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Abstract & Commentary
Synopsis: Failure of antibiotic therapy may result from lack of
laboratory detection of ESBL-producing Enterobacteriaceae.
Source: Paterson DL, et al. Outcome of cephalosporin treatment for
serious infections due to apparently susceptible organisms producing extended-spectrum B-lactamases: Implications for the clinical microbiology laboratory. J Clin Microbiol. 2001;39:2206-2212.
In the course of a multicenter observational study of Klebsiella pneumoniae bacteremia, Paterson and colleagues identified 85 organisms that produced extended-spectrum b-lactamases (ESBLs). Standard antibiotic susceptibility testing, however, had often failed to identify these organisms. The Table shows the actual proportion of isolates susceptible, intermediate, and resistant to cephalosporins (see Table).
|Table-Reported In Vitro Susceptibilities of
ESBL-Producing Klebsiella Isolates
Six patients with ESBL-producing strains were treated with a cephalosporin active according to routine in vitro testing (MIC £ 8 µg/mL). Two of these patients died of infection, and a third had clinical failure requiring a switch to meropenem. Three additional patients were treated with a cephalosporin to which the isolate showed intermediate susceptibility (MIC 16-32 µg/mL). One died, and the other 2 required alteration in therapy due to lack of clinical response.
Paterson et al identified a total of 32 patients with serious infections due to ESBL-producing Klebsiella species or Escherichia coli who received cephalosporin treatment, including 10 from centers participating in the bacteremia study and 22 reported in the literature. Eighty-three percent of patients were bacteremic. Fifteen of 28 patients (54%) had clinical failure when treated with a cephalosporin to which the infecting isolate was reported to be susceptible, as did all (4 of 4) of those treated with a cephalosporin to which the isolated showed intermediate susceptibility. Failure rates were significantly correlated with MIC: 100% (6 of 6) when the organism had an MIC of 8 µg/mL, compared with 27% when the MIC was < 2 µg/mL.
Comment by Robert Muder, MD
ESBLs produced by gram-negative bacilli have the ability to hydrolyze third-generation cephalosporins and aztreonam.1 They are distinct from the chromosomal b-lactamases of Enterobacter and Serratia. ESBL-producing organisms are typically, but not universally, susceptible to cephamycins (ceftoxin, cefotetan), which are more resistant to ESBL-mediated hydrolysis than are cephalosporins. Resistance to carbapenems (imipenem, meropenem) is extrememly rare. ESBLs are located on plasmids, most frequently carried by K pneumoniae, although increasingly found in other Enterobacteriaceae as well. The widespread dissemination of ESBL-carrying gram-negative bacilli has paralleled the widespread use of cephalosporins.
A major issue with ESBLs is that susceptibility tests in routine clinical use often incorrectly report these organisms as susceptible to cephalosporins. In an attempt to improve identification of ESBL-producing organisms, the NCCLS recently established new guidelines for suscptibility testing of K pneumoniae, K oxytoca, and E coli.2 These state that clinical laboratories should screen isolates with several third-generation cephalosporins. Isolates that show reduced zone diameter on disk susceptibility testing, or an MIC of > 1 µg/mL on broth dilution testing should undergo confirmatory testing. Isolates that show a greater than 4-fold reduction in MIC to a third-generation cephalosporin when clavulanate is added to the assay are confirmed as ESBL producers. The NCCLS recommends that these isolates be reported as resistant to all cephalosporins and penicillins, as well as to aztreonam.
These new recommendations are likely to lead to a considerable amount of additional work for most microbiology laboratories, as Klebsiella and E coli are extremely common organisms. Laboratories may be slow to adopt them citing cost concerns, and arguing that the data in the literature thus far does not definitively establish a relationship between ESBL production and clinical failure of cephalosporin therapy. I would argue that the data presented by Paterson et al represent fairly convincing observational evidence that cephalosporins are inadequate for treatment of serious infections caused by ESBL-producing organisms. Furthermore, outbreaks of nosocomial infection due to ESBL-producing Enterobactericeae are well documented.3,4 Obviously, the resistant organisms must be identified before control measures can be implemented. Failure to do so may result in the establishment of endemic resistance in a facility, with adverse effects on patient outcomes and antibiotic costs.
1. Paterson DL, Yu VL. Extended-spectrum B-lactamases: A call for improved detection and control. Clin Infect Dis. 1999;29:1419-1422.
2. NCCLS. Performance standards for antimicrobial susceptibility testin. Ninth informational supplement. Wayne, PA: National Committee for Clinical Laboratory Standards, 1999.
3. Rice LB, et al. Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center. Clin Infect Dis. 1996;23:118-124.
4. Lucet JC, et al. Control of a prolonged outbreak of extended-spectrum B-lactamase-producing enterobacteriaceae in a university hospital. Clin Infect Dis. 1999;29:1411-1418.