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3rd February 2025
Using procalcitonin (PCT) levels to guide intravenous antibiotic use in children hospitalised with bacterial infections does not shorten the duration of therapy compared with usual care, a large UK study finds.
Previous research had suggested that PCT – a rapid response biomarker for bacterial infection – could guide antibiotic discontinuation, but the test was not routinely used in the NHS, the study authors wrote in The Lancet Child & Adolescent Health.
In a multicentre trial at 15 hospitals in England and Wales, researchers assessed whether a PCT-guided algorithm would safely reduce the duration of antibiotic therapy in children hospitalised with confirmed or suspected bacterial infections compared with usual care, which commonly used C-reactive protein as a biomarker.
Children aged 72 hours to 18 years who were hospitalised and being treated with intravenous antibiotics for more than 48 hours were eligible for the trial.
Between 11 June 2018 and 12 October 2022, a total of 15,282 children were screened for eligibility, with 1,949 randomly assigned (1:1) to receive either current clinical management alone (usual care group) or clinical management with the addition of a PCT-guided algorithm (PCT group).
In the PCT group, plasma PCT levels were tested at baseline and every one to three days during intravenous antibiotic treatment.
Assay results were fed into an algorithm which provided guidance on antibiotic management; however, clinicians could decide to over-rule the algorithm.
The study found the addition of a PCT-guided algorithm was non-inferior in terms of safety but did not reduce the duration of intravenous antibiotic use compared with usual care.
In addition, a cost-effectiveness analysis showed that PCT-guided antibiotic management was more costly than usual care.
The median intravenous antibiotic duration was 96 hours in the PCT group and 99.7 hours in the usual care group (hazard ratio 0.96 [95% CI 0.87–1.05]), data showed.
Of the 917 participants in the PCT group, 78 (9%) had at least one event covered by the composite safety outcome measure compared with 85 (9%) of 904 participants in the usual care group (estimated adjusted risk difference –0.81% [95% CI upper bound 1.11]).
Among the study limitations, the researchers noted low adherence to the PTC-guided algorithm (36% at first clinical review and 54% at any clinical review).
In addition, the four hospitals who recruited the most participants had already implemented antimicrobial stewardship programmes.
Concluding, the authors recommended PCT-guided algorithms should be tested in subgroups of paediatric patients to establish whether they can reduce the duration of intravenous antibiotic treatment among patients with specific clinical characteristics.
Study chief investigator Professor Enitan Carrol, professor of paediatric infection at the University of Liverpool, UK, noted the study was a pragmatic trial in which clinicians did not have to adhere to the diagnostic algorithms.
‘Adherence to the algorithm was low in our study, and there were challenges in integrating the test into routine clinical workflows,’ he said.
‘The study highlights the importance of including behaviour change and implementation frameworks into pragmatic trial designs.’
The research, known as the ‘Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection’ (BATCH) trial, was led by the University of Liverpool and conducted in collaboration with Cardiff University’s Centre of Clinical Trials Research, with funding from the National Institute for Health and Care Research (NIHR).
It followed a National Institute for Health and Care Excellence recommendation for further studies to assess the effectiveness of adding PCT algorithms to guide antibiotic treatment in hospitalised adults and children with suspected or confirmed serious bacterial infections.
Late last year, a large NIHR-funded and commissioned trial in adults found PCT-monitoring could significantly reduce antibiotic overuse in sepsis.
19th December 2024
Daily monitoring of the blood biomarker procalcitonin (PCT) can pinpoint when to safely stop antibiotics in adults hospitalised for suspected sepsis, reducing the duration of therapy compared with standard care, a large study finds.
It was known that optimising duration of antibiotic therapy helped to reduce overtreatment, limit unwanted effects and preserve antibiotic effectiveness by minimising resistance, a team of UK-based researchers wrote in JAMA.
However, there was currently no agreed optimal duration for antibiotic therapy for sepsis.
Clinicians tended to use clinical judgment on when to cease antibiotics, with evidence remaining uncertain for the efficacy and safety of therapy guided by inflammatory biomarkers, such as PCT or C-reactive protein (CRP).
To close this evidence gap, the National Institute for Health and Care Research (NIHR) commissioned and funded a three-arm, randomised trial across 41 NHS intensive care units, which enrolled 2,760 adult patients requiring critical care for suspected sepsis.
Eligible patients, who had started intravenous antibiotics before study enrolment, were randomly assigned to either a daily PCT-protocol, a daily CRP-protocol or standard care.
Blood was drawn daily from all participants and sent for testing according to the treatment arm, but the results were concealed from the treating clinicians to minimise bias.
Instead, clinicians received daily written advice from their local clinical research team on either standard care or on PCT or CRP biomarker-guided antibiotic discontinuation.
From randomisation to 28 days, the PCT-guided protocol led to a significant reduction in antibiotic duration compared with standard care (mean duration, 10.7 days for standard care versus 9.8 days for PCT; mean difference, 0.88 days).
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%.
‘The duration reduction is in the order of 10% in antibiotic use for sepsis, which could provide significant cost and labour savings, and might also reduce the development of antimicrobial resistance,” the study authors wrote.
No difference was found in antibiotic duration for standard care compared with the daily CRP-guided protocol and the all-cause mortality for CRP compared with standard care was inconclusive.
The researchers from the University of Manchester, Northern Care Alliance NHS Foundation Trust and the Clinical Trials Unit of the University of Warwick’s Medical School also noted that the trial could not provide evidence for biomarker use in initiating antibiotic therapy as participants had commenced treatment before enrolling.
Chief investigator Professor Paul Dark, professor of critical care at the University of Manchester, said the simple protocol could significantly change the way sepsis is treated and combat antibiotic overuse and resistance.
‘It is also a powerful illustration of how precision medicine can make a real difference to patient care when treatment is tailored to individual test results of each patient,’ he said.
Professor Dark, who is also an NHS consultant in critical care medicine at Salford Royal, said sepsis had been at the forefront of UK policymaking since a 2013 Health Service Ombudsman report focusing on sepsis patients who were not treated urgently enough.
‘Ever since then, developing better diagnostics and treatment guidance for GPs and hospital clinicians to help them recognise sepsis at an early stage has been a national priority,’ he said.
Figures suggest there are at least 245,000 sepsis cases diagnosed in the UK every year.
In late 2023, research presented at the European Society of Emergency Medicine Congress suggested that two of the four internationally recommended sepsis screening tools are inadequate for recognising the condition.
Earlier this year, NICE released updated guidance on identifying and managing sepsis in over-16s recommending better targeting of antibiotics for suspected sepsis.
The updates specified that secondary care teams should target antibiotic use as more is learned about a patient’s condition to ensure the right people receive treatment as soon as possible but the medicines are not overused.
13th September 2021
Symptoms of community-acquired pneumonia (CAP) include shortness of breath, coughing, fever and chest pain some of which such as fever and coughing, overlap with COVID-19. Determining whether the causative agent in CAP is bacterial or viral can be difficult and measurement of procalcitonin levels can serve as an important biomarker for the presence of a bacterial cause. Given that higher procalcitonin levels are more likely to indicate a bacterial rather than viral cause for CAP, a team from the Emergency Department, University Libre Bruxelles, Belgium, wondered if the measurement of procalcitonin levels could help distinguish between viral and bacterial CAP in patients infected with COVID-19 and retrospectively analysed data for a cohort of patients admitted to their emergency department.
All patients who were admitted with a suspicion of CAP had their procalcitonin levels measured. Subsequently, enrolled patients were those with clinical signs of a lower respiratory tract infection and with at least one symptom of acute respiratory illness, e.g., cough, dyspnoea, sputum production, tachypnoea and pleuritic chest pain. Other inclusion criteria were those with signs of an acute infection, e.g., temperature > 38oC, chills, altered mental status and a leucocyte count > 10,000/microL and oxygen saturation < 94%. Only patients who underwent both bacteriological, viral and radiological imaging (CT) within 48 hours of admission were subsequently included. Patients were classified as having bacterial CAP based on both microbiological analysis and the findings from the CT scan. Alternatively, patients were classed as having viral CAP in the absence of positive bacteriological findings and where the CT scan indicated a high suspicion of viral pneumonia.
Findings
During the period of the study, 3593 patients visited the emergency department with symptoms potentially related to COVID-19 and 151 were subsequently included in the analysis after applying the inclusion criteria, of whom, 138 had a microbiologically confirmed bacterial pathogen. Among those with diagnosed viral CAP, 112 had COVID-19-related pneumonia. The discriminatory accuracy of procalcitonin levels for bacterial and viral CAP were calculated from receiver operating characteristic (ROC) curves. The median procalcitonin levels were higher in bacterial CAP (0.53ng/ml vs 0.16ng/ml, bacterial vs viral, p = 0.005). Using the ROC curves to discriminate between viral and bacterial CAP generated an area under the curve (AUC) of 0.68 (95% CI 0.53 – 0.83). Based on a threshold procalcitonin level of > 0.5ng/ml, to identify bacterial CAP, gave a sensitivity of 52.2% and a specificity of 82%.
Commenting on their findings, the authors noted that there were no procalcitonin levels which were able to differentiate between bacterial CAP and COVID-19 associated pneumonia. Based on their findings, the authors calculated that the administration of antibiotics to those with procalcitonin levels > 0.5ng/ml would have resulted in the inappropriate treatment of 65.7% of patients with radiological signs of CAP.
They concluded that procalcitonin measurements upon admission in those with suspected CAP cannot accurately differentiate between bacterial or viral CAP.
Citation
Malinverni S et al. Is procalcitonin a reliable marker of bacterial community-acquired pneumonia in adults admitted to the emergency department during SARS-CoV-2 pandemic? Eur J Emerg Med 2021
23rd July 2021
Knowledge about COVID-19 has advanced at rapid pace over the last 15 months and with a large number of patients being admitted to hospital, it is of upmost importance to be able to assess which patients are at the highest risk of disease progression. Based on earlier observational studies, it has become clear that older patients and those with co-morbidities are more likely to develop severe disease and several biomarkers including C-reactive protein and procalcitonin, have been shown to be associated with severe disease. A further potential complication of COVID-19 is bacterial co-infection though in an analysis of 24 studies including 3338 patients, the presence of bacterial co-infection in COVID-19 was found to be very low at 6.9%. Nevertheless, whether the use of biomarkers such as procalcitonin could be used to identify bacterial co-infection among patients with COVID-19 has been suggested as a potentially valid strategy, but there is a lack of evidence to support this approach.
This absence of evidence prompted a team from the Department of Internal Medicine, Haga Teaching Hospital, Den Haag, The Netherlands, to retrospectively evaluate the association between multiple biomarkers, including procalcitonin and the clinical and microbiological outcomes in patients hospitalised with COVID-19. The team used data from the PredictED study, a single centre, prospective observational study, designed to evaluate procalcitonin as a marker for bacteraemia in patients who present to the emergency department. While the original study was designed to examine all patients admitted to the emergency department, the authors turned to a subset of patients with PCR-confirmed COVID-19. A number of tests were undertaken, including blood cultures, C-reactive protein and procalcitonin although the results of this latter test were not immediately available to the treating clinician. The primary outcome of the study was the incidence of bacterial co-infection at the initial emergency department presentation and its association with procalcitonin.
Findings
The subset of COVID-19 patients testing positive for the virus was 142 with a mean age of 61 years (66% male). More than half of these patients had co-morbidities including diabetes (25%) and cardiovascular disease (24%) and from the complete cohort, 41 developed severe COVID-19, all of whom were hospitalised and 24 (17%) subsequently died within 30 days. Procalcitonin levels were significantly associated with the development of severe disease (odds ratio, OR = 1.8, 95% CL 1.3 – 2.2), as were higher levels of the biomarker. In addition, C reactive protein levels were also significantly associated with more severe disease (OR = 1.8, 95% CI 1.3–2.6). Using the area under the receiver operating curve for procalcitonin, the predictive value was 0.76.
Commenting on their results, the authors noted that procalcitonin demonstrated the highest discriminatory power between severe and non-severe COVID-19. Although only a small number of COVID-19 patients (1.4%) had a bacterial co-infection, the authors concluded that measurement of procalcitonin levels appeared to be a promising approach to help clinicians recognise patients a higher risk of more severe COVID-19 infection.
Citation
Kaal A et al. Diagnostic yield of bacteriological tests and predictors of severe outcome in adult patients with COVID-19 presenting to the emergency department. Emerg Med J 2021
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