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Drugs. 2016 Apr;76(5):567-88. doi: 10.1007/s40265-016-0545-8.

Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent.

Author information

1
Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca.
2
Department of Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca.
3
Department of Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada. ggzhanel@pcs.mb.ca.
4
Faculty of Science, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
5
Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
6
Department of Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada.
7
Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, Manitoba, Canada.
8
Department of Clinical Microbiology, Saint Boniface Hospital, Winnipeg, Manitoba, Canada.
9
Department of Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada.
10
Department of Pharmacy, Health Sciences Centre, Winnipeg, Manitoba, Canada.

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.

PMID:
26863149
DOI:
10.1007/s40265-016-0545-8
[Indexed for MEDLINE]

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