Serum Concentrations of Cefotaxime and its Metabolite Desacetyl-cefotaxime in Infants and Children During Continuous Infusion

Bertels, Robin A.; Semmekrot, B.A.; Gerrits, G. P. J. M.; Mouton, Johan W.

doi:10.1007/s15010-008-7274-1

Cited by 17 publications

(10 citation statements)

References 27 publications

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“…Interestingly, gestational age and postnatal age did not predict CL or V; other factors, such as disease state, protein binding, organ perfusion, etc., might be responsible. A study of 107 neonates (6) showed that clearance increased dramatically with PNA during the first week after birth, but there was no sign of this development in our data set. It is possible that critical illness in our ECMO patients, with the use of drugs influencing renal perfusion (i.e., high doses of norepinephrine and dopamine), led to a low baseline renal clearance that was artificially supplemented by CVVH; the median Q CVVH per individual did not vary much.…”

Section: Discussioncontrasting

confidence: 75%

“…The patient with the lowest t ϾMIC (49%) had negative cultures throughout his ECMO run, while the patients with positive cultures had t ϾMIC values of 90% or higher, but this could have been caused by resistance or lack of efficacy of other concomitant antibiotics. The CTX clearance estimate we found for ECMO patients (0.36 liter/h) was similar to those for non-ECMO-treated full-term neonates, which vary from 0.20 to 0.55 liter/h (6,19,23). The distribution volume, however, was larger than those for non-ECMO patients (1.82 liters versus 0.68 to 1.14 liters) (19,23), which could be caused by hemodilution or capillary leakage of protein-bound drug into the extravascular compartment, especially in the early phase of ECMO (24 to 36 h after cannulation).…”

Section: Discussionsupporting

confidence: 74%

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Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Ahsman

Wildschut

Tibboel

et al. 2010

Antimicrob Agents Chemother

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Extracorporeal membrane oxygenation (ECMO) is used to temporarily sustain cardiac and respiratory function in critically ill infants but can cause pharmacokinetic changes necessitating dose modifications. Cefotaxime (CTX) is used to prevent and treat infections during ECMO, but the current dose regimen is based on pharmacokinetic data obtained for non-ECMO patients. The objective of this study was to validate the standard dose regimen of 50 mg/kg of body weight twice a day (postnatal age [PNA], <1 week), 50 mg/kg three times a day (PNA, 1 to 4 weeks), or 37.5 mg/kg four times a day (PNA, >4 weeks). We included 37 neonates on ECMO, with a median (range) PNA of 3.3 (0.67 to 199) days and a median (range) body weight of 3.5 (2.0 to 6.2) kg at the onset of ECMO. Median (range) ECMO duration was 108 (16 to 374) h. Plasma samples were taken during routine care, and pharmacokinetic analysis of CTX and its active metabolite, desacetylcefotaxime (DACT), was done using nonlinear mixed-effects modeling (NONMEM). A one-compartment pharmacokinetic model for CTX and DACT adequately described the data. During ECMO, CTX clearance (CL CTX ) was 0. Extracorporeal membrane oxygenation (ECMO) is used as a standardized last resort to support critically ill infants who can no longer maintain sufficient cardiac and respiratory function with conventional life support techniques (5,8). Over a period of up to a maximum of 3 weeks, blood flow is continuously diverted via a venous cannula into an extracorporeal circuit, oxygenated via a membrane, and returned to the general circulation via a venous or arterial cannula. A hemofiltration unit can be added to the circuit to supplement insufficient renal function. Standard pharmacological treatment includes high doses of antibiotics for the treatment of preexisting or nosocomial infections, which are facilitated by the direct microbial access to the patient's general circulation via cannulae and circuit components (15). One of the antibiotics commonly used in neonates on ECMO is cefotaxime (CTX), which possesses antimicrobial activity against many of the pathogens commonly involved in neonatal and ECMO-related infections, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter, and Staphylococcus spp. (27). In adults, cefotaxime can be excreted unchanged via the renal system, but also after hepatic conversion into its active metabolite, desacetylcefotaxime (DACT) (for 15 to 25% of a dose) (33). There appears to be an inverse correlation between renal function and elimination half-life, particularly for DACT (32).In the absence of specific pharmacokinetic (PK) data, our current cefotaxime dose regimen is the same for both ECMO and non-ECMO patients. In general, however, ECMO is associated with altered pharmacokinetics for a variety of drugs, probably due to an increase in circulatory volume, a diseaserelated clearance reduction, or adsorption of drugs to membranes and other circuit components (7). We designed this study to evaluate the pharmacokinetics of cefotaxime and desacetylcefotaxim...

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionsupporting

confidence: 74%

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Ahsman

Wildschut

Tibboel

et al. 2010

Antimicrob Agents Chemother

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“…While a T MIC of at least 40 to 50% of the dosing interval is generally accepted in adults (39), the immunocompromised status of neonates (14, 15) requires a higher T MIC target to ensure efficacy and to avoid the induction of antibiotic resistance (40,41). We selected a T MIC target of 75% of the dosing interval, which is consistent with the value used in other pharmacokinetic-pharmacodynamic studies of ␤-lactams in neonates (42)(43)(44).…”

Section: Figmentioning

confidence: 97%

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Leroux

Roué

Gouyon

et al. 2016

Antimicrob Agents Chemother

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Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants. C efotaxime is one of the most frequently prescribed antibiotics in neonates (1). This third-generation cephalosporin is mainly used in the treatment of neonatal sepsis (2) and meningitis caused by Gram-negative bacteria. Because of the high rates of morbidity and mortality (3), the optimal use of cefotaxime is essential in neonatal infection management. However, the dosing regimens routinely used in clinical care vary considerably. As reported in our previous study, 25 different dosage regimens of cefotaxime were identified in the French neonatal intensive care unit (NICU) network, with median daily doses varying from 75 mg/kg of body weight/day to 180 mg/kg/day among NICUs (4). This huge variation can be partly explained by the different dosage recommendations available in reference textbooks and published guidelines (1). It also highlights the need for powerful pharmacokinetic (PK) data for neonates. As recently reviewed by Pacifici et al. (5), the pharmacokinetics of cefotaxime in neonates were mainly studied in the 1980s with a limited number of patients. The study design and analysis method limited the power to determine a precise dose of cefotaxime derived from pharmacokinetic data, as the quantitative impacts of covariates (i.e., maturation, organ function) on dose were not fully assessed. The simplification of the impacts of covariates could lead to signific...

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“…In addition, these authors found a significant variability in protein binding further contributing to the variability of active drug concentrations. In children, concentrations during continuous infusion of cefotaxime varied widely between patients age 0-17 years, especially in children younger than 1 week (Bertels et al 2008).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Continuous Infusion of Beta-lactam Antibiotics

Muller

Mouton

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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For beta-lactam antibiotics continuous infusion can be used to optimise antibiotic therapy. Pre-clinical studies in rodents and in vitro studies have shown the benefits of continuous infusion when compared to intermittent dosing. Pharmacokinetic studies in humans have shown an improved probability of target attainment for continuous infusion. However, the relationship between continuous infusion and improved clinical outcome is ambiguous. The superiority of continuous infusion over intermittent dosing in clinical outcome studies is most often documented in special subgroups, such as critically ill patients or patients infected with less-susceptible micro-organisms. Methods to calculate doses during continuous infusion and practical issues, such as stability of antimicrobial solutions, are described.

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Serum Concentrations of Cefotaxime and its Metabolite Desacetyl-cefotaxime in Infants and Children During Continuous Infusion

Abstract: Overall, cefotaxime concentrations varied widely between patients, in particular in those younger than 1 week. Our data suggest that liver metabolism as well as renal excretion contribute to total body clearance of cefotaxime and increase during the first few days of live.

Cited by 17 publications

References 27 publications

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Continuous Infusion of Beta-lactam Antibiotics

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