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Extended spectrum beta-lactamases (ESBL)

Hospitals are plagued by bacteria resistant to commonly used antibiotics. β-lactamase is an enzyme produced by some bacteria that destroys penicillin and other β-lactam antibiotics, thus allowing them to grow and proliferate and cause disease in an otherwise toxic environment. Humans have produced new synthetic and semi-synthetic antibiotics that are resistant to degredation by β-lactamases, but the appearance of extended spectrum β-lactamases is the next step in the arms race between humans and bacteria. Many hospitals find themselves forced to change their the antibiotics they use first-line, because of the increasing prevalence of ESBL-producing organisms.

Prevalence of ESBL-production are dependent on geography and are increasing: 4.5% in the US, 8.7% in Europe, 19.3% in Latin America, 25.5% in China (1999 figures).

The advance from second generation cephalosporins to third generation cephalosporins was achieved primarily through the addition of an oxyimino group in the C-7-amino position of the 7-ACA molecule. This increased the spectrum of cover of the cephalosporins to include most of the Enterobacteriaceae. The bulky oxyimino group prevent bacterial β-lactamases from attaching to the antibiotic molecule and destroying it.

The organisms most commonly found to produce β-lactamases are E. coli and Klebsiella pneumoniae. Other organisms include (but are not limited to) Pseudomonas aeruginosa, Enterobacter, Citrobacter, Proteus and Acinetobacter.

Types of ESBL

There are literally hundreds of β-lactamases described and the number of classification schemes is enormous. The simplest classification scheme divides the ESBLs into serine-ESBLs (which have a serine residue in the active site) and metallo-β-lactamases (where the enzyme includes a metal ion in its structure—usually a zinc ion).

The next simplest classification scheme divides the β-lactamases into four classes, A to D (Ambler 1980). A, C and D are serine-β-lactamases and B comprises the metallo-β-lactamases. Class A include the TEM-type, SHV-type and CTX-M-type β-lactamases; class C include the AmpC enzymes; class D include the OXA-type β-lactamases.

Detecting ESBL-producing organisms

The β-lactamases are usually inhibited by β-lactamase inhibitors such as clavulanic acid and tazobactam. Testing for ESBL production therefore usually involves looking for increased inhibition of growth in the presence of a β-lactamase inhibitor: e.g., when using a disc-diffusion method (BSAC or NCCLS), the zone of inhibition of bacterial growth is greater for ceftazidime and clavulanic acid than with ceftazidime alone (Sanders 1996).

The other main method of dection is by phenotyping (e.g., VITEK-2) (Leverstein-van Hall 2002). This is a method most commonly used in automated systems that are able to screen sensitivities to large numbers of antibiotics. The machine will compare the measured antibiotic sensitivities against a database, and make a prediction as to whether or not that organism is an ESBL-producer.

There are not currently any standardised methods for the detection of AmpC or cabapenemase producing organisms.

Treatment

There are no randomised, controlled trials in the literature describing the treatment of ESBL-producing organisms. Most papers describe small numbers of cases, using an antibiotic found to be sensitive on in vitro testing. It is difficult to generalise the results of these trials, because the enzymes and organisms will not be specific to the setting. Most of the data available is for E. coli and Klebsiella spp.: the use of carbapenems (meropenem, imipenem and ertapenem) seems to be associated with the best outcome, but cefepime and piperacillin-tazobactam are also used. In individual cases, treatment choices will be governed by the results of in vitro susceptibility testing.

Outbreak control

When an outbreak of ESBL-producing organisms occurs in a hospital, the two most effective actions are to limit the use of third-generation cephalosporins and barrier precautions (gloves, gowns and hand-washing). Substituting first-line antibiotics alone without any other precautions can however result in breeding organisms resistant to the new first-line antibiotic, which only creates new problems.

References

Ambler RP (1980) The structure of β-lactamases Philos Trans R Soc Lond B Biol Sci 289:321–23.
Hawkey PM, Munday CJ (2004) Extended spectrum β-lactamases Eurocommunica Ltd.
Jacoby GA, Munoz-Price LS (2005) Mechanisms of Disease: The New β-Lactamases NEJM 352:380–91
Leverstein-van Hall MA, Fluit AC, Paauw A et al (2002) Evaluation of the Etest and the BD Phoenix, VITEK 1, and VITEK 2 automated intruments for detection of extended-spectrum beta-lactamases in multiresistant Escherichia coli and Klebsiella spp. J Clin Microbiol 40:3703–3711
Sanders CC, Barry AL, Washington JA et al (1996) Detection of extended-spectrum beta-lactamase-producing members of the family Enterobacteriaceae with VITEK ESBL test J Clin Microbiol 34:2997–3001

This write-up created 21 Aug 2005. This information does not substitute for advice from a registered medical practitioner. No liability is accepted for damage arising from action taken on the basis of information provided in this write-up.

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