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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.)

The increasing resistance to conventional antibiotics is an urgent problem that can be addressed by the discovery of new antimicrobial drugs such as antimicrobial peptides (AMPs). AMPs are components of innate immune system of eukaryotes and are not prone to the conventional mechanisms that are responsible of drug resistance. Fish are an important source of AMPs and, recently, we have isolated and characterized a new 22 amino acid residues peptide, the chionodracine (Cnd), from the Antarctic icefish Chionodraco hamatus. In this paper we focused on a new Cnd-derived mutant peptide, namely Cnd-m3a, designed to improve the selectivity against prokaryotic cells and the antimicrobial activity against human pathogens of the initial Cnd template. Cnd-m3a was used for immunization of rabbits, which gave rise to a polyclonal antibody able to detect the peptide. The interaction kinetic of Cnd-m3a with the Antarctic bacterium Psychrobacter sp. (TAD1) was imaged using a transmission electron microscopy (TEM) immunogold method. Initially the peptide was associated with the plasma membrane, but after 180 min of incubation, it was found in the cytoplasm interacting with a DNA target inside the bacterial cells. Using fluorescent probes we showed that the newly designed mutant can create pores in the outer membrane of the bacteria E. coli and Psychrobacter sp. (TAD1), confirming the results of TEM analysis. Moreover, in vitro assays demonstrated that Cnd-m3a is able to bind lipid vesicles of different compositions with a preference toward negatively charged ones, which mimics the prokaryotic cell. The Cnd-m3a peptide showed quite low hemolytic activity and weak cytotoxic effect against human primary and tumor cell lines, but high antimicrobial activity against selected Gram - human pathogens. These results highlighted the high potential of the Cnd-m3a peptide as a starting point for developing a new human therapeutic agent., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We assessed the antimicrobial-inactivation capability of BacT/Alert (FA Plus and FN Plus) or Bactec (Plus Aerobic/F and Plus Anaerobic/F) media for 40 antibiotic-bacterium combinations in simulated adult blood cultures. Aside from high recovery rates (93.2% and 88.4%, respectively), we showed that at the lowest but clinically relevant antibiotic concentrations, both BacT/Alert and Bactec media recovered all the organisms tested with drugs except for Escherichia coli , which was tested in the presence of meropenem. Delayed recoveries were mainly associated with vancomycin., (Copyright © 2019 American Society for Microbiology.)

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.

Lipophilic substituents at benzodioxane C (7) of 3-(benzodioxan-2-ylmethoxy)-2,6-difluorobenzamide improve the antibacterial activity against methicillin-resistant Staphylococcus aureus strains to MIC values in the range of 0.2-2.5 μg/mL, whereas hydrophilic substituents at the same position and modifications at the benzodioxane substructure, excepting for replacement with 2-cromanyl, are deleterious. Some of the lead compounds also exhibit good activity against Mtb. Parallel SARs to those of 3-(2-benzothiazol-2-ylmethoxy)-2,6-difluorobenzamide, well known FtsZ inhibitor, and cells alterations typical of FtsZ inhibition indicate such a protein as the target of these potent antibacterial benzodioxane-benzamides., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)