Carbapenemase-producing Enterobacteriaceae isolates (n ϭ 110) from health care centers in central Indiana (from 2010 to 2013) were tested for susceptibility to combinations of avibactam (4 g/ml) with ceftazidime, ceftaroline, or aztreonam. MIC 50 /MIC 90 values were 1/2 g/ml (ceftazidime-avibactam), 0.5/2 g/ml (ceftaroline-avibactam), and 0.25/0.5 g/ml (aztreonam-avibactam.) A ␤-lactam MIC of 8 g/ml was reported for the three combinations against one Escherichia coli isolate with an unusual TIPY insertion following Tyr344 in penicillin-binding protein 3 (PBP 3) as the result of gene duplication.KEYWORDS carbapenem-resistant, CRE, avibactam, ceftazidime, ceftaroline, aztreonam, carbapenemase, resistance, PBP 3 C arbapenem-resistant Enterobacteriaceae (CRE) have been designated one of the most urgent antibiotic resistance threats by multiple global health organizations (1, 2). Carbapenemase-producing CRE are most worrisome, due primarily to plasmidencoded KPC, SME, and OXA families with serines at their active sites and the NDM and VIM metallo-␤-lactamase (MBL) families (3). The recently approved ␤-lactamase inhibitor combination ceftazidime-avibactam provides the potential for treating many CRE infections caused by pathogens with serine carbapenemases that are inhibited by avibactam (4). Although avibactam does not inhibit MBLs, its combination with aztreonam protects the monobactam against hydrolysis by serine enzymes, while aztreonam remains functionally active due to its stability to MBLs (5). In addition, a ceftarolineavibactam combination potentially could allow for the treatment of mixed infections due to methicillin-resistant Staphylococcus aureus and CRE (6). In this study, the three avibactam combinations were tested against 110 recent multidrug-resistant CRE isolates with well-characterized ␤-lactamase profiles (7) to determine whether there was a reservoir of contemporary isolates resistant to any of the combinations.Avibactam was furnished by Allergan; all other antibacterial agents were obtained from the U.S. Pharmacopeial Convention (USP, Rockville, MD). Consecutive carbapenemaseproducing CRE isolates from 172 discrete patients (from 2010 to 2013) were provided by a central clinical microbiology laboratory that serviced 14 Indiana health care centers and two large urban hospitals (5, 7). After a Vitek 2 system identified carbapenemresistant isolates, those isolates with positive results in the modified Hodge test (MHT) (8) were tested using the Carba NP test (9). Two SME-producing Serratia marcescens isolates from a second laboratory (2011) were included. Based on bacterial species, susceptibility profiles, and ␤-lactamase composition, 110 representative isolates were

Plazomicin demonstrated the most potent overall in vitro inhibitory activity of all the aminoglycosides and carbapenems in the study, and has the potential to be an effective agent for the treatment of infections caused by CRE.

Eravacycline is a novel, fully synthetic fluorocycline antibiotic of the tetracycline class being developed for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Eravacycline has activity against many key Gram-negative pathogens, including Enterobacteriaceae resistant to carbapenems, cephalosporins, fluoroquinolones and β-lactam/β-lactamase inhibitor combinations, including strains that are multidrug-resistant. Carbapenem-resistant Enterobacteriaceae (CRE) isolates from 2010 to 2013 (n=110) were characterized for carbapenemase genes by PCR and sequencing. MICs for eravacycline, tetracycline, tigecycline, amikacin, imipenem, ceftazidime, cefotaxime and levofloxacin were determined in broth microdilution assays. All isolates produced at least one carbapenemase, most frequently KPC-3. Nine isolates produced both a KPC serine carbapenemase and a metallo-β-lactamase, NDM-1 (n=1) or VIM-1 (n=8). The 110 isolates were highly resistant to all the β-lactams tested and to levofloxacin, and had MIC50/MIC90 values in the intermediate range for tetracycline and amikacin. MIC50/MIC90 values for eravacycline were 1/2 μg ml(-1) compared with 2/2 μg ml(-1) for tigecycline. Eravacycline MICs were often twofold lower than for tigecycline, with 64% of the eravacycline MICs <2 μg ml(-1) as compared with <4% of tigecycline MICs. Overall, eravacycline demonstrated the lowest cumulative MICs against this panel of recent CRE and may have the potential to treat infections caused by CRE.

The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria.

Inflammatory monocytes are key mediators of acute and chronic inflammation; yet, their functional diversity remains obscure. Single-cell transcriptome analyses of human inflammatory monocytes from COVID-19 and rheumatoid arthritis patients revealed a subset of cells positive for CD127, an IL-7 receptor subunit, and such positivity rendered otherwise inert monocytes responsive to IL-7. Active IL-7 signaling engaged epigenetically coupled, STAT5-coordinated transcriptional programs to restrain inflammatory gene expression, resulting in inverse correlation between CD127 expression and inflammatory phenotypes in a seemingly homogeneous monocyte population. In COVID-19 and rheumatoid arthritis, CD127 marked a subset of monocytes/macrophages that retained hypoinflammatory phenotypes within the highly inflammatory tissue environments. Furthermore, generation of an integrated expression atlas revealed unified features of human inflammatory monocytes across different diseases and different tissues, exemplified by those of the CD127high subset. Overall, we phenotypically and molecularly characterized CD127-imprinted functional heterogeneity of human inflammatory monocytes with direct relevance for inflammatory diseases.