Emma Harriet Baker

Aim: To assess how well pregnancy‐specific guidance within the British National Formulary supports healthcare professionals to facilitate safe and effective medication use. Methods: We performed a manifest content analysis of the text of all pregnancy sections within British National Formulary drug monographs, with inductive and iterative coding. We included all 1752 medications listed within the British National Formulary on 11 February 2025. No medications were excluded. Medications were categorized into combinations, specialist, monoclonal antibody or fragment crystallizable domain fusion proteins; and black triangle medications. We developed codes that classified the guidance provided, reasons for provided guidance and sources of guidance. Results: A pregnancy section was available for 1138 (65%) of medications listed within the British National Formulary. Information provided was heterogenous, with over 547 unique text statements. Of medications with a pregnancy section, only 41 (3.6%) were coded as ‘use without restriction’ and 186 (16%) did not provide clear guidance on whether the medication could be used in pregnancy. Reasons for provided guidance were primarily due to known toxicity in humans or animals (45%) or a lack of information on the medication's effect in pregnancy (24%). The source of guidance was primarily not stated (56%) or the manufacturer (40%). Conclusions: Information on prescribing in pregnancy within the British National Formulary does not facilitate safe and effective use of medicines in pregnancy. Improvements could include signposting to resources with more detailed information and by standardizing guidance statements. More widely, there is a need for better prescribing information in pregnancy.

Background: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal antimicrobial exposure has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness have not previously been described. Methods: Pharmacokinetic, clinical and demographic data were collected from critically ill adults receiving intravenous clarithromycin. Drug concentrations were measured using high-performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling was added, and periods of renal replacement therapy were excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic–pharmacodynamic (PKPD) target attainment. Results: The analysis included 121 samples taken from 19 participants. A two-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates of clearance and volume of distribution were lower than previously reported, with high interindividual variability. Simulations suggested reasonable pharmacokinetic–pharmacodynamic (PKPD) target attainment with current dosing regimens for most organisms that clarithromycin is used to treat with known clinical breakpoints. Conclusions: To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin in humans. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population.

Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal pharmacokinetic exposure of antimicrobials has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness has not previously been described. Pharmacokinetic, clinical and demographic data was collected from critically unwell adults receiving intravenous clarithromycin. Drug concentrations were measured using high performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling added and periods of renal replacement therapy excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic-pharmacodynamic (PKPD) target attainment. 121 samples were taken from 18 participants. A 2-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates were lower than previously reported, with high interindividual variability. Simulations suggested reasonable PKPD target attainment with current dosing regimens for most organisms with known clinical breakpoints. To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

The ChAdOx1 nCoV-19 vaccine has been associated with increased risk of thrombosis. Understanding of management of these rare events is evolving, and currently recommended treatments include human normal immunoglobulin and non-heparin anticoagulation such as direct oral anticoagulants. Our report describes three consecutive patients presenting to a London teaching hospital with vaccine induced thrombotic thrombocytopenia (VITT), also referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). The patients ranged in age from 40–54 years and two had no known previous medical comorbidities. Two patients had cerebral venous sinus thrombosis and one had a deep vein thrombosis. Two were treated with anticoagulation; one with oral rivaroxaban; and the other with an intravenous argotraban infusion that was later converted to oral apixaban. One patient received three doses of human normal immunoglobulin and five days of therapeutic plasma exchange. This case series may be used to improve understanding of the clinical course and management of VITT.

Background: Changes in brain structure and cognitive decline occur in Chronic Obstructive Pulmonary Disease (COPD). They also occur with smoking and coronary artery disease (CAD), but it is unclear whether a common mechanism is responsible. Methods: Brain MRI markers of brain structure were tested for association with disease markers in other organs. Where possible, principal component analysis (PCA) was used to group markers within organ systems into composite markers. Univariate relationships between brain structure and the disease markers were explored using hierarchical regression and then entered into multivariable regression models. Results: 100 participants were studied (53 COPD, 47 CAD). PCA identified two brain components: brain tissue volumes and white matter microstructure, and six components from other organ systems: respiratory function, plasma lipids, blood pressure, glucose dysregulation, retinal vessel calibre and retinal vessel tortuosity. Several markers could not be grouped into components and were analysed as single variables, these included brain white matter hyperintense lesion (WMH) volume. Multivariable regression models showed that less well organised white matter microstructure was associated with lower respiratory function (p = 0.028); WMH volume was associated with higher blood pressure (p = 0.036) and higher C-Reactive Protein (p = 0.011) and lower brain tissue volume was associated with lower cerebral blood flow (pp = 0.001). Smoking history was not an independent correlate of any brain marker. Conclusions: Measures of brain structure were associated with a range of markers of disease, some of which appeared to be common to both COPD and CAD. No single common pathway was identified, but the findings suggest that brain changes associated with smoking-related diseases may be due to vascular, respiratory, and inflammatory changes.

Background: This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon‐like peptide‐1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results: We applied 2‐sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome‐wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64–0.87; P =1.69×10 ⁻⁴ ), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03–0.42; P =0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions: This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.

Glucocorticoids are highly effective medicines in the treatment of inflammatory disorders. However, they cause severe adverse reactions, particularly where taken at high doses systemically for prolonged periods. Systemic glucocorticoids are therefore given at dosage sufficient to control the disease, then withdrawn as fast as is possible to minimise dose‐ and time‐related adverse drug reactions without losing disease control. Adverse withdrawal reactions present a major challenge in the withdrawal of long‐term glucocorticoids. Suppression of the hypothalamic–pituitary–adrenal (HPA) axis causes adrenal insufficiency, which is potentially life threatening and can become symptomatic as treatment is withdrawn. Adrenal insufficiency can be extremely difficult to differentiate from glucocorticoid withdrawal syndrome , where patients experience symptoms despite adequate adrenal function, and from psychological dependence. Long‐term systemic glucocorticoids should therefore be withdrawn slowly. The rate at which the dose is tapered should initially be determined by treatment requirements of the underlying disease. Once physiological doses are reached, the rate of reduction is determined by rate of HPA recovery and need for exogenous glucocorticoid cover while endogenous secretion recovers. If symptoms prevent treatment withdrawal, HPA testing should be used to look for adrenal insufficiency. Patients with adrenal insufficiency require physiological doses of glucocorticoids for adrenal replacement, which may be lifelong if the HPA axis fails to recover.

Background: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter.Objectives: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection.Methods: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months.Results: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0–2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3–4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5–7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71–0.83) and 0.77 (95% CI 0.72–0.82), respectively.Conclusions: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.