Sabrina Commeyne

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

Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%–79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC ≥400 and fAUC/MIC ≥200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 × total vancomycin concentration (mg/L)] − [0.085 × total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery.

Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration–time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.

Optimization of a model of out-of-hospital antibiotic therapy (OPAT) in a Belgian university hospital resulting in a proposal for national implementation

Objectives: Some infections require prolonged parenteral antimicrobial therapy, which can be continued in an outpatient setting. The Ghent University Hospital has 15 years of experience with Outpatient Parenteral Antimicrobial Therapy (OPAT) in the home setting of the patient. Methods: Multidisciplinary critical approach through identification of areas for improvement with the existing OPAT process within the Ghent University Hospital. Existing literature and guidelines were used as references. An improved model is proposed for implementation. Results: Several challenges and barriers were identified, including regulatory obstacles for OPAT in Belgium, such as lack of uniformity in ambulatory reimbursement of parenteral antimicrobials. There is no financial incentive for the patient with OPAT, as costs for the patient of outpatient therapy can be higher as compared with hospitalization. Other barriers include delayed approval of the certificate for reimbursement, low availability of medicines in the community pharmacies and limited knowledge of the medical devices for administration in ambulatory setting. All critical steps in the revised OPAT program are summarized in a flowchart with a checklist for all stakeholders. Firstly, a list with specific criteria to include patients in an OPAT program is provided. Secondly, the Multidisciplinary Infection Team received a formal mandate to review all eligible OPAT patients. In order to select the most appropriate catheter, a decision tree was developed and standardized packages with medical devices were developed. Thirdly, patients receive oral and written information about the treatment with practical and financial implications. Fourthly, information is provided toward the general practitioners, community pharmacist and home care nurse. Conclusion: Standardization of the OPAT program aims at improving quality and safety of intravenous antimicrobial therapy in the home setting.