Abstract & Commentary
Resistant infections cost $30,000 more a case
Synopsis: Emergence of antibiotic resistance in Enterobacter species results in increased mortality, hospital stay, and spiraling hospital charges.
Source: Cosgrove SE, et al. Health and economic outcomes of the emergence of third-generation cephalosporin resistance in Enterobacter species. Arch Intern Med 2002; 162:185-190.
Abstract: Emergence of cephalosporin-resistance among Enterobacter species during therapy is a well-recognized phenomenon. Cosgrove and colleagues examined a cohort of 477 patients with initial clinical cultures yielding Enterobacter species susceptible to third-generation cephalosporins by microbroth dilution assay. In 46 patients (10%), subsequent cultures yielded an Enterobacter isolate resistant to this class of beta-lactam antibiotics. 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. The median hospital stay for cases was 29.5 days and 19 days for controls. Median hospital charge for cases was $79,323, compared with $40,406 for controls. After adjusting for confounding by multivariable analysis, emergence of resistance had a significant association with mortality. Hospital stay for cases was significantly prolonged (1.5-fold), and hospital charges were significantly greater (1.5-fold). The increased length of stay attributable to emergence of resistance was nine days, and the attributable increase in hospital charges was $29,379.
Comment by Robert Muder, MD, hospital epidemiologist, Pittsburgh VA Medical Center.
Cephalosporin resistance in Enterobacter species is typically mediated by beta-lactamases of the AmpC type.1 These enzymes are chromosomally encoded and widely present in Enterobacter spp., Serratia spp., Citrobacter freundii, and Morganella morganii. They are produced in minute quantities, but production can be increased by exposure to beta-lactam antibiotics, including third generation of cephalosporins.
High levels of enzyme production after such exposure lead to dramatic increases in MIC and in vitro resistance of previously susceptible strains. More important is the selection of depressed mutants, reported to be present in Enterobacter spp. at a frequency of approximately 10-7. These strains are 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 induction of resistance by exposure to beta-lactamase was demonstrated by Chow and colleagues2 in a study of Enterobacter bacteremia.
Of those patients treated with a third-generation cephalosporin, 19% had subsequent isolation of a third-generation cephalosporin-resistant Enterobacter. 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 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. However, based on the data available from this report and Chow’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, but this may not always prevent the selection of resistant mutants. 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. Beta-lactamase-mediated resistance and opportunities for its control. J Antimicrob Chemother 1998; 27(Suppl 1):S100-106.
2. Chow JW, et al. Enterobacter bacteremia: Clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 1991; 115:585-590.
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