"Stormy waters ahead": global emergence of carbapenemases

Abstract

Carbapenems, once considered the last line of defense against of serious infections with Enterobacteriaceae, are threatened with extinction. The increasing isolation of carbapenem-resistant Gram-negative pathogens is forcing practitioners to rely on uncertain alternatives. As little as 5 years ago, reports of carbapenem resistance in Enterobacteriaceae, common causes of both community and healthcare-associated infections, were sporadic and primarily limited to case reports, tertiary care centers, intensive care units, and outbreak settings. Carbapenem resistance mediated by β-lactamases, or carbapenemases, has become widespread and with the paucity of reliable antimicrobials available or in development, international focus has shifted to early detection and infection control. However, as reports of Klebsiella pneumoniae carbapenemases, New Delhi metallo-β-lactamase-1, and more recently OXA-48 (oxacillinase-48) become more common and with the conveniences of travel, the assumption that infections with highly resistant Gram-negative pathogens are limited to the infirmed and the heavily antibiotic and healthcare exposed are quickly being dispelled. Herein, we provide a status report describing the increasing challenges clinicians are facing and forecast the "stormy waters" ahead.

Keywords: CHDL; KPC; NDM-1; OXA-48; carbapenemases; metallo-β-lactamases.

FIGURE 1

FIGURE 1. Basic genetic construct of select carbapenemase genes. (A) Schematic representation of Tn4401 type of transposon associated with bla_KPC which includes a transposase gene (tnpA), a resolvase gene (tnpR), as well as insertion sequences, ISKpn6 and ISKpn7 (Cuzon et al., 2010). (B) The bla_NDM-1 construct demonstrates ISAba125 insertion sequence(s) upstream of the bla_NDM-1 and a novel bleomycin resistance gene, ble_MBL, downstream (Dortet et al., 2012). (C) bla_OXA-48 is often mapped to a Tn1999 composite transposon where it is bracketed between two copies of the same insertion sequence, IS1999. Downstream of bla_OXA-48 lies a lysR gene which encodes for a regulatory protein (Poirel et al., 2012b).