By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a new parenteral, broad-spectrum antibiotic in the tetracycline class for the treatment of complicated intra-abdominal infections (cIAI). Eravacycline is a synthetic fluorocycline that is chemically similar to tigecycline. It received a qualified infectious disease product designation and priority review. It is marketed as Xerava.

INDICATIONS

Eravacycline is indicated for patients ≥ 18 years of age to treat cIAI caused by the following: Bacteroides species, Clostridium perfringens, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, and Parabacteroides distasonis.1 Eravacycline should be used for infections that are proven or strongly suspected to be caused by susceptible microorganisms.1 Because of inadequate efficacy, eravacycline is not indicated for the treatment of complicated urinary tract infection.1,2

DOSAGE

The recommended dose is 1 mg/kg by IV infusion (over 30 minutes) every 12 hours for four to 14 days.1 For patients with severe hepatic impairment, the dose is 1 mg/kg every 12 hours on day 1 and 1 mg/kg every 24 hours from day 2 for the duration. For patients on a concomitant strong cytochrome P450 isoenzyme 3A inducer, the dose is 1.5 mg/kg.

POTENTIAL ADVANTAGES

Eravacycline offers a treatment option against multidrug-resistant bacterial infections, including extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae, methicillin-resistant S. aureus, and vancomycin-resistant Enterococci.3-5 Generally, eravacycline exhibits greater in vitro activity against gram-positive and gram-negative organisms compared to tigecycline.3

POTENTIAL DISADVANTAGES

In general, eravacycline is bacteriostatic against gram-positive bacterial and only bactericidal at relatively high concentrations against certain strains of E. coli and Klebsiella pneumoniae.1,3 It is not active against Pseudomonas aeruginosa. Some beta-lactamase-producing isolates may confer resistance to eravacycline.1,3 The frequency of adverse reactions (vs. comparators) was infusion site reaction (7.7% vs. 1.9%) and nausea (6.5% vs. 0.6%).1 Life-threatening hypersensitivity (i.e., anaphylaxis) has been reported. Patients with known hypersensitivity to tetracycline should avoid eravacycline. Adverse reactions similar to other tetracycline classes of drugs may occur and may include photosensitivity, pseudotumor cerebri, and antianabolic actions. Use during pregnancy may cause reversible inhibition of bone growth, tooth discoloration, and enamel hypoplasia in the fetus.

COMMENTS

The efficacy of eravacycline was evaluated in two Phase III, randomized, double-blind, active-controlled trials in subjects with cIAI.1,6 Acceptable diagnoses for cIAI include appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis.1 In trial 1, subjects were randomized to eravacycline (1 mg/kg every 12 hours; n = 220) or ertapenem (1 g every 24 hours; n = 226). In trial 2, subjects were randomized to eravacycline (1 mg/kg every 12 hours; n = 195) or meropenem (1 g every eight hours; n = 205). The analysis was based on the microbiologic intent-to-treat population, which included all patients who presented with at least one baseline intra-abdominal pathogen. Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection at the test-of-cure visit, which occurred 25-31 days after randomization. Clinical cure rates were 86.8% for eravacycline vs. 87.6% for ertapenem in trial 1 and 90.8% vs. 91.2% for meropenem in trial 2. Both studies met the statistical criteria for noninferiority (lower limit of -10%). Eravacycline did not demonstrate noninferiority to levofloxacin for the treatment of complicated urinary tract infections and is not approved for this indication currently.1,2

CLINICAL IMPLICATIONS

cIAI is a polymicrobial, heterogenous infection generally involving gram-positive cocci, gram-negative bacilli, and anaerobic bacteria. It may be community-acquired or healthcare-associated.7 cIAI is the second-leading cause of infection-related mortality in ICUs.8 In previous guidelines, the recommendation for single-agent empiric antimicrobial treatment included cefoxitin, ertapenem, tigecycline, meropenem, or a combination of a cephalosporin and metronidazole.7 However, multidrug-resistant bacteria have emerged, particularly with E. coli and K. pneumoniae.4 Eravacycline is one of the newer agents in development that has received FDA approval and has shown activity against multidrug-resistant bacteria. It should be reserved for infections that are proven or strongly suspected to be caused by susceptible bacteria.1 The cost for eravacycline was not available at the time of this review.

REFERENCES

  1. Xerava Prescribing Information. Tetraphase Pharmaceuticals, Inc., August 2018. Available online at: https://bit.ly/2MJRgzf. Accessed Sept. 26, 2018.
  2. Decision Resources Group. Tetraphase reports negative results of eravacycline in cUTI trial, Feb. 15, 2018. Available online at: https://bit.ly/2DvJTYb. Accessed Sept. 26, 2018.
  3. Zhanet GG, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs 2016;76:567-588.
  4. Syue LS, et al. New drugs for the treatment of complicated intra-abdominal infections in the era of increasing antimicrobial resistance. Int J Antimicrob Agents 2016;47:250-258.
  5. Lin SY, et al. Recent developments in antibiotic agents for the treatment of complicated intra-abdominal infections. Expert Opin Pharmacother 2016;17:339-354.
  6. Solomkin J, 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 (IGNITE 1) trial: A randomized clinical trial. JAMA Surg 2017;152:224-232.
  7. Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133-164.
  8. Tetraphase Pharmaceuticals. Tetraphase Pharmaceuticals announces FDA approval of Xerava (eravacycline) for complicated intra-abdominal infections (cIAI), Aug. 27, 2018. Available online at: https://bit.ly/2oewiKi. Accessed Sept. 26, 2018.