Population pharmacokinetics of cefepime in neonates with severe nosocomial infections

Lima‐Rogel, Victoria; Medina-Rojas, E L; Milán‐Segovia, Rosa del Carmen; Noyola, Daniel E.; Nieto-Aguirre, K; López-Delarosa, A; Romano‐Moreno, Silvia

doi:10.1111/j.1365-2710.2008.00913.x

Cited by 27 publications

(28 citation statements)

References 22 publications

(27 reference statements)

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“…Lima-Rogel et al reported PK of cefepime from neonates and young infants (35). Their CL, Vss, and half-life values were similar to those in neonates in our study.…”

Section: Discussionsupporting

confidence: 73%

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

Shoji

Bradley

Reed

et al. 2016

Antimicrob Agents Chemother

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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...

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“…Lima-Rogel et al reported PK of cefepime from neonates and young infants (35). Their CL, Vss, and half-life values were similar to those in neonates in our study.…”

Section: Discussionsupporting

confidence: 73%

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

Shoji

Bradley

Reed

et al. 2016

Antimicrob Agents Chemother

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“…The pharmacokinetic parameters by Lima-Rogel et al [64] and those by Capparelli et al [52] were obtained in infants with similar demographic data t 1/2 and Cl are comparable in these two studies. Reed et al [63] described the pharmacokinetics of cefepime in older infants and children and in this study, t 1/2 was one half and Cl was double those in the neonates.…”

Section: Cephalosporinssupporting

confidence: 60%

Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review

Pacifici

2010

Pharmaceuticals

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Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2), clearance (Cl), and volume of distribution (Vd) change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides) AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based.

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“…Although there have been several cefepime population pharmacokinetic models developed in the literature (16,23), there are few that specifically observe an adult critically ill patient population (8,22), and only one has explored the utilization of a prolonged infusion of cefepime (24). The importance of observing this patient population is centered upon the patient heterogeneity and the large interindividual pharmacokinetic parameters within the ICU populations.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia

Nicasio

Ariano

Zelenitsky

et al. 2009

Antimicrob Agents Chemother

112

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A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups-26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K slope pharmacokinetic model relating the elimination rate constant (K 10 ) to renal function, as defined by creatinine clearance (CL CR ), and central distribution volume (V 1 ) to total body weight (TBW). The final model was described by the following equations: K 10 ‫؍‬ 0.0027 ؋ CL CR ؉ 0.071 h ؊1 and V 1 ‫؍‬ TBW ؋ 0.21 liter/kg. The median intercompartmental transfer constants K 12 and K 21 were 0.780 h ؊1 and 0.472 h ؊1 , respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 g/ml, 24.0 g/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of ؊1.64 g/ml, 17.1 g/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 g/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

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Population pharmacokinetics of cefepime in neonates with severe nosocomial infections

Cited by 27 publications

References 22 publications

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

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

Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review

Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia

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