Jeffrey J. Cies

Nephrotoxicity in patients with vancomycin trough concentrations of 15-20 μg/ml in a Pediatric Intensive Care Unit.

To determine if a higher serum vancomycin (Vt) target trough concentration of 15–20 μg/ml or greater is associated with an increased rate of vancomycin‐induced nephrotoxicity in children admitted to a pediatric intensive care unit (PICU), and to determine risk factors for developing vancomycin‐induced nephrotoxicity.

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 &ggr;. 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 &mgr;g/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 &mgr;g/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 &mgr;g/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 &mgr;g/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 &mgr;g/mL.

Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis

The activity of ceftolozane/tazobactam was tested against 50 nonduplicate Pseudomonas aeruginosa from 18 cystic fibrosis children collected in 2012-2014. These isolates were multidrug resistant with susceptibility to meropenem, ceftazidime, and piperacillin/tazobactam of 46%, 58%, and 50%, respectively. Ceftolozane/tazobactam was the most active with MIC50, MIC90, and percent susceptibility of 2mg/L, 8 mg/L, and 86%.

Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support.

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.

Procalcitonin use in a pediatric intensive care unit.

We evaluated whether procalcitonin (PCT) might aid diagnosing serious bacterial infections in a general pediatric intensive care unit population. Two-hundred and one patients accounted for 332 PCT samples. A PCT ≥1.45 ng/mL had a positive predictive value of 30%, a negative predictive value of 93% and a sensitivity of 72% and a specificity of 75%. These data suggest PCT can assist in identifying patients without serious bacterial infections and limit antimicrobial use.

Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia

To describe the population pharmacokinetics of the piperacillin component of piperacillin/tazobactam.Background To describe the population pharmacokinetics of the piperacillin component of piperacillin/tazobactam. Procedure This pharmacokinetic study included 21 pediatric (age 3–10 years) patients receiving piperacillin/tazobactam to treat fever with neutropenia. Each patient contributed 1–3 blood samples for piperacillin concentration determination. Population pharmacokinetic analyses were conducted using Pmetrics software. A 5,000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for multiple dosing regimens, using 50% of free drug time above the minimum inhibitory concentration (MIC) as the primary pharmacodynamic threshold. Results Mean ± SD body weight was 28.5 ± 9.7 kg. Piperacillin concentration data best fit a two-compartment model with linear clearance, using total body weight as a covariate for clearance (CLθ) and volume of the central compartment (Vcθ). Population estimates for CLθ, Vcθ, and intercompartment transfer constants were 0.204 ± 0.076 L/h/kg, 0.199 ± 0.107 L/kg, 0.897 ± 1.050 h−1, and 1.427 ± 1.609 h−1, respectively. R2, bias, and precision for the Bayesian fit were 0.998, −0.032, and 2.2 µg/ml, respectively. At the MIC breakpoint of 16 µg/ml for Pseudomonas aeruginosa, PTAs for 50 mg/kg q4h as a 0.5 hr infusion was 93.9%; for 100 mg/kg q8h as 0.5 and 4 hr infusion: 64.6% and 100%; for 100 mg/kg q6h as 0.5 and 3 hr infusion: 86.5% and 100%; and for 400 mg/kg continuous infusion: 100%, respectively. Conclusions In children with fever and neutropenia, piperacillin/tazobactam dosing regimens that are administered every 4 hr or that employ prolonged or continuous infusions should be considered to optimize pharmacodynamic exposure. Pediatr Blood Cancer 2015;62:477–482.

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

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.

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

To describe the population pharmacokinetics and pharmacodynamic target attainment of ampicillin in neonates with hypoxic‐ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH).

Pharmacokinetics of Continuous Infusion Meropenem With Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy: A Case Report.

Pharmacokinetic parameters can be significantly altered for both extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT). This case report describes the pharmacokinetics of continuous-infusion meropenem in a patient on ECLS with concurrent CRRT. A 2.8-kg, 10-day-old, full-term neonate born via spontaneous vaginal delivery presented with hypothermia, lethargy, and a ~500-g weight loss from birth. She progressed to respiratory failure on hospital day 2 (HD 2) and developed sepsis, disseminated intravascular coagulation, and liver failure as a result of disseminated adenoviral infection. By HD 6, acute kidney injury was evident, with progressive fluid overload >1500 mL (+) for the admission. On HD 6 venoarterial ECLS was instituted for lung protection and fluid removal. On HD 7 she was initiated on CRRT. On HD 12, a blood culture returned positive and subsequently grew Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) for meropenem of 0.25 mg/L. She was started on vancomycin, meropenem, and amikacin. A meropenem bolus of 40 mg/kg was given, followed by a continuous infusion of 10 mg/kg/hr (240 mg/kg/day). On HD 15 (ECLS day 9) a meropenem serum concentration of 21 mcg/mL was obtained, corresponding to a clearance of 7.9 mL/kg/min. Repeat cultures from HDs 13 to 15 (ECLS days 7-9) were sterile. This meropenem regimen was successful in providing a target attainment of 100% for serum concentrations above the MIC for ≥40% of the dosing interval and was associated with a sterilization of blood in this complex patient on concurrent ECLS and CRRT circuits.

Therapeutic drug monitoring of continuous-infusion acylovir for disseminated herpes simplex virus infection in a neonate receiving concurrent extracorporeal life support and continuous renal replacement therapy.

Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life‐threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14‐day‐old female with disseminated HSV‐1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patients dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 × 108 copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patients acyclovir serum concentrations measured at 24 and 72 hours after starting continuous‐infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn. This is the first report to describe the pharmacokinetics of continuous‐infusion acyclovir in a neonate receiving ECLS with concurrent CRRT. These data suggest that adding acyclovir to the dialysate fluid during CRRT is effective in achieving therapeutic drug concentrations despite the complications of adding ECLS and CRRT circuits to a small patient.