P N A Harris1, J F McNamara2, D C Lye3, J S Davis4, L Bernard5, A C Cheng6, Y Doi7, V G Fowler8, K S Kaye9, L Leibovici10, J Lipman11, M J Llewelyn12, S Munoz-Price13, M Paul14, A Y Peleg15, J Rodríguez-Baño16, B A Rogers17, H Seifert18, V Thamlikitkul19, G Thwaites20, S Y C Tong21, J Turnidge22, R Utili23, S A R Webb24, D L Paterson25. 1. University of Queensland, UQ Centre for Clinical Research, Brisbane, Qld, Australia; Department of Microbiology, Pathology Queensland, Central Laboratory, Royal Brisbane & Women's Hospital, Brisbane, Qld, Australia. Electronic address: p.harris@uq.edu.au. 2. University of Queensland, UQ Centre for Clinical Research, Brisbane, Qld, Australia; Department of Microbiology, Pathology Queensland, Central Laboratory, Royal Brisbane & Women's Hospital, Brisbane, Qld, Australia. 3. Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital and Yong Loo Lin School of Medicine, Singapore. 4. Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT, Australia; Department of Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia. 5. Infectious Diseases Unit, Tours University Hospital, Tours, France. 6. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia; Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Vic., Australia. 7. Division of Infectious Diseases, University of Pittsburgh School of Medicine, PA, USA. 8. Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA. 9. Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI, USA. 10. Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah-Tiqva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 11. Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Qld, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia; The University of Witwatersrand, Johannesburg, South Africa. 12. Division of Medicine, Brighton and Sussex Medical School, Brighton, UK. 13. Froedtert & Medical College of Wisconsin, Milwaukee, WI, USA. 14. Division of Infectious Diseases, Rambam Health Care Campus and The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. 15. Department of Microbiology, Monash University, Melbourne, Vic., Australia; School of Clinical Sciences, Monash Medical Centre, Monash University, and Monash Infectious Diseases, Monash Health, Clayton, Vic., Australia. 16. Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBiS and Departamento de Medicina, Universidad de Sevilla, Seville, Spain. 17. School of Clinical Sciences, Monash Medical Centre, Monash University, and Monash Infectious Diseases, Monash Health, Clayton, Vic., Australia. 18. German Centre for Infection Research (DZIF), Braunschweig, Germany; Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany. 19. Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 20. Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; Nuffield Department of Medicine, University of Oxford, UK. 21. Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT, Australia. 22. Pathology, Paediatrics and Molecular Biosciences, University of Adelaide, SA, Australia. 23. Internal Medicine, Second University of Naples, Italy. 24. Royal Perth Hospital, and School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia. 25. University of Queensland, UQ Centre for Clinical Research, Brisbane, Qld, Australia; Wesley Medical Research, Wesley Hospital, Toowong, Qld, Australia.
Abstract
OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.
OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.
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