The use of national reimbursement reports to support formulary decisions of the hospital's Drug and Therapeutics Committee: a comparative analysis.

Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access to patients by compiling a formulary on rational grounds. An evolving landscape of innovative molecules challenges timely formulary adaptation after national reimbursement. Aim To integrate national reimbursement reports in the hospital's appraisal, thereby promoting access for patients without delay. Method For 2019, the rationale for new molecules at Ghent University Hospital, Belgium, was compared with the public assessment report of the National Institute for Health and Disability Insurance, assessing a medicine in a specific indication following a reimbursement request by the manufacturer. Decision criteria (therapeutic value and cost) between matching medicines in both databases (national & hospital) were retrospectively compared [no (%), mean (SD)]. Results Two-hundred public reports and 30 formulary decisions were analysed (with antineoplastic & immunomodulating as most prevalent class: 41.0% resp. 36.7%). National decision often concerned hospital-only medicines (89; 44.5%) without patient co-payment (101; 50.5%). Of 13 matched medicines (same indication), time delay between national decision and formulary admission was on average 3.1 (SD 2.3) months. Comparative analysis showed that assessment in both committees was mostly based on the efficacy endpoints of Randomised Controlled Trials. Literature used in hospital appraisals was of more recent publication date: + 0.78 (SD 2.2) years. Using public reports as a horizon scan could enable quick identification of new indications. Conclusion To speed up patient access, the scientific evidence of national reimbursement reports can be used for the purpose of hospital formulary decisions.

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 f AUC/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.

[Drug shortages in the hospital: management, causes and budget impact]. / Indisponibilité des medicaments dans les hôpitaux: gestation, causes et impact sur le budget.

INTRODUCTION: Drug shortages have become an issue of growing interest for pharmacists. Both number and type of shortages have increased over the past decade and it is challenging to provide drug continuity. Aim To describe management and impact of drug shortages for the hospital pharmacy. To gain insight into the causes of shortages. METHODS: The management process for drug shortages was analysed for the hospital pharmacies of the Ghent University Hospital (GUH) and the Acute Care Hospital Sint-Lucas Ghent. Insights in possible causes were obtained by semi-structured interview with the Federation for Belgian Pharmacists (Association Pharmaceutique beIge (APB)), the Belgian association of the pharmaceutical industry (pharma.bel and the Federal Agency for Medicines and Health Products (FAMHPI. A database of 1329 drug shortages (Jan 2001-Feb 2014 of the GUH was used to define drug classes affected by shortages (mean shortage days per year, standard deviation (SDI), type of shortage [urgent/ important] %, total number (n)), formulation (parenteral:oral and duration of the shortages (median, interquartile range (IQR)). The total cost impact for the GUH pharmacy was estimated by calculating average, minimum and maximum time investment by the pharmacy team (Delphi-techniquel and by calculating the cost difference between original and alternative drug acquisition costs. Impact is presented as base case scenario (minimum as best and maximum as worst case scenario). RESULTS: The different management phases for the pharmacist are problem identification, preparation of solution and implementation. Communication and extensive administration are essential components. Causes are production related, next to distribution inequivalences, quota and European market flows. Shortages with anti-infectious, cardiovascular and hormonal system drugs have the highest and constant proportion of drug shortage days, with recently appearance of other important drug classes such as anticancer therapy [2011 and further). The average number of drug shortage days in 2011-2013 is 8020 (SD 2142 compared to period 2001-2010 with on average 4633 days (SD 1731]. Fifty-four percent of the shortages is important for the direct hospital care and 22.9% needs urgent action. The proportion parenteral versus oral in the database is 3.3:1. Median duration of a shortage is 29 [IQR 11-65]1 days. The average excess cost of an equipotent dose of the alternative drug was 4.9 (SD 31.3) Euro. Total cost impact (gross salary and drug acquisition cost] for GUH pharmacy in 2013 is 117 281.4 Euro (best case: 88 345.06 and worst case: 151,208.2 Euro. CONCLUSION: The importance of the shortages and the diversification of the drug classes involved have an impact on the hospital pharmacy management. For the GUH this represents an important workload and an increased drug acquisition cost. Causes of shortages are production related but also distributional inequivalences and quota play an important role.