Antifungal stewardship in the UK: where are we now?

Background: Antifungal stewardship (AFS) is the judicious use of today's antifungal agents with the aim of improving patient outcomes and preserving their future effectiveness. Antifungal resistance (AFR) is increasing globally, with more patients at risk of Invasive Fungal Disease (IFD), highlighting the urgent need to standardize AFS practices in the UK. The aim of this position paper is to understand the current AFS landscape in the UK.

Decoding community-acquired pneumonia: a systematic review and analysis of diagnostic criteria and definitions used in clinical trials.

Background: Community-acquired pneumonia (CAP) is a frequent and potentially life-threatening condition. Even though the disease is common, evidence on CAP management is often of variable quality. This may be reinforced by the lack of a systematic and homogeneous way of defining the disease in randomized controlled trials (RCTs).

A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.

Background And Objectives: The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (f). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life.

Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial.

Importance: For hospitalized critically ill adults with suspected sepsis, procalcitonin (PCT) and C-reactive protein (CRP) monitoring protocols can guide the duration of antibiotic therapy, but the evidence of the effect and safety of these protocols remains uncertain.

Objective: To determine whether decisions based on assessment of CRP or PCT safely results in a reduction in the duration of antibiotic therapy.

Design, Setting, And Participants: A multicenter, intervention-concealed randomized clinical trial, involving 2760 adults (≥18 years), in 41 UK National Health Service (NHS) intensive care units, requiring critical care within 24 hours of initiating intravenous antibiotics for suspected sepsis and likely to continue antibiotics for at least 72 hours.

Insights into durability against resistance from the antibiotic nitrofurantoin.

Nitrofurantoin has shown exceptional durability against resistance over 70 years of use. This longevity stems from factors such as rapid achievement of therapeutic concentrations, multiple physiological targets against bacteria, low risk of horizontal gene transfer, and the need to acquire multiple mutations to achieve resistance. These combined features limit resistance emergence and spread of nitrofurantoin resistance.

Small volume fluid resuscitation and supplementation with 20% albumin versus buffered crystalloids in adults with septic shock: A protocol for a randomised feasibility trial.

Background: Fluid therapy is universally administered in the management of patients with sepsis, however excessive cumulative fluid balance has been shown to result in worse outcomes. Hyperoncotic albumin results in both lower fluid volumes and early cumulative fluid balance, and may reduce short-term mortality in patients with septic shock.

Methods: In this single centre, open label, feasibility trial; patients with early septic shock will be randomly allocated either 20% albumin for resuscitation and daily supplementation, versus buffered crystalloids alone for all fluid therapy.

The efficacy, safety and effectiveness of hyperoncotic albumin solutions in patients with sepsis: A systematic review and meta-analysis.

Background: Intravenous fluid therapy is a ubiquitous intervention for the management of patients with sepsis, however excessive cumulative fluid balance has been shown to result in worse outcomes. Hyperoncotic albumin is presented in low volumes, is an effective resuscitation fluid and may have effects beyond plasma volume expansion alone. This systematic review aimed to assess the efficacy, safety and effectiveness of hyperoncotic albumin solutions in the management of sepsis.

Retrospective service evaluation of a specialist weaning unit.

Specialist weaning units (SWUs) aim to liberate patients with complex weaning failure from mechanical ventilation and facilitate their discharge from the ICU. This retrospective service evaluation reports the outcomes of a SWU at Wythenshawe Hospital, Manchester between 2017 and 2019. In total, 75.

Unravelling the complexity of ventilator-associated pneumonia: a systematic methodological literature review of diagnostic criteria and definitions used in clinical research.

Background: Ventilator-associated pneumonia (VAP) is a prevalent and grave hospital-acquired infection that affects mechanically ventilated patients. Diverse diagnostic criteria can significantly affect VAP research by complicating the identification and management of the condition, which may also impact clinical management.

Objectives: We conducted this review to assess the diagnostic criteria and the definitions of the term "ventilator-associated" used in randomised controlled trials (RCTs) of VAP management.

Sepsis and case fatality rates and associations with deprivation, ethnicity, and clinical characteristics: population-based case-control study with linked primary care and hospital data in England.

Purpose: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. The purpose of the study was to measure the associations of specific exposures (deprivation, ethnicity, and clinical characteristics) with incident sepsis and case fatality.

Methods: Two research databases in England were used including anonymized patient-level records from primary care linked to hospital admission, death certificate, and small-area deprivation.

Immunomodulatory drugs in sepsis: a systematic review and meta-analysis.

Dysregulation of the host immune response has a central role in the pathophysiology of sepsis. There has been much interest in immunomodulatory drugs as potential therapeutic adjuncts in sepsis. We conducted a systematic review and meta-analysis of randomised controlled trials evaluating the safety and clinical effectiveness of immunomodulatory drugs as adjuncts to standard care in the treatment of adults with sepsis.

Covariates in population pharmacokinetic studies of critically ill adults receiving β-lactam antimicrobials: a systematic review and narrative synthesis.

Introduction: Population pharmacokinetic studies of β-lactam antimicrobials in critically ill patients derive models that inform their dosing. In non-linear mixed-effects modelling, covariates are often used to improve model fit and explain variability. We aimed to investigate which covariates are most commonly assessed and which are found to be significant, along with global patterns of publication.

Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

Importance: Sepsis and septic shock are major healthcare problems that need early and appropriate management.

Objectives: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement.

Design Setting And Participants: This is a retrospective study.

Association of piperacillin and vancomycin exposure on acute kidney injury during combination therapy.

Objectives: Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these antibiotics when given in combination have not been previously evaluated. The purpose of this study was to compare the exposure of vancomycin + piperacillin/tazobactam in patients with and without AKI.

Control of successive unequal cell divisions by neural cell fate regulators determines embryonic neuroblast cell size.

Asymmetric cell divisions often generate daughter cells of unequal size in addition to different fates. In some contexts, daughter cell size asymmetry is thought to be a key input to specific binary cell fate decisions. An alternative possibility is that unequal division is a mechanism by which a variety of cells of different sizes are generated during embryonic development.

Clinical and health inequality risk factors for non-COVID-related sepsis during the global COVID-19 pandemic: a national case-control and cohort study.

Background: Sepsis, characterised by significant morbidity and mortality, is intricately linked to socioeconomic disparities and pre-admission clinical histories. This study aspires to elucidate the association between non-COVID-19 related sepsis and health inequality risk factors amidst the pandemic in England, with a secondary focus on their association with 30-day sepsis mortality.

Methods: With the approval of NHS England, we harnessed the OpenSAFELY platform to execute a cohort study and a 1:6 matched case-control study.

Impact of Beta-Lactam Target Attainment on Resistance Development in Patients with Gram-Negative Infections.

Background: The objective was to identify associations between beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets and Gram-negative bacteria resistance emergence in patients.

Methods: Retrospective data were collected between 2016 to 2019 at the University of Florida Health-Shands Hospital in Gainesville, FL. Adult patients with two Gram-negative isolates receiving cefepime, meropenem, or piperacillin-tazobactam and who had plasma beta-lactam concentrations were included.

Clinical trials of pneumonia management assess heterogeneous outcomes and measurement instruments.

Objectives: To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes.

Study Design And Setting: Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting.

biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis.

Design: Multicentre three-arm randomised controlled trial.

Setting: UK NHS hospitals.

A qualitative interview study applying the COM-B model to explore how hospital-based trainers implement antimicrobial stewardship education and training in UK hospital-based care.

Background: Antimicrobial resistance (AMR) is a major global health threat caused by the inappropriate use of antimicrobials in healthcare and other settings. Antimicrobial stewardship (AMS) is a broad multi-component health services intervention that promotes and monitors the judicious use of antimicrobials to preserve their future effectiveness. A main component of AMS is education and training (E&T).

Rapid Generation of Pulmonary Organoids from Induced Pluripotent Stem Cells by Co-Culturing Endodermal and Mesodermal Progenitors for Pulmonary Disease Modelling.

Differentiation of induced pluripotent stem cells to a range of target cell types is ubiquitous in monolayer culture. To further improve the phenotype of the cells produced, 3D organoid culture is becoming increasingly prevalent. Mature organoids typically require the involvement of cells from multiple germ layers.

Barriers to Genetic Testing in Vascular Malformations.

Importance: Vascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options.

Objectives: To examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM.