Extended-Spectrum

Extended-Spectrum b-Lactamases (ESBLs): An Overview
By Seema Singh, SCM (ASM), May 1999

Introduction

Cephalosporins are a group of antibiotics produced by a mold “Acremonium (Cephalosporium) spp” which are resistant to penicillinase and are active against both gram positive and gram negative organisms. They are separated into “generations” based upon their spectrum of activity against bacteria. Table 1 shows the classification of cephalosporins. The introduction of “third generation” cephalosporins has resulted in several resistances that have compromised their clinical use.

What are ESBLs?

Some members of Enterobacteriacae (commonly, E.coli and Klebsiella pneumoniae) have TEM and SHV beta-lactamases conferring resistance to various antibiotics. A point mutation which alters the configuration around the active site of the TEM and SHV type enzymes has led to b-lactamases that are now known as “Extended Spectrum b-Lactamases” (ESBLs). ESBLs can hydrolyze cefotaxime, ceftazidime, aztreonam and other expanded spectrum cephalosporins to varying degrees.

Ceftazadime and aztreonam are affected the most, while cephamycins (cefoxitin and cefotetan) are hydrolyzed to a lesser extent. ESBLs do not hydrolyze imipenem. Genes for ESBL are distributed on large plasmids, which confer multiple drug resistance (e.g. aminoglycosides, tetracyclines, chloroamphenicol, trimethoprim). They are inhibited by the beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam. In vitro, the organisms with ESBL may appear to be resistant to third generation cephalosporin and susceptible to second-generation cephalosporins. ESBLs are most commonly seen in E.coli and K.pneumoniae but also have been described in other Enterobacteriacae as the resistant plasmid can be readily transferred among Enterobacteriacae.

Extent of the Problem

The first Klebsiella isolate with plasmid mediated resistance to broad-spectrum cephalosporins was reported in the Federal Republic of Germany in 1983. Since then this has been a growing problem all over the world. In the United States, the frequency of resistance to ceftazadime has increased from 1.5% (1987 to 1990) to 3.6% (1990 to1991) as reported by the National Nosocomial Infections Surveillance system. A surveillance trial involving 102 medical centers in the United States detected 10.3% and 23.8% ceftazadime resistant E.coli and K.pneumoniae respectively. Hospital outbreaks of ESBL have been reported from the United States and other countries. The gastrointestinal tract of patients is the probable reservoir for these organisms.

Detection of ESBLs

The problem of resistance mediated by ESBLs has been compounded by the lack of detection methods of ESBL. One approach had been the disk-approximation method. This method works by the placement of cefuroxime and/or ceftazadime disks close (20 or 30 mm) to an amoxicillin-clavulanic disk on a plate inoculated with the test organism. Enhancement of the zone of inhibition or a so-called ghost zone between either of the cephalosporins disks and clavulanate containing disk indicates the presence of an ESBL. A modified three-dimensional susceptibility test method has also been used to recognize ESBLs. This method has reported a sensitivity of 95% for ESBL detection compared to disk approximation test, which has a sensitivity of 79%.

The newest approach has been to use commercially available products of ESBL detection. The Vitek (bioMereiux Vitek, Hazelwood, Mo.) ESBL test and an ESBL screening Etest (AB Biodisk, Solna, Sweden) strip are based on recognition of a reduction in ceftazidime MICs in the presence of a fixed concentration (2 ug/ml) of clavulanic acid. Both of these commercially available tests have not yet been approved by the Food and Drug Administration (FDA). However, the National Committee for Clinical Laboratory Standards (NCCLS) has recently published performance standards for screening and confirmatory tests for ESBLs in publication M7-A5, January 2000.

Treatment

There are very limited drugs to choose from to treat a patient with an ESBL producing isolate (see Table 2). Although penicillins, cephalosporins, or aztreonam will appear to be susceptible in vitro, ESBL producing E. coli or Klebsiella spp. may be clinically resistant to therapy with these antibiotics. Infectious disease specialists are good resources when consultation for therapy of ESBL producing organisms is needed.

Our Laboratory

Clinicians depend on the antibiotic data available nationally and locally for the treatment of infectious diseases. In our laboratory, we have seen an increase in the resistant strains of Enterobacteriacae in the last few years for both inpatients and outpatients. From 8/4/98 – 3/20/99 our laboratory conducted an ESBL survey on a total of 45 E. coli and Klebsiella pneumoniae isolates from the Queen’s Medical Center intensive care units. All isolates were evaluated using the double-disk diffusion, the E-test ESBL strip, and a Cefpodoxime screening disk. None of the isolates tested were ESBL positive however, ESBL producing organisms may exist among other patient populations.

Because we feel that the number of ESBL producing gram negative isolates will probably increase in Hawaii’s patient population, DLS will continue to monitor clinical isolates for ESBL production and confirm suspected isolates by the methods recommended by NCCLS.

References

  1. Jacoby, G.A. Extended-spectrum b-lactamases and other enzymes providing resistance to oxyimino-b-lactams. Infect. Dis. Clin. North America 1997;11:875-887.
  2. Comican,M.G, et al. Detection of extended-spectrum b-lactamases (ESBL) producing strains by the Etest ESBL screen. J. Clin. Microbiol 1996, 34:1880-1884.
  3. Mortensen,J.E. Antimicrobial agents: Mechanisms of action, Mechanisms of resistance. Self study course #51, Colorado Association for Continuing Medical Laboratory Education, INC.
  4. Jones, R.N. et al. Antimicrobial activity and spectrum investigation of eight broad-spectrum b-lactam drugs: A 1997 surveillance trial in 102 medical centers in the United States. Diag. Microbiol. Infect. Dis 1998, 30:215-228.

Table 1: Classification of Cephalosporins

First Generation Second Generation Third Generation Fourth Generation
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cephapirin
Cephadrine
Cefaclor
Cefamandole
Cefatazole
Cefonicid
Cefotetan
Cefoxitin
Cefprozil
Cefuroxime
Loracarbef
Cefexime
Cefoperazone
Cefotaxime
Ceftibuten
Cefpodoxime
Ceftazadime
Ceftizoxime
Ceftriaxone
Cefepime

Table 2: Impact on Therapy

Activity poor/Lost Activity Retained
Cefotaxime
Ceftazidime
Ceftriaxone
Aztreonam
Tiarcillin
Mezlocillin
Piperacillin
Imipenem
Meropenem
Cefoxitin(?)
Cefotetan(?)
Piperacillin/tazobactam(?)