These classes include:
Narrow Spectrum Beta lactamases
ESBL (Extended Spectrum Beta Lactamase)
ESBL (Extended Spectrum Beta Lactamase):
Extended-Spectrum Beta-Lactamases (ESBLs) are actually enzymes produced by certain
types of bacteria, which renders the bacteria resistant to the antibiotics commonly
used to treat them. ESBLs were first discovered in the mid-1980s. At the time they
were mostly found in the Klebsiella species of bacteria, in hospital intensive care
units. Until recently, few people were affected by these mutated bacteria and it
didn't appear to be a major growing concern. That has changed, however. According
to the British Health Protection Agency (HPA), a new class of ESBL (called CTX-M
enzymes) has emerged, which are now being widely detected among E.Coli bacteria.
These ESBL-producing E. Coli are resistant to penicillins and cephalosporins, and
are becoming more frequent in urinary tract infections. ESBLs defined as β-lactamases
that are capable of hydrolysing oxyimino-cephalosporins and which (unlike AmpC types)
are inhibited by clavulanic acid in vitro Some Species in Which ESBLs Are Found:
Klebsiella
Escherichia coli
Enterobacter
Proteus
Citrobacter
Pseudomonas*
Major classes include:
TEM
SHV
CTX-M
OXA
TEM
TEM-type ESBLs derivatives of TEM-1 and TEM-2
Possible first TEM-ESBL isolated in Liverpool in 1982; Klebsiella oxytoca harboured
a gene encoding resistance to ceftazidime (TEM-12)
Well over 100 TEM-type β-lactamases have been described, of which the majority
are ESBLs
Amino acid substitutions that occur within the TEM enzyme occur at a limited number
of positions
Combinations of these amino acid changes results in subtle alterations in the ESBL
phenotype, e.g. the ability to hydrolyse ceftazidime or cefotaxime
TEM-1 is the most commonly-encountered beta-lactamase in gram-negative bacteria.
Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1.
Also responsible for the ampicillin and penicillin resistance that is seen in H.
influenzae and N. gonorrhoeae in increasing numbers. Although TEM-type beta-lactamases
are most often found in E. coli and K. pneumoniae, they are also found in other
species of gram-negative bacteria with increasing frequency. The amino acid substitutions
responsible for the ESBL phenotype cluster around the active site of the enzyme
and change its configuration, allowing access to oxyimino-beta-lactam substrates.
Opening the active site to beta-lactam substrates also typically enhances the susceptibility
of the enzyme to b-lactamase inhibitors, such as clavulanic acid. Single amino acid
substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but
ESBLs with the broadest spectrum usually have more than a single amino acid substitution.
Based upon different combinations of changes, currently 140 TEM-type enzymes have
been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United
States
SHV
To date, the majority of SHV-type derivatives possess ESBL phenotype
Majority found in Klebsiella pneumoniae
In 1983, a Klebsiella ozaenae isolate from Germany was discovered to possess a beta
-lactamase that hydrolysed cefotaxime
Differed from SHV-1 by replacement of glycine by serine at the 238 position
This mutation alone accounted for its extended spectrum properties
Designated as SHV-2 - later found in organisms in every inhabited continent within
15 years of its discovery
Selection pressure from 3rd generation cephalosporins thought responsible
SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall
structure. The SHV-1 beta-lactamase is most commonly found in K. pneumoniae and
is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this
species. ESBLs in this family also have amino acid changes around the active site,
most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known.
They are the predominant ESBL type in Europe and the United States and are found
worldwide. SHV-5 and SHV-12 are among the most common.
CTX-M
Fast growing - important group
Preferentially hydrolyse, and confer resistance to cefotaxime
Escape of chromosomal β-lactamase genes from Kluyvera spp (a bug of no clinical
importance!)
Having migrated to mobile DNA, CTX-M β-lactamases genes may evolve further
- undergoing mutations that increase activity against ceftazidime
The first CTX-M ESBL in the UK was found as recently as 2000, in a solitary isolate
of K. oxytoca
First outbreak, caused by K. pneumoniae producing the new enzyme CTX-M-26, was recorded
in Birmingham in 2001
These enzymes were named for their greater activity against cefotaxime than other
oxyimino-beta-lactam substrates (eg, ceftazidime, ceftriaxone, or cefepime). Rather
than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase
genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic
commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases
in that they show only approximately 40% identity with these two commonly isolated
beta-lactamases. More than 40 CTX-M enzymes are currently known. Despite their name,
a few are more active on ceftazidime than cefotaxime. They have mainly been found
in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also
been described in other species of Enterobacteriaceae and are the predominant ESBL
type in parts of South America. (They are also seen in eastern Europe) CTX-M-14,
CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most
widespread type in E. coli the UK and is widely prevalent in the community.
July 2004 : Media 'discovers' CTX-M
OXA
OXA beta-lactamases were long recognized as a less common but also plasmid-mediated
beta-lactamase variety that could hydrolyze oxacillin and related anti-staphylococcal
penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they
belong to molecular class D and functional group 2d . The OXA-type beta-lactamases
confer resistance to ampicillin and cephalothin and are characterized by their high
hydrolytic activity against oxacillin and cloxacillin and the fact that they are
poorly inhibited by clavulanic acid. Amino acid substitutions in OXA enzymes can
also give the ESBL phenotype. While most ESBLs have been found in E. coli, K. pneumoniae,
and other Enterobacteriaceae, the OXA-type ESBLs have been found mainly in P. aeruginosa.
OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey
and France. The OXA beta-lactamase family was originally created as a phenotypic
rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis
profile. Therefore, there is as little as 20% sequence homology among some of the
members of this family. However, recent additions to this family show some degree
of homology to one or more of the existing members of the OXA beta-lactamase family.
Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater
resistance to cefotaxime and cefepime than it does resistance to ceftazidime.
Recognising ESBLs in the Laboratory
Choice of Indicator Cephalosporin
TEM & SHV - obvious resistance to ceftazidime, variable to cefotaxime
CTX-M - obvious resistance to cefotaxime, variable to ceftazidime
All ESBLs - obvious resistance to cefpodoxime
Confirmatory Tests for ESBLs
Double-disc tests
Practical and cost effective approach for routine detection
However, optimal disc separation varies with the strain and some producers may be
missed
Combination disc methods
Compare zones of inhibition of ceph alone, and ceph plus clavulanate
Inexpensive and do not require critical disc spacing
Etest ESBL strips
Accurate and precise but more expensive than combination discs
Treatment Choice?
ESBL-producing organisms hydrolyse many ß-lactam antibiotics, so choice of
treatment is much reduced!
Plasmids bearing the genes encoding ESBLs frequently carry genes encoding resistance
to aminoglycosides and trimethoprim
Increasing reports of plasmid-encoded decrease in susceptibility to quinolones,
frequently in association with cephalosporin resistance
Multiple ESBLs may reduce the effectiveness of β-lactam/β-lactamase inhibitor
combinations
Cephamycins are stable to ESBLs but loss of outer membrane porins may lead to resistance
Studies assessing clinical outcomes of 3GC-treated ESBL infections have produced
mixed results
Failure with ceftazidime does not preclude success with another 3GC (e.g. cefotaxime)
Success may depend on the type of ESBL being expressed, e.g. TEM-10 being resistant
to ceftazidime but not other 3GCs
However, poor choices for the treatment of serious infections due to ESBL-producing
organisms
ESBLS - Conclusion
ESBLs have evolved greatly over the last 20 years, with CTX-M type ESBLs becoming
an increasing problem in the UK
Overuse of the cephalosporins in the hospital setting has most likely caused the
spread of ESBLs
There is a need for formal treatment guidelines to be developed
Screening for ESBLs in microbiology laboratories should be routine
Presence of ESBLs will be sure to create significant therapeutic problems in the
future, with resistance spreading
Infection-control measures and reduction in use of third-generation cephalosporins
are critical for limiting ESBLs in institutions
ESBLs have evolved greatly over the last 20 years, with CTX-M type ESBLs becoming
an increasing problem in the UK
Overuse of the cephalosporins in the hospital setting has most likely caused the
spread of ESBLs
There is a need for formal treatment guidelines to be developed
Screening for ESBLs in microbiology laboratories should be routine
Presence of ESBLs will be sure to create significant therapeutic problems in the
future, with resistance spreading
Infection-control measures and reduction in use of third-generation cephalosporins
are critical for limiting ESBLs in institutions
