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BACKGROUND: Many hospitals introduced procalcitonin (PCT) testing to help diagnose bacterial coinfection in individuals with COVID-19, and guide antibiotic decision-making during the COVID-19 pandemic in the UK. OBJECTIVES: Evaluating cost-effectiveness of using PCT to guide antibiotic decisions in individuals hospitalized with COVID-19, as part of a wider research programme. METHODS: Retrospective individual-level data on patients hospitalized with COVID-19 were collected from 11 NHS acute hospital Trusts and Health Boards from England and Wales, which varied in their use of baseline PCT testing during the first COVID-19 pandemic wave. A matched analysis (part of a wider analysis reported elsewhere) created groups of patients whose PCT was/was not tested at baseline. A model was created with combined decision tree/Markov phases, parameterized with quality-of-life/unit cost estimates from the literature, and used to estimate costs and quality-adjusted life years (QALYs). Cost-effectiveness was judged at a £20â000/QALY threshold. Uncertainty was characterized using bootstrapping. RESULTS: People who had baseline PCT testing had shorter general ward/ICU stays and spent less time on antibiotics, though with overlap between the groups' 95% CIs. Those with baseline PCT testing accrued more QALYs (8.76 versus 8.62) and lower costs (£9830 versus £10â700). The point estimate was baseline PCT testing being dominant over no baseline testing, though with uncertainty: the probability of cost-effectiveness was 0.579 with a 1 year horizon and 0.872 with a lifetime horizon. CONCLUSIONS: Using PCT to guide antibiotic therapy in individuals hospitalized with COVID-19 is more likely to be cost-effective than not, albeit with uncertainty.
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Antibacterianos , COVID-19 , Análisis Costo-Beneficio , Polipéptido alfa Relacionado con Calcitonina , Humanos , Polipéptido alfa Relacionado con Calcitonina/sangre , Antibacterianos/uso terapéutico , Antibacterianos/economía , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Anciano , Hospitalización/economía , SARS-CoV-2 , Años de Vida Ajustados por Calidad de Vida , Adulto , Tratamiento Farmacológico de COVID-19 , Reino Unido , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/economíaRESUMEN
Background: Information on the quality of life of people hospitalised with COVID-19 is important, both in assessing the burden of disease and the cost-effectiveness of treatments. However, there were potential barriers to collecting such evidence. Objective: To review the existing evidence on quality of life for people hospitalised with COVID-19, with a focus on the amount of evidence available and methods used. Design: A scoping review with systematic searches. Results: A total of 35 papers were selected for data extraction. The most common study type was economic evaluation (Nâ =â 13), followed by cross-sectional (Nâ =â 10). All economic evaluations used published utility values for other conditions to represent COVID-19 inpatients' quality of life. The most popular quality-of-life survey measure was the Pittsburgh Sleep Quality Index (Nâ =â 8). There were 12 studies that used a mental health-related survey and 12 that used a sleep-related survey. Five studies used EQ-5D, but only one collected responses from people in the acute phase of COVID-19. Studies reported a negative impact on quality of life for people hospitalised with COVID-19, although many studies did not include a formal comparison group. Limitations: Although it used systematic searches, this was not a full systematic review. Conclusion: Quality-of-life data were collected from people hospitalised with COVID-19 from relatively early in the pandemic. However, there was a lack of consensus as to what survey measures to use, and few studies used generic health measures. Economic evaluations for COVID-19 treatments did not use utilities collected from people with COVID-19. In future health crises, researchers should be vigilant for opportunities to collect quality-of-life data from hospitalised patients but should try to co-ordinate as well as ensuring generic health measures are used more. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132254.
Quality of life can be measured using short, simple surveys. It is important to assess quality of life in this way, as it can show how health conditions affect people. Quality-of-life surveys can also be used to measure how treatments benefit people and to judge whether it is cost-effective to fund them. COVID-19 is a new disease, with new treatments developed to treat it. COVID-19 also created possible barriers to collecting quality-of-life survey data, especially from people in hospital at the start of the pandemic. This paper reviews studies which report data on quality of life for people hospitalised with COVID-19, especially how much evidence is available and how the studies were carried out. There were 35 studies included in the review. Of these, 13 assessed how cost-effective treatments for COVID-19 were. None of them collected survey responses directly from patients. Instead, they used data previously collected from people with other conditions such as influenza to represent people with COVID-19's quality of life. The studies which did collect data from patients used a wide variety of different surveys, which made comparing their results difficult. Mental health-related surveys were used by 12 studies, and a further 12 used sleep-related surveys. Relatively few studies used general surveys which could assess the overall effect of COVID-19 on people's quality of life. In future health crises, we recommend using more general quality-of-life measures. We also recommend that researchers co-ordinate to reduce the number of different surveys they use, as this will make comparing results easier.
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Previously we reported that a novel αvß6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. Previously we reported that the KPC mouse transgenic PDAC model that closely recapitulates most stages of development of human PDAC, unlike in humans, failed to express αvß6 on their tumours or metastases. In this study we have taken the KPC-derived PDAC line TB32043 and engineered a variant line (TB32043mb6S2) that expresses mouse integrin αvß6. We report that orthotopic implantation of the αvß6 over-expressing TB32043mb6S2 cells promotes shorter overall survival and increase in metastases. Moreover, systemic treatment of mice with established TB32043mb6S2 tumours in the pancreas with SG2399 lived significantly longer (p < 0.001; mean OS 48d) compared with PBS or control SG3511 (mean OS 25.5d and 26d, respectively). Thus SG3299 is confirmed as a promising candidate therapeutic for the therapy of PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Línea Celular Tumoral , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Integrinas/uso terapéutico , Péptidos/uso terapéutico , Antígenos de NeoplasiasRESUMEN
This editorial highlights the different barriers and enablers of antibiotic amnesty campaigns in community pharmacies. The main enablers of antibiotic amnesties included effective counselling and successful use of promotional resources, whilst the main barriers included lack of education in patients and staff. Enabling factors such as effective counselling and use of promotional resources should be continued with patients, whilst the main barriers can be tackled with provision of sufficient education, training, and knowledge for patients. Educating staff, by providing appropriate training to all staff members present in the pharmacy, can positively contribute to the success of antibiotic amnesty campaigns. The findings of this work can inform the development of interventions needed to improve antibiotic amnesties, resulting in more antibiotics being returned and contributing towards tackling the issue of antimicrobial resistance (AMR).
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OBJECTIVE: To explore and model factors affecting antibiotic prescribing decision-making early in the pandemic. DESIGN: Semistructured qualitative interview study. SETTING: National Health Service (NHS) trusts/health boards in England and Wales. PARTICIPANTS: Clinicians from NHS trusts/health boards in England and Wales. METHOD: Individual semistructured interviews were conducted with clinicians in six NHS trusts/health boards in England and Wales as part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients study, a wider study that included statistical analysis of procalcitonin (PCT) use in hospitals during the first wave of the pandemic. Thematic analysis was used to identify key factors influencing antibiotic prescribing decisions for patients with COVID-19 pneumonia during the first wave of the pandemic (March to May 2020), including how much influence PCT test results had on these decisions. RESULTS: During the first wave of the pandemic, recommendations to prescribe antibiotics for patients with COVID-19 pneumonia were based on concerns about secondary bacterial infections. However, as clinicians gained more experience with COVID-19, they reported increasing confidence in their ability to distinguish between symptoms and signs caused by SARS-CoV-2 viral infection alone, and secondary bacterial infections. Antibiotic prescribing decisions were influenced by factors such as clinician experience, confidence, senior support, situational factors and organisational influences. A decision-making model was developed. CONCLUSION: This study provides insight into the decision-making process around antibiotic prescribing for patients with COVID-19 pneumonia during the first wave of the pandemic. The importance of clinician experience and of senior review of decisions as factors in optimising antibiotic stewardship is highlighted. In addition, situational and organisational factors were identified that could be optimised. The model presented in the study can be used as a tool to aid understanding of the complexity of the decision-making process around antibiotic prescribing and planning antimicrobial stewardship support in the context of a pandemic. TRIAL REGISTRATION NUMBER: ISRCTN66682918.
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Infecciones Bacterianas , COVID-19 , Humanos , Antibacterianos/uso terapéutico , Polipéptido alfa Relacionado con Calcitonina , Pandemias , Medicina Estatal , SARS-CoV-2 , Infecciones Bacterianas/tratamiento farmacológico , HospitalesRESUMEN
INTRODUCTION: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing. METHODS AND ANALYSIS: The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation. ETHICS AND DISSEMINATION: This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal. TRIAL REGISTRATION: ISRCTN20579216.
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Hipersensibilidad a las Drogas , Hipersensibilidad , Adulto , Humanos , Alabama , Antibacterianos/efectos adversos , Farmacorresistencia Bacteriana , Estudios Multicéntricos como Asunto , Penicilinas/efectos adversos , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto , Medicina Estatal , Ensayos Clínicos Pragmáticos como AsuntoRESUMEN
Contemporary communication requires both a supply of content and a digital information infrastructure. Modern campaigns of misinformation are especially dependent on that back-end infrastructure for tracking and targeting a sympathetic audience and generating revenue that can sustain the campaign financially-if not enable profiteering. However, little is known about the political economy of misinformation, particularly those campaigns spreading misleading or harmful content about public health guidelines and vaccination programs. To understand the political economy of health misinformation, we analyze the content and infrastructure networks of 59 groups involved in communicating misinformation about vaccination programs. With a unique collection of tracker and communication infrastructure data, we demonstrate how the political economy of misinformation depends on platform monetization infrastructures. We offer a theory of communication resource mobilization that advances understanding of the communicative context, organizational interactions, and political outcomes of misinformation production.
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Infective endocarditis (IE) remains a difficult condition to diagnose and treat and is an infection of high consequence for patients, causing long hospital stays, life-changing complications and high mortality. A new multidisciplinary, multiprofessional, British Society for Antimicrobial Chemotherapy (BSAC)-ledWorking Party was convened to undertake a focused systematical review of the literature and to update the previous BSAC guidelines relating delivery of services for patients with IE. A scoping exercise identified new questions concerning optimal delivery of care, and the systematic review identified 16 231 papers of which 20 met the inclusion criteria. Recommendations relating to endocarditis teams, infrastructure and support, endocarditis referral processes, patient follow-up and patient information, and governance are made as well as research recommendations. This is a report of a joint Working Party of the BSAC, British Cardiovascular Society, British Heart Valve Society, British Society of Echocardiography, Society of Cardiothoracic Surgeons of Great Britain and Ireland, British Congenital Cardiac Association and British Infection Association.
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Endocarditis Bacteriana , Endocarditis , Humanos , Consenso , Endocarditis Bacteriana/diagnóstico , Endocarditis/terapia , Endocarditis/tratamiento farmacológico , Reino Unido , IrlandaRESUMEN
Antibody-drug conjugates (ADC) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers are currently being evaluated in clinical trials, with encouraging results in Hodgkin and non-Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA cross-linker (loncastuximab tesirine) has been recently approved by the FDA for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogs. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA-binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as "pseudo cross-linking," as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses 3-fold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the MTD of the PBD mono-alkylator ADC was approximately 3-fold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine, indicating possible differences in toxicologic profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmacotoxicologic properties distinct from their cross-linking analogs and support their potential utility as a novel class of ADC payload.
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Inmunoconjugados , Linfoma no Hodgkin , Humanos , Animales , Ratones , Ratas , Alquilación , ADN , Iminas , Inmunoconjugados/farmacologíaRESUMEN
PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.
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Inmunoconjugados , Neoplasias , Ratas , Humanos , Animales , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Inhibidores de Topoisomerasa I , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/genéticaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is a viral illness, many patients admitted to hospital are prescribed antibiotics, based on concerns that COVID-19 patients may experience secondary bacterial infections, and the assumption that they may respond well to antibiotic therapy. This has led to an increase in antibiotic use for some hospitalised patients at a time when accumulating antibiotic resistance is a major global threat to health. Procalcitonin (PCT) is an inflammatory marker measured in blood samples and widely recommended to help diagnose bacterial infections and guide antibiotic treatment. The PEACH study will compare patient outcomes from English and Welsh hospitals that used PCT testing during the first wave of the COVID-19 pandemic with those from hospitals not using PCT. It will help to determine whether, and how, PCT testing should be used in the NHS in future waves of COVID-19 to protect patients from antibiotic overuse. PEACH is a retrospective observational cohort study using patient-level clinical data from acute hospital Trusts and Health Boards in England and Wales. The primary objective is to measure the difference in antibiotic use between COVID-19 patients who did or did not have PCT testing at the time of diagnosis. Secondary objectives include measuring differences in length of stay, mortality, intensive care unit admission, and resistant bacterial infections between these groups.
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BACKGROUND: Pharmacists are identified as key members of hospital antimicrobial stewardship (AMS) teams in international guidelines. Developing an international standardized tool to measure hospital pharmacists' confidence and practices of AMS will encourage knowledge sharing and better networking between hospital pharmacists internationally. OBJECTIVES: To develop a survey tool that can be used internationally to assess pharmacists' knowledge, confidence, perceived barriers and current AMS practices. METHODS: A project team was formed to refine the survey tool that was initially used in a previous survey study. Following revision by the project team, a revised survey tool was sent to the ESCMID Study Group for Antimicrobial Stewardship (ESGAP). Feedback from the ESGAP members was considered by the project team to finalize the survey tool. RESULTS: A total of 88 changes were made to the survey tool after revision by the project team. A total of 43/216 (19.9%) of ESGAP members provided feedback on the survey tool, which led to a further 19 revisions. ESGAP members were agreeable to the questions in the survey tool, with >50% agreeing that each question was suitable. The final survey tool consisted of 42 questions, reduced from 72 questions in the original survey. CONCLUSIONS: An international survey tool to measure hospital pharmacists' confidence and practices of AMS was developed. This tool will help the wider hospital pharmacy community in conducting local studies on current AMS practices and to identify areas where further support is needed. Use of a standardized survey tool will also allow individual regions/countries to compare their data with other countries to identify potential quality improvement programmes.
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Programas de Optimización del Uso de los Antimicrobianos , Servicios Comunitarios de Farmacia , Humanos , Farmacéuticos , Encuestas y Cuestionarios , HospitalesRESUMEN
Turkey has vastly increased the scale of its investment in public diplomacy tools. Although Turkey is considered one of the world's worst jailers of journalists, its media market is one of the fastest-growing in the world. In 2015, the Istanbul-based English-language TRT World was launched with the slogan 'where news inspires change', The channel promised to provide impartial coverage of global news, with its experienced journalists addressing global audiences. In this study, we investigate the interplay between public diplomacy and editorial policies at TRT World. After conducting in-depth interviews with TRT World journalists, we argue that the channel has shifted its style from being Turkey's public diplomacy tool into becoming the AKP's voice to the world. By examining TRT World, this study provides a framework to understand how international broadcasters operate in countries where media freedom is restricted.
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Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted.
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Antineoplásicos , Inmunoconjugados , Animales , Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Línea Celular Tumoral , Humanos , Inmunoconjugados/uso terapéutico , Pirroles , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The community pharmacy antimicrobial stewardship intervention (PAMSI) is multi-faceted and underpinned by behavioural science, consisting of the TARGET Antibiotic Checklist, staff e-Learning, and patient-facing materials. This mixed-method study evaluated the effect of PAMSI on community pharmacy staffs' self-reported antimicrobial stewardship (AMS) behaviours. Data collection included staff pre- and post-intervention questionnaires, qualitative interviews, and TARGET Antibiotic Checklists. Quantitative data were analysed by a multivariate ordinal linear mixed effect model; qualitative data were analysed thematically. A total of 101 staff participated from 66 pharmacies, and six completed semi-structured interviews. The statistical model indicated very strong evidence (p < 0.001) that post-intervention, staff increased their antibiotic appropriateness checks and patient advice, covering antibiotic adherence, antibiotic resistance, infection self-care, and safety-netting. Staff reported feeling empowered to query antibiotic appropriateness with prescribing clinicians. The TARGET Antibiotic Checklist was completed with 2043 patients. Topics patients identified as requiring advice from the pharmacy team included symptom duration, alcohol and food consumption guidance, antibiotic side-effects, and returning unused antibiotics to pharmacies. Pharmacy staff acknowledged the need for improved communication across the primary care pathway to optimise antimicrobial use, and PAMSI has potential to support this ambition if implemented nationally. To support patients not attending a pharmacy in person, an online information tool will be developed.
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INTRODUCTION: Sepsis is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes prompt antibiotics and intravenous fluids, facilitated by its early and accurate recognition. Currently, clinicians identify and assess severity of suspected sepsis using validated clinical scoring systems. In England, the National Early Warning Score 2 (NEWS2) has been mandated across all National Health Service (NHS) trusts and ambulance organisations. Like many clinical scoring systems, NEWS2 should not be used without clinical judgement to determine either the level of acuity or a diagnosis. Despite this, there is a tendency to overemphasise the score in isolation in patients with suspected infection, leading to the overprescription of antibiotics and potentially treatment-related complications and rising antimicrobial resistance. The biomarker procalcitonin (PCT) has been shown to be useful in specific circumstances to support appropriate antibiotics prescribing by identifying bacterial infection. PCT is not routinely used in the care of undifferentiated patients presenting to emergency departments (EDs), and the evidence base of its optimal usage is poor. The PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal (PRONTO) study is a randomised controlled trial (RCT) in adults with suspected sepsis presenting to the ED to compare standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment with standard clinical management based on NEWS2 scoring alone and compare if this approach reduces prescriptions of antibiotics without increasing mortality. METHODS AND ANALYSIS: PRONTO is a parallel two-arm open-label individually RCT set in up to 20 NHS EDs in the UK with a target sample size of 7676 participants. Participants will be randomised in a ratio of 1:1 to standard clinical management based on NEWS2 scoring or standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment. We will compare whether the addition of PCT measurement to NEWS2 scoring can lead to a reduction in intravenous antibiotic initiation in ED patients managed as suspected sepsis, with at least no increase in 28-day mortality compared with NEWS2 scoring alone (in conjunction with local standard care pathways). PRONTO has two coprimary endpoints: initiation of intravenous antibiotics at 3 hours (superiority comparison) and 28-day mortality (non-inferiority comparison). The study has an internal pilot phase and group-sequential stopping rules for effectiveness and futility/safety, as well as a qualitative substudy and a health economic evaluation. ETHICS AND DISSEMINATION: The trial protocol was approved by the Health Research Authority (HRA) and NHS Research Ethics Committee (Wales REC 2, reference 20/WA/0058). In England and Wales, the law allows the use of deferred consent in approved research situations (including ED studies) where the time dependent nature of intervention would not allow true informed consent to be obtained. PRONTO has approval for a deferred consent process to be used. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN54006056.
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Infecciones Bacterianas , Sepsis , Adulto , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Servicio de Urgencia en Hospital , Humanos , Estudios Multicéntricos como Asunto , Polipéptido alfa Relacionado con Calcitonina , Ensayos Clínicos Controlados Aleatorios como Asunto , Sepsis/diagnóstico , Sepsis/tratamiento farmacológicoRESUMEN
Resilience is having the ability to respond to adversity proactively and resourcefully. The coronavirus disease 2019 (COVID-19) pandemic's profound impact on antimicrobial stewardship programs (ASP) requires clinicians to call on their own resilience to manage the demands of the pandemic and the disruption of ASP activities. This article provides examples of ASP resilience from pharmacists and physicians from seven countries with different resources and approaches to ASP-The United States, The United Kingdom, Canada, Nigeria, Lebanon, South Africa, and Colombia. The lessons learned pertain to providing ASP clinical services in the context of a global pandemic, developing new ASP paradigms in the face of COVID-19, leveraging technology to extend the reach of ASP, and conducting international collaborative ASP research remotely. This article serves as an example of how resilience and global collaboration is sustaining our ASPs by sharing new "how to" do antimicrobial stewardship practices during the COVID-19 pandemic.
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BACKGROUND: Blood biomarkers have the potential to help identify COVID-19 patients with bacterial coinfection in whom antibiotics are indicated. During the COVID-19 pandemic, procalcitonin testing was widely introduced at hospitals in the UK to guide antibiotic prescribing. We have determined the impact of this on hospital-level antibiotic consumption. METHODS: We conducted a retrospective, controlled interrupted time series analysis of organization-level data describing antibiotic dispensing, hospital activity and procalcitonin testing for acute hospitals/hospital trusts in England and Wales during the first wave of COVID-19 (24 February to 5 July 2020). RESULTS: In the main analysis of 105 hospitals in England, introduction of procalcitonin testing in emergency departments/acute medical admission units was associated with a statistically significant decrease in total antibiotic use of -1.08 (95% CI: -1.81 to -0.36) DDDs of antibiotic per admission per week per trust. This effect was then lost at a rate of 0.05 (95% CI: 0.02-0.08) DDDs per admission per week. Similar results were found specifically for first-line antibiotics for community-acquired pneumonia and for COVID-19 admissions rather than all admissions. Introduction of procalcitonin in the ICU setting was not associated with any significant change in antibiotic use. CONCLUSIONS: At hospitals where procalcitonin testing was introduced in emergency departments/acute medical units this was associated with an initial, but unsustained, reduction in antibiotic use. Further research should establish the patient-level impact of procalcitonin testing in this population and understand its potential for clinical effectiveness.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Polipéptido alfa Relacionado con Calcitonina , Antibacterianos/uso terapéutico , COVID-19/diagnóstico , Hospitales , Humanos , Análisis de Series de Tiempo Interrumpido , Pandemias , Estudios Retrospectivos , Medicina Estatal , Reino UnidoRESUMEN
Antibody-drug conjugates (ADCs) are an emerging class of oncology treatments combining the unique specificity of monoclonal antibodies with the highly cytotoxic properties of small molecule compounds. Pyrrolobenzodiazepines (PBDs) are highly potent agents capable of inhibiting cellular DNA replication which leads to apoptosis. To ensure efficacy and patient safety upon administration of such toxic and heterogeneous molecules, their structure and quality attributes must be closely monitored. Size exclusion chromatography (SEC) is a powerful, fast and robust tool for the separation of compounds varying in molecular weight. When using volatile components in the chromatographic mobile phase, SEC has also been shown to be amenable for interfacing to mass spectrometry, providing potential for reliable identification of protein isoforms across the size variants present. Here, we present a SEC-MS method developed for the characterisation of PBD-based ADCs on the intact molecular level. We demonstrate that information on ADC monomers such as the glycoform distribution and the average drug-antibody ratio (DAR) can be obtained in 15 minutes of analysis time. Qualitative and quantitative information on low and high molecular weight impurities such as aggregates and fragments, fundamental for critical quality attribute analysis of biopharmaceuticals, can be generated simultaneously. SEC-MS enables the characterisation of multiple product quality attributes of complex biotherapeutics at the same time.