Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent

Abstract

Eravacycline is an investigational, synthetic fluorocycline antibacterial agent that is structurally similar to tigecycline with two modifications to the D-ring of its tetracycline core: a fluorine atom replaces the dimethylamine moiety at C-7 and a pyrrolidinoacetamido group replaces the 2-tertiary-butyl glycylamido at C-9. Like other tetracyclines, eravacycline inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit. Eravacycline demonstrates broad-spectrum antimicrobial activity against Gram-positive, Gram-negative, and anaerobic bacteria with the exception of Pseudomonas aeruginosa. Eravacycline is two- to fourfold more potent than tigecycline versus Gram-positive cocci and two- to eightfold more potent than tigecycline versus Gram-negative bacilli. Intravenous eravacycline demonstrates linear pharmacokinetics that have been described by a four-compartment model. Oral bioavailability of eravacycline is estimated at 28 % (range 26-32 %) and a single oral dose of 200 mg achieves a maximum plasma concentration (C max) and area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 0.23 ± 0.04 mg/L and 3.34 ± 1.11 mg·h/L, respectively. A population pharmacokinetic study of intravenous (IV) eravacycline demonstrated a mean steady-state volume of distribution (V ss) of 320 L or 4.2 L/kg, a mean terminal elimination half-life (t ½) of 48 h, and a mean total clearance (CL) of 13.5 L/h. In a neutropenic murine thigh infection model, the pharmacodynamic parameter that demonstrated the best correlation with antibacterial response was the ratio of area under the plasma concentration-time curve over 24 h to the minimum inhibitory concentration (AUC0-24h/MIC). Several animal model studies including mouse systemic infection, thigh infection, lung infection, and pyelonephritis models have been published and demonstrated the in vivo efficacy of eravacycline. A phase II clinical trial evaluating the efficacy and safety of eravacycline in the treatment of community-acquired complicated intra-abdominal infection (cIAI) has been published as well, and phase III clinical trials in cIAI and complicated urinary tract infection (cUTI) have been completed. The eravacycline phase III program, known as IGNITE (Investigating Gram-Negative Infections Treated with Eravacycline), investigated its safety and efficacy in cIAI (IGNITE 1) and cUTI (IGNITE 2). Eravacycline met the primary endpoint in IGNITE 1, while data analysis for IGNITE 2 is currently ongoing. Common adverse events reported in phase I-III studies included gastrointestinal effects such as nausea and vomiting. Eravacycline is a promising intravenous and oral fluorocycline that may offer an alternative treatment option for patients with serious infections, particularly those caused by multidrug-resistant Gram-negative pathogens.

In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model

“…The present studies demonstrated the activity of eravacycline against a diverse group of E. coli strains. This potent activity has been observed in previous in vitro and in vivo studies against both E. coli and methicillin-resistant Staphylococcus aureus (2,(12)(13)(14). We observed cidal activity against all isolates, and the shapes of the exposure-…”

“…Given this, In Vivo PK/PD of Eravacycline against Escherichia coli Antimicrobial Agents and Chemotherapy enhance activity against tetracycline-resistant bacteria (11). More recently, eravacycline, a novel fluorocycline antibiotic, was developed by a total synthetic method (12) and has been shown to be a potent translation inhibitor against strains expressing acquired tetracycline-specific resistance mechanisms (2). The present studies demonstrated the activity of eravacycline against a diverse group of E. coli strains.…”

“…Eravacycline is a novel synthetic fluorocycline that belongs to the tetracycline class of antibacterial agents and is currently in development for the treatment of complicated intraabdominal infection (cIAI) (1) and complicated urinary tract infection (cUTI) (2). Oral and intravenous formulations have been developed.…”

“…As with other tetracyclines, eravacycline inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit and demonstrates potent and broad-spectrum antimicrobial activity. Importantly, the drug maintains activity against many drug-resistant bacteria, including bacteria exhibiting tetracycline-specific efflux and ribosomal protection (2).…”

In Vitro Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii

“…q24h, with step-down to 200 mg oral [p.o.] q12h from day 3) as noninferior to levofloxacin in complicated urinary tract infection, although revised regimens continue to merit study (10). Against this background, we tested eravacycline in vitro against circulating carbapenem-resistant Enterobacteriaceae and A. baumannii isolates from the United Kingdom and sought to define the interrelationship between eravacycline and tigecycline MICs.…”