Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates

Abstract

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.

What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline

“…The present results, along with previously published data for aminoglycosides [7], underscore the considerable resistance of many carbapenemase-producers.…”

“…It represents a diversity of carbapenem resistance types and host species, including organisms with carbapenemases and with combinations of ESBL or AmpC and impermeability, but does not comprise consecutive producer isolates, nor was it matched to the (everchanging) relative prevalence of different resistance types. Transformants and transconjugants of Escherichia coli DH5 and J62-1 with carbapenemase-encoding plasmids were prepared as described previously [7].…”

“…Most carbapenemase-producers are almost completely resistant to -lactam antibiotics except that: (i) those with OXA-48 alone remain susceptible to several oxyimino-cephalosporins [5]; and (ii) those with metallo-carbapenemases alone, lacking AmpC or extended-spectrum -lactamases (ESBLs), remain susceptible to aztreonam [6]. Aminoglycoside resistance is extensive but more variable: strains with NDM-1 enzyme mostly co-produce an ArmA or RmtC 16S rRNA methylase, conferring broad resistance, whereas those with other carbapenemases have variable arrays of modifying enzymes, with isepamicin often spared and with gentamicin retaining activity against the internationally widespread KPC + sequence type (ST) 258 Klebsiella pneumoniae strain [7].…”

Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

“…Indeed, the target AUC from 0 to 24 h (AUC 0 -24 ) associated with plazomicin doses recommended in a phase 3 study of serious infections due to carbapenem-resistant Enterobacteriaceae was 262 g · h/ml, and mean maximum concentration of drug in serum (C max ) values ranged from 62 to 107 g/ml (Achaogen data on file). Our findings are consistent with previous studies that showed plazomicin to be highly active against Enterobacteriaceae that do not carry 16S rRNA methyltransferase (8,10). It is important to acknowledge that we did not test NDM-1-producing K. pneumoniae strains, which have been reported to harbor 16S rRNA methyltransferase.…”

“…Plazomicin, a derivative of sisomicin, is a next-generation aminoglycoside that is in clinical development for the treatment of serious infections due to carbapenem-resistant Enterobacteriaceae. It has broad-spectrum in vitro activity against Klebsiella pneumoniae and other Gram-negative bacteria, including carbapenem-resistant strains (8)(9)(10)(11)(12). The agent has side-chain substituents that shield it from the action of most AMEs.…”