<i>In Vitro</i>
            Activity of Eravacycline against Gram-Negative Bacilli Isolated in Clinical Laboratories Worldwide from 2013 to 2017

Morrissey, Ian; Hawser, Stephen; Lob, Sibylle; Karlowsky, James A.; Bassetti, Matteo; Corey, G. Ralph; Olesky, Melanie; Newman, Joseph V.; Fyfe, Corey

doi:10.1128/aac.01699-19

Cited by 56 publications

(56 citation statements)

References 33 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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“…Moreover, a basic drawback is a significant number of adverse events (i.e., nausea, vomiting, pancreatitis, hepatotoxicity [72]) as well as more severe ones, consisting of decreased fibrinogen levels and alterations in coagulation parameters [101]. Eravacycline and omadacycline are novel tetracycline derivatives with significant activity against ESBL Gram-negative bacilli [102,103]. Eravacycline has recently been approved by FDA and EMA for adult patients with cIAI [104,105].…”

Section: Tigecycline-eravacycline-omadacyclinementioning

confidence: 99%

Carbapenem-Sparing Strategies for ESBL Producers: When and How

Karaiskos

Giamarellou

2020

Antibiotics

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Extended spectrum β-lactamase (ESBL)-producing bacteria are prevalent worldwide and correlated with hospital infections, but they have been evolving as an increasing cause of community acquired infections. The spread of ESBL constitutes a major threat for public health, and infections with ESBL-producing organisms have been associated with poor outcomes. Established therapeutic options for severe infections caused by ESBL-producing organisms are considered the carbapenems. However, under the pressure of carbapenem overuse and the emergence of resistance, carbapenem-sparing strategies have been implemented. The administration of carbapenem-sparing antibiotics for the treatment of ESBL infections has yielded conflicting results. Herein, the current available knowledge regarding carbapenem-sparing strategies for ESBL producers is reviewed, and the optimal conditions for the “when and how” of carbapenem-sparing agents is discussed. An important point of the review focuses on piperacillin–tazobactam as the agent arousing the most debate. The most available data regarding non-carbapenem β-lactams (i.e., ceftolozane–tazobactam, ceftazidime–avibactam, temocillin, cephamycins and cefepime) are also thoroughly presented as well as non β-lactams (i.e., aminoglycosides, quinolones, tigecycline, eravacycline and fosfomycin).

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“…In the 2017 World Health Organization Priority Pathogen List, carbapenem-resistant Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacteriaceae are identified as the “Priority 1: Critical” pathogens, which desperately require new antibiotics ( World Health Organization, 2017 ). Even though several new antibiotics have been approved by the US Food and Drug Administration (FDA) over the last few years, emergence of resistance has already been reported ( Abdallah et al, 2015 ; de Man et al, 2018 ; Giddins et al, 2018 ; Karaiskos et al, 2019 ; Morrissey et al, 2020 ). Many clinicians worldwide have been forced to use polymyxins as the last-line therapy to treat life-threatening infections caused by the three aforementioned Gram negative “superbugs” because of their resistance to all currently available antibiotics ( Wertheim et al, 2013 ; Andrei et al, 2019 ; Zhang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Rescuing the Last-Line Polymyxins: Achievements and Challenges

et al. 2021

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Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of “safer” antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative “superbugs,” every effort must be made to improve the clinical utility of the last-line polymyxins. Significance Statement Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.

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

Cited by 56 publications

References 33 publications

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Carbapenem-Sparing Strategies for ESBL Producers: When and How

Rescuing the Last-Line Polymyxins: Achievements and Challenges

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