Title: Antifungal stewardship opportunities with rapid tests for fungal infection in critically-ill patients (The A-Stop Study)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: DESIGN: Multicentre, prospective, diagnostic test accuracy study SETTING: 35 UK adult and paediatric ICUs. TARGET POPULATION: Critically-ill adults and children INCLUSION CRITERIA: Patients started empirically on systemic antifungal therapy for suspected Candida infection; age over 4 weeks EXCLUSIONS: Treatment with systemic antifungal for more than 24hr in the past 7 days; antifungal treatment for suspected non-Candida infection; neutropenia; BMT/acute leukaemia; proven invasive candidiasis in past 28 days. HEALTH TECHNOLOGIES: Two PCR tests that detect Candida species (Renishaw Diagnostics and T2 biosystems assays) and a fungal antigen test (beta-D-glucan, BDG). MEASUREMENT OF COSTS AND OUTCOMES: At enrolment, patients will have a blood sample taken that will be tested by conventional culture (forming part of the reference standard) and each of the three index tests being assessed; all samples will undergo all tests. The study primary outcome of diagnostic accuracy will be derived for each index test alone and in combination: sensitivity; specificity; positive/negative predictive values; and positive/negative likelihood ratios. This analysis will be conducted using an expert consensus definition for proven infection as the reference standard and then repeated using a combination of both this and the new consensus definition for probable infection (to take account of no perfect reference standard being available). A comparison of the primary outcome in subgroups of interest will be included. Data will be collected to measure the cost of care, including antifungal drug use, with follow-up until hospital discharge enabled by data linkage to the ICNARC case-mix programme. The number of patients receiving unnecessary antifungal treatment will be estimated and cost-utility analyses will be conducted. Recommendations for future research will focus on trialling a test-based protocol in a subsequent RCT. This protocol (using a single test or combination) will be based on the diagnostic accuracy metrics and clinical/cost-effectiveness modelling data we produce; physician and patient risk preferences will also contribute. SAMPLE SIZE: The sample size of 1720 gives 90% power to exclude the NPV being below 99%. Furthermore, this sample gives the study 97% power for producing a point estimate for sensitivity above 90% - a decisive threshold for clinicians. With an expected point sensitivity of 95% for the best index test (or combination), the 95% CI around this would be 88%-98.7% which reflects a degree of precision that is likely to be acceptable to clinicians. PROJECT TIMETABLE AND RECRUITMENT: 48 months comprising: 6-month set-up; 12-month internal pilot to confirm feasibility; a 24-month main recruitment period; and 6-months trial close down/analysis. Recruitment will average 1-2 patients per ICU per month and is achievable based on FIRE Study data with, on average, 4 eligible patients per ICU/month. TEAM EXPERTISE: Expertise includes: microbiologists experienced in trialling novel fungal diagnostic tests, particularly PCR; intensivists with experience of large clinical trials in ICU, including previous NIHR-funded studies; and a cost-effectiveness modeller with experience of NICE/HTA assessments. There is also input from ICNARC, experienced trials methodologists/statisticians, a UKCRC-registered CTU, and NIHR DEC, Newcastle.

Lay abstract: The clinical problem we address is over-prescription of drugs used to treat a particular infection (fungal infection) in adults and children in intensive care units (ICU). Treatment with these ‘antifungal’ drugs is started when patients are thought to be at risk of fungal infection, even though the large majority turn out not to have this infection. We propose to focus on patients in ICU because there is a need for new laboratory tests to be studied so that they can be used to improve how antifungal drugs are used in ICU. By comparison, there is already a large amount of published research to guide how rapid tests for fungal infection could best be used in haemato-oncology. The way that decisions to start treatment for fungal infection are made in UK ICUs reflects uncertainty about when this type of infection is truly present, because currently used laboratory tests for fungal infection are not rapid enough to direct treatment decisions. Therefore, the majority of ICU patients who are treated with an antifungal drug receive treatment on a ‘best-guess’ basis. Moreover, most patients treated not only fail to benefit but are disadvantaged by the risk of side effects. Other disadvantages of over-treatment are the avoidable spread of resistance to these drugs in the wider population, and financial cost to the NHS. Typically, 7% of patients in ICU receive treatment for fungal infection and the majority are started on a best-guess, or presumptive, basis. Of these 7%, only 1 in 20 have fungal infection confirmed. The result of the present best-guess approach is that almost 11,000 patients in the NHS receive potentially unnecessary antifungal treatment each year, at a cost of up to £12million. Therefore, there is immense scope to use new, recently approved, rapid tests to improve prescribing in this group of patients; this could benefit individual patients, the wider population, and the NHS. We propose to thoroughly evaluate how accurately three different rapid tests can diagnose fungal infection in adults and children, started presumptively on antifungal treatment. We have calculated that we will need to study 1720 patients to give us a statistically reliable result. The research will be conducted in 35 UK ICUs to ensure that its findings are broadly applicable across the UK. After obtaining their consent, we will test blood samples from patients who are being started on antifungal treatment, but the results of the tests will not be made available to their doctors in this study. Hence, their treatment will not be affected by participating. We will determine the clinical and economic impact of implementing these rapid tests, based on how accurately they diagnose fungal infection. The main aim of this study is to establish the ability of these tests, either singly or in combination, to rule out fungal infection in this patient group. We will use these results to develop a guideline that could be used by ICU staff to reduce unnecessary antifungal drug use. Following this study, a large trial will be needed to directly assess the clinical and cost-effectiveness of implementing the guideline as part of routine patient care in the NHS, compared to currently used tests.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION