Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

Abstract

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints for Enterobacteriaceae in 2014, and MICs of 4 and 8 g/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 g/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, >30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 g/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 g/ml. Prolonged i.v. infusions may be useful for this population. Health care-associated infections (HAI), such as ventilator-associated pneumonia, catheter-associated urinary tract infection, surgical site infection, and catheter-related bloodstream infection, may lead to morbidity and mortality in children (1-3). Infections caused by Gram-negative bacilli (GNB) are a major cause of HAI, including infections caused by Pseudomonas aeruginosa and the Enterobacteriaceae, such as Klebsiella pneumoniae and Escherichia coli (4, 5). The incidence of multidrug-resistant GNB, based on the presence of extended-spectrum ␤-lactamases (ESBLs) and AmpC ␤-lactamases, is increasing globally (6-9). Infections caused by these organisms are associated with a poor prognosis (10, 11). Further complicating this clinical challenge is that development of new antibiotics effective against these important pathogens has been slow (12). It is important to use existing antibiotics effectively whenever possible, using pharmacokinetics (PK) and pharmacodynamics (PD) analyses. Cefepime (CFP), a fourth-generation cephalosporin, is widely used to treat infections caused by GNB in both adult and pediatric patients (13,14). Several studies have shown the effectiveness and safety of CFP in treating urinary tract and lower respiratory infections in children (15,16). Further, CFP is also an important choice to treat multidrug-resistant GNB, such as AmpC ␤-lactamase-producing strains and several strains of ESBL-producing organisms with MICs that correspond to clinically achievable pl...

Developmental Population Pharmacokinetics and Dosing Optimization of Cefepime in Neonates and Young Infants

“…In this study, the mean cefepime CL to neonates was 0.18 (0.13-0.24) l/h/kg. Previous reports showed that cefepime CL in neonates was approximately 0.07 to 0.20 l/h/kg (Capparelli et al, 2005;Lima-Rogel et al, 2008;Shoji et al, 2016). Thus, our results were consistent well with former research.…”

“…Therefore, the function and maturation of the kidneys affects cefepime performance; the pharmacokinetics of neonates differ from those of adults and older children (Reed et al, 1997;Blumer et al, 2001). To the best of our knowledge, pharmacokinetic studies of cefepime has only been conducted in preterm neonates with narrow age range and the developed population pharmacokinetic models had not been externally validated (Capparelli et al, 2005;Lima-Rogel et al, 2008;Shoji et al, 2016). In addition, the developmental pharmacokineticpharmacodynamic based dosing recommendation of cefepime was not available in China.…”

Comparison of Antibiotic Dosing Before and After Implementation of an Electronic Order Set

“…Additionally, every 12-hour regimens of cefepime remain common in tertiary dosing references despite questionable pharmacokinetic and pharmacodynamic optimization. 26 Tobramycin orders were significantly more appropriate when ordered through the electronic antibiotic order set versus a blank order sheet, which could indicate less prescriber familiarity despite similarity in dosing to gentamicin.…”

Cefepime Dosing in Neonates: What is the Evidence?

“…11 For organisms with higher MICs of 4 to 8 mg/L, Shoji et al and Lima-Rogel et al both recommended a dose of approximately 50 mg/kg per dose to ensure serum concentrations above the MIC for 60% of the dosing interval. 11,12 For inherently resistant pathogens, such as P. aeruginosa, or difficult to treat infections, such as meningitis, some references suggest higher dosing (50 mg/kg per dose) should be utilized. [6][7][8] This recommendation is consistent with the results and conclusions of the studies presented, corroborated by current CLSI breakpoints of 8 mg/L for Pseudomonas and non-Enterobacteriaceae species and 2 mg/mL for Enterobacteriaceae species.…”

“…In the Monte Carlo simulation, preterm neonatal patients (<36 weeks of GA) receiving cefepime doses of 30 to 50 mg/kg every 12 hours attained a time above an MIC of 8 for 60% of the dosing interval with both doses in more than 94% of the population. 12 In term infants, neonates less than 30 days of age, time above MIC for 60% of the dosing interval was achieved in 86.4 and 95.3% of infants with doses of 30 and 50 mg/kg, respectively, every 12 hours. Even when the target attainment rates increased to 70% of time above MIC, this was achieved in 90% of term neonates and 96% of preterm neonates.…”