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In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care., Competing Interests: Potential conflicts of interest. M. P. C. reports grants from McGill Interdisciplinary Initiative in Infection and Immunity and grants from Canadian Institutes of Health Research during the conduct of the study; personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and personal fees from nplex biosciences (as a member of the scientific advisory board) and consulting fees from Astra Zaneca outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, M. P. C. has a patent Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling pending (Cornell Reference number 9401-01-US), and a patent Methods for assessing the severity and progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using cell-free DNA pending (Cornell Reference number 9561-01-US) and rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridization (Cooley Reference: BEEB-001/00US 342794-2002). T. C. L. and E. G. M. receive research salary support from the Fonds de recherche du Québec – Santé. M. L. reports having served on advisory boards for Sanofi, Pfizer, Medicago, Merck, Seqirus, Paladin Labs; Pan Data Safety, and Monitoring Committees for Medicago, CanSino biologics, National Institutes of Health (NIH), the World Health Organization (WHO) EML Antibiotic Working Group. E. G. M. reports being co-investigator on the SNAP staph aureus platform trial CIHR outside of the submitted work. T. C. L. reports operating funds for other studies from Canadian Institutes of Health Research and McGill Interdisciplinary Institute Infection and Immunity. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis., Methods: We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics., Results: A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T 2  = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T 2  = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC., Conclusion: In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies., Objectives: We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time., Data Sources: The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021., Study Eligibility Criteria: Human observational studies on patients with S. aureus bloodstream infection were included., Participants: The study analyzed data of patients with a positive blood culture for S. aureus., Methods: Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates., Results: A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward)., Conclusions: SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)