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

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.

Download Full-text

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

Download Full-text

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

Download Full-text

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

European Journal of Clinical Microbiology & Infectious Diseases ◽

10.1007/s10096-019-03535-w ◽

2019 ◽

Vol 38 (7) ◽

pp. 1255-1260 ◽

Cited By ~ 2

Author(s):

Stan J. F. Hartman ◽

Navin P. Boeddha ◽

Ebru Ekinci ◽

Birgit C. P. Koch ◽

Rogier Donders ◽

...

Keyword(s):

Septic Shock ◽

Critically Ill ◽

Critically Ill Children ◽

Target Attainment ◽

Meningococcal Septic Shock ◽

Pediatric Sepsis

Download Full-text

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

Clinical Pharmacokinetics ◽

10.1007/s40262-019-00813-w ◽

2019 ◽

Vol 59 (2) ◽

pp. 173-205 ◽

Cited By ~ 2

Author(s):

Stan J. F. Hartman ◽

Roger J. Brüggemann ◽

Lynn Orriëns ◽

Nada Dia ◽

Michiel F. Schreuder ◽

...

Keyword(s):

Systematic Review ◽

Critically Ill ◽

Current Literature ◽

Critically Ill Children ◽

Target Attainment

Download Full-text

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-22.4.276 ◽

2017 ◽

Vol 22 (4) ◽

pp. 276-285 ◽

Cited By ~ 10

Author(s):

Jeffrey J. Cies ◽

Wayne S. Moore ◽

Adela Enache ◽

Arun Chopra

Keyword(s):

Continuous Infusion ◽

Critically Ill ◽

Critically Ill Children ◽

Gram Negative Bacteria ◽

Target Attainment ◽

Gram Negative ◽

Patients Âgés ◽

Dosage Regimens ◽

Optimal Probability ◽

Gram Negative Organisms

OBJECTIVE This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children. METHODS The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring. RESULTS There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R2 and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R2, bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and Vc was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L. CONCLUSION These data suggest the reference dosage regimens for meropenem (20–40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.

Download Full-text

P103 Target attainment of amikacin therapy in critically ill children

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.141 ◽

2019 ◽

Vol 104 (6) ◽

pp. e60.2-e61

Author(s):

J Verbruggen ◽

K Jakipbayeva ◽

T Van Der Heggen ◽

E Dhont ◽

L Dhondt ◽

...

Keyword(s):

Steady State ◽

Pilot Study ◽

Critically Ill ◽

Critically Ill Children ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

List Type ◽

Dosing Regimen ◽

Target Attainment ◽

Clinical Pharmacokinetics

BackgroundResearch regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).MethodsChildren admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).ResultsTwenty-one patients (median age1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].ConclusionThis pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.ReferencesIllamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.Disclosure(s)Nothing to disclose

Download Full-text

Social Support and Functioning Among Mothers of Critically Ill Children

PsycEXTRA Dataset ◽

10.1037/e518622008-001 ◽

2008 ◽

Author(s):

Christine Rini ◽

Sharon Manne ◽

Katherine Duhamel ◽

Jane Austin ◽

Jamie Ostroff ◽

...

Keyword(s):

Social Support ◽

Critically Ill ◽

Critically Ill Children

Download Full-text