Resistance in Gram-Negative Bacteria: Enterobacteriaceae

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Abstract

The emergence and spread of resistance in Enterobacteriaceae are complicating the treatment of serious nosocomial infections and threatening to create species resistant to all currently available agents. Approximately 20% of Klebsiella pneumoniae infections and 31% of Enterobacter spp infections in intensive care units in the United States now involve strains not susceptible to third-generation cephalosporins. Such resistance in K pneumoniae to third-generation cephalosporins is typically caused by the acquisition of plasmids containing genes that encode for extended-spectrum β-lactamases (ESBLs), and these plasmids often carry other resistance genes as well. ESBL-producing K pneumoniae and Escherichia coli are now relatively common in healthcare settings and often exhibit multidrug resistance. ESBL-producing Enterobacteriaceae have now emerged in the community as well. Salmonella and other Enterobacteriaceae that cause gastroenteritis may also be ESBL producers, which is of relevance when children require treatment for invasive infections. Resistance of Enterobacter spp to third-generation cephalosporins is most typically caused by overproduction of AmpC β-lactamases, and treatment with third-generation cephalosporins may select for AmpC-overproducing mutants. Some Enterobacter cloacae strains are now ESBL and AmpC producers, conferring resistance to both third- and fourth-generation cephalosporins. Quinolone resistance in Enterobacteriaceae is usually the result of chromosomal mutations leading to alterations in target enzymes or drug accumulation. More recently, however, plasmid-mediated quinolone resistance has been reported in K pneumoniae and E coli, associated with acquisition of the qnr gene. The vast majority of Enterobacteriaceae, including ESBL producers, remain susceptible to carbapenems, and these agents are considered preferred empiric therapy for serious Enterobacteriaceae infections. Carbapenem resistance, although rare, appears to be increasing. Particularly troublesome is the emergence of KPC-type carbapenemases in New York City. Better antibiotic stewardship and infection control are needed to prevent further spread of ESBLs and other forms of resistance in Enterobacteriaceae throughout the world.

Section snippets

Overview of resistance trends and outcomes

Third-generation cephalosporins were originally developed as β-lactams able to overcome resistance caused by common β-lactamases. When first introduced, third-generation agents like ceftriaxone, cefotaxime, and ceftazidime were stable in the presence of common β-lactamases. However, within a few years, hospital-acquired gram-negative bacilli like Klebsiella pneumoniae and others began producing mutated versions of these β-lactamases that made them resistant to third-generation cephalosporins

General Issues and Nomenclature

Infections caused by ESBL-producing Enterobacteriaceae are serious concerns in the current environment. Many ESBLs represent enzymes that have evolved from class A β-lactamases—namely, TEM-1, TEM-2, and SHV-1, which are frequently expressed in gram-negative bacteria and which confer resistance to ampicillin, amoxicillin, and other penicillins, as well as to early- but not later-generation cephalosporins. ESBLs arose when mutations of the genes encoding TEM-1, TEM-2, or SHV-1 gave rise to new

Antibiotic resistance in Enterobacter species

Enterobacter spp are significant causes of nosocomial infection and are intrinsically resistant to aminopenicillins, cefazolin, and cefoxitin due to production of constitutive chromosomal AmpC β-lactamases.42 Moreover, β-lactam exposure is capable of inducing expression of AmpC β-lactamases in Enterobacter spp—with consequent resistance to third-generation cephalosporins—and mutations may result in permanent hyperproduction and persistent resistance. Treatment of Enterobacter infections with

Quinolone Resistance

Quinolones are used widely for the treatment of serious E coli UTIs and may also be used to treat other infections caused by other members of the Enterobacteriaceae family.52, 53 Hence, quinolone resistance in Enterobacteriaceae may lead to treatment failures and is a significant concern, as is the recent emergence of plasmid-mediated resistance to quinolones. According to the 2004 NNIS report, means of 7.3% and 8.2% of E coli isolates from US patients in both ICUs and non-ICU areas of

Summary

Enterobacteriaceae are significant causes of serious infections, and many of the most important members of this family are becoming increasingly resistant to currently available antibiotics. This is a troubling trend, and one that requires vigilance and intensified measures to control the further spread of resistance by these important gram-negative pathogens. Although improvements in antibiotic stewardship and infection control are discussed in greater detail by others in this supplement, it

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