Review
Carbapenem resistance in Enterobacteriaceae: here is the storm!

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The current worldwide emergence of resistance to the powerful antibiotic carbapenem in Enterobacteriaceae constitutes an important growing public health threat. Sporadic outbreaks or endemic situations with enterobacterial isolates not susceptible to carbapenems are now reported not only in hospital settings but also in the community. Acquired class A (KPC), class B (IMP, VIM, NDM), or class D (OXA-48, OXA-181) carbapenemases, are the most important determinants sustaining resistance to carbapenems. The corresponding genes are mostly plasmid-located and associated with various mobile genetic structures (insertion sequences, integrons, transposons), further enhancing their spread. This review summarizes the current knowledge on carbapenem resistance in Enterobacteriaceae, including activity, distribution, clinical impact, and possible novel antibiotic pathways.

Section snippets

Carbapenem resistance: a worsening situation

Enterobacteriaceae are rod-shaped, Gram-negative bacteria that are normal inhabitants of the intestinal flora and among the most common human pathogens, causing infections that range from cystitis to pyelonephritis, septicemia, pneumonia, peritonitis, meningitis, and device-associated infections. They are the most common source of both community- and hospital-acquired infections, with Escherichia coli being by far the most important pathogen for humans. Enterobacteriaceae spread easily between

Non-carbapenemase mediated carbapenem resistance in Enterobacteriaceae

The outer membrane of Gram-negative bacteria forms a hydrophobic barrier that protects the cell against external agents such as heavy metals and detergents. This membrane contains specific proteins, called porins, that form hydrophilic channels to allow the selective uptake of essential nutrients and other compounds, including antibiotics (Figure 1) 5, 6. The primary porins in Enterobacteriaceae involved in taking up antibiotics belong to the OmpF or OmpC families [6]. Thus, any changes in the

Carbapenemase-mediated carbapenem resistance in Enterobacteriaceae

The first carbapenemases identified in Enterobacteriaceae were SME-1 in London in 1982 [22] and IMI-1 in the USA in 1984 [23]. The first carbapenemase reported as a serine carbapenemase in the primary literature was the chromosomally-encoded NmcA from an Enterobacter cloacae clinical isolate [24]. Since then, carbapenem-resistant Enterobacteriaceae have been reported worldwide, primarily as a consequence of widespread acquisition of carbapenemase genes [25]. A large variety of carbapenemases

The Ambler class A carbapenemases

Three major types of class A carbapenemases are known, corresponding to the NmcA/IMI, SME, and KPC enzymes [26]. All three enzyme types hydrolyze a broad variety of β-lactams including penicillins, cephalosporins, carbapenems, and aztreonam (Table 1) by a hydrolytic mechanism involving an active site serine at position 70 (Ambler numbering of class A β-lactamases) [27]. Their hydrolytic activity is inhibited in vitro by clavulanic acid and tazobactam (Table 1). A fourth type of enzyme

The class B metallo β-lactamases (MBL)

Class B β-lactamases exhibit a broad spectrum of hydrolytic activity including all penicillins, cephalosporins, and carbapenems, with the exception of monobactam aztreonam (Table 1). Their activity is not inhibited by commercially available β-lactamase inhibitors (clavulanic acid, tazobactam, or sulbactam). Hydrolysis is dependent on the interaction of the β-lactam with Zn2+ ion(s) in the active site, explaining the inhibition of their activity by EDTA, a chelator of divalent cations (Table 1).

The class D carbapenemases of the OXA-48 type

Class D β-lactamases, also named OXAs for ‘oxacillinases’, include 232 enzymes, with a few variants possessing some carbapenemase activity. With the exception of one variant (OXA-163) that has a very weak carbapenemase activity, carbapenem-hydrolyzing class D β-lactamases (CHDLs) do not hydrolyze expanded-spectrum cephalosporins (Table 1). Overall, the carbapenemase activity of CHDLs is weak and is not inhibited by either clavulanic acid or by EDTA, but is inhibited by NaCl (Table 1).

Although

Concluding remarks

As highlighted in this review, resistance to carbapenems in Enterobacteriaceae may result either from expression of carbapenemases or by combined effects of β-lactamases with no (or very weak) intrinsic carbapenemase activity (i.e. ESBLs or cephalosporinases) and decreased outer membrane permeability.

The real prevalence of carbapenemase-producing bacterial strains remains unknown because many countries worldwide do not report rates of antibiotic susceptibility. Therefore, the worldwide spread

Acknowledgments

This work was funded by grants from the UMRS 914 (INSERM and Université Paris XI).

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