Original Article | Published:

In vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline

The Journal of Antibiotics volume 69, pages 600604 (2016) | Download Citation

This article is dedicated to the fond memory of the late Professor Lester Mitscher, a great scholar, teacher and Emeritus Editor of The Journal of Antibiotics.


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Centers for Disease Control and PreventionAntibiotic Resistance Threats in the United States, United States Department of Health and Human Services, Atlanta, GA, USA, (2013).

  2. 2.

    et al. Challenges in the management of infections due to carbapenem-resistant Enterobacteriaceae. Infect. Control Hosp. Epidemiol. 35, 437–439 (2014).

  3. 3.

    , & The global challenge of carbapenem-resistant Enterobacteriaceae in transplant recipients and patients with hematologic malignancies. Clin. Infect. Dis. 58, 1274–1283 (2014).

  4. 4.

    & New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections. Curr. Opin. Crit. Care 21, 402–411 (2015).

  5. 5.

    Investigational agents for the treatment of Gram-negative bacterial infections: a reality check. ACS Infect. Dis. 1, 509–511 (2015).

  6. 6.

    & Healthcare-associated infections, infection control and the potential of new antibiotics in development in the USA. Future Microbiol. 10, 1049–1062 (2015).

  7. 7.

    & Discovery and development of new antibacterial agents targeting Gram-negative bacteria in the era of pandrug resistance: is the future promising? Curr. Opin. Pharmacol. 18, 91–97 (2014).

  8. 8.

    A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Intl. J. Antimicrob. Agents 46, 483–493 (2015).

  9. 9.

    Infectious Diseases Society of Americaet al. Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 52(suppl. 5), S397–S428 (2011).

  10. 10.

    et al. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. Antimicrob. Agents Chemother. 59, 1802–1805 (2015).

  11. 11.

    , , & Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob. Agents Chemother. 57, 5548–5558 (2013).

  12. 12.

    et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob. Agents Chemother. 56, 2559–2564 (2012).

  13. 13.

    , , & Eravacycline (TP-434) is active in vitro against biofilms formed by uropathogenic Escherichia coli. Antimicrob. Agents Chemother. 59, 2446–2449 (2015).

  14. 14.

    , , , & Eravacycline (TP-434) is efficacious in animal models of infection. Antimicrob. Agents Chemother. 59, 2567–2571 (2015).

  15. 15.

    et al. Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. Antimicrob. Agents Chemother. 58, 1847–1854 (2014).

  16. 16.

    , , & Activity of eravacycline against carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii. Abstract F-769. in 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, (2015).

  17. 17.

    et alActivity of eravacycline and comparators against 3,174 pathogens isolated from Canadian hospitals: CANWARD 2014. Abstract F-771. in 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, (2015).

  18. 18.

    et alChanging epidemiology and molecular characterization of carbapenem-resistant Enterobacteriaceae (CRE) in Indiana Health Care Centers (HCCs) over a 3-year period. Abstract # C2-1445. in: 53rd Conf. Antimicrobial Agents and Chemotherapy, Denver, CO, USA, (2013).

  19. 19.

    et al. Detection systems for carbapenemase gene identification should include the SME serine carbapenemase. Intl. J. Antimicrob. Agents 41, 1–4 (2013).

  20. 20.

    et alKPC-2 and VIM carbapenemases decreased in carbapenem-resistant Enterobacteriaceae in Indiana health care centers from 2009 to 2013. in 54th Interscience Conference on Antimicrobial Agents & Chemotherapy, Washington, DC, USA, (2014).

  21. 21.

    et alOccurrence of VIM and NDM carbapenemases in Indiana health care centers from 2009 to 2013. Abstract C-1095. in 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, (2015).

  22. 22.

    CLSIPerformance Standards for Antimicrobial Susceptibility Testing. CLSI supplement M100S, 26th edn (Clinical and Laboratory Standards Institute, Wayne, PA, (2016).

  23. 23.

    , & Rapid detection of carbapenemase-producing Enterobacteriaceae. Emerg. Infect. Dis. 18, 1503–1507 (2012).

  24. 24.

    et al. Detection of 2 SME-1 carbapenemase-producing Serratia marcescens in Detroit. Diagn. Microbiol. Infect. Dis. 71, 325–326 (2011).

  25. 25.

    et al. SME-type carbapenem-hydrolyzing class A β-lactamases from geographically diverse Serratia marcescens strains. Antimicrob. Agents Chemother. 44, 3035–3039 (2000).

  26. 26.

    et al. Novel carbapenem-hydrolyzing β-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 45, 1151–1161 (2001).

  27. 27.

    , , , & First nosocomial outbreak of Pseudomonas aeruginosa producing an integron-borne metallo-β-lactamase (VIM-2) in the United States. Antimicrob. Agents Chemother. 49, 3538–3540 (2005).

  28. 28.

    et al. SME-3, a novel member of the Serratia marcescens SME family of carbapenem-hydrolyzing β-lactamases. Antimicrob. Agents Chemother. 50, 3485–3487 (2006).

  29. 29.

    et al. Molecular epidemiology of CTX-M-producing Escherichia coli isolates at a tertiary medical center in western Pennsylvania. Antimicrob Agents Chemother. 53, 4733–4739 (2009).

  30. 30.

    , , & Multiplex PCR for detection of acquired carbapenemase genes. Diagn. Microbiol. Infect. Dis. 70, 119–123 (2011).

  31. 31.

    CLSIM07-A9: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard. 9th edn (Clinical and Laboratory Standards Institute, Wayne, PA, (2013).

  32. 32.

    , , & Activity of eravacycline against Escherichia coli clinical isolates collected from U.S. veterans in 2011 in relation to coresistance phenotype and sequence type 131 genotype. Antimicrob. Agents Chemother 60, 1888–1891 (2015).

  33. 33.

    , , , & Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother. 58, 833–838 (2014).

  34. 34.

    Centers for Disease Control & Prevention Notes from the field: New Delhi metallo-β-lactamase-producing Escherichia coli associated with endoscopic retrograde cholangiopancreatography - Illinois, 2013. Morbid. Mortal. Week Rep. 62, 1051 (2014).

  35. 35.

    et al. In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother. 59, 1789–1793 (2015).

Download references


We acknowledge the support of Tetraphase Pharmaceuticals to conduct this study.

Author information


  1. Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA

    • Yunliang Zhang
    • , Xiaoyan Lin
    •  & Karen Bush


  1. Search for Yunliang Zhang in:

  2. Search for Xiaoyan Lin in:

  3. Search for Karen Bush in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Karen Bush.

About this article

Publication history