A systematic review of antimicrobial susceptibility testing as a tool in clinical trials assessing antimicrobials against infections due to Gram negative pathogens. Intended category: systematic review.

Abstract

BACKGROUND\nAntimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time.\n\n\nOBJECTIVES\nTo determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorisation on the trials primary outcomes.\n\n\nDATA SOURCES\nWe systematically searched PubMed, Embase, PsychINFO and Web of Science.\n\n\nELIGIBILITY CRITERIA\nWe included registered randomized-controlled trials published in journals between January 2015 and December 2019.\n\n\nPARTICIPANTS\nand interventions: We included trials comparing between different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria.\n\n\nMETHODS\nPrimary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible vs. non-susceptible bacteria. Results are described narratively.\n\n\nRESULTS\nOf 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients outcomes were superior when patients with infections due to susceptible and non-susceptible pathogens were compared post-hoc (median difference 14%, IQR 8 to 24%) in trials allowing this comparison (7 antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible vs. colistin-resistant carbapenem-resistant A. baumannii. When excluding patients with pathogens non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in 5 out of 6 trials.\n\n\nCONCLUSIONS\nTrials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing.