title: Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates.
abstract: BACKGROUND
  the emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. We tested ACHN-490, a sisomicin derivative that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. Methods The isolates variously had KPC (n = 12), SME-1 (n = 1), IMP (n = 13), VIM (n = 5), NDM (n = 17) or OXA-48 (n = 19) carbapenemases, or had combinations of impermeability with AmpC (n = 5) or extended-spectrum β-lactamases (n = 10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar dilution.
  
  
  RESULTS
  ACHN-490 was active at ≤ 2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12-0.5 mg/L; isepamicin was active against 63/65 at ≤ 8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs ≥ 64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behaviour was associated with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4-8 mg/L versus strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC ≥ 256 mg/L).
  
  
  CONCLUSIONS
  ACHN-490 has potent activity versus carbapenem-resistant isolates, except those also harbouring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, HPA Microbiology Services, London, UK. david.livermore@hpa.org.uk
authors.forename: D M
authors.initials: DM
authors.lastname: Livermore
authors.forename: S
authors.initials: S
authors.lastname: Mushtaq
authors.forename: M
authors.initials: M
authors.lastname: Warner
authors.forename: J-C
authors.initials: JC
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Maharjan
authors.forename: M
authors.initials: M
authors.lastname: Doumith
authors.forename: N
authors.initials: N
authors.lastname: Woodford
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012853:Sisomicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000235:genetics; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D012359:tRNA Methyltransferases; D001618:beta-Lactamases; C550938:plazomicin; D012853:Sisomicin