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; six from primary care; seven from secondary care; and six from emergency guidelines. Eighty‐eight per cent 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 Duncan, Chris F.; Youngstein, Taryn; Kirrane, Marianne D. ...
Current infectious disease reports,
12/2021, Letnik:
23, Številka:
12
Journal Article
Recenzirano
Odprti dostop
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.
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.
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.
Abstract
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.
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.
Aims
Beta‐lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta‐lactams (amoxicillin ± clavulanate, ...piperacillin–tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life.
Methods
A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function.
Results
A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9–200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight‐adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates.
Conclusions
Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta‐lactam dosing, although a prospective, age‐inclusive study is warranted for external validation.
Introduction: Sepsis from bacterial infection remains a significant cause of morbidity and mortality. Antibiotic use continues to increase in the community and secondary care. This is driven by the ...potential benefits to the individual patient of a course of antibiotics. Far less attention is given to the potential adverse effects of antibiotic use in our view. These costs may be significant to both the individual and society.
Areas covered: We review the evidence underpinning the costs and benefits of antibiotic use. We also discuss strategies to personalize medicine in this area that maximize the benefit to cost ratio for patients and society.
Expert opinion: The body's innate immune response to infection is similar to that of other inflammatory insults. Our view is as clinicians we need to differentiate these responses and hence require an accurate method to determine a diagnosis of a bacterial infection and monitor illness severity. Without this, clinicians will continue to prescribe significant volumes of unnecessary antibiotics in cases of non-bacterial inflammatory states.
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.
This report illustrates the difficulty in managing CNS infection in neurosurgical patients, the altered drug pharmacokinetics associated with critical illness, and the role that therapeutic drug ...monitoring (TDM) of CSF can play in assisting clinical decision making. The authors present a case of external ventricular drain-related ventriculitis in a critically ill patient who initially presented with a subarachnoid hemorrhage. They discuss the physiological changes found in such patients, in particular augmented renal clearance (demonstrated in this patient by a measured creatinine clearance of 375 ml/min/1.73 m(2)), noting the effect this had on drug pharmacokinetics and leading to dosing requirements 2-3 times those recommended in standard regimens. The authors consider the bacterial "kill" characteristics of 2 different antibacterial agents (meropenem and vancomycin) and describe the unique approach of using plasma and CSF TDM to achieve optimal drug exposure at the site of infection while limiting toxic side effects. The authors demonstrate that simply using plasma TDM as a surrogate marker for drug concentration in the CNS may lead to underdosing, exemplified in this patient by CSF vancomycin concentrations as little as 13% of that in plasma. Finally, by measuring CSF and plasma ratios, the authors illustrate the disparity in pharmacokinetic properties between drugs, reminding the clinician of the importance of CNS penetration when selecting antibacterial agents in such cases. This work raises an important hypothesis in the accurate prescription of antibacterial agents in neurosurgical critical care, namely underdosing in the context of augmented elimination and impaired target site penetration. However, prior to any recommendations regarding empirical dose modification, more data are clearly needed, particularly with respect to the safety and efficacy of such an approach. In this respect, the authors would advocate further research using TDM in the management of CNS infection in this setting, in addition to work defining plasma and CSF concentrations associated with antibacterial efficacy and toxicity.
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