Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response.

OBJECTIVES: Neonatal seizures are common complications. Phenobarbital is the agent of choice but leads to adverse neurologic outcomes. There has been increased use of newer agents like levetiracetam. The objective of this study was determining the rate of seizure resolution in neonates treated with phenobarbital or levetiracetam. METHODS: This was a retrospective, single-center, cohort study from June 1, 2012-June 1, 2018 evaluating seizure resolution in neonates following first-line treatment with phenobarbital versus levetiracetam. Data were collected via review of the patient's charts in the electronic medical record. The primary outcome was seizure resolution without addition of a second antiepileptic agent. Logistic regression was used to assess the impact of pertinent variables. RESULTS: Each group included 73 patients. The mean gestational age was 36.01 and 37.91 weeks for the phenobarbital and levetiracetam groups, respectively (p = 0.011). The phenobarbital group had higher rates of intraventricular hemorrhage at baseline. The median birth weight was 2750 and 3002 grams in the phenobarbital and levetiracetam groups, respectively (p = 0.10). Forty-five neonates (61.6%) achieved seizure resolution with phenobarbital compared with 30 neonates (41.1%) with levetiracetam (p = 0.01). In neonates who did not receive a benzodiazepine, seizure resolution was similar between groups (51-52%). In neonates who received a benzodiazepine, seizure resolution rate was 94.1% (16/17 neonates) for phenobarbital and 18.2% (4/22 neonates) for levetiracetam. CONCLUSIONS: These findings suggest seizure resolution with levetiracetam, and phenobarbital may be impacted by benzodiazepine administration. If no benzodiazepine is used, these agents demonstrated similar efficacy. Further research into the pharmacodynamic interaction with benzodiazepines is necessary.

Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age.

OBJECTIVES: The objectives of the study were to compare the free serum concentrations after different fosphenytoin loading dose strategies in patients younger than 6 months old and to investigate the frequency of seizure cessation following a loading dose of fosphenytoin. METHODS: This retrospective cohort study included neonates and infants admitted to a 150-bed children's hospital between August 1, 2014, and February 1, 2018. Patients were included if they were younger than 6 months old and had a postload free phenytoin serum concentration collected during the specified time frame. Patients were identified through a database query screening for the inclusion criteria. Patients were separated into 2 groups with the 15 mg/kg group as per protocol and the 20 mg/kg group as noted in common practice. Data collection included demographic information, fosphenytoin dose, time of administration of the fosphenytoin loading dose, time of sampling, free phenytoin serum concentration results, concomitant antiepileptic agents, albumin serum concentration, and total bilirubin serum concentration. RESULTS: Forty-one patients were included for analysis, 12 in the 15 mg/kg group and 29 in the 20 mg/kg group. The average free phenytoin concentration after the loading dose was 2.45 ± 0.54 mg/L in the 15 mg/kg group and 2.52 ± 0.66 mg/L in the 20 mg/kg group. Seizure cessation after the fosphenytoin loading dose was achieved in 3 of 12 (25%) patients in the 15 mg/kg group and in 13 of 29 (45%) patients in the 20 mg/kg group (p = 0.305). CONCLUSIONS: The study demonstrates that a traditional range of fosphenytoin loading dose (15-20 mg/kg) led to elevated postloading dose free phenytoin serum concentrations in the majority of patients with a seizure cessation rate of approximately 39%. The question remains as to what the optimal dose and target concentration should be in this patient population to achieve the best efficacy without risking associated toxicities.

Effectiveness of Levetiracetam as a First-Line Anticonvulsant for Neonatal Seizures.

OBJECTIVE: Optimal treatment for neonatal seizures remains unclear, and management among US hospitals is highly varied. The purpose of this study was to evaluate the effectiveness of levetiracetam as a first-line treatment for seizures in a neonatal population. METHODS: A single-center, retrospective review of neonates at a tertiary medical center who received levetiracetam as a first-line agent after benzodiazepines for seizure control between 2015 and 2017 was conducted. Chart review was completed to analyze patient and treatment characteristics. The primary outcome was seizure control, defined as clinical seizure cessation and video electroencephalogram resolution, with no new seizures documented prior to discharge. RESULTS: A total of 36 patients met inclusion criteria. Seventeen patients (47%) had seizure control after intravenous levetiracetam as monotherapy. Eighteen patients required a second anticonvulsant, of which 13 (72%) had seizure control. In total, 30 patients (83%) had seizure control with levetiracetam monotherapy or combination therapy of levetiracetam plus fosphenytoin or phenobarbital. CONCLUSIONS: Levetiracetam monotherapy provided seizure control in about 50% of the patients reviewed. Overall, seizure control was observed in 83% of the study population that received either levetiracetam monotherapy or combination therapy of levetiracetam plus fosphenytoin or phenobarbital as a second-line agent. Further studies are warranted to directly compare historical therapies with levetiracetam for neonatal seizure control.

Pharmacokinetic and Pharmacodynamic Analyses of Ceftaroline in Adults with Cystic Fibrosis.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of ceftaroline in adults with cystic fibrosis (CF). DESIGN: Open-label, single-center, prospective study. SETTING: University-affiliated teaching institution. PATIENTS: Eight patients with a diagnosis of CF and a history of methicillin-resistant Staphylococcus aureus who were treated with ceftaroline between November 2013 and September 2014. INTERVENTION: All patients received at least three doses of intravenous ceftaroline 600 mg every 12 hours, administered as a 60-minute infusion, to achieve steady-state concentrations before blood sample collection. After an interim analysis of the first four patients' pharmacokinetic data, the remaining four patients received a change in dosage of ceftaroline to 600 mg every 8 hours. MEASUREMENTS AND MAIN RESULTS: Patients' blood samples were collected at two time points, 2 and 6 hours after infusion initiation, after administration of at least three doses of ceftaroline. Serum ceftaroline concentrations were determined by using a validated mass spectrometry, with a lower limit of detection of 20 ng/ml. These ceftaroline concentrations were used to estimate patient-specific pharmacokinetic parameters, and 10,000-patient Monte Carlo simulations were performed to determine the pharmacodynamic probability of target attainment (PTA) for ceftaroline in adults with CF. A PTA of 90% or higher for the desired pharmacodynamic target was considered adequate. The PTA for 60% or higher of the dosing interval during which free (unbound) drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) was simulated for various MICs. Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and the estimated half-life was shorter. Monte Carlo simulations revealed that a dose of ceftaroline 600 mg every 8 hours, infused over 60 minutes, maintained a higher than 90% PTA for %fT > MIC of 60% or higher for an MIC at the susceptibility breakpoint of 1 mg/L. CONCLUSION: The pharmacokinetics of ceftaroline is altered in adults with CF, which suggests the need for modified dosing in this patient population to achieve adequate %fT > MIC. A dosage of intravenous ceftaroline 600 mg every 8 hours administered as a 60-minute infusion should be considered to achieve 60% fT > MIC.

Levetiracetam in neonatal seizures: a review.

Phenobarbital and phenytoin have been the mainstay treatment modalities for neonatal seizures. Studies have revealed these agents control seizures in less than half of neonates, can cause neuronal apoptosis in vitro, and have highly variable pharmacokinetics in neonates. In contrast, there have been no reports of levetiracetam causing these neurotoxic effects. Due to its favorable side effect and pharmacokinetic profiles and positive efficacy outcomes in neonatal studies to date, there is great interest in the use of levetiracetam for neonatal seizures. This article reviews the literature regarding the safety of levetiracetam in neonates and its efficacy in neonatal seizures.