Current epidemiology and growing resistance of gram-negative pathogens

Abstract

In the 1980s, gram-negative pathogens appeared to have been beaten by oxyimino-cephalosporins, carbapenems, and fluoroquinolones. Yet these pathogens have fought back, aided by their membrane organization, which promotes the exclusion and efflux of antibiotics, and by a remarkable propensity to recruit, transfer, and modify the expression of resistance genes, including those for extended-spectrum β-lactamases (ESBLs), carbapenemases, aminoglycoside-blocking 16S rRNA methylases, and even a quinolone-modifying variant of an aminoglycoside-modifying enzyme. Gram-negative isolates--both fermenters and non-fermenters--susceptible only to colistin and, more variably, fosfomycin and tigecycline, are encountered with increasing frequency, including in Korea. Some ESBLs and carbapenemases have become associated with strains that have great epidemic potential, spreading across countries and continents; examples include Escherichia coli sequence type (ST)131 with CTX-M-15 ESBL and Klebsiella pneumoniae ST258 with KPC carbapenemases. Both of these high-risk lineages have reached Korea. In other cases, notably New Delhi Metallo carbapenemase, the relevant gene is carried by promiscuous plasmids that readily transfer among strains and species. Unless antibiotic stewardship is reinforced, microbiological diagnosis accelerated, and antibiotic development reinvigorated, there is a real prospect that the antibiotic revolution of the 20th century will crumble.

Keywords: Acinetobacter; Carbapenemase; Enterobacteriaceae; Pseudomonas; β-lactamase.

Figure 1

Outer layers of the Gram-negative cell. To reach its target, the antibiotic must diffuse across the outer membrane, normally via porins, which form water-filled channels and exclude large or hydrophobic molecules. The drug must then evade periplasmic β-lactamases and efflux pumps; depending on its target, it may also need to cross the cytoplasmic membrane, often by energy-dependent uptake.

Figure 2

International spread of Escherichia coli ST131 [25,40] . This strain has played a major role in the dissemination of CTX-M-15 extended-spectrum β-lactamase (ESBL), but occasionally hosts other types. It occurs in Korea, where CTX-M-14 ESBL (not linked to a particular clone) is also widespread [48].

Figure 3

International dissemination of ST258 Klebsiella pneumoniae with KPC carbapenemases [68]. This lineage occurs internationally and has been reported in Korea [85].

Figure 4

Spread of OXA-48 and related carbapenemases. Until 2007-2008, the OXA-48 enzyme was confined to Turkey. Carried by 50- and 70-kb plasmids, it has since spread to North Africa, the Middle East, and, increasingly Europe. A related enzyme, OXA-181, is circulating in India, but is rarer than the NDM-1 metallo-carbapenemase. These enzymes have not yet reached Korea.

Figure 5

Reported outbreaks due to metallo-β-lactamase-producing Pseudomonas aeruginosa. Most carbapenem resistance in P. aeruginosa, including in Korea, is due to porin loss, but carbapenemase producers occur and may be strongly persistent in some hospitals. Korea has a particular concern regarding a nationally distributed strain that harbors the IMP-6 enzyme [97].