The impact of vancomycin protein binding on target attainment in critically ill children

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

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O-10 An observational study on plasma protein binding and target attainment of teicoplanin in critically ill children

Archives of Disease in Childhood ◽

10.1136/archdischild-2017-esdppp.10 ◽

2017 ◽

Vol 102 (10) ◽

pp. A5.1-A5

Author(s):

De Cock ◽

Wollaert ◽

Desmet ◽

McWhinney ◽

De Jaeger ◽

...

Keyword(s):

Observational Study ◽

Protein Binding ◽

Critically Ill ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Critically Ill Children ◽

Target Attainment ◽

O 10

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Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board?

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkw495 ◽

2016 ◽

pp. dkw495 ◽

Cited By ~ 3

Author(s):

Pieter A. J. G. De Cock ◽

Sarah Desmet ◽

Annick De Jaeger ◽

Dominique Biarent ◽

Evelyn Dhont ◽

...

Keyword(s):

Protein Binding ◽

Critically Ill ◽

Critically Ill Children ◽

Target Attainment ◽

Drawing Board

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The long and the short of it – the impact of acute kidney injury in critically ill children

Jornal de Pediatria (Versão em Português) ◽

10.1016/j.jpedp.2020.01.004 ◽

2020 ◽

Vol 96 (5) ◽

pp. 533-536

Author(s):

Michael Zappitelli ◽

Damien Noone

Keyword(s):

Acute Kidney Injury ◽

Critically Ill ◽

Kidney Injury ◽

Critically Ill Children ◽

The Impact

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P42 External validation of model-based dosing guidelines for vancomycin, gentamicin and tobramycin in critically ill children

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.80 ◽

2019 ◽

Vol 104 (6) ◽

pp. e34.2-e34

Author(s):

S Hartman ◽

S Zwaag ◽

L Orriëns ◽

T Poel ◽

M de Hoop - Sommen ◽

...

Keyword(s):

Critically Ill ◽

Clinical Laboratory ◽

External Validation ◽

Interindividual Variation ◽

Critically Ill Children ◽

Target Range ◽

Future Research ◽

Target Attainment ◽

Model Based ◽

Trough Concentrations

BackgroundPharmacokinetic models are frequently used to simulate dosing strategies for special populations, including critically ill children. The Dutch Pediatric Formulary (DPF) partially bases its guidelines on these models. However, prospective validation of updated dosing regimens is rare. We aimed to identify target attainment and safety of vancomycin, gentamicin and tobramycin after a dose update in the DPF for critically ill neonates and children.MethodsRetropsective cohort study in PICU and NICU patients receiving vancomycin, gentamicin or tobramycin between January 2015 and March 2017 in 2 university hospitals. Demographic clinical laboratory and TDM-data were collected. Target (steady state) trough concentrations for vancomycin, gentamicin and tobramycin used were 10–15, ≤1 and ≤1 mg/l, respectively. Target gentamicin peak concentrations used were 8–12 mg/l.Results486 patients were included in total (165 vancomycin, 97 gentamicin and 224 tobramycin). Trough concentrations of vancomycin, gentamicin and tobramycin were within the target range in 37.5%, 85.3% and 77.2% of patients, respectively. Target attainment of gentamicin peak concentrations in NICU patients was 31%. Non-target trough concentrations were most prevalent in term NICU patients (vancomycin 70%, gentamicin 26% and tobramycin 36.8%). Gentamicin peak concentrations were subtherapeutic in 91% and 45.5% for term and preterm NICU patients, respectively. Creatinine concentrations correlated positively with antibiotic concentrations (correlation coefficient range 0.46–0.54, p≤0.01 in all cohorts).ConclusionDespite recent model-based dosing alterations, sub- and supratherapeutic concentrations of vancomycin, gentamicin and tobramycin are still frequent in critically ill children. Linear dose alterations did offer improvements in target attainment, but did not fully address all relevant covariates that contribute to the large interindividual variation in clearance and/or volume of distribution in these patients. Creatinine clearance was consistently correlated with concentrations of all 3 drugs, but future research is needed to identify whether including this parameter in dosing can improve target attainment and safety.Disclosure(s)Nothing to disclose

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2 Systemic glucocorticoids and bradycardia in critically ill children: a retrospective study

Paediatrics & Child Health ◽

10.1093/pch/pxaa068.001 ◽

2020 ◽

Vol 25 (Supplement_2) ◽

pp. e1-e1

Author(s):

Camille Maltais-Bilodeau ◽

Maryse Frenette ◽

Geneviève Morissette ◽

Dennis Bailey ◽

Karine Cloutier ◽

...

Keyword(s):

Intensive Care Unit ◽

Heart Rate ◽

Intensive Care ◽

Retrospective Study ◽

Critically Ill ◽

Medical Staff ◽

Pediatric Population ◽

Critically Ill Children ◽

Rate Variation ◽

The Impact

Abstract Background Glucocorticoids are widely used in the pediatric population. They are associated with numerous side effects including repercussions on the cardiovascular system. The impact on heart rate is not well known, but bradycardia has been reported, mostly with high doses. Objectives We described the occurrence of bradycardias and the variation of heart rate in critically ill children receiving glucocorticoids. Design/Methods We conducted a retrospective study including 1 month old to 18 year old children admitted to the Pediatric Intensive Care Unit between 2014 and 2017, who received a glucocorticoid dose equivalent to 1 to 15 mg/kg/day of prednisone. We collected data on exposition to glucocorticoids, heart rate before, during and after the exposition, and interventions from the medical staff in response to bradycardia. The primary outcome was the occurrence of bradycardia and the secondary outcomes were the magnitude of heart rate variation and the clinical management of bradycardias. Results We included 92 admissions (85 patients). The median dose of glucocorticoid used was 2.80 mg/kg/day of prednisone (2.08—3.80). We found 70 cases (76%) with at least one bradycardia. Before treatment, all patients had a mean heart rate higher than the 5th percentile for age. During exposition to glucocorticoids, 8 patients (10%, n = 83) had a median heart rate ≤ 5th percentile. We noted 46 cases of bradycardia (50%) that led to an intervention from the medical staff, but no patient had a major event associated to bradycardia. We found a significant association between bradycardia and age (estimate -0.136, 95% CI -0.207—-0.065, p < 0.001), glucocorticoid dose (estimate 4.820, 95% CI 2.048—7.592, p < 0.001) and intravenous administration (estimate 8.709, 95% CI 1.893—15.524, p = 0.012). Conclusion In our study, most children hospitalized at the intensive care unit receiving standard doses of glucocorticoid experienced bradycardia. The majority of episodes led to an intervention from the medical staff. Presence of bradycardia was associated with younger age, higher dose and IV administration of glucocorticoids.

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P43 Pharmacokinetics and target attainment of antibiotics in critically ill children – a systematic review of current literature

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.81 ◽

2019 ◽

Vol 104 (6) ◽

pp. e35.1-e35

Author(s):

S Hartman ◽

R Brüggemann ◽

L Orriëns ◽

N Dia ◽

M Schreuder ◽

...

Keyword(s):

Critically Ill ◽

Patient Population ◽

Current Knowledge ◽

Volume Of Distribution ◽

Critically Ill Children ◽

Therapeutic Drug ◽

Healthy Children ◽

Target Attainment ◽

Critically Ill Adults ◽

Ill Adults

BackgroundPharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). To what extent this affects the PK of antibiotics in critically children is largely unknown. 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.MethodsSystematic 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.Results45 relevant articles were identified. Studies focusing on vancomycin were most prevalent (15/45). 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 larger Vd and higher Cl 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. 32/45 articles included information on both Vd and Cl, but a dosing advice was given in only 18 articles.ConclusionThe majority of studies focus on agents where therapeutic drug monitoring is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl that is observed 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.Disclosure(s)Nothing to disclose

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