Population pharmacokinetics of cefotaxime in intensive care patients

Abstract

Purpose To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. Methods This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. Results A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. Conclusion A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

“…Cefotaxime and desacetylcefotaxime are eliminated by the kidneys and estimated creatinine clearance (using eGFR) was able to be included on the clearance of cefotaxime. This finding concords with data from critically ill adult patients that have shown clearance to be proportional to estimated creatinine clearance 27 . No other studies have found an association between body surface area and clearance of desacetylcefotaxime, although a relationship between body surface area and liver volume has been recently identified in children 28 and this may account for the relationship identified for the metabolite in our study.…”

Dose optimization of cefotaxime as pre‐emptive treatment in critically ill adult patients: A population pharmacokinetic study

“…In this heterogeneous study population, 2 significant covariates were found to be positively related to an increase in clearance, namely the eGFR and the albumin concentration. The effect of the eGFR is probably explained by the predominant renal clearance of cefotaxime and has also been identified by the studies of Swartling et al and Aardema et al 11,32 In the study of Swartling et al, a change in eGFR of 10 mL min À1 increased clearance by 0.74 L h À1 for eGFRs at or below 120 mL min À1 . In our exponential model, the increases in clearance are consistent with these result ranging from 0.42-0.99 L h À1 per 10 mL min À1 with a smaller increase in clearance at higher eGFRs.…”

“…21.6 L on average in healthy volunteers, which is probably due to expansion of the interstitial space because of capillary leakage combined with fluid loading 4,16–20 . Compared to a previous popPK study of cefotaxime as empirical treatment in critically ill patients, clearance was lower and volume of distribution higher 32 . The former might be explained by the high median eGFR of the patients included by Swartling et al .…”

“…The effect of the eGFR is probably explained by the predominant renal clearance of cefotaxime and has also been identified by the studies of Swartling et al . and Aardema et al 11,32 …”

“… 4 , 16 , 17 , 18 , 19 , 20 Compared to a previous popPK study of cefotaxime as empirical treatment in critically ill patients, clearance was lower and volume of distribution higher. 32 The former might be explained by the high median eGFR of the patients included by Swartling et al . namely 94 mL min −1 compared to 57 mL min −1 in our population.…”