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The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35 < ES < 0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Timely detection of antimicrobial (cephalosporin/carbapenem) resistance (AMR) determinants is crucial to the clinical management of bloodstream infections caused by Gram-negative bacteria (GNB)., Objectives: To review and meta-analyse the evidence for using commercially available molecular tests for the direct detection of AMR determinants in GNB-positive blood cultures (PBCs)., Data Sources: PubMed, Scopus and ISI Web of Knowledge., Study Eligibility Criteria: Clinical studies evaluating the performance of two major commercial systems, namely the Verigene® and FilmArray® systems, for rapid testing of GNB-PBCs, in comparison with the phenotypic or genotypic methods performed on GNB-PBC isolates., Methods: Literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria and, for meta-analysis of sensitivity and specificity of both systems, bivariate random-effects model., Results: Twenty studies were identified (3310 isolates) from 2006 to 2019. Nine studies were conducted in East Asia. In 15 studies using phenotypic comparators (1930 isolates), 1014 (52.5%) isolates were Escherichia coli, and 287 (14.9%) of all the isolates displayed AMR phenotypes. In five studies using genotypic comparators (1380 isolates), 585 (42.4%) were E. coli, and 100 (7.2%) of all the isolates displayed AMR genotypes. Pooled sensitivity and specificity estimates for detection of AMR determinants by the Verigene (i.e. CTX-M, IMP, KPC, NDM, OXA and VIM) and/or FilmArray (i.e. KPC) systems were 85.3% (95% CI 79.9%-89.4%) and 99.1% (95% CI 98.2%-99.5%), respectively, across the 15 studies, and 95.5% (95% CI 89.2%-98.2%) and 99.7% (95% CI 99.1%-99.9%), respectively, across the five studies., Conclusions: Our findings show that the Verigene and FilmArray systems may be a valid adjunct to the conventional microbiology (phenotypic or genotypic) methods used to identify AMR in GNBs. The FilmArray system detects only one AMR genotype, namely KPC, limiting its use. Both Verigene and FilmArray systems can miss important cephalosporin/carbapenem resistance phenotypes in a minority of cases. However, the sensitivity and specificity of both systems render them valuable clinical tools in timely identification of resistant isolates. Further studies will establish the prominence of such rapid diagnostics as standard of care in individuals with bloodstream infections., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To compare the performance of the Accelerate Pheno™ system with that of the conventional phenotypic VITEK® 2 system for rapid antimicrobial susceptibility testing (AST) of bacterial pathogens from positive blood culture (PBC) samples, based on the reference broth microdilution (BMD) method., Methods: Prospectively collected PBCs that represented patient-unique bloodstream infection episodes were included. For PBC samples showing monomicrobial growth (n = 86), AST was performed using both Accelerate Pheno™ and VITEK® 2 systems directly from PBC broth. Colony isolates derived from subculture of PBC broth were then used for BMD testing. AST results were interpreted according to 2017 EUCAST breakpoints., Results: The overall categorical agreement between Accelerate Pheno™ system and BMD was 92.7% (467/504) for Gram-negative organisms and 99.0% (95/96) for Gram-positive organisms, with rates for very major errors of 3.6% (6/166), major errors 2.2% (9/416) and minor errors 3.8% (23/600). The overall categorical agreement between the VITEK® 2 system and BMD was 91.7% (463/505) for Gram-negative organisms and 99.0% (97/98) for Gram-positive organisms, with rates of very major errors of 2.4% (4/169), major errors 1.0% (4/416) and minor errors 5.8% (35/603). Importantly, unlike the VITEK® 2 system, no false-susceptible results occurred with two colistin-resistant organism-growing PBCs tested using the Accelerate Pheno™ system., Conclusions: Based on these findings, the Accelerate Pheno™ system can be a valid alternative for the rapid AST of Gram-negative and Gram-positive bacteria in bloodstream infections.