Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition

P N A Harris; J F McNamara; D C Lye; J S Davis; L Bernard; A C Cheng; Y Doi; V G Fowler Jr; K S Kaye; L Leibovici; J Lipman; M J Llewelyn; S Munoz-Price; M Paul; A Y Peleg; J Rodríguez-Baño; B A Rogers; H Seifert; V Thamlikitkul; G Thwaites; S Y C Tong; J Turnidge; R Utili; S A R Webb; D L Paterson

doi:10.1016/j.cmi.2016.10.023

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition

Clin Microbiol Infect. 2017 Aug;23(8):533-541. doi: 10.1016/j.cmi.2016.10.023. Epub 2016 Nov 1.

Authors

P N A Harris¹, J F McNamara², D C Lye³, J S Davis⁴, L Bernard⁵, A C Cheng⁶, Y Doi⁷, V G Fowler Jr⁸, 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

Affiliations

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: [email protected].
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.

PMID: 27810466
DOI: 10.1016/j.cmi.2016.10.023

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.

Keywords: Antibiotic therapy; Bacteraemia; Bacterial infections; Clinical trials; Treatment outcome.

Publication types

Review

MeSH terms

Adult
Anti-Bacterial Agents / therapeutic use*
Bacteremia / drug therapy*
Clinical Trials as Topic*
Comparative Effectiveness Research / standards*
Endpoint Determination / standards*
Gram-Negative Bacterial Infections
Humans
Staphylococcal Infections / drug therapy
Treatment Outcome

Substances

Anti-Bacterial Agents