Target attainment of cefotaxime in critically ill children with meningococcal septic shock as a model for cefotaxime dosing in severe pediatric sepsis

Hartman, Stan; Boeddha, Navin P.; Ekinci, Ebru; Koch, Birgit C. P.; Donders, Rogier; Hazelzet, Jan A.

doi:10.1007/s10096-019-03535-w

Cited by 9 publications

(7 citation statements)

References 21 publications

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“…Béranger et al and Hartman et al defined higher targets of 100% f T> MIC and 100% f T> 4x MIC. They only found satisfactory target achievement against strains with low MIC ( ≤ 0.5 mg/L) with usual dose regimens of 100–150 mg/kg/day and suggested applying continuous infusion in septic children ( 22 , 23 ).…”

Section: Resultsmentioning

confidence: 99%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely treatment of life-threatening infections. We conducted a literature scoping review to identify therapeutic targets of beta-lactam antibiotics in septic pediatric patients and the strategies that have been applied to overcome sepsis-related altered pharmacokinetics and increase target attainment against susceptible pathogens. A systematic search was conducted in the MEDLINE, EMBASE and Web of Science databases to select studies conducted since 2010 with therapeutic monitoring data of beta-lactams in septic children. Last searches were performed on 02 September 2021. Two independent authors selected the studies and extracted the data. A narrative and qualitative approach was used to summarize the findings. Out of the 118 identified articles, 21 met the eligibility criteria. Population pharmacokinetic modeling was performed in 12 studies, while nine studies reported data from bedside monitoring of beta-lactams. Most studies were conducted in the United States of America (n = 9) and France (n = 5) and reported PK/PD data of amoxicillin, ampicillin, azlocillin, aztreonam, cefazolin, cefepime, cefotaxime, ceftaroline, ceftazidime, doripenem, meropenem and piperacillin/tazobactam. Therapeutic targets ranged from to 40% fT> MIC to 100% fT> 6 × MIC. Prolonging the infusion time and frequency were most described strategies to increase target attainment. Monitoring beta-lactam serum concentrations in clinical practice may potentially maximize therapeutic target attainment. Further studies are required to define the therapeutic target associated with the best clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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“…eGFR, serum creatinin, albumin, C-reactive protein, transaminases) as covariate were limited [21,25,26,28,51,52,55,57]. Of the 48 studies, only 5 PK models have incorporated eGFR in their estimations for drug Cl [21,26,51,55,57] and only 3 additional studies found a significant relation between serum creatinine and drug concentration [29,45,60]. Other studies have either not investigated this relationship or found the addition of creatinine clearance to be non-significant.…”

Section: Discussionmentioning

confidence: 99%

“…While three studies were found reporting cefotaxime PK in critically ill children [27][28][29], most children in the study by Von Hattingberg et al were neonates, with only two patients > 1 month of age included in the PK analysis [27]. Doses used varied from 100 to 300 mg/kg/day in 3-4 daily doses, with patients > 50 kg receiving adult doses of three daily doses of 1000 mg in the study by Béranger et al [28].…”

Section: Cefotaximementioning

confidence: 99%

“…Doses used varied from 100 to 300 mg/kg/day in 3-4 daily doses, with patients > 50 kg receiving adult doses of three daily doses of 1000 mg in the study by Béranger et al [28]. Although the exact reason for admission was only clear from the study by Hartman et al [29], organ dysfunction scores and length of PICU stay was reported in two studies [28,29]. Organ dysfunction scores and disease severity were highest among the meningococcal septic shock patients studied by Hartman et al PELOD scores were included in both the model building and validation cohorts by Béranger et al [28].…”

Section: Cefotaximementioning

confidence: 99%

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Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

et al. 2019

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Background Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. Methods Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. Results 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. Conclusion The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

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“…Additionally, an MIC non-species related breakpoint of 1 mg/L is commonly used for the treatment of a susceptible pathogen, with an MIC of >2 mg/L indicating a resistant pathogen 13 . Current cefotaxime dosing regimens of 50 mg/kg every 6 h, with a maximum dose of 2 g (a total daily dose of up to 8 g), are commonly used for critically ill paediatric patients (>one month old of life) [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

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

Valero

Dorofaeff

Coulthard

et al. 2022

Preprint

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Objectives: This study aimed 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 PK/PD targets, including 100% fT>MIC with an MIC breakpoint of 1 mg/L. Results: 36 patients (0.2 - 12 y) 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 and 39.4 L/h, 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% fT>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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Target attainment of cefotaxime in critically ill children with meningococcal septic shock as a model for cefotaxime dosing in severe pediatric sepsis

Cited by 9 publications

References 21 publications

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

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

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