Role of immunosuppression in an antibiotic stewardship intervention and its association with clinical outcomes and antibiotic use: protocol for an observational study (RISC-sepsis)

\ua9 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. Introduction Sepsis is characterised by a dysregulated immune response to infection, with exaggerated pro-inflammatory and anti-inflammatory responses. A predominant immunosuppressive profile affecting both innate and adaptive immune responses is associated with increased hospital-acquired infection and reduced infection-free survival. While hospital-acquired infection leads to additional antibiotic use, the role of the immunosuppressive phenotype in guiding complex decisions, such as those affecting antibiotic stewardship, is uncertain. This study is a mechanistic substudy embedded within a multicentre clinical and cost-effectiveness trial of biomarker-guided antibiotic stewardship. This mechanistic study aims to determine the effect of sepsis-associated immunosuppression on the trial outcome measures. Methods and analysis RISC-sepsis is a prospective, multicentre, exploratory, observational study embedded within the ADAPT-sepsis trial. A subgroup of 180 participants with antibiotics commenced for suspected sepsis, enrolled in the ADAPT-sepsis trial, will be recruited. Blood samples will be collected on alternate days until day 7. At each time point, blood will be collected for flow cytometric analysis into cell preservation tubes. Immunophenotyping will be performed at a central testing hub by flow cytometry. The primary outcome measures are monocyte human leucocyte antigen-DR; neutrophil CD88; programmed cell death-1 on monocytes, neutrophils and T lymphocytes and the percentage of regulatory T cells. Secondary outcome measures will link to trial outcomes from the ADAPT-sepsis trial including antibiotic days; occurrence of hospital-acquired infection and length of ICU-stay and hospital-stay. Ethics and dissemination Ethical approval has been granted (IRAS 209815) and RISC-sepsis is registered with the ISRCTN (86837685). Study results will be disseminated by peer-reviewed publications, presentations at scientific meetings and via patient and public participation groups and social media

A retrospective propensity-score-matched cohort study of the impact of procalcitonin testing on antibiotic use in hospitalized patients during the first wave of COVID-19

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.BACKGROUND: Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK. OBJECTIVES: Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups. METHODS: Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020. RESULTS: Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections. CONCLUSIONS: Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility. STUDY REGISTRATION NUMBER: ISRCTN66682918

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

\ua9 2025 American Medical Association. All rights reserved.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. Intervention: From January 1, 2018, to June 5, 2024, 918 patients were assigned to the daily PCT-guided protocol, 924 to the daily CRP-guided protocol, and 918 assigned to standard care. Main Outcomes and Measures: The primary outcomes were total duration of antibiotics (effectiveness) and all-cause mortality (safety) to 28 days. Secondary outcomes included critical care unit data and hospital stay data. Ninety-day all-cause mortality was also collected. Results: Among the randomized patients (mean age 60.2 [SD, 15.4] years; 60.3% males), there was a significant reduction in antibiotic duration from randomization to 28 days for those in the daily PCT-guided protocol compared with standard care (mean duration, 10.7 [SD, 7.6] days for standard care and 9.8 [SD, 7.2] days for PCT; mean difference, 0.88 days; 95% CI, 0.19 to 1.58, P =.01). For all-cause mortality up to 28 days, the daily PCT-guided protocol was noninferior to standard care, where the noninferiority margin was set at 5.4% (19.4% [170 of 878] of patients receiving standard care; 20.9% [184 of 879], PCT; absolute difference, 1.57; 95% CI, -2.18 to 5.32; P =.02). No difference was found in antibiotic duration for standard care vs daily CRP-guided protocol (mean duration, 10.6 [7.7] days for CRP; mean difference, 0.09; 95% CI, -0.60 to 0.79; P =.79). For all-cause mortality, the daily CRP-guided protocol was inconclusive compared with standard care (21.1% [184 of 874] for CRP; absolute difference, 1.69; 95% CI, -2.07 to 5.45; P =.03). Conclusions and Relevance: Care guided by measurement of PCT reduces antibiotic duration safely compared with standard care, but CRP does not. All-cause mortality for CRP was inconclusive. Trial Registration: isrctn.org Identifier: ISRCTN47473244

The cost-effectiveness of procalcitonin for guiding antibiotic prescribing in individuals hospitalized with COVID-19: part of the PEACH study

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.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 \ua320000/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 (\ua39830 versus \ua310 700). 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

Pleural cancer mortality in Spain: time-trends and updating of predictions up to 2020

Background A total of 2,514,346 metric tons (Mt) of asbestos were imported into Spain from 1906 until the ban on asbestos in 2002. Our objective was to study pleural cancer mortality trends as an indicator of mesothelioma mortality and update mortality predictions for the periods 2011–2015 and 2016–2020 in Spain.Methods Log-linear Poisson models were fitted to study the effect of age, period of death and birth cohort (APC) on mortality trends. Change points in cohort- and period-effect curvatures were assessed using segmented regression. Fractional power-link APC models were used to predict mortality until 2020. In addition, an alternative model based on national asbestos consumption figures was also used to perform long-term predictions.Results Pleural cancer deaths increased across the study period, rising from 491 in 1976–1980 to 1,249 in 2006–2010. Predictions for the five-year period 2016–2020 indicated a total of 1,319 pleural cancer deaths (264 deaths/year). Forecasts up to 2020 indicated that this increase would continue, though the age-adjusted rates showed a levelling-off in male mortality from 2001 to 2005, corresponding to the lower risk in post-1960 generations. Among women, rates were lower and the mortality trend was also different, indicating that occupational exposure was possibly the single factor having most influence on pleural cancer mortality.Conclusion The cancer mortality-related consequences of human exposure to asbestos are set to persist and remain in evidence until the last surviving members of the exposed cohorts have disappeared. It can thus be assumed that occupationally-related deaths due to pleural mesothelioma will continue to occur in Spain until at least 2040.The study was partially supported by a research grant from the Spanish Health Research Fund (FIS PI11/00871) and the HAR2009-07543 project of the Ministry of Science and Innovation. The Department of Labour of the Government of Catalonia provided the asbestos consumption data

Use of Procalcitonin during the First Wave of COVID-19 in the Acute NHS Hospitals: A Retrospective Observational Study

A minority of patients presenting to hospital with COVID-19 have bacterial co-infection. Procalcitonin testing may help identify patients for whom antibiotics should be prescribed or withheld. This study describes the use of procalcitonin in English and Welsh hospitals during the first wave of the COVID-19 pandemic. A web-based survey of antimicrobial leads gathered data about the use of procalcitonin testing. Responses were received from 148/151 (98%) eligible hospitals. During the first wave of the COVID-19 pandemic, there was widespread introduction and expansion of PCT use in NHS hospitals. The number of hospitals using PCT in emergency/acute admissions rose from 17 (11%) to 74/146 (50.7%) and use in Intensive Care Units (ICU) increased from 70 (47.6%) to 124/147 (84.4%). This increase happened predominantly in March and April 2020, preceding NICE guidance. Approximately half of hospitals used PCT as a single test to guide decisions to discontinue antibiotics and half used repeated measurements. There was marked variation in the thresholds used for empiric antibiotic cessation and guidance about interpretation of values. Procalcitonin testing has been widely adopted in the NHS during the COVID-19 pandemic in an unevidenced, heterogeneous way and in conflict with relevant NICE guidance. Further research is needed urgently that assesses the impact of this change on antibiotic prescribing and patient safety

Procalcitonin to guide antibiotic use during the first wave of COVID-19 in English and Welsh hospitals: integration and triangulation of findings from quantitative and qualitative sources

\ua9 Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.Aim To integrate the quantitative and qualitative data collected as part of the PEACH (Procalcitonin: Evaluation of Antibiotic use in COVID-19 Hospitalised patients) study, which evaluated whether procalcitonin (PCT) testing should be used to guide antibiotic prescribing and safely reduce antibiotic use among patients admitted to acute UK National Health Service (NHS) hospitals. Design Triangulation to integrate quantitative and qualitative data. Setting and participants Four data sources in 148 NHS hospitals in England and Wales including data from 6089 patients. Method A triangulation protocol was used to integrate three quantitative data sources (survey, organisation-level data and patient-level data: data sources 1, 2 and 3) and one qualitative data source (clinician interviews: data source 4) collected as part of the PEACH study. Analysis of data sources initially took place independently, and then, key findings for each data source were added to a matrix. A series of interactive discussion meetings took place with quantitative, qualitative and clinical researchers, together with patient and public involvement (PPI) representatives, to group the key findings and produce seven statements relating to the study objectives. Each statement and the key findings related to that statement were considered alongside an assessment of whether there was agreement, partial agreement, dissonance or silence across all four data sources (convergence coding). The matrix was then interpreted to produce a narrative for each statement. Objective To explore whether PCT testing safely reduced antibiotic use during the first wave of the COVID-19 pandemic. Results Seven statements were produced relating to the PEACH study objective. There was agreement across all four data sources for our first key statement, € During the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing reduced antibiotic prescribing\u27. The second statement was related to this key statement, € During the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing safely reduced antibiotic prescribing\u27. Partial agreement was found between data sources 3 (quantitative patient-level data) and 4 (qualitative clinician interviews). There were no data regarding safety from data sources 1 or 2 (quantitative survey and organisational-level data) to contribute to this statement. For statements three and four, € PCT was not used as a central factor influencing antibiotic prescribing\u27, and € PCT testing reduced antibiotic prescribing in the emergency department (ED)/acute medical unit (AMU),\u27 there was agreement between data source 2 (organisational-level data) and data source 4 (interviews with clinicians). The remaining two data sources (survey and patient-level data) contributed no data on this statement. For statement five, € PCT testing reduced antibiotic prescribing in the intensive care unit (ICU)\u27, there was disagreement between data sources 2 and 3 (organisational-level data and patient-level data) and data source 4 (clinician interviews). Data source 1 (survey) did not provide data on this statement. We therefore assigned dissonance to this statement. For statement six, € There were many barriers to implementing PCT testing during the first wave of COVID-19\u27, there was partial agreement between data source 1 (survey) and data source 4 (clinician interviews) and no data provided by the two remaining data sources (organisational-level data and patient-level data). For statement seven, € Local PCT guidelines/protocols were perceived to be valuable\u27, only data source 4 (clinician interviews) provided data. The clinicians expressed that guidelines were valuable, but as there was no data from the other three data sources, we assigned silence to this statement. Conclusion There was agreement between all four data sources on our key finding € during the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing reduced antibiotic prescribing\u27. Data, methodological and investigator triangulation, and a transparent triangulation protocol give validity to this finding