Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Infants during Extracorporeal Membrane Oxygenation

Abstract

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...

Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation

“…Our results are different from those of other studies, in which the volume of distribution was generally increased and the clearance was decreased for drugs administered during ECMO (8,(15)(16)(17). Several explanations for our findings are possible.…”

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

“…All these observations of routine care highlight the urgent requirement for powerful pharmacokinetic data for this vulnerable population. Previous studies assessing the pharmacokinetics of cefotaxime in neonates included a relatively small number of patients (n Յ 37) (18,(22)(23)(24)(25)(26)(27)(28)(29) and did not precisely quantify the impact of maturation on the disposition of cefotaxime. Previous mean estimates of cefotaxime clearance in term neonates varied from 0.09 liter/ h/kg to 0.14 liter/h/kg (5).…”

Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation

“…The PK of cefotaxime and its active metabolite, desacetylcefotaxime, was described in 37 neonates receiving ECMO [80]. The standard cefotaxime dose regimen (50 mg/ kg of body weight twice a day [postnatal age, or PNA], b1 week), 50 mg/kg 3 times a day (PNA, 1-4 weeks), or 37.5 mg/kg 4 times a day (PNA, N4 weeks) provided sufficiently long periods of supra-minimum inhibitory concentration to provide adequate treatment of infants on ECMO.…”