In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii
Introduction
Multidrug-resistance in Acinetobacter baumannii is a growing threat that leaves few therapeutic options [1]. In the past decade, there has been a dramatic increase in carbapenem–resistant A. baumannii mediated mainly through the action of intrinsic and acquired OXA–type carbapenem hydrolysing class D beta–lactamases (CHDL) and, less frequently, metallo-beta–lactamases [2], [3]. Drug efflux, particularly through the resistance-nodulation-division (RND) type efflux pumps, does not significantly affect carbapenems; however, it is involved in resistance to fluoroquinolones, tetracyclines, aminoglycosides and macrolides, and these efflux pumps have been shown to be overexpressed during antimicrobial therapy [4]. Colistin is often the only antimicrobial to retain activity, but even with this drug resistance has developed [5].
Eravacycline is a novel, fully-synthetic fluorocycline antibiotic that is structurally similar to tigecycline and, like other tetracyclines, inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit [6]. It differs from tigecycline by two modifications within the D–ring structure, i.e. a fluorine atom replacing the dimethylamine moiety at C-7 and a pyrrolidinoacetamido group replacing the 2-tertiary-butyl glycylamido at C-9. Eravacycline has demonstrated antimicrobial activity against a wide range of Gram-positive, Gram–negative, and anaerobic bacteria, including multidrug-resistant Enterobacteriaceae and A. baumannii, as well as strains with acquired tetracycline efflux determinants and ribosomal protection [7], [8].
In this study, the activity of eravacycline was compared with anti-Acinetobacter reference drugs, including beta-lactams, tetracyclines, fluoroquinolones, aminoglycosides and colistin, against defined multidrug-resistant, carbapenem non-susceptible A. baumannii isolates that possessed an acquired OXA or a metallo-beta–lactamase, or up-regulated their intrinsic OXA-51-like enzyme.
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Materials and methods
Antimicrobial susceptibility testing was performed by broth microdilution in cation-adjusted Mueller-Hinton broth according to Clinical Laboratory Standard Institute (CLSI) guidelines [9]. Microtitre plates containing dehydrated antibacterial agents were purchased from Merlin Diagnostica (Bornheim, Germany).
Two hundred and eighty-six non-duplicate, carbapenem non-susceptible (as previously determined by Etest [bioMérieux, Nürtingen, Germany]), A. baumannii isolates were tested against
Results
MIC distribution, MIC50 and MIC90 values and percent susceptibility rates are summarised in Table 1. All isolates were non-susceptible to imipenem and/or meropenem and the majority of isolates (>65%) were resistant to aminoglycosides and levofloxacin, and had high sulbactam MICs. Resistance to colistin was substantial at 13.3%.
The eravacycline MIC50/90 values were 0.5/1 mg/L. Eravacycline showed greater activity than the tetracycline comparators, tigecycline, minocycline and doxycycline.
Discussion
There is now an ever-greater need for the development of new drugs that show anti–Acinetobacter activity. Outbreaks caused by multidrug-resistant A. baumannii have been reported in all parts of the world with ever increasing frequency [12], [13], [14]. In particular, it is the development of carbapenem-resistance that has left clinicians with few viable alternatives [15]. Colistin is often the only antimicrobial showing measurable activity, but because of toxicity and low serum concentrations,
Declarations
Funding: This work was supported in part by Tetraphase Pharmaceuticals, Inc., Watertown, MA, USA.
Competing interests: H.S. has received grants or research support from the German Centre for Infection Research (DZIF), the German Research Foundation, Accelerate, and Novartis, has been a consultant for Astellas, Basilea, Cubist, Durata, Roche Pharma, and Tetraphase, and has received payments for lectures from Astellas, Cubist, Gilead, MSD, and Infectopharm. J.A.S. is a former employee of
References (20)
- et al.
Carbapenem resistance in Acinetobacter baumannii: mechanisms and epidemiology
Clin Microbiol Infect
(2006) - et al.
Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp
Int J Antimicrob Agents
(2006) - et al.
In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with avibactam against European Gram-negative and Gram-positive clinical isolates
Int J Antimicrob Agents
(2015) - et al.
Acinetobacter baumannii: emergence of a successful pathogen
Clin Microbiol Rev
(2008) - et al.
Global spread of carbapenem-resistant Acinetobacter baumannii
J Antimicrob Chemother
(2010) - et al.
Efflux-mediated antibiotic resistance in Acinetobacter spp
Antimicrob Agents Chemother
(2011) - et al.
Colistin and polymyxin B dosage regimens against Acinetobacter baumannii: differences in activity and the emergence of resistance
Antimicrob Agents Chemother
(2016) - et al.
Review of eravacycline, a novel fluorocycline antibacterial agent
Drugs
(2016) - et al.
In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii
Antimicrob Agents Chemother
(2016) - et al.
Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City
Antimicrob Agents Chemother
(2015)
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Present address: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany.