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      In Vitro Activity of Eravacycline against Gram-Positive Bacteria Isolated in Clinical Laboratories Worldwide from 2013 to 2017

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          Abstract

          Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp.

          ABSTRACT

          Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp. ( n = 2,807), Staphylococcus spp. ( n = 4,331), and Streptococcus spp. ( n = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC 90 values for different species/organism groups over time or by region. Eravacycline showed MIC 50 and MIC 90 results of 0.06 and 0.12 μg/ml, respectively, when tested against Staphylococcus aureus, regardless of methicillin susceptibility. The MIC 90 values of eravacycline for Staphylococcus epidermidis and Staphylococcus haemolyticus were equal (0.5 μg/ml). The eravacycline MIC 90s for Enterococcus faecalis and Enterococcus faecium were 0.06 μg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC 90 results of ≤0.06 μg/ml when tested against Streptococcus pneumoniae and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent in vitro activity against frequently isolated clinical isolates of Gram-positive bacteria ( Enterococcus, Staphylococcus, and Streptococcus spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.

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          Most cited references14

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          Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.

          Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recently isolated aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad-spectrum activity against 90% of the isolates (MIC90) in each panel at concentrations ranging from ≤0.008 to 2 μg/ml for all species panels except those of Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC90 values of 32 μg/ml for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Furthermore, eravacycline was active against multidrug-resistant bacteria, including those expressing extended-spectrum β-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new intravenous (i.v.)/oral antibiotic for the empirical treatment of complicated hospital/health care infections and moderate-to-severe community-acquired infections.
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            Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic.

            TP-434 is a novel, broad-spectrum fluorocycline antibiotic with activity against bacteria expressing major antibiotic resistance mechanisms, including tetracycline-specific efflux and ribosomal protection. The mechanism of action of TP-434 was assessed using both cell-based and in vitro assays. In Escherichia coli cells expressing recombinant tetracycline resistance genes, the MIC of TP-434 (0.063 μg/ml) was unaffected by tet(M), tet(K), and tet(B) and increased to 0.25 and 4 μg/ml in the presence of tet(A) and tet(X), respectively. Tetracycline, in contrast, was significantly less potent (MIC ≥ 128 μg/ml) against E. coli cells when any of these resistance mechanisms were present. TP-434 showed potent inhibition in E. coli in vitro transcription/translation (50% inhibitory concentration [IC(50)] = 0.29 ± 0.09 μg/ml) and [(3)H]tetracycline ribosome-binding competition (IC(50) = 0.22 ± 0.07 μM) assays. The antibacterial potencies of TP-434 and all other tetracycline class antibiotics tested were reduced by 4- to 16-fold, compared to that of the wild-type control strain, against Propionibacterium acnes strains carrying a 16S rRNA mutation, G1058C, a modification that changes the conformation of the primary binding site of tetracycline in the ribosome. Taken together, the findings support the idea that TP-434, like other tetracyclines, binds the ribosome and inhibits protein synthesis and that this activity is largely unaffected by the common tetracycline resistance mechanisms.
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              Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

              Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC 50 /MIC 90 values, respectively, for Escherichia coli of 0.12/0.5 μg/ml, Klebsiella pneumoniae of 0.25/1 μg/ml, Enterobacter aerogenes of 0.25/1 μg/ml, Enterobacter cloacae 0.5/1 μg/ml, and Acinetobacter baumannii of 0.5/1 μg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii , eravacycline MICs correlated with increased expression of the adeB gene.
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                Author and article information

                Journal
                Antimicrob Agents Chemother
                Antimicrob. Agents Chemother
                aac
                aac
                AAC
                Antimicrobial Agents and Chemotherapy
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0066-4804
                1098-6596
                16 December 2019
                21 February 2020
                March 2020
                21 February 2020
                : 64
                : 3
                : e01715-19
                Affiliations
                [a ]IHMA Europe Sàrl, Monthey, Switzerland
                [b ]International Health Management Associates, Inc., Schaumburg, Illinois, USA
                [c ]Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
                [d ]Infectious Diseases Clinic, Department of Medicine, University of Udine, Udine, Italy
                [e ]Duke University Medical Center, Durham, North Carolina, USA
                [f ]Tetraphase Pharmaceuticals, Watertown, Massachusetts, USA
                Author notes
                Address correspondence to Ian Morrissey, imorrissey@ 123456ihma.com .

                For a companion article on this topic, see [Related article:]https://doi.org/10.1128/AAC.01699-19.

                Citation Morrissey I, Hawser S, Lob SH, Karlowsky JA, Bassetti M, Corey GR, Olesky M, Newman J, Fyfe C. 2020. In vitro activity of eravacycline against Gram-positive bacteria isolated in clinical laboratories worldwide from 2013 to 2017. Antimicrob Agents Chemother 64:e01715-19. https://doi.org/10.1128/AAC.01715-19.

                Article
                01715-19
                10.1128/AAC.01715-19
                7038300
                31843997
                736696e9-5173-4a90-af28-6ee00ab8d707
                Copyright © 2020 Morrissey et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 22 August 2019
                : 20 October 2019
                : 9 December 2019
                Page count
                supplementary-material: 1, Figures: 0, Tables: 4, Equations: 0, References: 21, Pages: 10, Words: 7062
                Categories
                Clinical Therapeutics
                Custom metadata
                March 2020

                Infectious disease & Microbiology
                eravacycline,gram positive,mrsa,vre,streptococci,streptococcus
                Infectious disease & Microbiology
                eravacycline, gram positive, mrsa, vre, streptococci, streptococcus

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