Third-Generation Cephalosporin Resistance in Enterobacter Species: Health and Economic Outcomes
Third-Generation Cephalosporin Resistance in Enterobacter Species: Health and Economic Outcomes
Abstract & Commentary
Synopsis: The emergence of resistance to third-generation cephalosporins by Enterobacter spp. is a common phenomenon in infected patients treated with these agents and is associated with adverse outcomes.
Source: Cosgrove SE, et al. Arch Intern Med. 2002;162:185-190.
Emergence of cephalosporin resistance by Enterobacter species during therapy is a well-recognized phenomenon. Cosgrove and colleagues examined a cohort of 477 patients with initial cultures yielding Enterobacter species susceptible to third-generation cephalosporins by microbroth dilution assay. In 46 of these patients (10%), subsequent cultures yielded an Enterobacter isolate resistant to third-generation cephalosporins. These case patients were matched to 113 control patients by anatomic site of isolation and duration of prior hospitalization. The outcomes of interest were mortality, length of hospital stay, and hospital charges.
The crude mortality rate among cases was 26% compared with 13% among controls (P = .06). The median hospital stay for cases was 29.5 days and 19 days for controls (P < .001). Median hospital charge for cases was $79,323, compared with $40,406 for controls (P < .001). After adjusting for confounding by multivariable analysis, the emergence of resistance had a significant association with mortality (relative risk, 5.02; P = .01). Hospital stay for cases was significantly prolonged (1.5 fold; P < .001) and hospital charges were significantly higher (1.5 fold; P < .001). The increased length of stay attributable to emergence of resistance was 9 days, and the attributable increase in hospital charges was $29,379.
Comment by Robert Muder, MD
Beta-lactam resistance by Enterobacter species is typically mediated by beta-lactamases of the AmpC type.1 These enzymes are chromosomally encoded and are widely present in Enterobacter spp., Serratia spp., Citrobacter freundii, and Morganella morganii. While they are normally produced in minute quantities, increased production can be induced by exposure to some beta-lactam antibiotics, including third-generation cephalosporins. High levels of enzyme production after such exposure lead to dramatic increases in MIC, a marked inoculum effect, and in vitro resistance of previously susceptible strains. More important, however, is the selection of preexisting mutants, usually present at a frequency of approximately 10-7, with mutations in their AmpD regulatory genes causing constitutive high level production of the AmpC enzyme. These strains are typically resistant to third-generation cephalosporins, extended-spectrum penicillins, and aztreonam. AmpC beta-lactamases are not subject to inhibition by beta-lactamase inhibitors such as clavulanate, sulbactam, or tazobactam. AmpC producing Enterobacteriaceae are nearly always susceptible to imipenem and meropenem.
The clinical importance of selection of mutant clones consistantly expressing large amounts of the AmpC enzyme of resistance by exposure to beta-lactamase was demonstrated by Chow and colleagues in a study of Enterobacter bacteremia.2 Of those patients treated with a third-generation cephalosporin, 19% had subsequent isolation of a third-generation cephalosporin resistant to Entertobacter. In contrast, only 1% of patients treated with aminoglycosides had subsequent isolation of an aminoglycoside-resistant Enterobacter. Emergence of resistance was not encountered among patients receiving other classes of beta-lactam antibiotics.
The study by Cosgrove et al shows convincingly that emergence of in vitro cephalosporin resistance is associated with adverse clinical outcomes and increased costs. They did not report details of antimicrobial therapy, and thus did not relate emergence of resistance or outcome to use of cephalosporins. This might have provided additional useful information had they done so.
However, based on the data available from this report and Chow et al’s prior study, it is clear that third-generation cephalosporins are poor choices in the treatment of serious infections due to Enterobacter spp., and by extension, Serratia spp. If they are used at all, a second agent to which the isolate is susceptible, such as a quinolone or aminoglycoside, should be added.
Finally, indiscriminate use of third-generation cephalosporins increases the likelihood of emergence of resistant strains. Although originally chromosomally mediated, AmpC beta-lactamases are now encoded on a number of plasmids that can be transferred to species that don’t normally carry these enzymes, such as E coli and Klebsiella. Thus, the widespread dissemination of these enzymes, with major adverse clinical and economic consequences, is a real possibility.
References
1. Livermore DM. J Antimicrob Chemother. 1998;27(Suppl 1):S100-S106.
2. Chow JW, et al. Ann Intern Med. 1991;115:585-590.
Dr. Muder, MD, Hospital Epidemiologist, Pittsburgh VA Medical Center, Pittsburgh, is Associate Editor of Infectious Disease Alert.
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