Activity of ACHN-490 and other aminoglycosides vs. carbapenem-resistant Enterobacteriaceae isolated in the United Kingdom

Abstract number: O377

Mushtaq S., Warner M., Zhang J-C., Maharjan S., Doumith M., Woodford N., Livermore D.

Objectives: ACHN-490 is a novel sisomicin derivative stable to nearly all aminoglycoside-modifying enzymes. We compared its activity with that of other aminoglycosides vs. clinical Enterobacteriaceae representing the diversity of carbapenem resistance types now emerging in the UK. Most were multiresistant.

Methods: The 81 isolates comprised those with the Class A carbapenemases KPC (n = 10) or SME-1 (1); Class B enzymes, IMP (13), VIM (5) and NDM (17) and the Class D enzyme, OXA-48 (19) or with combinations of impermeability plus an AmpC or ESBL (16). They included 52 Klebsiella spp., 18 Enterobacter spp., 6 E. coli and 5 others. Carbapenemase genes were identified by PCR and sequencing as were those encoding the 16S rRNA methylases ArmA and RmtA-C. MICs were measured by CLSI agar dilution.

Results: ACHN-490 was active against all 64 non-NDM+ isolates at <2 mg/L, with 95% of MICs between 0.06 and 0.5 mg/L. Isepamicin was active at 8 mg/L against 62 of these 64 whereas 35%, 61% and 19% were resistant to gentamicin at 4 mg/L, tobramycin at 4 mg/L and amikacin at 16 mg/L, respectively. Among the 17 isolates with the NDM-1 enzyme – many from patients with prior medical contact on the Indian subcontinent – 16 harboured armA or rmtC and were resistant to ACHN-490 and to all other human-use aminoglycosides at >32 mg/L; armA and rmtC were absent from the sole ACHN-490-susceptible NDM-1-positive strain. Apramycin, a veterinary analogue, was active at 4–8 mg/L against (i) control strains, (ii) the NDM-1-positive isolates with armA or rmtC and (iii) all other strains except a Serratia with SME-1 enzyme (MIC  > 128 mg/L).

Conclusion: ACHN-490 had potent activity vs. all the carbapenem-resistant isolates screened except those with combinations of NDM-1 enzyme and ArmA or RmtC rRNA methylases; the international prevalence of these enzymes needs urgent surveillance. Evasion of ArmA and RmtC by apramycin is striking and may facilitate future human drug development.

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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