Advertisement

Drugs

, Volume 79, Issue 3, pp 315–324 | Cite as

Eravacycline: A Review in Complicated Intra-Abdominal Infections

  • Lesley J. ScottEmail author
Adis Drug Evaluation

Abstract

Eravacycline (Xerava™), a novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring; consequently, it exhibits potent in vitro activity against Gram-positive and -negative bacterial strains expressing certain common tetracycline-specific acquired resistance mechanisms. In vitro, eravacycline exhibits potent activity against a broad spectrum of clinically relevant Gram-positive and -negative aerobic and anaerobic bacteria. Intravenous eravacycline is approved in several countries for the treatment of complicated intra-abdominal infections (cIAIs) in adult patients. In two pivotal double-blind, multinational trials in this patient population, eravacycline (infusion ≈ 1 h) was noninferior to intravenous ertapenem or meropenem at the test-of-cure visit in terms of clinical response rates in all prespecified populations. Eravacycline had an acceptable tolerability profile, with infusion site reactions, nausea, vomiting and diarrhoea the most commonly reported adverse reactions, most of which were of mild to moderate severity. Given its broad spectrum of activity against common clinically relevant pathogens (including those expressing certain tetracycline- and other antibacterial-specific acquired resistance mechanisms) and its more potent in vitro activity and better tolerability profile than tigecycline, eravacycline provides a novel emerging option for the treatment of adult patients with cIAIs, especially as empirical therapy when coverage of resistant pathogens is required.

Notes

Acknowledgments

During the peer review process, the manufacturer of eravacycline was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Lesley Scott is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

References

  1. 1.
    Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society revised guidelines on the management of intra-abdombinal infection. Surg Infect. 2017;18(1):1–76.CrossRefGoogle Scholar
  2. 2.
    Sartelli M, Chichom-Mefire A, Labricciosa FM, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2017;12:29.CrossRefGoogle Scholar
  3. 3.
    Ventola CL. The antibiotic resistance crisis. Part 2: management strategies and new agents. Pharm Therap. 2015;40(5):344–52.Google Scholar
  4. 4.
    Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017;23(10):704–12.CrossRefGoogle Scholar
  5. 5.
    Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathogens Glob Health. 2015;109(7):309–18.CrossRefGoogle Scholar
  6. 6.
    Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15(10):1351–70.CrossRefGoogle Scholar
  7. 7.
    Sartelli M, Weber DG, Ruppé E, et al. Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg. 2016;11:33.CrossRefGoogle Scholar
  8. 8.
    Xiao X-Y, Hunt DK, Zhou J, et al. Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem. 2012;55(2):597–605.CrossRefGoogle Scholar
  9. 9.
    Clark RB, Hunt DK, He M, et al. Fluorocyclines. 2. Optimization of the C-9 side chain for antibacterial activity and oral efficacy. J Med Chem. 2012;55(2):606–22.CrossRefGoogle Scholar
  10. 10.
    Grossman TH, Starosta AL, Fyfe C, et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother. 2012;56(5):2559–64.CrossRefGoogle Scholar
  11. 11.
    Tetraphase Pharmaceuticals Inc. Xerava (Eravacycline): US prescribing information. 2018. http://www.fda.gov. Accessed 21 Oct 2018.
  12. 12.
    Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567–88.CrossRefGoogle Scholar
  13. 13.
    European Medicines Agency. Xerava (Eravacycline): summary of product characteristics. 2018. http://www.ema.europa.eu/. Accessed 1 Nov 2018.
  14. 14.
    Nguyen F, Starosta AL, Arenz S, et al. Tetracycline antibiotics and resistance mechanisms. Biol Chem. 2014;395(5):559–75.CrossRefGoogle Scholar
  15. 15.
    Snydman DR, McDermott LA, Jacobus NV, et al. Evaluation of the in vitro activity of eravacycline against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother. 2018;62(5):e02206–17.CrossRefGoogle Scholar
  16. 16.
    Zhanel GG, Baxter MR, Adam HJ, et al. In vitro activity of eravacycline against 2213 Gram-negative and 2424 Gram-positive bacterial pathogens isolated in Canadian hospital laboratories: CANWARD surveillance study 2014-2015. Diagn Microbiol Infect Dis. 2018;91(1):55–62.CrossRefGoogle Scholar
  17. 17.
    Abdallah M, Olafisoye O, Cortes C, et al. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. Antimicrob Agents Chemother. 2015;59(3):1802–5.CrossRefGoogle Scholar
  18. 18.
    Sutcliffe JA, O’Brien W, Fyfe C, et al. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013;57(11):5548–58.CrossRefGoogle Scholar
  19. 19.
    Olesky M, Morrissey I, Hawser S, et al. In vitro activity of eravacycline and comparators against resistant Gram-negative isolates collected in 2016 from patients in Europe. [abstract no. P0099]. In: 28th ECCMID. 2018.Google Scholar
  20. 20.
    Lawrence K, Olesky M, Fyfe C, et al. Global surveillance of in vitro activity of eravacycline and comparators against Enteroacteriaceae, Stenotrophomonas maltophilia, Staphylococcus aureus and Enterococcus spp. collected during 2016. [abstract no. P0101]. In: 28th ECCMID. 2018.Google Scholar
  21. 21.
    Morrissey I, Bassetti M, Magnet S, et al. In vitro activity of eravacycline and comparators against Staphylococcus aureus and Enterococci, including methicillin-resistant and vancomycin-resistant subgroups, collected from European hospitals in 2015. [abstract no. P1358]. In: 27th ECCMID. 2017.Google Scholar
  22. 22.
    Morrissey I, Bassetti M, Magnet S, et al. In vitro activity of eravacycline and comparators against Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae, including carbapenem-resistant and ESBL phenotype subgroups, collected from European hospitals in 2015. [abstract no. P1260]. In: 27th ECCMID. 2017.Google Scholar
  23. 23.
    Olesky M, Bassetti M, Corey R, et al. In vitro global surveillance of eravacycline and comparators against Enterobacteriaceae, Acinetobacter baumannii, Stenotrophomonas maltophilia, including multidrug-resistant (MDR) isolates, over a three-year period (2013–15). [abstract no. 20]. In: ASM/ESCMID conference on drug development to meet the challenges of antimicrobial resistance. 2017.Google Scholar
  24. 24.
    Olesky M, Bassetti M, Corey R, et al. In vitro global surveillance of eravacycline and comparators against Staphylococcus spp. and Enterococcus spp. over a three-year period (2013-15) [abstract no. 22]. In: ASM/ESCMID conference on drug development to meet the challenges of antimicrobial resistance. 2017.Google Scholar
  25. 25.
    Bouchillon S, Hawser S, Monti F, et al. Surveillance of the in vitro activity of eravacycline and comparators against clinical isolates from the US from 2013-2016. [abstract no. Global-MO11]. In: Surgical Infection Society Meeting. 2018.Google Scholar
  26. 26.
    Efimova E, Bassetti M, Hawser S, et al. Eravacycline in vitro activity against European clinical isolates obtained in 2016 from urinary and gastrointestinal sources, including drug resistant pathogens. [abstract no. P0100]. In: 28th ECCMID. 2018.Google Scholar
  27. 27.
    Seifert H, Stefanik D, Sutcliffe JA, et al. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents. 2018;51(1):62–4.CrossRefGoogle Scholar
  28. 28.
    Livermore DM, Mushtaq S, Warner M, et al. In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60(6):3840–4.CrossRefGoogle Scholar
  29. 29.
    Rhoads DD, Bajaksouzian S, Abdelhamed AM, et al. Activity of eravacycline against carbapenem resistant Enterobacteriaceae and Acinetobacter baumannii [poster]. In: ASM Microbe. 2017.Google Scholar
  30. 30.
    Monogue ML, Thabit AK, Hamada Y, et al. Antibacterial efficacy of eravacycline in vivo against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother. 2016;60(8):5001–5.CrossRefGoogle Scholar
  31. 31.
    Grossman TH, Murphy TM, Slee AM, et al. Eravacycline (TP-434) is efficacious in animal models of infection. Antimicrob Agents Chemother. 2015;59(5):2567–71.CrossRefGoogle Scholar
  32. 32.
    Thabit AK, Monogue ML, Newman JV, et al. Assessment of in vivo efficacy of eravacycline against Enterobacteriaceae exhibiting various resistance mechanisms: a dose-ranging study and pharmacokinetic/pharmacodynamic analysis. Int J Antimicrob Agents. 2018;51(5):727–32.CrossRefGoogle Scholar
  33. 33.
    Fyfe C, LeBlanc G, Close B, et al. Eravacycline is active against bacterial isolates expressing the polymyxin resistance gene mcr-1. Antimicrob Agents Chem. 2016;60(11):6989–90.CrossRefGoogle Scholar
  34. 34.
    El-Bouseary M, Tyrrell J, Walsh TR, et al. Comparative in vitro activity of eravacycline, a novel fluorocycline, against mcr-1-positive Escherichia coli and Klebsiella pneumoniae. [abstract no. P058]. In: 27th ECCMID. 2017.Google Scholar
  35. 35.
    Zhao M, Lepak AJ, Marchillo K, et al. In vivo pharmacodynamic target assessment of eravacycline against Escherichia coli in a murine thigh infection model. Antimicrob Agents Chemother. 2017;61(7):e00250-17.CrossRefGoogle Scholar
  36. 36.
    VanScoy BD, Lakota EA, Adams J, et al. Pharmacokinetics-pharmacodynamics (PK-PD) of efficacy for eravacycline against Escherichia coli in an in vitro infection model. [abstract no. 24]. In: ASM/ESCMID conference on drug development to meet the challenges of antimicrobial resistance. 2017.Google Scholar
  37. 37.
    Horn PT, Redican S, Wei X, et al. Eravacycline does not prolong corrected QT intervals in a thorough QT study conducted in healthy subjects [abstract no. P0310]. In: 24th ECCMID. 2014.Google Scholar
  38. 38.
    Newman JV, Zhou J, Izmailyan S, et al. Randomized, double-blind, placebo-controlled studies of the safety and pharmacokinetics of single and multiple ascending doses of eravacycline. Antimicrob Agents Chemother. 2018;62(11):e01174-18.CrossRefGoogle Scholar
  39. 39.
    Horn P, Redican S, Olesky M. Pharmacokinetics (PK) of eravacycline in subjects with renal or hepatic impairment compared to healthy subjects. [abstract no. 1829]. In: IDWeek. 2017.Google Scholar
  40. 40.
    Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224–32.CrossRefGoogle Scholar
  41. 41.
    Solomkin JS, Gardovskis J, Lawrence K, et al. IGNITE4: results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs. meropenem in the treatment of complicated intra-abdominal infections. Clin Infect Dis. 2018.  https://doi.org/10.1093/cid/ciy1029/5250914.Google Scholar
  42. 42.
    Solomkin JS, Ramesh MK, Cesnauskas G, 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. 2014;58(4):1847–54.CrossRefGoogle Scholar
  43. 43.
    Fonte A, Lawrence K, Izmailyan S, et al. Efficacy of eravacycline in obese patients: pooled analsysis of IGNITE1 and IGNITE4 [abstract no. 448 plus poster]. J Am Coll Clin Pharm. 2018;1(2):291.Google Scholar
  44. 44.
    Ditch K, Newman J, Izmailyan S, et al. Microbiological efficacy of eravacycline against Enterobacteriaceae and Acinetobacter, including MDR isolates: a pooled analysis from IGNITE1 and IGNITE4, two phase 3 trials of complicated intra-abdominal infection [abstract no. 629 plus poster]. In: ASM Microbe. 2018.Google Scholar
  45. 45.
    Michaud M, Hoffman-Roberts H, Marsh A. Evaluation of patients with complicated intra-abdominal infections (cIAI) and concomitant bacteremia (CB) from IGNITE1: a phase 3 study to evaluate the efficacy and safety of eravacycline (ERV) versus ertapenem (ETP) in complicated intra-abdominal infections (cIAI) [abstract no. 426]. In: ASM Microbe. 2016.Google Scholar
  46. 46.
    Lawrence K, Olesky M, Izmailyan S, et al. Efficacy of eravacycline in secondary bacteremia: a post hoc analysis of two phase 3 studies of complicated intra-abdominal infection [abstract no. 1978 plus poster]. In: ID Week. 2018.Google Scholar
  47. 47.
    Fonte A, Lawrence K, Izmailyan S, et al. Effect of renal function in IGNITE1 and IGNITE4: two phase 3 studies to evaluate the efficacy and safety of eravacycline [abstract no. 447 plus poster]. J Am Coll Clin Pharm. 2018;1(2):290–1.Google Scholar
  48. 48.
    Efimova E, Olesky M, Izmailyan S, et al. Pooled analysis of safety data from phase 2 and 3 clinical trials evaluating eravacycline in complicated intra-abdominal infections [abstract no. 1976 plus poster]. In: ID Week. 2018.Google Scholar
  49. 49.
    Wyeth Pharmaceuticals Inc. TYGACIL® (tigecylcine) for injection for intravenous use: US prescribing information. 2017. http://www.fda.gov. Accessed 14 Jan 2019.

Copyright information

© Springer Nature Switzerland AG 2019
corrected publication 2019

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

Personalised recommendations