INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia
Virve I. Enne, Susan Stirling, Julie Barber, Juliet High, Charlotte Russell, David Brealey, Zaneeta Dhesi, Antony Colles, Suveer Singh, Robert Parker, Mark Peters, Benny P. Cherian, P. J. Riley, Matthew Dryden, Ruan Simpson, Nehal Patel, J. Cassidy, Daniel E. Martin, Ingeborg Welters, Valérie Page, Hala Kandil, Eleanor Tudtud, David Turner, Robert Horne, Justin O’Grady, Ann Marie Swart, David M. Livermore, Vanya Gant, Ian Turner-Bone, Laura Wilding, Helen Winmill, Carly Tooke, Philip Milner, Jeronimo Cuesta, Zoran Aman, Rhian Bull, Jaime Carungcong, Paulo Costa, Luke Moore, Nabeela Mughal, Julian Sonksen, Karen Reid, Olugbenga Akinugbe, Lauran O’Neill, Michael Karlikowski, Julie North, Angela Aramburo, Justin Z. Wang, Kamal Liyanage, Laura Tous, Jenny Tan, Pooja Patel, Mark de Neef, Helder Filipe, Sara Mingo, Damian Mack, David Shaw, Karen Williams, Victoria Waugh, Naseem Ahmed, Nigel Klein, Federico Ricciardi, Alyssa M. Pandolfo, Sarah-Jane Stewart, Laura Shallcross, Georgia Bercades, Ingrid Hass, Deborah Smyth, Minnie Gellamucho, Kerry Dresser, Adam P. Wagner, Xiaobei Zhao, Giovanni Pipi, Paul Dark, André Charlett, Susan Bennett, Paul Aveyard, R.G. Masterton, Martin Llewelyn, Katie Saunders, A. John Simpson, Rosy Reynolds, Giovanni Satta, Benny P. Cherian, Matthew Dryden, P. J. Riley, David M. Livermore, Elizabeth Cooper, Jennie Griffiths, Margaret McWilliams, Patrick Thompson, Penny Vicary, Amander Wellings, Rebecca Harmston
Abstract
PURPOSE: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). METHODS: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. RESULTS: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13-28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference - 6%, 95% CI - 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. CONCLUSIONS: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.