Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

Katja Becker,Vincent Aranzana-Climent,Sha Cao,Anna Nilsson,Reza Shariatgorji,Klara Haldimann,Björn Platzack,Diarmaid Hughes,Per E Andrén,Erik C Böttger,Lena E Friberg,Sven N Hobbie

doi:10.1016/j.cmi.2020.12.004

Abstract

ObjectivesNovel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections. MethodsThe genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time–kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling. ResultsResistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time–kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of –2 log target attainment for MICs up to 16 μg/mL. ConclusionsThis study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited.

Highlights

We wanted to understand the prevalence of aminoglycoside resistance in a large panel of CRAB isolates
Towards this end we analysed the resistance gene annotations of 5707 clinical A. baumannii isolates deposited in the National Database of Antibiotic Resistant Organisms (NDARO) and classified 5451 isolates (95.5%) as carbapenem-resistant (CRAB) based on carbapenemase annotations in those genomes; 4305 (78.0%) of these CRAB genomes contained at least one aminoglycoside resistance gene
The only colistin resistance gene in the CRAB isolates was mcr-4 found in two genome annotations (0.04%)

Summary

Introduction

CRAB strains are primarily of concern in ventilator-associated bacterial pneumonia (VABP) and bloodstream infections (BSIs) in critical ill patients, and treatment options often rely on combination therapy that includes a last-resort drug, often colistin [3,4]. Drug resistance is prevalent among clinical A. baumannii isolates, and the proportion of CRAB strains has reached a concerning level of up to 90% in some parts of the world [5]. Aminoglycosides used to play an important role in treatment of CRAB, representing a common constituent in drug combination therapy. RMTase-mediated pan-aminoglycoside resistance has been observed with high prevalence in CRAB and other carbapenem-resistant Gram-negative isolates, stressing the serious threat of antimicrobial resistance and the pressing need for new treatment options [9,10]

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