Clinical Pharmacokinetics and Pharmacodynamics of Eravacycline

McCarthy, Matthew W

doi:10.1007/s40262-019-00767-z

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…In this study, we investigated the in vitro antimicrobial activity of Erava against 276 non-duplicate clinical E. faecalis isolates from China. Consistent with the in vitro antimicrobial activity analyses results of Erava against clinical isolates collected globally (Hackel et al, 2013;Sutcliffe et al, 2013;Olesky et al, 2017), in Canada (Zhanel et al, 2018), and the USA (Bouchillon et al, 2018) (Sutcliffe et al, 2013;Bai et al, 2018;Lan et al, 2019;McCarthy, 2019;Morrissey et al, 2019;Wang et al, 2019). Two primary mechanisms known to confer acquired resistance to Tet, the presence of Tet resistance genes encoding efflux pumps tet(K) and tet(L) and ribosomal protection proteins tet(M), had minimal or no effect on the in vitro antibacterial activity of Erava against clinical E. faecalis isolates.…”

Section: Discussionsupporting

confidence: 61%

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Wen

Shang

et al. 2020

Front. Microbiol.

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Opportunistic infections caused by multidrug-resistant Enterococcus faecalis strains are a significant clinical challenge. Eravacycline (Erava) is a synthetic fluorocycline structurally similar to tigecycline (Tige) that exhibits robust antimicrobial activity against Gram-positive bacteria. This study investigated the in vitro antimicrobial activity and heteroresistance risk of Eravacycline (Erava) in clinical E. faecalis isolates from China along with the mechanism of Erava resistance. A total of 276 non-duplicate E. faecalis isolates were retrospectively collected from a tertiary care hospital in China. Heteroresistance to Erava and the influence of tetracycline (Tet) resistance genes on Erava susceptibility were examined. To clarify the molecular basis for Erava resistance, E. faecalis variants exhibiting Erava-induced resistance were selected under Erava pressure. The relative transcript levels of six candidate genes linked to Erava susceptibility were determined by quantitative reverse-transcription PCR, and their role in Erava resistance and heteroresistance was evaluated by in vitro overexpression experiments. We found that Erava minimum inhibitory concentrations (MICs) against clinical E. faecalis isolates ranged from ≤0.015 to 0.25 mg/l even in strains harboring Tet resistance genes. The detection frequency of Erava heteroresistance in isolates with MICs ≤ 0.06, 0.125, and 0.25 mg/l were 0.43% (1/231), 7.5% (3/40), and 0 (0/5), respectively. No mutations were detected in the 30S ribosomal subunit gene in Erava heteroresistance-derived clones, although mutations in this subunit conferred cross resistance to Tige in Erava-induced resistant E. faecalis. Overexpressing RS00630 (encoding a bone morphogenetic protein family ATP-binding cassette transporter substrate-binding protein) in E. faecalis increased the frequency of Erava and Tige heteroresistance, whereas RS12140, RS06145, and RS06880 overexpression conferred heteroresistance to Tige only. These results indicate that Erava has potent in vitro antimicrobial activity against clinical E. faecalis isolates from China and that Erava heteroresistance can be induced by RS00630 overexpression.

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Section: Discussionsupporting

confidence: 61%

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Wen

Shang

et al. 2020

Front. Microbiol.

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“…Well pharmacokinetics, pharmacodynamics, tolerability, and in vitro activity (Lan et al, 2019; McCarthy, 2019)…”

Section: Treatment Of Cre Infectionsmentioning

confidence: 99%

Carbapenemases in Enterobacteriaceae: Detection and Antimicrobial Therapy

2019

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Carbapenem-resistant Enterobacteriaceae (CRE) have spread rapidly around the world in the past few years, posing great challenges to human health. The plasmid-mediated horizontal transmission of carbapenem-resistance genes is the main cause of the surge in the prevalence of CRE. Therefore, the timely and accurate detection of CRE, especially carbapenemase-producing Enterobacteriaceae, is very important for the clinical prevention and treatment of these infections. A variety of methods for the rapid detection of CRE phenotypes and genotypes have been developed for use in clinical microbiology laboratories. To overcome the lack of efficient antibiotics, CRE infections are often treated with combination therapies. Moreover, novel drugs and emerging strategies appeared successively and in various stages of development. In this article, we summarized the global distribution of various carbapenemases. And we focused on summarizing and comparing the advantages and limitations of the detection methods and the therapeutic strategies of CRE primarily.

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“…Eravacycline is available in an IV formulation and is primarily excreted via the faeces in its active form, making it a potential option for the treatment of CDI. 24 Two previous small-scale studies evaluated the activity of eravacycline against C. difficile isolates; however, neither had a specific focus on C. difficile or tested a broad range of different C. difficile ribotypes. 6 , 7 In these previous studies, eravacycline MIC 50/90 was 0.12/1 and 0.06/0.13 mg/L, consistent with our current study (≤0.0078/0.016 mg/L).…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of eravacycline against common ribotypes of Clostridioides difficile

Bassères

Begum

Lancaster

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Eravacycline is a novel synthetic fluorocycline antibacterial approved for complicated intra-abdominal infections. Objectives The purpose of this study was to assess the in vitro activities of eravacycline and comparator antibiotics against contemporary clinical isolates of Clostridioides difficile representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin. Methods Clinical C. difficile strains from six common or emerging ribotypes were used to test the in vitro activities of eravacycline and comparator antibiotics (fidaxomicin, vancomycin and metronidazole) by broth microdilution. In addition, MBC experiments, time–kill kinetic studies and WGS experiments were performed. Results A total of 234 isolates were tested, including ribotypes RT001 (n = 37), RT002 (n = 41), RT014-020 (n = 39), RT027 (n = 42), RT106 (n = 38) and RT255 (n = 37). MIC50/90 values were lowest for eravacycline (≤0.0078/0.016 mg/L), followed by fidaxomicin (0.016/0.063 mg/L), metronidazole (0.25/1.0 mg/L) and vancomycin (2.0/4.0 mg/L). MBCs were lower for eravacycline compared with vancomycin for all ribotypes tested. Both vancomycin and eravacycline demonstrated bactericidal killing, including for epidemic RT027. The presence of the tetM or tetW resistance genes did not affect the MIC of eravacycline. Conclusions This study demonstrated potent in vitro activity of eravacycline against a large collection of clinical C. difficile strains that was not affected by ribotype, susceptibility to vancomycin or the presence of certain tet resistance genes. Further development of eravacycline as an antibiotic to be used in patients with Clostridioides difficile infection is warranted.

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Clinical Pharmacokinetics and Pharmacodynamics of Eravacycline

Cited by 16 publications

References 32 publications

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Carbapenemases in Enterobacteriaceae: Detection and Antimicrobial Therapy

In vitro activity of eravacycline against common ribotypes of Clostridioides difficile

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