Diagnosis-linked antibiotic prescribing quality indicators: demonstrating feasibility using practice-based routine primary care data, reliability, validity and their potential in antimicrobial stewardship.

BACKGROUND: Quality indicators (QIs) can be used to obtain valuable insights into prescribing quality. Five quantitative and nine diagnosis-linked QIs, aiming to provide general practitioners (GP) with feedback on their antibiotic prescribing quantity and quality, were previously developed and evaluated in a controlled study. OBJECTIVE: To confirm, in a larger non-controlled study, the feasibility of using routinely collected and extracted electronic patient records to calculate the diagnosis-linked QI outcomes for antibiotic prescribing, and their reliability and validity. METHODS: Retrospective study involving 299 Dutch general practices using routine care data (2018-2020). QIs describe total antibiotic and subgroup prescribing, prescribing percentages and first-choice prescribing for several clinical diagnoses. Practice variation in QI outcomes, inter-QI outcome correlations and sensitivity of QI outcomes to pandemic-induced change were determined. RESULTS: QI outcomes were successfully obtained for 278/299 practices. With respect to reliability, outcomes for 2018 and 2019 were comparable, between-practice variation in outcomes was similar to the controlled pilot, and inter-QI outcome correlations were as expected, for example: high prescribing of second choice antibiotics with low first-choice prescribing for clinical diagnoses. Validity was confirmed by their sensitivity to pandemic-induced change: total antibiotic prescribing decreased from 282 prescriptions/1000 registered patients in 2018 to 216 in 2020, with a decrease in prescribing percentages for upper and lower respiratory infections, from 26% to 18.5%, and from 28% to 16%. CONCLUSIONS: This study confirmed the fit-for-purpose (feasibility, reliability and validity) of the antibiotic prescribing QIs (including clinical diagnosis-linked ones) using routinely registered primary health care data as a source. This feedback can therefore be used in antibiotic stewardship programmes to improve GPs' prescribing routines.

Poor performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal dysfunction.

PURPOSE: Clinical decision support systems (CDSS) are used to identify drugs with potential need for dose modification in patients with renal impairment. ChatGPT holds the potential to be integrated in the electronic health record (EHR) system to give such dosing advices. In this study, we aim to evaluate the performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal impairment. METHODS: This cross-sectional study was performed at Tergooi Medical Center, the Netherlands. CDSS alerts regarding renal dysfunction were collected from the electronic health record (EHR) during a 2-week period and were presented to ChatGPT and an expert panel. Alerts were presented with and without patient variables. To evaluate the performance, suggested medication interventions were compared. RESULTS: In total, 172 CDDS alerts were generated for 80 patients. Indecisive responses by ChatGPT to alerts were excluded. For alerts presented without patient variables, ChatGPT provided "correct and identical" responses to 19.9%, "correct and different" responses to 26.7%, and "incorrect responses to 53.4% of the alerts. For alerts including patient variables, ChatGPT provided "correct and identical" responses to 16.7%, "correct and different" responses to 16.0%, and "incorrect responses to 67.3% of the alerts. Accuracy was better for newer drugs such as direct oral anticoagulants. CONCLUSION: The performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal dysfunction was poor. Based on these results, we conclude that ChatGPT, in its current state, is not appropriate for automatic integration into our EHR to handle CDSS alerts related to renal dysfunction.

Women on diuretics have a higher risk of hospital admission because of hyponatremia than men.

PURPOSE: Recent studies suggest that women are more susceptible to diuretic-induced hyponatremia resulting in hospital admission than men. The aim of this study was to confirm whether these sex differences in hyponatremia-related hospital admissions in diuretic users remain after adjusting for several confounding variables such as age, dose, and concurrent medication. METHODS: In a case-control design nested in diuretic users, cases of hyponatremia associated hospital admissions between 2005 and 2017 were identified from the PHARMO Data Network. Cases were 1:10 matched to diuretic users as controls. Odds ratios (OR) with 95%CIs were calculated for women versus men and adjusted for potential confounders (age, number of diuretics, other hyponatremia-inducing drugs, chronic disease score) using unconditional logistic regression analysis. A subgroup analysis was performed for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists). RESULTS: Women had a statistically significantly higher risk of a hospital admission associated with hyponatremia than men while using diuretics (OR 1.86, 95%CI 1.64-2.11). Adjusting for the potential confounders resulted in an increased risk for women compared to men (ORadj 2.65, 95% CI 2.31-3.04). This higher risk in women was also seen in the three subgroup analyses after adjustment. CONCLUSION: Our findings show a higher risk of hyponatremia-related hospital admission in women than men while using diuretics. Further research is needed to understand the underlying mechanism of this sex difference to be able to provide sex-specific recommendations.

Assessment of drug-related problems at the emergency department in older patients living with frailty: pharmacist-led medication reviews within a geriatric care team.

BACKGROUND: Older patients are vulnerable to experiencing drug related problems (DRPs), which may result in emergency department (ED) visits. However, it is not standard practice to conduct medications reviews during ED visit. The aim of this study was to assess the number of DRPs in older patients living with frailty at the ED, identified through pharmacist-led medication reviews within a geriatric care team, and to determine the acceptance rate of pharmacists' recommendations among hospital physicians and general practitioners or elderly care specialists. METHODS: A retrospective observational study was performed in patients ≥ 70 years living with frailty at the ED at Tergooi Medical Center. Pharmacist-led medication reviews were conducted to identify and classify DRPs as part of a larger geriatric assessment. The acceptance rate of given recommendations was determined during follow-up. RESULTS: A total of 356 ED visits were included. The mean (standard deviation, SD) age of patients was 83 (6.8) years. About 76% of patients had at least one DRP. In total, 548 DRPs were identified with a mean of 1.5 DRP (SD 1.3) per patient. The acceptance rate of medication recommendations in admitted patients was 55%, and 32% among general practitioners/elderly care specialists in discharged patients. CONCLUSIONS: Pharmacist-led medication reviews as part of a geriatric care team identified DRPs in 76% of older patients living with frailty at the ED. The acceptance rate was substantially higher in admitted patients compared to discharged patients.

Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults.

BACKGROUND: Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. METHODS: We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. RESULTS: A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants. CONCLUSIONS: In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.

The 2021 Dutch Working Party on Antibiotic Policy (SWAB) guidelines for empirical antibacterial therapy of sepsis in adults.

BACKGROUND: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. METHODS: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). RESULTS: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. CONCLUSIONS: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

Women are started on a lower daily dose of metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology.

PURPOSE: Current guidelines have no sex-specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population-based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data. METHODS: The mean daily starting doses of metoprolol in both sexes were compared with independent-samples t-tests and a linear regression analysis was used to adjust in the RS for co-variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI-database, adjustment was for age only. RESULTS: The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI -7.8, -1.8) and 4.6 mg (95%CI -5.3,-4.0), respectively. Statistical significance remained after adjustment in both databases. CONCLUSIONS: Women received lower starting doses of metoprolol than men in two independent data collections despite non-sex specific cardiovascular guideline recommendations. This example of real-life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

Consecutive antibiotic use in the outpatient setting: an extensive, longitudinal descriptive analysis of antibiotic dispensing data in the Netherlands.

INTRODUCTION: Taking consecutive antibiotic use into account is of importance to obtain insight in treatment within disease episodes, use of 2nd- and 3rd-choice antibiotics, therapy failure and/or side effects. Nevertheless, studies dealing with consecutive antibiotic use are scarce. We aimed at evaluating switch patterns in antibiotic use in the outpatient setting in the Netherlands. METHODS: Outpatient antibiotic dispensing data was processed to antibiotic treatment episodes consisting of single prescriptions or consecutive prescriptions (2006 to 2014). Consecutive prescriptions were categorised into prolongations and switches. Switches were further analysed to obtain antibiotic switch percentages and trends over time. Outcomes were compared with recommendations of Dutch guidelines. RESULTS: A total of 43,179,867 antibiotic prescriptions were included in the analysis, consisting of single prescriptions (95%), prolongations (2%) and switches (3%). The highest switch percentages were found for trimethoprim (7.6%) and nitrofurantoin (5.4%). For fosfomycin, ciprofloxacin, flucloxacillin and trimethoprim we found the highest yearly increase in switching. Amoxicillin/clavulanic acid was most often used as second antibiotic in a switch. A surprisingly high number of 2nd- and 3rd-choice antibiotics are prescribed as first antibiotic in a treatment. CONCLUSIONS: Although the actual reason for a switch is unknown, switch patterns can reveal problems concerning treatment failure and guideline adherence. In general, switch percentages of antibiotics in the Netherlands are low. The data contributes to the knowledge regarding antibiotic switch patterns in the outpatient setting.

Diabetes and Glucose Dysregulation and Transition to Delirium in ICU Patients.

OBJECTIVES: To investigate whether diabetes and glucose dysregulation (hyperglycemia and/or hypoglycemia) are associated with ICU delirium. DESIGN: Prospective cohort study. SETTING: Thirty-two-bed mixed intensive care in a tertiary care center. PATIENTS: Critically ill patients admitted to the ICU with transitions of mental status from awake and nondelirious to delirious or remaining awake and nondelirious on the next day. Patients admitted because of a neurologic illness were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 2,745 patients with 1,720 transitions from awake and nondelirious to delirious and 11,421 nontransitions remaining awake and nondelirious. Generalized mixed effects models with logit link function were performed to study the association between diabetes mellitus, glucose dysregulation, and delirium, adjusting for potential confounders. Diabetes was not associated with delirium (odds ratio adjusted, 0.93; 95% CI, 0.73-1.18). In all patients, the occurrence of hyperglycemia (odds ratio adjusted, 1.35; 95% CI, 1.15-1.59) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.65; 95% CI, 1.12-2.28) compared with normoglycemia were associated with transition to delirium. Hypoglycemia was not associated with transition to delirium (odds ratio adjusted, 1.86; 95% CI, 0.73-3.71). In patients without diabetes, the occurrence of hyperglycemia (odds ratio adjusted, 1.41; 95% CI, 1.16-1.68) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.87; 95% CI, 1.07-2.89) were associated with transition to delirium. In patients with diabetes, glucose dysregulation was not associated with ICU delirium. CONCLUSIONS: Diabetes mellitus was not associated with the development of ICU delirium. For hypoglycemia, only a nonsignificant odds ratio for ICU delirium could be noted. Hyperglycemia and the occurrence of hyperglycemia and hypoglycemia on the same day were associated with ICU delirium but only in patients without diabetes. Our study supports the institution of measures to prevent glucose dysregulation in nondiabetic ICU patients and contributes to the understanding of the determinants of delirium.

Sepsis calculator implementation reduces empiric antibiotics for suspected early-onset sepsis.

Significant overtreatment with antibiotics for suspected early onset sepsis (EOS) constitutes a persisting clinical problem, generating unnecessary risks, harms, and costs for many newborns. We aimed to study feasibility and impact of a sepsis calculator to help guide antibiotic for suspected EOS in a European setting. In this single-center study, the sepsis calculator was implemented as an addition to and in accordance with existing protocols. One thousand eight hundred seventy-seven newborns ≥ 35 weeks of gestational age were prospectively evaluated; an analogous retrospective control group (n = 2076) was used for impact analysis. We found that empirical treatment with intravenous antibiotics for suspected EOS was reduced from 4.8 to 2.7% after sepsis calculator implementation (relative risk reduction 44% (95% confidence interval 21.4-59.5%)). No evidence for changes in time to treatment start, treatment duration, or proven sepsis rates was found. Adherence to sepsis calculator recommendation was 91%. CONCLUSION: Pragmatic and feasible implementation of the sepsis calculator yields a 44% reduction of empirical use of antibiotics for EOS, without signs of delay or prolongation of treatment. These findings warrant a multicenter, nation-wide, randomized study evaluating systematic use of the sepsis calculator prediction model and its effects in clinical practice outside of the USA. What is known: • Significant overtreatment with antibiotics for suspected early-onset sepsis results in unnecessary costs, risks, and harms. • Implementation of the sepsis calculator in the USA has resulted in a significant decrease in empirical antibiotic treatment, without apparent adverse events. What is new: • Implementation of the sepsis calculator in daily clinical decision-making in a Dutch teaching hospital is feasible in conjunction with existing protocols, with high adherence. • Antibiotic therapy for suspected early-onset sepsis was reduced by 44% following implementation of the calculator.