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. 2022 Jul 28;77(8):2227-2237.
doi: 10.1093/jac/dkac168.

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

Yarmarly C Guerra Valero  1 , Tavey Dorofaeff  1   2 , Mark G Coulthard  2   3 , Louise Sparkes  2 , Jeffrey Lipman  1   4   5 , Steven C Wallis  1 , Jason A Roberts  1   4   6 , Suzanne L Parker  1
Affiliations

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

Yarmarly C Guerra Valero et al. J Antimicrob Chemother. .

Abstract

Objectives: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling.

Methods: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L.

Results: Thirty-six patients (0.2-12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function.

Conclusions: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.

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Figures

Figure 1.
Figure 1.
Diagnostic plots for the final covariate model for plasma concentrations (mg/L) of cefotaxime (top) and desacetylcefotaxime (bottom). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 2.
Figure 2.
Flow chart to support dosing recommendations in Tables 3–5. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 3.
Figure 3.
External validation linear regression plots of cefotaxime (top) and desacetylcefotaxime (bottom) comparing observed concentrations (capillary microsampling) with model-predicted concentrations (using conventional sampling). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 4.
Figure 4.
Bland–Altman weighted residual plots for external validation of cefotaxime (top) and desacetylcefotaxime (bottom) comparing observed concentrations (capillary microsampling) with model-predicted concentrations (using conventional sampling). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 5.
Figure 5.
Scatter plots (top) and Bland–Altman plots (bottom) of conventional sampling and capillary microsampling (CMS) of cefotaxime (left) and desacetylcefotaxime (right). ULoA, upper 95% limit of agreement; LLoA, lower 95% limit of agreement.
See this image and copyright information in PMC

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