h, 15 mg/kg/dose IV q12h, and 20 mg/kg/dose IV q12h, and the 20, 25, and 30 mg/kg/d continuous infusion regimens, respectively. All regimens allowed for an area under the concentration:minimum inhibitory concentration ratio of 400:1 for minimum inhibitory concentrations of less than or equal to 0.5 mg/L for a 90% PTA. None of the simulated regimens had a greater than 90% probability of achieving an area under the concentration:minimum inhibitory concentration ratio of 400:1 for vancomycin minimum inhibitory concentrations greater than or equal to 1 mg/L while maintaining trough concentrations in the range of 10-20 mg/L. CONCLUSIONS: To our knowledge, this is the first pharmacokinetic and pharmacodynamic study of neonates receiving vancomycin with a contemporary »-inch extracorporeal life support circuit including the Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC). The data suggest differences in vancomycin pharmacokinetics compared with previous extracorporeal life support data, notably a more rapid clearance, which could result in lower vancomycin concentrations. Considering this, a more aggressive initial dosing regimen may need to be employed in infants on extracorporeal life support.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Ampicillin in Neonates with Hypoxemic-Ischemic Encephalopathy in the Setting of Controlled Hypothermia.

STUDY OBJECTIVE: To describe the population pharmacokinetics and pharmacodynamic target attainment of ampicillin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). DESIGN: Prospective, open-label pharmacokinetic study. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital. PATIENTS: Thirteen neonates (three females and 10 males) with HIE encephalopathy receiving CH and ampicillin 100 mg/kg/dose intravenously every 8 hours who were admitted to the neonatal intensive care unit between May 2013 and June 2014. INTERVENTION: Blood (0.5 ml) was collected at 8, 10, and 14 hours of life coinciding with other scheduled laboratory investigations for ampicillin concentration analysis, providing a total of three ampicillin serum concentrations/patient. MEASUREMENTS AND MAIN RESULTS: The patients had a median gestational age of 39 weeks, mean ± SD birth weight of 3.34 ± 0.61 kg, and mean ± SD estimated glomerular filtration rate of 43 ± 12.6 ml/minute/1.73 m2 . Ampicillin concentrations were best described by a two-compartment model with gestational age as a covariate with allometric scaling on total body clearance. The mean ± SD total body clearance for the population was 0.43 ± 0.12 ml/minute/kg (median 0.36 ml/min/kg), volume of the central compartment was 0.35 ± 0.46 L/kg, and the calculated population estimate for the total volume of distribution (Vd ) was 0.52 ± 0.28 L/kg. The R2 , bias, and precision were 0.497, 0.538, and 10.5 µg/ml and 0.972, -0.125, and 0.938 µg/ml for the observed versus population and observed versus individual predicted concentrations, respectively. Monte Carlo simulation was conducted to determine the probability of target attainment for 12 simulated ampicillin dosing regimens using 50% and 100% of the dosing interval that free drug concentration remains above the minimum inhibitory concentration (fT > MIC) in 5000 simulated neonates with HIE receiving CH. Dosing regimens of 25 and 50 mg/kg/dose every 24 hours provided for an appropriate pharmacodynamic target attainment of 50% and 100% fT > MIC. CONCLUSION: To our knowledge, this study describes the first pharmacokinetic data of ampicillin in neonates with HIE receiving CH and demonstrates a reduced total body clearance and an increased Vd for ampicillin. Based on these data, modifications to the ampicillin dosing regimens seem appropriate during the period of CH. Dosing regimens of ampicillin 25 and 50 mg/kg/day were able achieve optimal probability of target attainment against all susceptible gram-negative and gram-positive bacteria in a population of neonates with HIE receiving CH for 50% and 100% fT > MIC.

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 µg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ±â€Š0.23 L/h/kg and 0.30 ±â€Š0.17 L/kg, respectively. Half-life was 1.11 ±â€Š0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Population pharmacokinetics of piperacillin/tazobactam in critically ill young children.

INTRODUCTION: Piperacillin/tazobactam is a frequently prescribed antibiotic in pediatric intensive care units, but pharmacokinetic data to justify the optimal piperacillin/tazobactam dosing regimen are sparse in critically ill children. METHODS: Blood samples (2-4 per child) were collected from 13 children ages 9 months to 6 years admitted to the pediatric intensive care unit who were receiving standard piperacillin/tazobactam dosing regimens to treat infections. Piperacillin concentrations were measured by a bioassay, and the population pharmacokinetics of the piperacillin component was conducted using nonparametric adaptive grid (BigNPAG) with adaptive γ. Multiple models were tested to determine the best fit of the data. A 5000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for piperacillin/tazobactam 50 mg/kg (of the piperacillin component) every 4 hours, 80 mg/kg every 8 hours and 100 mg/kg every 6 hours as 0.5-, 3- or 4-hour infusions in a population of 1- to 6-year-old male children. Centers for Disease Control and Prevention weight for age charts were used as weight distributions. The percent of the dosing interval of the free drug is above the minimum inhibitory concentration (MIC) (fT>MIC) was calculated over a range of MICs from 0.03 to 128 µg/mL. The bactericidal target attainment was defined as ≥50% fT>MIC for piperacillin/tazobactam. PTA ≥90% at each MIC was defined as optimal. RESULTS: A 2 compartment model fitted piperacillin concentration data the best. Mean (standard deviation) population estimates for clearance, volume of the central compartment (Vc) and intercompartment transfer constants were 0.299 (0.128) L/hr/kg, 0.249 (0.211) L/kg, 6.663 (6.871) hours(-1) and 8.48 (7.74) hours(-1), respectively. This resulted in a mean (standard deviation) elimination half-life of 1.39 (0.62) hours. The bias, precision and r² for the individual predicted versus observed concentrations were -0.055, 0.96 µg/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 µg/mL against Psuedomonas aeruginosa were 100 mg/kg every 6 hours administered as a 3-hour prolonged infusion and 400 mg/kg administered as a 24-hour continuous infusion. These dosing regimens also achieved 77.7% and 74.8% PTA, respectively, at a MIC of 32 µg/mL. CONCLUSION: These are the first pharmacokinetic data of piperacillin/tazobactam (piperacillin component) in critically ill pediatric patients (1-6 years of age). Based on these data, 100 mg/kg q6h as a 3-hour infusion and 400 mg/kg continuous infusion were the only regimens to provide optimal PTA at the Clinical Laboratory Standards Institute breakpoint of 16 µg/mL.

Clinical pharmacist impact on care, length of stay, and cost in pediatric cystic fibrosis (CF) patients.

BACKGROUND: Cystic fibrosis (CF) patients are often treated with aminoglycoside (AG) antibiotics during infective pulmonary exacerbations. Achieving pharmacokinetic and pharmacodynamic (PK/PD) targets to improve outcomes and counteract resistance is paramount. PURPOSE: The primary objective was to compare the number of pediatric CF patients achieving AG PK/PD targets when a clinical pharmacist (CP) managed therapeutic drug monitoring (TDM) compared with usual care (UC). METHODS: A retrospective cohort study was conducted on the records of 40 CF patients that received AGs and ≥2 serum samples between 1/2007 and 5/2009. Chi-square and Student's t-test were used to analyze nominal and continuous variables, respectively. RESULTS: Twenty-nine patients with 52 courses of AGs were included the CP group, and 22 patients with 42 courses were included the UC group. Ninety-eight percent of patients in the CP group reached AG PK/PD targets compared with 71% in the UC group, P < 0.001. Patients in the CP group reached the AG PK/PD target in a mean of 1.9 ± 0.8 days compared with 4.8 ± 3.4 days in the UC group, P < 0.0001. The average LOS in the CP group was 9 ± 5 days compared with 12 ± 7.5 days in the UC group, P = 0.033. The mean number of levels per patient was 2.7 in the CP group compared with 5.2 (range of 2-20) in the UC group, P < 0.001. Resource utilization associated with drug levels, dosing adjustments and LOS were $26,549, $14,069, and $1,680,000 in the CP group as compared with $40,683, $27,812, and $1,940,000, respectively, in the UC group. CONCLUSION: CP managed TDM resulted in a significantly higher percentage of pediatric CF patients achieving AG PK/PD targets 3 days sooner with an average LOS that was 3 days shorter. CP managed TDM resulted in significantly fewer dosage adjustments, drug levels, and cost associated with serum sampling, drug wastage, and LOS.