Population Pharmacokinetics of Cefepime in the Neonate

Capparelli, Edmund V.; Hochwald, Christine; Rasmussen, Maynard; Parham, A L; Bradley, John S.; Moya, Fernando

doi:10.1128/aac.49.7.2760-2766.2005

Cited by 52 publications

(62 citation statements)

References 27 publications

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“…Individual time-concentration curves of intravenous PEN in VLBW infants receiving PEN doses of 50,000 IU/kg (left) and 25,000 IU/kg (right). Dotted line, the patient accidentally received PEN at a dose of 83,300 IU (50 mg)/kg; the data for this patient were excluded from calculations of the PK parameter values for group 1; bold line, an infant born at the 26th week of gestation with a BW of 700 g had clinical edema and a PEN t 1/2 of 35.1 h; the data for this patient were included in the calculations of the PK parameter values for group 1. and especially immature tubular function, the renal elimination of other beta-lactam antibiotics within the first week(s) of life has been shown to be proportional to the glomerular filtration rate, with total CL R exceeding the glomerular filtration rate only after several weeks, when significant maturation of tubular function has been achieved (5,16,25). A significant correlation between the amount of PEN excreted into urine and CL CR was demonstrated in more mature neonates by McCracken et al (24) and was also shown in this study, suggesting that as with other beta-lactam antibiotics, glomerular filtration is the predominant renal excretion mechanism of PEN in VLBW neonates.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

Metsvaht

Oselin

Ilmoja

et al. 2007

Antimicrob Agents Chemother

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Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1; n ‫؍‬ 9) and 25,000 IU (15 mg)/kg q12h (group 2; n ‫؍‬ 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a highperformance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 g/ml (lower and upper quartiles, 109 and 157 g/ml, respectively) and 7 g/ml (lower and upper quartiles, 5 and 13 g/ml, respectively) after administration of the dose of 50,000 IU and 59 g/ml (lower and upper quartiles, 53 and 78 g/ml, respectively) and 3 g/ml (lower and upper quartiles, 3 and 4 g/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance (R 2 ‫؍‬ 0.309596; P ‫؍‬ 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC 90 for group B streptococci for the entire dosing interval.Antibiotics are widely used in neonatal intensive care units (NICUs), and their widespread use has been associated with the development of antibiotic resistance. These developments have led to the preferred use of antibiotics known or assumed to have lower potentials for the selection of resistant microorganisms (22).Penicillin G (PEN) is a safe and narrow-spectrum antibiotic that, in combination with gentamicin, is recommended for use for the empirical therapy of neonatal sepsis (31). It has many advantages over wide-spectrum penicillins and cephalosporins. First, it has demonstrated favorable efficacy against the majority of organisms that cause neonatal sepsis (14, 27); second, it is well tolerated and does not cause allergic reactions in neonates; third, compared to other beta-lactam antibiotics, penicillin has the least effect on the development of resistance by gram-negative bacteria (9); and fourth, narrow-spectrum penicillins have a minimal effect on the normal bowel colonization in neonates and young infants (4, 17).The currently recommended PEN dosage for infants born at less than 29 weeks of gestation is 25,000...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

Metsvaht

Oselin

Ilmoja

et al. 2007

Antimicrob Agents Chemother

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“…were assembled for analysis (22,23). In both studies, CFP concentrations were measured by a validated high-performance liquid chromatography method.…”

Section: Methodsmentioning

confidence: 99%

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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“…It is a white to pale yellow powder and is highly soluble in water (Capparelli et al, 2005;Gutierrez, 2004;Kessler et al, 1985;Shahid, 2008).…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage

Chen

Min

Zhao

et al. 2015

Drug and Chemical Toxicology

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Shuanghuanglian injection (SHLI) has been widely used for administration with cephalosporin in China for long time. The objective of this study was to evaluate the pharmacological properties and biochemical changes of cefepime combined with SHLI. The SD rats included were received either an intravenous (iv. 4 mL/kg) dose of normal saline, or intravenous (iv. 0.74, 0.37, 0.185 g/kg, respectively) doses of SHLI once daily for 7 days. After last administration, cefepime (0.41 g/kg) was intravenous injected to the animals. The serum and urine samples were acquired and stored at 4 °C. They were used for quantitative determination of urea nitrogen (BUN), creatinine (CRE), urine protein, alkaline phosphatase (ALP) and N-acetyl-B-d-glucosaminidase (NAG). At different time points, the levels of cefepime in rat plasma were estimated for pharmacokinetic measures by HPLC. Aspirin was selected as internal standard (IS). The results showed that there were positive effects by increasing the total amount of CRE, BUN, NAG and urine protein (p < 0.01 or <0.05) and decreasing the levels of ALP (especially the high dose group of SHLI with cefepime) (p < 0.01). Besides, the pharmacokinetic results indicated that cefepime was distributed as non-compartment model after intravenous administration. Compared with the corresponding values for the compounds given alone, the area under the blood drug concentration time curve (AUC0-t and AUC0-∞) was better increased in middle- and high-dose groups (pall < 0.01), the mean residence time (MRT) of cefepime was larger (pall < 0.01) and the total clearance (CL) was lower at different levels. The results mean that the duration and concentration of cefepime could be prolonged and the clearance reduced while in combination with SHLI. Furthermore, the cefepime in the three tested doses caused changes of renal tubular epithelial cells while the severity of changes mainly dependent on the specific doses. In conclusion, the results above-mentioned suggest a possible contribution of drug combination in the nephrotoxicity and biochemical alterations especially at high doses. Further, monitoring measures for the renal functions are warranted to evaluate during the combination of these two drugs.

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Population Pharmacokinetics of Cefepime in the Neonate

Cited by 52 publications

References 27 publications

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

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

The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage

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