Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.
OBJECTIVE
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.
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.
P N A
PNA
Harris
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.
J F
JF
McNamara
Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital and Yong Loo Lin School of Medicine, Singapore.
D C
DC
Lye
Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT, Australia; Department of Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia.
J S
JS
Davis
Infectious Diseases Unit, Tours University Hospital, Tours, France.
L
L
Bernard
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.
A C
AC
Cheng
Division of Infectious Diseases, University of Pittsburgh School of Medicine, PA, USA.
Y
Y
Doi
Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA.
V G
VG
Fowler
Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI, USA.
K S
KS
Kaye
Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah-Tiqva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
L
L
Leibovici
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.
J
J
Lipman
Division of Medicine, Brighton and Sussex Medical School, Brighton, UK.
M J
MJ
Llewelyn
Froedtert & Medical College of Wisconsin, Milwaukee, WI, USA.
S
S
Munoz-Price
Division of Infectious Diseases, Rambam Health Care Campus and The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
M
M
Paul
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.
A Y
AY
Peleg
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.
J
J
Rodríguez-Baño
School of Clinical Sciences, Monash Medical Centre, Monash University, and Monash Infectious Diseases, Monash Health, Clayton, Vic., Australia.
B A
BA
Rogers
German Centre for Infection Research (DZIF), Braunschweig, Germany; Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
H
H
Seifert
Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
V
V
Thamlikitkul
Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; Nuffield Department of Medicine, University of Oxford, UK.
G
G
Thwaites
Global and Tropical Health Division, Menzies School of Health Research, Darwin, NT, Australia.
S Y C
SYC
Tong
Pathology, Paediatrics and Molecular Biosciences, University of Adelaide, SA, Australia.
J
J
Turnidge
Internal Medicine, Second University of Naples, Italy.
R
R
Utili
Royal Perth Hospital, and School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
S A R
SAR
Webb
University of Queensland, UQ Centre for Clinical Research, Brisbane, Qld, Australia; Wesley Medical Research, Wesley Hospital, Toowong, Qld, Australia.
D L
DL
Paterson
D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D057186:Comparative Effectiveness Research / Q000592:standards*; D023381:Endpoint Determination / Q000592:standards*; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D013203:Staphylococcal Infections / Q000188:drug therapy; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents
Antibiotic therapy; Bacteraemia; Bacterial infections; Clinical trials; Treatment outcome