Eravacycline: The IGNITE Growth of the Tetracyclines

The US Food and Drug Administration approved eravacycline (Xerava, Tetraphase Pharmaceuticals) in August 2018 for complicated intra-abdominal infections in adults 18 years and older.¹ It was investigated for urinary tract infections (UTIs), but the outcomes were not advantageous.² Eravacycline is a synthetic novel tetracycline antibiotic, structurally similar to tigecycline (Tygacil, Wyeth Pharmaceuticals).³ It preserves activity against the 2 acquired tetracycline-specific acquired-resistance mechanisms: efflux pumps and ribosomal protection.

PHARMACOLOGY

In a similar matter to other members of the tetracycline class, eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit. This process prevents amino acid residues from being integrated into the peptide chains.^3-5 Although bacteriostatic against gram-positive bacteria, bactericidal activity had been observed against strains of Escherichia coli and Klebsiella pneumoniae in vitro.

SPECTRUM

Eravacycline established broad-spectrum antimicrobial activity against several multidrug-resistant organisms identi­fied by the US Center for Diseases Control and Prevention as urgent or serious threats.^3-6 Examples of these include: carbapenem-resistant Enterobacteriaceae, methicillin-re­sistant Staphylococcus aureus, extended-spectrum beta-lact­amases—producing Enterobacteriaceae, vancomycin-resistant enterococci, and multidrug-resistant Acinetobacter and Bacteroides fragilis. Notably, eravacycline is inactive against Pseudomonas aeru­ginosa and Burkholderia cenocepacia. Compared with tige­cycline, eravacycline is at least twice more potent against gram-negative bacilli and gram-positive cocci.^3,6

RESISTANCE

Because of substitution patterns that are not present in other tetracyclines, eravacycline is uniquely positioned to overcome the most common tetracycline-specific resistance mechanisms: ribosomal protection proteins (tetM) and efflux pumps (tetA, tetB, tetK).^4-5 Resistance to eravacycline is thought to be associated with target-site modifications and upregulated intrinsic multidrug-resistant efflux.

PHARMACODYNAMICS AND PHARMACOKINETICS

Eravacycline is at least 79% protein bound.⁴ The volume of distribution at steady state is approximately 321 liters. The elimination half-life is about 20 hours. Eravacycline is metab­olized by the liver; specifically, cytochrome P450 3A4 (CYP3A4) and flavin-containing monooxygenase mediated oxidation and excreted in the urine and feces.

DOSAGE AND ADMINISTRATION

The recommended dosage for patients with normal hepatic func­tion is 1 mg/kg every 12 hours administered as an intravenous infusion over 60 minutes.^4,6-7 Because the drug is hepatically metab­olized, it does not warrant dose adjustment in renally impaired patients. Patients with severe hepatic impairment should have their dose adjusted to 1 mg/kg every 24 hours on the second day and for the remaining duration of therapy. The dose should be calculated based on actual bodyweight for all patients, including those with a body mass index over 30 kg/m².⁸

SUPPLY AND STORAGE

Eravacycline is supplied as a yellow-orange, preservative-free powder for reconstitution in a single-dose 50-mg/10-mL clear glass vial.⁴ Each should be kept in its original carton until usage. Vials should be stored at 2 °C to 8 °C (36 °F-46 °F) prior to reconstitution.

DRUG INTERACTIONS AND CONTRAINDICATIONS

Use of strong CYP3A4 inducers may decrease eravacycline expo­sure and potentially efficacy, therefore the dose may need to be adjusted.⁴ In addition, since tetracyclines have the potential to decrease prothrombin activity, the dose of anticoagulants should be reduced.

ADVERSE REACTIONS, WARNINGS, AND PRECAUTIONS

In general, eravacycline has a favorable safety profile. The most common adverse reactions are infusion-site reactions, nausea, and vomiting.^4,10 Clinically significant warnings and precautions include hypersensitivity reactions and Clostridium difficile—asso­ciated diarrhea. Similar to other members of the tetracycline class, eravacycline can cause tooth discoloration, enamel hypo­plasia, bone growth inhibition during development, azotemia, pancreatitis, and hyperphosphatemia.

PREGNANCY AND LACTATION

Because eravacycline is a synthetic tetracycline, it has the potential to cause tooth discoloration and bone growth inhi­bition during the second and third trimesters of pregnancy.⁴ Although, eravacycline is excreted in human milk, the degree of absorption is unknown.

CLINICAL STUDIES

Eravacycline was approved for complicated intra-abdominal infections in adults following the IGNITE1 and IGNITE4 studies. The 2 trials were phase 3, randomized, double-blind, active controlled multicenter trials in patients with complicated intra-abdominal infections requiring surgery or percutaneous drainage and compared eravacycline (1 mg/kg every 12 hours) with ertapenem (Invanz, Merck; 1 g every 24 hours) or meropenem (Merrem, Pfizer; 1 g every 8 hours) for 4 to 14 days.^6-7 Patients who had at least 1 baseline intra-abdominal infection microor­ganism were included in the intent to treat (ITT) population.

The primary endpoint was clinical cure, defined as complete resolution or significant improvement of signs or symptoms at the test of cure (TOC). The clinical cure rates in the eravacycline and ertapenem groups were 86.8% and 87.6%, respectively in IGNITE1. In IGNITE4, eravacycline had cure rates of 90.8% compared with 91.2% in the meropenem group. Such difference exceeded the predetermined noninferiority margin.

Two phase 3, randomized, double-blind, active controlled multicenter trials also assessed the efficacy and safety of eravacycline in complicated UTIs: the IGNITE2 and IGNITE3 trials. In IGNITE2, eravacycline (1.5 mg/kg intravenously [IV] every 24 hours followed by 200 mg orally every 24 hours) was compared with levofloxacin (750 mg IV every 24 hours followed by 750 mg orally every 24 hours).³ The IGNITE3 trial compared eravacycline (1 mg/kg IV every 24 hours) to ertapenem (1 g IV every 24 hours). The coprimary efficacy endpoint was a combination of clinical cure and microbiological success in the ITT population at the end of intravenous treatment and TOC. Both trials could not demonstrate efficacy for eravacy­cline compared with ertapenem or levofloxacin.

PATIENT COUNSELING

Clinicians should ask patients about previous hypersensitivity reactions to antibacterial drugs, particularly within the tetra­cycline class, as serious allergic reactions may occur.⁴ Because of its effect on tooth color and bone growth, women of child-bearing age should be counseled to avoid eravacycline during the second and third trimesters of pregnancy. Lactating women should be advised not to breastfeed during therapy and for 4 days after the last dose.

PLACE IN THERAPY

Although eravacycline may not be used as a first line treatment for complicated intra-abdominal infections, infectious diseases experts have anticipated several clinical scenarios for which eravacycline may have a signifi­cant place in therapy.^12-13 First, eravacycline may replace tige­cycline due to its favorable tolerability profile including, but not limited to, side effects, drug interactions, and serum levels. Second, eravacycline can serve as a last resort for patients with multidrug-resistant and multiple drug allergies, particularly carbap­enems and fluoroquinolones. Third, patients who are at high risk for C difficile infections may benefit from the relatively safe profile for eravacycline, particularly if proven to be as safe as the other tetracyclines.

FUTURE RESEARCH

Even with the observed similarities between eravacycline and tigecycline, it remains unclear how the 2 would compare in terms of efficacy, resistance, and adverse effect profile in the real-world setting. It would be interesting to see if Tetraphase continues to develop oral eravacycline, particularly if this formulation would be investigated for other indications.

Dr. Alosaimy is a first-year infectious diseases pharmacotherapy fellow at Wayne State University in Detroit, Michigan. She completed a PharmD at the University of Illinois at Chicago, and a PGY1 and PGY2-ID residency at Brigham and Women's Hospital, in Boston, Massachusetts. She is an active member of the American College of Clinical Pharmacy.

References:

1. FDA approves XERAVA (Eravacycline) for complicated intra-abdominal infections in patients 18 years of age and older [news release]. Silver Spring, MD; August 28, 2018.
2. Tetraphase announces FDA approval of Xerava (Eravacycline) for complicated intra-abdominal Infections [news release]. Watertown, MA; August 27, 2018. https://ir.tphase.com/news-releases/news-release-details/tetraphase-pharmaceuticals-announces-fda-approval-xeravatm. Accessed November 16, 2018.
3. Tetraphase announces top-line results from IGNITE3 phase 3 clinical trial of eravacycline in complicated urinary tract infections (cUTI) [news release]. Watertown, MA; February 13, 2018. https://ir.tphase.com/news-releases/news-release-details/tetraphase-announces-top-line-results-ignite3-phase-3-clinical. Accessed November 16, 2018.
4. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588. doi: 10.1007/s40265-016-0545-8.
5. XERAVA [package insert]. Watertown, MA: Tetraphase Pharmaceuticals, Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf. Accessed November 16, 2018.
6. Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013;57(11):5548-5558.
7. Tsai L, Horn P, Solomkin J, Evans D, Gardovskis J. Fonte A. Results of IGNITE4: A phase 3 study to evaluate the efficacy and safety of eravacycline versus meropenem in complicated intra-abdominal infections. Poster presented at: 28th ECCMID; April 21, 2018; Madrid, Spain.
8. Newman JV, Zhou J, Izmailyan S, Tsai L. 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. Published Oct 24, 2018. doi:10.1128/AAC.01174-18.
9. Fonte A, Kolkin S, Lawrence K, Izmailyan S. Efficacy of eravacycline in obese patients: pooled analysis of IGNITE1 and IGNITE4. American College of Clinical Pharmacy Annual Meeting, October 21-23, 2018, Seattle, WA, Abstract E-48219.
10. Newman JV, Zhou J, Izmailyan S, Tsai L. Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline. Antimicrob Agents Chemother. 2018;
11. 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 (IGNITE 1) trial: A randomized clinical trial. JAMA Surg. 2017;152(3):224-232. doi: 10.1001/jamasurg.2016.4237.
12. Tsai L, et al. Risk factors for change in microbiological outcomes between the end of therapy and post-treatment evaluations in patients with complicated uti treated with eravacycline: Analysis from a randomized, double-blind, multicenter, phase 3 trial (Ignite2). Presented at: ASM Microbe; June 16-20, 2016; Boston.
13. New England Journal of Medicine Journal Watch. Eravacycline Approved by FDA — How Might It Be Used, Today and in the Future?. NEJM Journal Watch website. blogs.jwatch.org/hiv-id-observations/index.php/eravacycline-approved-fda-might-used-today-future/2018/09/03/. Published September 2018. Accessed November 16, 2018.
14. Infectious Diseases Stewardship. A comparison of eravacycline (Xerava) versus tigecycline (Tygacil). ID stewardship. www.idstewardship.com/comparison-eravacycline-xerava-versus-tigecycline-tygacil. Published September 2018. Accessed November 16, 2018.