In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii

https://doi.org/10.1016/j.ijantimicag.2017.06.022Get rights and content

Highlights

  • Eravacycline is one of the few novel antimicrobials with activity against Acinetobacter baumannii.

  • Eravacycline has activity superior to the comparators of the tetracycline class.

  • The activity of eravacycline was not impacted by carbapenem resistance determinant or clonal type.

Abstract

The activity of eravacycline was compared with that of anti-Acinetobacter reference antimicrobials against carbapenem non-susceptible Acinetobacter baumannii isolates associated with an acquired OXA or up-regulation of the intrinsic OXA-51-like enzyme. Antimicrobial susceptibility testing was performed by broth microdilution of 286 non–duplicate, carbapenem non-susceptible A. baumannii isolates to eravacycline, amikacin colistin, doxycycline, imipenem, levofloxacin, meropenem, minocycline, sulbactam, tigecycline and tobramycin.

Eravacycline showed greater activity than the comparators of the tetracycline class, levofloxacin, amikacin, tobramycin and colistin. The eravacycline MIC50/90 values were 0.5/1 mg/L and those for tigecycline, minocycline and doxycycline were 1/2, 4/8 and 32/ ≥ 64 mg/L, respectively. In conclusion, eravacycline was the most potent antibiotic of those tested against A. baumannii, including isolates that were resistant to sulbactam, imipenem/meropenem, levofloxacin and amikacin/tobramycin. Eravacycline has the potential to become a useful addition to the limited armamentarium of drugs that can be used to treat this problem pathogen.

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.

Section snippets

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

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1

Present address: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany.

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