Antimicrobial Resistance: We Must Pursue a Collaborative, Global Approach and Use a "One Health" Approach.

Treating infection is a key part of the work of most clinicians [...]

Infection, Sepsis and the Inflammatory Response: Mechanisms and Therapy

Sepsis secondary to bacterial infection remains a significant cause of morbidity and mortality globally. Recent decades have seen the evolution of international collaborations to improve care for these patients and identify areas for research. In this article we discuss the pathophysiology underlying the condition, review the current recommended management strategies, discuss areas of controversy, and highlight the need for ongoing research, particularly in diagnostics

The 'top 100' drugs and classes in England An updated 'starter formulary' for trainee prescribers.

AIMS: Prescribing is a complex skill required of doctors and, increasingly, other healthcare professionals. Use of a personal formulary can help to develop this skill. In 2006-9, we developed a core list of the 100 most commonly prescribed drugs. Our aim in the present study was to update this 'starter formulary' to ensure its continued relevance for prescriber training. METHODS: We analysed large contemporary primary and secondary care datasets to identify the most frequently prescribed medicinal products. Items were classified into natural groups, broadly following their British National Formulary classification. The resulting drug groups were included in the core list if they comprised ≥0.1% prescriptions in both settings or ≥0.2-0.3% prescriptions in one setting. Drugs from emergency guidelines that did not qualify by prescribing frequency completed the list. RESULTS: Over 1 billion primary care items and approximately 1.8 million secondary care prescriptions were analysed. The updated list comprises 81 drug groups commonly prescribed in both settings; 6 from primary care; 7 from secondary care; and 6 from emergency guidelines. 88% of the formulary was unchanged. Notable changes include entry of newer anti-epileptics and dipeptidyl peptidase-4 inhibitors and exit of phenytoin and thiazolidinediones. CONCLUSIONS: The relative stability of the core drug list over 9 years and the current update ensure that learning based on this list remains relevant to practice. Trainee prescribers may be encouraged to use this 'starter formulary' to develop a sound basis of prescribing knowledge and skills that they can subsequently apply more widely

Diagnostic Challenges in Sepsis.

Purpose of Review: Sepsis is a leading cause of death worldwide. Groundbreaking international collaborative efforts have culminated in the widely accepted surviving sepsis guidelines, with iterative improvements in management strategies and definitions providing important advances in care for patients. Key to the diagnosis of sepsis is identification of infection, and whilst the diagnostic criteria for sepsis is now clear, the diagnosis of infection remains a challenge and there is often discordance between clinician assessments for infection. Recent Findings: We review the utility of common biochemical, microbiological and radiological tools employed by clinicians to diagnose infection and explore the difficulty of making a diagnosis of infection in severe inflammatory states through illustrative case reports. Finally, we discuss some of the novel and emerging approaches in diagnosis of infection and sepsis. Summary: While prompt diagnosis and treatment of sepsis is essential to improve outcomes in sepsis, there remains no single tool to reliably identify or exclude infection. This contributes to unnecessary antimicrobial use that is harmful to individuals and populations. There is therefore a pressing need for novel solutions. Machine learning approaches using multiple diagnostic and clinical inputs may offer a potential solution but as yet these approaches remain experimental

Defining International Critical Care Pharmacist Contributions to Sepsis and Exploring Variability

Purpose of Review To define international clinical pharmacist contributions to managing sepsis in critically unwell patients and explore variation. Recent Findings Clinical pharmacists improve clinical outcomes and cost efficiencies. They provide pharmaceutical advice on selection, administration, plus monitoring of antimicrobials and supportive therapies. Logistical activities reduce drug administration times. Guideline production, patient/clinician education, prescribing error identification, plus therapeutic optimisation activities are also reported. Summary A survey incorporating semi-structured interviews identified further antimicrobial stewardship, prescribing and digital contributions to optimise sepsis management. However, disparities associated with multidisciplinary team integration and intensive care unit service provision were found. Variability was attributed to multifaceted physical, social, financial, training and education themes. Findings empower collaborations between pharmacists and stakeholders to identify and overcome contribution barriers. Strategies to mitigate barriers and enhance sepsis contributions were envisaged by reported aspirations. These emphasised the importance of professional advocacy, interprofessional education and impactful implementation research

Localizing Sagittarius A* and M87 on Microarcsecond Scales with Millimeter VLBI

With the advent of the Event Horizon Telescope (EHT), a millimeter/sub-millimeter very-long baseline interferometer (VLBI), it has become possible to image a handful of black holes with sub-horizon resolutions. However, these images do not translate into microarcsecond absolute positions due to the lack of absolute phase information when an external phase reference is not used. Due to the short atmospheric coherence time at these wavelengths, nodding between the source and phase reference is impractical. However, here we suggest an alternative scheme which makes use of the fact that many of the VLBI stations within the EHT are arrays in their own right. With this we show that it should be possible to absolutely position the supermassive black holes at the centers of the Milky Way (Sgr A*) and M87 relative to nearby objects with precisions of roughly 1 microarcsecond. This is sufficient to detect the perturbations to Sgr A*'s position resulting from interactions with the stars and stellar-mass black holes in the Galactic cusp on year timescales, and severely constrain the astrophysically relevant parameter space for an orbiting intermediate mass black hole, implicated in some mechanisms for producing the young massive stars in the Galactic center. For M87, it allows the registering of millimeter images, in which the black hole may be identified by its silhouette against nearby emission, and existing larger scale radio images, eliminating present ambiguities in the nature of the radio core and inclination, opening angle, and source of the radio jet.Comment: 18 pages, 4 figures, Accepted for publication in Ap

Systematic Review and Patient-Level Meta-Analysis of SARS-CoV-2 Viral Dynamics to Model Response to Antiviral Therapies

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral loads change rapidly following symptom onset, so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient-level meta-analysis of SARS-CoV-2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to date. This systematic review identified case reports, case series, and clinical trial data from publications between January 1, 2020, and May 31, 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A multivariable Cox proportional hazards (Cox-PH) regression model of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed-effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modeling of respiratory viral dynamics was performed to quantify time-dependent drug effects. Patient-level data from 645 individuals (age 1 month to 100 years) with 6,316 viral loads were extracted. Model-based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions, and breast milk were generated. Cox-PH modeling showed longer time to viral clearance in older patients, men, and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, P < 0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, P = 0.015; AHR = 6.04, P = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analyzing antiviral trials has been established

The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin

Comparative assessment of viral dynamic models for SARS‐CoV‐2 for pharmacodynamic assessment in early treatment trials

Pharmacometric analyses of time series viral load data may detect drug effects with greater power than approaches using single time points. Because SARS-CoV-2 viral load rapidly rises and then falls, viral dynamic models have been used. We compared different modelling approaches when analysing Phase II-type viral dynamic data. Using two SARS-CoV-2 datasets of viral load starting within 7 days of symptoms, we fitted the slope-intercept exponential decay (SI), reduced target cell limited (rTCL), target cell limited (TCL) and TCL with eclipse phase (TCLE) models using nlmixr. Model performance was assessed via Bayesian information criterion (BIC), visual predictive checks (VPCs), goodness-of-fit plots, and parameter precision. The most complex (TCLE) model had the highest BIC for both datasets. The estimated viral decline rate was similar for all models except the TCL model for dataset A with a higher rate [median (range) day-1: dataset A; 0.63 (0.56 – 1.84); dataset B: 0.81 (0.74-0.85)]. Our findings suggest simple models should be considered during pharmacodynamic model development