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Eravacycline’s potential in the pipeline
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It is clear that our health care industry, government and general public have become increasingly concerned with the disturbing rise in antimicrobial resistance — and the alarm is justified. The CDC’s Antibiotic Resistance Threats in the United States, 2013 report recently estimated that more than 20,000 annual deaths in the United States were attributed to infections caused by resistant pathogens. Furthermore, the report highlighted a growing array of increasingly resistant pathogens, ranging from Clostridium difficile to Pseudomonas. Despite the clear evidence of this disturbing trend, the demand for more novel antimicrobials has outpaced the nation’s pipeline of new treatments. However, optimism has grown as eight medications are now undergoing phase 3 trials, including eravacycline. This novel fluorocycline has fueled much anticipation with its claimed improvements upon the properties of earlier tetracyclines, but will clinical trial data meet everyone’s high expectations?
Spectrum of activity
Eravacycline (TP-434), manufactured by Tetraphase Pharmaceuticals, is an oral and intravenous fluorocycline that features an additional fluorine and pyrrolidineacetamide group within the D-ring of the traditional tetracycline structure. Naturally, the medication possesses the same ribosomal mechanism of action as conventional tetracyclines. Compared with tetracycline, initial in vitro studies showed eravacycline to have a sevenfold higher inhibitory effect on ribosomes, and it also displayed activity against several gram-positive and gram-negative bacteria possessing tet efflux and ribosomal protection genes. Furthermore, in vivo mice models showed the compound’s efficacy in septicemia and neutropenic thigh infection using extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli and MRSA, respectively.
With the promising results of these earlier studies, Sutcliffe and colleagues examined eravacycline’s potency against a wide range of resistant microorganisms. For resistant gram-positive organisms, it showed particularly low MIC90 values for MRSA, Enterococcus faecalis and E. faecium isolates that were not susceptible to Zyvox (linezolid, Pfizer) and Cubicin (daptomycin, Cubist Pharmaceuticals). Similar results were found for macrolide- and fluoroquinolone-resistant MRSA strains. Eravacycline also showed low MIC values for Streptococcus pneumoniae isolates resistant to penicillins and macrolides as well as doxycycline.
In terms of resistant gram-negative coverage, Sutcliffe and colleagues also found eravacycline to hold potent in vitro activity against key resistant organisms. Eravacycline had adequate MICs for Acinetobacter, ESBL-producing E. coli strains, and other Enterobacteriaceae not susceptible to tetracyclines, fluoroquinolones, cephalosporins and aminoglycosides. Eravacycline also shows adequate MICs for Klebsiella pneumoniae and Enterobacter spp. that were not susceptible to tetracyclines or carbapenems. Eravacycline showed twofold higher activity against the majority of Acinetobacter spp., Enterobacter spp. and Proteus spp. when compared with Tygacil (tigecycline, Pfizer). However, like traditional tetracyclines, eravacycline showed elevated MIC90 values (32 g/mL) to Pseudomonas. Overall, these results suggested eravacycline has a broad spectrum of antimicrobial activity, which also includes many clinically important antimicrobial-resistant organisms such as those that have tetracycline resistance due to tet gene expression.
Preliminary clinical trial data
The phase 3 IGNITE — multicenter, double dummy clinical trials — completed enrollment in June 2014 and include two separate studies that analyze eravacycline’s efficacy in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). In IGNITE 1, patients with cIAIs were randomly assigned to eravacycline 1 mg/kg IV every 12 hours or ertapenem 1 g IV every 24 hours. Participants were evaluated for test-of-cure at 25 to 31 days after starting eravacycline. For the IGNITE 2 trial, patients with cUTIs were randomly assigned either eravacycline 1.5 mg/kg IV every 24 hours with a transition to 200 mg orally every 12 hours or levofloxacin 750 mg IV every 24 hours with a transition to 750 mg orally every 24 hours. Participants were evaluated for microbiological and clinical response 6 to 8 days after completing treatment. For both IGNITE trials, the noninferiority margin was set at 10%.
In April 2015, Tetraphase announced preliminary results for the IGNITE 1 and 2 trials at the European Congress of Clinical Microbiology and Infectious Diseases. At that time, it included 446 patients with cIAI caused by E. coli, K. pneumoniae, Pseudomonas, and Acinetobacter in the IGNITE 1 trial. Eravacycline met noninferiority where clinical cure was achieved in 86.8% vs. 87.6% of cases for eravacycline and Invanz (ertapenem, Merck), respectively. According to the manufacturer, the most common adverse events included nausea (3.3%) and vomiting (2.2%).
Although eravacycline performed favorably in the IGNITE 1 trial, the same could not be said for IGNITE 2. Preliminary data released by Tetraphase in early 2015 showed 70.8% of the eravacycline group in IGNITE 2 met the clinic endpoint compared with 52.2% of the levofloxacin group. Despite the anticipation from this initial data, eravacycline did not meet the primary endpoint after the trial was completed in 908 cUTI patients. (The final results of IGNITE 2 have not been published at the time of this publication.)
Regardless of eravacycline’s inability to achieve the primary endpoint in cUTI, the antimicrobial appears to have some clinical advantages in cIAI in addition to its noninferiority to ertapenem. The available in vitro susceptibility data suggest eravacycline can circumvent the frustrating resistance mechanisms of notable resistant pathogens. Pseudomonas, however, showed high MICs to the compound. This bacterium is known for its intrinsic resistance to traditional tetracyclines. Still, Pseudomonas is an extremely important and prevalent pathogen in terms of antimicrobial resistance, and its exclusion from eravacycline’s spectrum of activity may detract from its clinical utility at a time when antimicrobials with Pseudomonas coverage are needed. On the other hand, if the final results of the IGNITE 1 trial show positive results for eravacycline, it would be useful for pathogens that are resistant to other antibiotics commonly used in cIAI such as fluoroquinolones or cephalosporins. In addition, the low incidence of adverse effects observed thus far may represent an advantage over the toxicity profiles of other available antimicrobials for cIAI such as tigecycline. Nonetheless, final results for the IGNITE trials will need to be published before any definitive conclusions can be made regarding eravacycline’s safety or place in therapy.
Antimicrobial resistance has taken a notable financial and human toll on our nation’s health care, but the antimicrobial research pipeline includes several diverse drugs that may combat the rising trends in resistance. Eravacycline has shown promising results regarding its spectrum of coverage and efficacy during initial in vitro and clinical investigations. Ongoing research will help define eravacycline’s use in cIAI if it is eventually FDA-approved. Until then, the health care community waits in anticipation at a time when the arrival of new antimicrobials has been few and far between.
- References:
- CDC. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/index.html. Accessed November 23, 2015.
- Sutcliffe JA, et al. Antimicrob Agents Chemother. 2013;doi:10.1128/AAC.01288-13.
- Tetraphase Pharmaceuticals. Tetraphase Pharmaceuticals Presents Detailed Results From Phase 3 Trials of Eravacycline at 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). April 27, 2015. http://ir.tphase.com/releasedetail.cfm?ReleaseID=908636. Accessed November 23, 2015.
- Tetraphase Pharmaceuticals. Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI. September 8, 2015. http://ir.tphase.com/releasedetail.cfm?ReleaseID=930613. Accessed November 23, 2015.
- Xiao X-Y, et al. J Med Chem. 2012;doi:10.1021/jm201465w.
For more information:
Katherine C. Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Stephen M. Small, PharmD, is a pharmacy practice resident at Denver Health Medical Center.
Disclosures: Shihadeh and Small report no relevant financial disclosures.