Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design

Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour opportunistic, “scavenged” sampling. This study aimed to develop a small volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modelling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modelling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 hours. Modelling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring

Classifying antibiotics in the WHO Essential Medicines List for optimal use—be AWaRe

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Translating clinicians' beliefs into implementation interventions (TRACII) : a protocol for an intervention modeling experiment to change clinicians' intentions to implement evidence-based practice

Background: Biomedical research constantly produces new findings, but these are not routinely incorporated into health care practice. Currently, a range of interventions to promote the uptake of emerging evidence are available. While their effectiveness has been tested in pragmatic trials, these do not form a basis from which to generalise to routine care settings. Implementation research is the scientific study of methods to promote the uptake of research findings, and hence to reduce inappropriate care. As clinical practice is a form of human behaviour, theories of human behaviour that have proved to be useful in other settings offer a basis for developing a scientific rationale for the choice of interventions. Aims: The aims of this protocol are 1) to develop interventions to change beliefs that have already been identified as antecedents to antibiotic prescribing for sore throats, and 2) to experimentally evaluate these interventions to identify those that have the largest impact on behavioural intention and behavioural simulation. Design: The clinical focus for this work will be the management of uncomplicated sore throat in general practice. Symptoms of upper respiratory tract infections are common presenting features in primary care. They are frequently treated with antibiotics, and research evidence is clear that antibiotic treatment offers little or no benefit to otherwise healthy adult patients. Reducing antibiotic prescribing in the community by the "prudent" use of antibiotics is seen as one way to slow the rise in antibiotic resistance, and appears safe, at least in children. However, our understanding of how to do this is limited. Participants will be general medical practitioners. Two theory-based interventions will be designed to address the discriminant beliefs in the prescribing of antibiotics for sore throat, using empirically derived resources. The interventions will be evaluated in a 2 × 2 factorial randomised controlled trial delivered in a postal questionnaire survey. Two outcome measures will be assessed: behavioural intention and behavioural simulation.This study is funded by the European Commission Research Directorate as part of a multi-partner program: Research Based Education and Quality Improvement (ReBEQI): A Framework and tools to develop effective quality improvement programs in European healthcare. (Proposal No: QLRT-2001-00657)

Diagnostic and antibiotic use practices among COVID-19 and non-COVID-19 patients in the Indonesian National Referral Hospital.

BACKGROUND: Little is known about diagnostic and antibiotic use practices in low and middle-income countries (LMICs) before and during COVID-19 pandemic. This information is crucial for monitoring and evaluation of diagnostic and antimicrobial stewardships in healthcare facilities. METHODS: We linked and analyzed routine databases of hospital admission, microbiology laboratory and drug dispensing of Indonesian National Referral Hospital from 2019 to 2020. Patients were classified as COVID-19 cases if their SARS-CoV-2 RT-PCR result were positive. Blood culture (BC) practices and time to discontinuation of parenteral antibiotics among inpatients who received a parenteral antibiotic for at least four consecutive days were used to assess diagnostic and antibiotic use practices, respectively. Fine and Grey subdistribution hazard model was used. RESULTS: Of 1,311 COVID-19 and 58,917 non-COVID-19 inpatients, 333 (25.4%) and 18,837 (32.0%) received a parenteral antibiotic for at least four consecutive days. Proportion of patients having BC taken within ±1 calendar day of parenteral antibiotics being started was higher in COVID-19 than in non-COVID-19 patients (21.0% [70/333] vs. 18.7% [3,529/18,837]; p<0.001). Cumulative incidence of having a BC taken within 28 days was higher in COVID-19 than in non-COVID-19 patients (44.7% [149/333] vs. 33.2% [6,254/18,837]; adjusted subdistribution-hazard ratio [aSHR] 1.71, 95% confidence interval [CI] 1.47-1.99, p<0.001). The median time to discontinuation of parenteral antibiotics was longer in COVID-19 than in non-COVID-19 patients (13 days vs. 8 days; aSHR 0.73, 95%Cl 0.65-0.83, p<0.001). CONCLUSIONS: Routine electronic data could be used to inform diagnostic and antibiotic use practices in LMICs. In Indonesia, the proportion of timely blood culture is low in both COVID-19 and non-COVID-19 patients, and duration of parenteral antibiotics is longer in COVID-19 patients. Improving diagnostic and antimicrobial stewardship is critically needed

How do the epidemiology of paediatric methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus bacteraemia differ?

Purpose: To examine whether the epidemiology of bacteraemia caused by MSSA and MRSA differed in children aged <1 year and in comparison to older age groups. Methodology: English mandatory MRSA and MSSA surveillance data from 2006 and 2011, respectively, were collected. Epidemiological information was descriptively analysed in relation to methicillin susceptibility and patient age. Ninety-five percent confidence intervals (CIs) are reported. Results/key findings: The average incidence rate of MSSA and MRSA bacteraemia in <1 year olds was 60.2 and 4.8 episodes per 100,000 population per year, respectively. Of the cases of MSSA bacteraemia in children aged <1 year, 47.5% (95% CI: 45.1-50.0; n=760/1,599) were in neonates. With increasing age up to one year, more MSSA bacteraemias were detected ≥ seven days after admission, ranging from 0% (95% CI: 0-2.5%) in 0-2 day olds to 68.4% (95% CI: 64.0-72.5%; 333/487) in 8-28 day olds and 50.5% (95% CI: 47.1-54.0%; 423/837) in 29 day-1 year olds, a higher proportion than in older children but similar to MRSA bacteraemia. Amongst <1 year olds with MSSA bacteraemia, the underlying source was most commonly recorded as intravascular devices (34.4% [95% CI: 30.5-38.6%]; n=190/552) whilst in older age groups this declined. A similar trend was observed for MRSA bacteraemia. Conclusions: Our analysis indicates that S. aureus bacteraemia in <1 year olds is primarily healthcare-associated, unlike MSSA bacteraemia in older age groups. Paediatric-specific interventions targeted at the healthcare setting, such as neonatal unit-specific care bundles and paediatric device-specific strategies, are required

The ethics of setting national antibiotic policies using financial incentives

Antimicrobial resistance (AMR) is an increasingly urgent global public health issue. Data from Public Health England- English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) - quantifies the scale of antibiotic resistance in key bacterial pathogens. The Department of Health’s 5 year strategy to reduce morbidity and mortality associated with AMR (2013-2018) focused on optimising antibiotic prescribing and improving infection prevention and control. In April 2015 NHS England introduced a Quality Premium (QP) focussing on reducing antibiotics. QPs are financial rewards, with a maximal value equivalent to £5 per patient, intended to reward clinical commissioning groups (CCGs) for improvements in the quality of the services that they commission and for associated improvements in health outcomes and reducing inequalities. The AMR QP provided commissioners with financial incentives to reduce antibiotic prescribing; 80% linked to primary care quality measures (reduction in absolute number of antibiotic prescriptions by 1%, decrease in use of broad spectrum antibiotics by 10%) and 20% linked to improving availability of antibiotic prescribing data from secondary care.</p