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Eravacycline
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Solomkin et al. (2014) reported the results of a phase II, randomized, double-blind, double-dummy clin-ical study evaluating two dosage regimens of eravacycline and one of ertapenem for the treatment of community-acquired complicated intra-abdominal infections. One hundred forty three adult hospitalized patients with the diagnosis of complicated intra-abdominal infection requiring percutaneous drainage and/or surgery were randomized (2:2:1) to one of three antibiotic study regimens: (1) eravacycline 1.5 mg/kg intravenously infused over 60 minutes every 24 hours (56 patients), (2) eravacycline 1.0 mg/kg intravenously infused over 60 minutes every 12 hours (57 patients), and (3) ertapenem 1 g intravenously infused over 30 minutes every 24 hours (30 patients). The duration of antibiotic therapy was between 4 and 14 days. The primary efficacy end point for this study was positive clinical response at the test-of-cure (TOC) visit (at 10 to 14 days after the last dose of the study drug) in the microbiologically evaluable (ME) population. Overall, patients were predominantly male (72.0%), Caucasian (68.5%), had a mean age of 41.8 years, a mean APACHE II score of 6.9, and 54% of the modified intent-to-treat (MITT) population had complicated appendicitis as their primary intra-abdominal infection. Clinical success rates in the ME population at the TOC visit were 92.9% in 42 patients receiving eravacycline 1.5 mg/kg every 24 hours, 100% in 41 patients receiving eravacycline 1.0 mg/kg every 12 hours, and 92.3% in 26 patients receiving ertapenem. The respective microbiological response rates in the ME population at the end-of-therapy (EOT) were: 95.2%, 100%, and 96.2%; at the TOC visit: 92.9%, 100%, and 92.3%; and at the follow-up visit, at 28 to 42 days after the last dose of the study drug: 88.1%, 97.6%, and 88.5%. The median times to clinical response and percentages of patients in the MITT population who achieved defervescence of body temperature were 15.7 hours and 96.4%, for patients receiving eravacycline 1.0 mg/kg every 12 hours; 31.3 hours and 100%, for patients receiving ertapenem; and 60.0 hours and 88.9%, for patients receiving eravacycline 1.5 mg/kg every 24 hours. The most common TEAEs were nausea (1.9% for eravacycline 1.5 mg/kg every 24 hours; 10.7% for eravacycline 1.0 mg/kg every 12 hours; and 6.7% for ertapenem) and vomiting (5.7% for eravacycline 1.5 mg/kg every 24 hours; 1.8% for eravacycline 1.0 mg/kg every 12 hours; and 0% for ertapenem). This study is lending clinical support and study procedures to the pivotal phase III trial (IGNITE 1) of eravacycline for the treatment of complicated intra-abdominal infections.
Eravacycline for the treatment of complicated intra-abdominal infections
Published in Expert Review of Anti-infective Therapy, 2019
Philippe Montravers, Nathalie Zappella, Alexy Tran-Dinh
Despite a limited number of publications, the microbiological and pharmacokinetic characteristics of eravacycline suggest that it could be a useful and innovative agent for the treatment of cIAIs. Eravacycline has interesting documented serum and tissue levels and pharmacokinetic characteristics. The absence of dose adjustment in renally impaired and obese patients also constitutes an advantage. Microbiological analyses have reported a broad spectrum of activity against most Gram-positive and Gram-negative organisms, including Enterobacteriaceae and anaerobes cultured from cIAIs. In addition, eravacycline is also active against a large number of MDR microorganisms cultured from IAI specimens, including Gram-positive cocci, and ESBL- and carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii. Clinical efficacy has been demonstrated in two phase 3 trials showing non-inferiority compared to ertapenem and meropenem. Eravacycline has been shown to be highly effective even in MDR Gram-negative microorganisms. Eravacycline is well tolerated, with adverse events mainly limited to gastrointestinal effects. The cost-effectiveness and clinical performance of this agent have yet to be confirmed on larger cohorts and in more severe cases. However, its interesting microbiological and pharmacokinetic characteristics suggest that eravacycline may be particularly well suited for treatment of cIAIs. The characteristics of eravacycline could make it an alternative therapy to other broad-spectrum agents and it could play an important role as a beta-lactam-sparing agent.
The antibiotic arms race: current and emerging therapy for Klebsiella pneumoniae carbapenemase (KPC) - producing bacteria
Published in Expert Opinion on Pharmacotherapy, 2018
Michael E. Plazak, Pranita D. Tamma, Emily L. Heil
Eravacycline is a novel, synthetic tetracycline analog that evades the primary mechanisms of tetracycline resistance (drug efflux and ribosomal protection proteins) and has activity against KPC-producing Enterobacteriaceae [89]. Similar to the traditional tetracyclines, eravacycline binds to the 30S ribosomal subunit, allowing for termination of chain elongation, resulting in cessation of bacterial protein synthesis and bactericidal activity against certain bacterial populations. Interestingly, eravacycline achieves greater plasma concentrations when compared to tigecycline, potentially negating one of the obstacles of tigecycline therapy [89]. Further clinical trial data is needed to translate these pharmacokinetic parameters into improved clinical outcomes. The in vitro data of eravacycline suggests potent activity against CRE isolates. A study conducted by Zhang and colleagues in 110 clinical isolates of CRE demonstrated activity of eravacycline against KPC, NDM, and VIM CPE. The majority of the isolates tested displayed MIC values for eravacycline that were often twofold lower than those of tigecycline [90]. To date, eravacycline has demonstrated activity in complicated intra-abdominal infections in the IGNITE 1 trial. However, only one patient with a confirmed KPC-producing Enterobacteriaceae was included [91].
Antimicrobial resistance and treatment: an unmet clinical safety need
Published in Expert Opinion on Drug Safety, 2018
Matteo Bassetti, Alessandro Russo, Alessia Carnelutti, Alessandro La Rosa, Elda Righi
Eravacycline is a novel fluorocycline similar to tigecycline but not affected by resistance mechanisms that cause tetracycline resistance, such as efflux pumps and ribosomal protection proteins [109]. Eravacycline is characterized by a broad-spectrum activity against both Gram-positive and Gram-negative bacteria, including MRSA, vancomycin-resistant Enterococci, multidrug resistant Enterobacteriacae (e.g. ESBL, KPC, and OXA) and A. baumanii [110]. Eravacycline is in Phase 3 of clinical development for cIAI and cUTI and showed efficacy of both intravenous and oral formulations, representing an attractive option for step-down therapy in patients with infections due to MDR Gram-negative bacteria [111]. A randomized, double-blind, multicenter study demonstrated eravacycline noninferiority compared to ertapenem in cIAI [112]. A Phase 1 study in 20 healthy adult volunteers showed that eravacycline was well tolerated, with no serious adverse events and no treatment discontinuations [113]. In the cIAI trial, eravacycline demonstrated an overall favorable profile. Compared to ertapenem, patients in the eravacycline arm had higher number of episodes of nausea and phlebitis (8.1% vs. 0.7% and 3% vs. 0.4%, respectively). The number of patients who experienced treatment-emergent adverse events such as vomiting, anemia, pyrexia, and diarrhea as well as the number of SAE was similar in the two groups (n = 13) [112].