Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF).

BACKGROUND: Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. METHODS: This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. RESULTS: A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs-Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. CONCLUSIONS: PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Medication details documented on hospital discharge: cross-sectional observational study of factors associated with medication non-reconciliation.

AIMS: Movement into or out of hospital is a vulnerable period for medication safety. Reconciling the medication a patient is using before admission with the medication prescribed on discharge, and documenting any changes (medication reconciliation) is recommended to improve safety. The aims of the study were to investigate the factors contributing to medication reconciliation on discharge, and identify the prevalence of non-reconciliation. METHODS: The study was a cross-sectional, observational survey using consecutive discharges from purposively selected services in two acute public hospitals in Ireland. Medication reconciliation, potential for harm and unplanned re-admission were investigated. RESULTS: Medication non-reconciliation was identified in 50% of 1245 inpatient episodes, involving 16% of 9569 medications. The majority of non-reconciled episodes had potential to result in moderate (63%) or severe (2%) harm. Handwritten rather than computerized discharges (adjusted odds ratio (adjusted OR) 1.60, 95% CI 1.11, 2.99), increasing number of medications (adjusted OR 1.26, 95% CI 1.21, 1.31) or chronic illness (adjusted OR 2.08, 95% CI 1.33, 3.24) were associated with non-reconciliation. Omission of endocrine, central nervous system and nutrition and blood drugs was more likely on discharge, whilst omission on admission and throughout inpatient care, without documentation, was more likely for obstetric, gynaecology and urinary tract (OGU) or respiratory drugs. Documentation in the discharge communication that medication was intentionally stopped during inpatient care was less likely for cardiovascular, musculoskeletal and OGU drugs. Errors involving the dose were most likely for respiratory drugs. CONCLUSIONS: The findings inform strategies to facilitate medication reconciliation on discharge from acute hospital care.

Compliance with the Health Information and Quality Authority of Ireland National Standard for Patient Discharge Summary Information: a retrospective study in secondary care.

BACKGROUND: Unexplained changes to medication are common at hospital discharge and underscore the need to standardise patient discharge clinical documentation. In 2013, the Health Information and Quality Authority in Ireland published a Standard on the structure and content of discharge summaries. The intention was to ensure that all necessary information was complete and communicated to the next care provider. OBJECTIVES: This study investigated one Hospital's compliance with the Standard, and appraised two methods of electronic discharge communication (Symphony or Tallaght Education and Audit Management System (TEAMS)). METHOD: A retrospective survey of 198 randomly selected discharge summaries was conducted at the study hospital, a 600 bed academic teaching hospital located in Dublin, Ireland. RESULTS: Of the 198 evaluated summaries, mean total compliance was 77%±4.2 (95% CI 76.3 to 77.5). Most (84.7%, n=173) summaries were completed using one of the systems (TEAMS). Absence of communication about alteration of preadmission medication was frequent (107 out of 130 patients (82.3%, CI 76.2 to 89.2)). Higher compliance rates were observed however, when information was interfaced or where there were dedicated fields to be completed. CONCLUSIONS: Efforts to improve compliance with the National Standard for Patient Discharge Summary Information should focus on reporting changes made to medication during hospitalisation.

Impact of the Collaborative Pharmaceutical Care at Tallaght Hospital (PACT) model on medication appropriateness of older patients.

OBJECTIVES: A high prevalence of potentially inappropriate prescribing (PIP) has been identified in older patients in Ireland. The impact of the Collaborative Pharmaceutical Care at Tallaght Hospital (PACT) model on the medication appropriateness of acute hospitalised older patients during admission and at discharge is reported. METHODS: Uncontrolled before-after study. The study population for this study was medical patients aged ≥65 years, using ≥3 regular medicines at admission, taken from a previous before-after study. Standard care involved clinical pharmacists being ward-based, contributing to medication history taking and prescription review, but not involved at discharge. The innovative PACT model involved clinical pharmacists being physician team-based, leading admission and discharge medication reconciliation and undertaking prescription review, with authority to change the prescription during admission or at discharge. The primary outcome was the Medication Appropriateness Index (MAI) score applied pre-admission, during admission and at discharge. RESULTS: Some 108 patients were included (48 PACT, 60 standard). PACT significantly improved the MAI score from pre-admission to admission (mean difference 2.4, 95% CI 1.0 to 3.9, p<0.005), and from pre-admission to discharge (mean difference 4.0, 95 CI 1.7 to 6.4, p<0.005). PACT resulted in significantly fewer drugs with one or more inappropriate rating at discharge (PACT 15.0%, standard 30.5%, p<0.001). The MAI criteria responsible for most inappropriate ratings were 'correct directions' (4.8% PACT, 17.3% standard), expense (5.3% PACT, 5.7% standard) and dosage (0.6% PACT, 4.0% standard). PACT suggestions to optimise medication use were accepted more frequently, and earlier in the hospital episode, than standard care (96.7% PACT, 69.3% standard, p<0.05). CONCLUSIONS: Collaborative pharmaceutical care between physicians and pharmacists from admission to discharge, with authority for pharmacists to amend the prescription, improves medication appropriateness in older hospitalised Irish patients.

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.

Collaborative pharmaceutical care in an Irish hospital: uncontrolled before-after study.

BACKGROUND: We investigated the benefits of the Collaborative Pharmaceutical Care in Tallaght Hospital (PACT) service versus standard ward-based clinical pharmacy in adult inpatients receiving acute medical care, particularly on prevalence of medication error and quality of prescribing. METHODS: Uncontrolled before-after study, undertaken in consecutive adult medical inpatients admitted and discharged alive, using at least three medications. Standard care involved clinical pharmacists being ward-based, contributing to medication history taking and prescription review, but not involved at discharge. The innovative PACT intervention involved clinical pharmacists being team-based, leading admission and discharge medication reconciliation and undertaking prescription review. Primary outcome measures were prevalence per patient of medication error and potentially severe error. Secondary measures included quality of prescribing using the Medication Appropriateness Index (MAI) in patients aged ≥65 years. FINDINGS: Some 233 patients (112 PACT, 121 standard) were included. PACT decreased the prevalence of any medication error at discharge (adjusted OR 0.07 (95% CI 0.03 to 0.15)); number needed to treat (NNT) 3 (95% CI 2 to 3) and no PACT patient experienced a potentially severe error (NNT 20, 95% CI 10 to 142). In patients aged ≥65 years (n=108), PACT improved the MAI score from preadmission to discharge (Mann-Whitney U p<0.05; PACT median -1, IQR -3.75 to 0; standard care median +1, IQR -1 to +6). CONCLUSIONS: PACT, a collaborative model of pharmaceutical care involving medication reconciliation and review, delivered by clinical pharmacists and physicians, at admission, during inpatient care and at discharge was protective against potentially severe medication errors in acute medical patients and improved the quality of prescribing in older patients.