www.thelancet.com/infection Published online August 4, 2020 https://doi.org/10.1016/S1473-3099(20)30447-3 1 Articles Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study Richard Kuehl, Laura Morata, Christian Boeing, Isaac Subirana, Harald Seifert, Siegbert Rieg, Winfried V Kern, Hong Bin Kim, Eu Suk Kim, Chun-Hsing Liao, Robert Tilley, Luis Eduardo Lopez-Cortés, Martin J Llewelyn, Vance G Fowler, Guy Thwaites, José Miguel Cisneros, Matt Scarborough, Emmanuel Nsutebu, Mercedes Gurgui Ferrer, José L Pérez, Gavin Barlow, Susan Hopkins, Hugo Guillermo Ternavasio-de la Vega, M Estée Török, Peter Wilson, Achim J Kaasch, Alex Soriano, on behalf of the International Staphylococcus aureus collaboration study group and the ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis* Summary Background Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia. Methods We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1. Findings Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51–75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2–4 days, 43% (30 of 69) with 5–7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51–2·46; p<0·0001). Interpretation We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection. Funding None. Copyright © 2020 Elsevier Ltd. All rights reserved. Introduction Staphylococcus aureus bacteraemia is a medical emergency leading to two to ten deaths per 100 000 population per year globally. 1 Although many bacterial species can invade the bloodstream, S aureus is by far the most common cause of persistent bacteraemia. 2 Persistent bacteraemia occurs in 8–39% of cases of S aureus bacteraemia, 3–7 and has been associated with increased mortality, 3,6 increased risk of metastatic spread, 4 and an increased relapse rate. 8 However, persistent bacteraemia is poorly defined and the applied cutoff durations to define persistent bacteraemia vary from 2 days or more, 9 3 days, 4,10 4 days, 11–13 5 days 14 to 7 days, 3,5,6,15 or even longer. 16 Some studies count bacteraemic days from the first positive blood culture, and others assess bacteraemic days after initiation of active therapy. The Infectious Diseases Society of America recom- mends re-evaluation of treatment when meticillin- resistant S aureus (MRSA) bacteraemia persists for 7 days despite active antibiotic therapy 17 based on two studies in which a median duration of 7–9 days was reported in patients with endocarditis. 18,19 As other cohorts documented shorter median durations of 2–3 days in S aureus bacteraemia that was both meticillin-susceptible and meticillin-resistant, 4,11,20 an earlier cutoff could be prudent. Given the heterogeneity of definitions, our primary aim was to analyse mortality according to duration of S aureus bacteraemia in a large, prospective, European, multicentre cohort. 21 This analysis served to derive a clinically relevant cutoff for the definition of persistent bacteraemia. Lancet Infect Dis 2020 Published Online August 4, 2020 https://doi.org/10.1016/ S1473-3099(20)30447-3 See Online/Comment https://doi.org/10.1016/ S1473-3099(20)30590-9 For the German translation of the summary see Online for appendix 1 *Members of the study group are listed in the acknowledgments Service of Infectious Diseases, Hospital Clínic of Barcelona, Barcelona, Spain (R Kuehl MD, L Morata PhD, Prof A Soriano PhD); Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland (R Kuehl); Institute of Medical Microbiology and Hospital Hygiene, Faculty of Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (C Boeing, Prof A J Kaasch MD); CIBER en Epidemiología y Salud Pública, Barcelona, Spain (I Subirana PhD); Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University of Cologne, Cologne, Germany (Prof H Seifert MD); German Center for Infection Research, Partner site Bonn-Cologne, Cologne, Germany (Prof H Seifert); Division of Infectious Diseases, Department of Medicine II, Medical Center–University of Freiburg, Freiburg, Germany (Prof S Rieg MD, Prof W V Kern MD); Division of Infectious Diseases, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, South Korea (Prof H B Kim MD, E S Kim MD); Infectious Diseases, Department of Internal