Population pharmacokinetics of flucloxacillin as intermittent bolus infusion in patients with Staphylococcus aureus bloodstream infection.

BACKGROUND: Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients. OBJECTIVES: To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens. METHODS: Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling. RESULTS: Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin. CONCLUSIONS: By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.

Residents' Knowledge regarding Recreational Drug Screening Immunoassays at a Swiss Hospital Group.

Introduction: In case of suspected acute recreational drug toxicity, immunoassays are commonly used as diagnostic tools. Although easy to handle, understanding of their limitations is necessary for a correct interpretation of the results. The aim of this project was to investigate residents' knowledge regarding drug screening immunoassays at a Swiss hospital group. Methods: All residents of a large hospital group in Switzerland were invited by e-mail to participate in an anonymous survey. Following ten multiple choice questions on drug screening tests, the participants were also asked about their demographics, whether they used drug screening tests on a regular basis, and how confident they felt in their ability to interpret test results. Results: The ten knowledge questions were answered by 110 of the 1026 residents (11%). Among the 108 participants with available demographics, 90% were 25-35 years old, 63% were female, and 70% were at least in their 4th year of residency. The median score of correct answers was 4 out of 10 (range 0-7) and in 50% of the questions, the correct answer was the most frequently selected response. No significant differences in the knowledge scores were found based on the training, confidence level, or the frequency of drug tests used in daily work. Conclusion: This survey revealed widespread knowledge gaps among residents regarding the interpretation of immunoassay-based drug test results. These findings can be used to implement educational measures on this topic and might provide a basis for targeted information on common pitfalls to be included in laboratory reports.

Pharmacokinetics and pharmacodynamics of inhaled nicotine salt and free-base using an e-cigarette: A randomized crossover study.

BACKGROUND: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. We aimed to investigate the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes. METHODS: In this randomized, double-blind, within-subject crossover study, 20 non nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20mg/mL, nicotine salt 20mg/mL, nicotine salt 40mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed. RESULTS: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0ng/mL (1.6-27.3), 5.4ng/mL (1.9-18.7) and 3.0ng/mL (1.3-8.8) for nicotine salt 40mg/mL, nicotine salt 20mg/mL and free-base 20mg/mL, respectively). All groups reached Cmax 2.0-2.5min (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed. CONCLUSION: Free-base 20mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20mg/mL, while 40mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation. IMPLICATIONS: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and non-smokers.

Solar-powered O2 delivery for the treatment of children with hypoxaemia in Uganda: a stepped-wedge, cluster randomised controlled trial.

BACKGROUND: Supplemental O2 is not always available at health facilities in low-income and middle-income countries (LMICs). Solar-powered O2 delivery can overcome gaps in O2 access, generating O2 independent of grid electricity. We hypothesized that installation of solar-powered O2 systems on the paediatrics ward of rural Ugandan hospitals would lead to a reduction in mortality among hypoxaemic children. METHODS: In this pragmatic, country-wide, stepped-wedge, cluster randomised controlled trial, solar-powered O2 systems (ie, photovoltaic cells, battery bank, and O2 concentrator) were sequentially installed at 20 rural health facilities in Uganda. Sites were selected for inclusion based on the following criteria: District Hospital or Health Centre IV with paediatric inpatient services; supplemental O2 on the paediatric ward was not available or was unreliable; and adequate space to install solar panels, a battery bank, and electrical wiring. Allocation concealment was achieved for sites up to 2 weeks before installation, but the study was not masked overall. Children younger than 5 years admitted to hospital with hypoxaemia and respiratory signs were included. The primary outcome was mortality within 48 h of detection of hypoxaemia. The statistical analysis used a linear mixed effects logistic regression model accounting for cluster as random effect and calendar time as fixed effect. The trial is registered at ClinicalTrials.gov, NCT03851783. FINDINGS: Between June 28, 2019, and Nov 30, 2021, 2409 children were enrolled across 20 hospitals and, after exclusions, 2405 children were analysed. 964 children were enrolled before site randomisation and 1441 children were enrolled after site randomisation (intention to treat). There were 104 deaths, 91 of which occurred within 48 h of detection of hypoxaemia. The 48 h mortality was 49 (5·1%) of 964 children before randomisation and 42 (2·9%) of 1440 (one individual did not have vital status documented at 48 h) after randomisation (adjusted odds ratio 0·50, 95% CI 0·27-0·91, p=0·023). Results were sensitive to alternative parameterisations of the secular trend. There was a relative risk reduction of 48·7% (95% CI 8·5-71·5), and a number needed to treat with solar-powered O2 of 45 (95% CI 28-230) to save one life. Use of O2 increased from 484 (50·2%) of 964 children before randomisation to 1424 (98·8%) of 1441 children after randomisation (p<0·0001). Adverse events were similar before and after randomisation and were not considered to be related to the intervention. The estimated cost-effectiveness was US$25 (6-505) per disability-adjusted life-year saved. INTERPRETATION: This stepped-wedge, cluster randomised controlled trial shows the mortality benefit of improving O2 access with solar-powered O2. This study could serve as a model for scale-up of solar-powered O2 as one solution to O2 insecurity in LMICs. FUNDING: Grand Challenges Canada and The Women and Children's Health Research Institute.