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Review Article

Indian J Med Res 126, November 2007, pp 417-427

An update on newer β-lactamases

Varsha Gupta

Department of Microbiology, Government Medical College & Hospital, Chandigarh, India

Received July 11, 2006

The resistance to β -lactam antibiotics is an increasing problem worldwide and β lactamases production
is the most common mechanism of drug resistance. Both global and Indian figures showed a marked
increase in the number of β -lactamases producing organisms. These enzymes extended spectrum β -
lactamases (ESBLs) are numerous and continuous mutation has led to the development of enzymes
having expanded substrate profile. To date, there are more than 130 TEM type and more than 50
sulphydryl variable (SHV) type β -lactamases found in Gram negative bacilli. ESBL producing
Enterobacteriaceae are, as a rule, resistant to all cephalosporins and extended spectrum penicillins
including the monobactam, aztreonam, while resistance to trimethoprim - sulphamethaxazole and
aminoglycosides is frequently co-transferred on the same plasmid. Many ESBL producing organisms
also express Amp C β-lactamases. Amp C- β-lactamases are clinically significant, as these confer resistance
to cephalosporins in the oxyimino group, 7α α -methoxy cephalosporins, and are poorly inhibited by
clavulanic acid. Carbepenems are the drugs of choice for the treatment of infections caused by ESBL
producing organisms but carbapenemases (MBLs) have emerged and have spread from Pseudomonas
aeruginosa to Enterobacteriaceae. The routine clinical microbiology laboratories should employ simple
methods to recognize these enzymes using various substrates and inhibitors. These organisms may lead
to therapeutic dead ends. Presently, the therapy relies on β -lactam/ β -lactamases inhibitor combinations,
carbepenems and piperacillin – tazobactam plus aminoglycoside combination. Proper infection control
practices and barrier precautions are essential to contain the organisms producing β -lactamases.

Key words β-lactamases - ESBL - MBL - resistance - SHV - TEM

The first β -lactamase was identified in Escherichia and mutation of β-lactamases. These β-lactamases are
coli prior to the release of penicillin for use in medical now capable of hydrolyzing penicillins, broad-spectrum
practice1. In Gram negative pathogens, β-lactamase cephalosporins and monobactams. Thus these are new
production remains the most important contributing β-lactamases and are called as extended spectrum beta
factor to β-lactam resistance2. lactamases (ESBLs)4. In Gram negative bacteria these
The four major groups of β-lactams penicillin, enzymes remain in the periplasmic space, where they
cephalosporins, monobactams and carbapenems have attack the antibiotic before it can reach its receptor site5.
a β-lactam ring which can be hydrolysed by β- The first plasmid mediated β-lactamase was described
lactamases resulting in microbiologically ineffective in early 19606. ESBLs have been isolated from a wide
compounds3. The persistent exposure of bacterial strains variety of Enterobacteriaceae, Pseudomonas
to a multitude of β-lactams has led to overproduction aeruginosa and Capnocytophaga ochracea7- 9.

On the basis of mechanism of action, most common environmental surfaces facilitates cross infection within
β-lactamases are divided into three major classes (A,C hospitals20.
& D) depending on amino acid sequences. These
An individual acquires an ESBL strain either due to
enzymes act on many penicillins, cephalosporins and
contact with the colonized health care worker or
monobactams. Class B β-lactamases called as metallo
contaminated fomites. After this, the isolate emerges as
beta lactamases (MBLs), act on penicillins,
a result of selective effect of antibiotic use21. Removal of
cephalosporins and carbapenems but not on
selective pressure by drug class restriction leads to the
monobactams10. MBLs differ from other β-lactamases
disappearance of ESBL producing strains 22. Some
in using metal ion zinc, linked to a histidine or cysteine
important factors related to acquisition and infection with
residue to react with the carbonyl group of the amide
ESBL producing organisms are seriously ill patients with
bond of most penicillins, cephalosporins and
prolonged hospital stays, in whom invasive medical
carbapenems11. Another class, Amp C- β-lactamases are
devices are present23-25. Heavy antibiotic use is also a
also clinically significant, since they confer resistance
risk factor for acquisition of an ESBL producing
to cephalosporins in the oxyimino group, 7α-methoxy
organism26. Use of many third generation cephalosporins,
cephalosporins and are not affected by available β-
ceftazidime, quinolones, and aminoglycosides has been
lactamase inhibitors12. Amp C β-lactamases have been
shown to be associated with emergence of ESBLs27-30.
reported in E. coli, Klebsiella pneumoniae, Salmonella
Patient to patient transmission has also been described23.
spp., Citrobacter freundii, Enterobacter aerogenes and
However, same ESBLs in a particular unit of a hospital
Proteus mirabilis13-15.
may be mediated by different plasmids and many different
Origin & spread ESBLs may be found in the same unit at a same time31.
Intensive care units are usually the epicenters of ESBLs
Many Gram negative bacteria possess a naturally
production. Transfer of genotypically related ESBLs may
occurring, chromosomally mediated β-lactamase. These
occur from hospital to hospital32, from city to city33,
enzymes may have evolved from penicillin binding
country to country34 and even intercontinental transfer
proteins with which they show some sequence
has been described35. Community acquired infection with
homology. This development was likely due to selective
ESBLs have also been found36.
pressure exerted by β-lactam producing soil organisms
found in the environment16. The TEM 1 enzyme was Classification
originally found in E. coli isolated from a patient named
β-lactamases are increasing in number and
Temoniera hence named as TEM17. Being plasmid and
diversification of the group of enzymes is occurring that
transposon mediated has facilitated the spread of TEM
inactivates β-lactam type of antibacterials. These can
1 to other species of bacteria. The second common
be classified based on two major approaches. One is
plasmid mediated β-lactamase found in K. pneumoniae
based on the biochemical and functional characteristics
and E. coli is SHV 1 (sulphydryl variable). The SHV1
of the enzymes and the second is based on the molecular
β-lactamase is chromosomally encoded in the majority
structure of the enzyme.
of isolates of K. pneumoniae but is usually plasmid
mediated in E. coli18. The first real ESBL to be described Functional classification of the β-lactamases is
in 1983 was TEM 3, and now over 100 additional TEMs based on spectrum of antimicrobial substrate profile,
have been isolated7. Unlike the TEM type β-lactamases, enzyme inhibition profile, enzyme net charge,
there are fewer derivatives of SHV 1. However, a multi- hydrolysis rate and other parameters. Bush et al 37
resistant transferable plasmid encoding the SHV 5 β- presented the classification based on 4 major groups
lactamase causing unusually high resistance to (1-4) and subgroups (a-f) 37 . According to this
ceftazidime and aztreonam and combination of classification, most ESBLs belong to group 2 B e, which
acetylating enzymes producing resistance to all is β-lactamases inhibited by clavulanic acid, which can
clinically available aminoglycosides was identified in hydrolyze penicillins, narrow and extended spectrum
K. pneumoniae19. K. pneumoniae has been considered cephalosporins and monobactams.
as the main agent producing ESBL. This may be
Characterization and types of ESBLs
attributed to presence of large mult-iresistant plasmids
and presence of ESBL genes on these plasmids. Also Classical ESBLs have evolved from the widespread
Klebsiella is more adapted to hospital environment and plasmid-encoded enzymes families TEM, SHV,
longer survival of this organism on hands, cefotaxime (CTX-M) and oxacillin (OXA).

TEM (Class A): TEM 1 is capable of hydrolyzing SFO-1, GES-1) 7. These novel enzymes are found
penicillins and first generation cephalosporins but is infrequently.
unable to attack the oxyimino cephalosporin. The first
TEM variant with increased activity against extended
spectrum cephalosporins was TEM 338,39. To date, there The spread of β-lactamases may be chromosomal
are > 130 TEM type and > 50 SHV type β-lactamases, or plasmid mediated. The genes encoding some β-
and it appears that new ones are being found every week. lactamases are carried by transposons49. Many genes
They are mainly found in E.coli, K.pneumoniae and P. may be found in integrons. Sometimes, β-lactamase
mirabilis 7 but can occur in other members of the resistance markers are a part of the integron that has
Enterobacteriaceae family and in some non-enteric gene cassettes encoding resistance genes for other
organisms such as Acinetobacter species. classes of antibiotics as well 50 . Decreased porin
production and overproduction of β-lactamases can also
SHV (Class A): The progenitor of the SHV class of result in enhanced resistance, e.g. in K. pneumoniae K
enzymes, SHV-1, is universally found in K. pneumoniae. 6 strain there is novel ESBL - SHV 18 and it also
SHV 1 confers resistance to broad spectrum penicillins exhibits the loss of two outer membrane porins51. In
such as ampicillin, ticarcillin and piperacillin but not this case although the enzyme hydrolyzed cephotaxime
to oxyimino substituted cephalosporins14. In 1983, a new more than the ceftazidime but K6 strain was more
SHV derived from a mutation in SHV 1 which is called resistant to ceftazidime because of possible increased
plasmidic SHV 2, was isolated from three isolates of penetration of cefotaxime or increased efflux of
K. pneumoniae which demonstrated, transferable ceftazidime52. This combination of mechanisms for
resistance to cefotaxime as well as to other newer resistance have been described in group 1
cephalosporins40. To date, more than 50 SHV type β- cephalosporinases as well53.
lactamases have been described7.
The gene for TEM 1 and TEM 2 are carried by
CTX-M (Class A): A new family of β-lactamases that transposons54. The gene encoding SHV 1 is found on
preferentially hydrolyzes cefotaxime has arisen. It has the chromosome of most isolates of K. pneumoniae55,56.
been found in isolates of Salmonella enterica serovar. SHV genes may also occur on transmissible plasmids57.
Typhimurium and E.coli mainly and some other species
of Enterobacteriaceae40-41. These are not very closely Genes for the remaining new types of β-lactamases
related to TEM or SHV β-lactamases43. In addition to are usually found incorporated into integrons. Integrons
the rapid hydrolysis of cefotaxime, another unique are involved in the acquisition of AmpC type β-
feature of these enzymes is that they are better inhibited lactamases by plasmids58 . Carbapenemases of the
by the β-lactamase inhibitor tazobactam than by Imimenem (IMP) and Verona integrons encoded (VIM)
sulbactam and clavulanate44,45. families are also found within integrons. Conjugational
transfer of wide host range R – plasmids bearing blaIMP
Recently CTX -M enzymes have been recognized gene is the mechanism of dissemination of blaIMP gene
in a number of focal outbreaks from many parts of the cassettes onto various Gram negative bacterial species59.
world, e.g. in Japan (Toho-2)45, India (CTX-M-15)46 and Another mode of resistance is that impenem and
UK47 suggesting their wide dispersal. meropenem resistant mutants of Enterobacter cloacae
OXA (Class D): The OXA type oxacillin hydrolyzing and Proteus rettgeri lack porins60.
enzymes are another family of β-lactamases and have Epidemiology
been found mainly in P. aeruginosa 47 . OXA β-
lactamases belong to Ambler class D48. These enzymes Due to difficulties in detecting ESBL producers and
confer resistance to ampicillin and cephalothin and are inconsistencies in reporting it is difficult to determine
characterized by their high hydrolytic activity against the true prevalence of ESBL producing organisms.
oxacillin and cloxacillin and are poorly inhibited by However, the ESBL producing organisms are distributed
clavulanic acid37. Many of the newer members of the worldwide and their prevalence is increasing. The
OXA β-lactamase family have been found in bacterial incidence of ESBL varies depending on the area of the
isolates originating in Turkey and in France. world the isolates belong to. The first ESBL producing
organism was detected in Europe. Although, the initial
Other unusual enzymes having ESBL have also reports were from Germany and England40,61, later on
been described (e.g., BES-1, CME-1, VE-B-1, PER, many reports came from France39,62. The proliferation

of ESBLs in France was quite dramatic. Up to 35 per Carbapenem resistant Serratia marcescens and P.
cent of hospital acquired K. pneumoniae were found to aeruginosa emerged in Japan nearly 10 years ago95,96.
be ESBL producers by early 1990s63. Strict infection These strains produced IMP 1 which is plasmid
control interventions led to the decline in the incidence mediated. Strains carrying bla (IMP-1) with a class 1
of ESBL producers. However, ESBL producing K. integron are the most prevalent types in Japan 97 .
pneumoniae are rising in Eastern Europe, in addition However, now these have also been identified in Europe
30.2 per cent of Enterobacter are showing ESBL and Singapore98,99.
production64. In USA, the first report occurred in 198865. In the last 4-5 yr, new transferable MBLs have
National Nosocomial Infections Surveillance (NNIS) spread rapidly. In some countries, P. aeruginosa
figures revealed 6.1 per cent of K. pneumoniae isolates possessing MBLs constitute nearly 20 per cent of all
from ICU while only 1.8 per cent of outpatient isolates nosocomial isolates, whereas in other countries the
of K. pneumoniae to be ESBL producers66. CTX-M type number is comparatively low100,101. The spread of MBL
ESBL has recently been described in USA and Canada67-69. genes is likely to rise further highlights the importance
Various ESBL types reported from South America are of reporting and studying the epidemic spread of these
SHV 2, SHV 5, CTX-M 2, GES-1 and BES 170-73. As enzymes by various surveillance projects like SENTRY,
high as 32 to 60 per cent of Klebsiellae isolates from MYSTIC, Alexander and EARSS102.
ICU in Brazil, Columbia and Venezuela have been found
Many bacterial species like Enterobacter, S.
to be ESBL producers74-77. From Africa and Middle East,
marcescens, E. coli, P. aeruginosa and C. freundii
the ESBL production has been reported in 6.1 per cent
possess β-lactamases of the Amp C type103. The product
of K. pneumoniae isolates in a single South African
of Amp C gene is an enzyme that is broadly active
Hospital78. CTX-M-12 has been found in Kenya79. TEM
against cephalosporins but is not inhibited by
and SHV types of ESBLs have been characterized from
clavulanate. This differentiated Amp C enzymes from
South Africa80,81. GES-2 has also been reported from P. ESBLs. Further, migration of chromosomal Amp C
aeruginosa82. In Australian hospitals the proportion of genes into plasmids poses a serious threat. Usually, the
ESBL GES-2 producing K. pneumoniae isolates was plasmid encoded Amp C β-lactamases are present in
about 5 per cent76. From China, the figures of ESBL species that do not possess a chromosome encoded
producers varies between 25-40 per cent83. SHV-2 has version of the enzymes104. CTX-M types of ESBLs are
also been found in China84. About 12-24 per cent of regarded as emerging pathogens. A recent study from
isolates from Thailand, Taiwan, Philippines and Spain showed 70 per cent of the ESBL producing E.
Indonesia have been described by national surveys to coli from bacteraemia cases to be of CTX-M types105.
be ESBL producers 7 . In Japan, 5 per cent of K.
pneumoniae are ESBL producers85. The various lineage Indian scenario
of SHV viz., SHV 2, SHV 5, SHV 12 and others have In India, ESBL producing strains of
been described from Japan86. Recently, CTX-M types Enterobacteriaceae have emerged as a challenge in
have been reported from China, Japan, Korea and hospitalized as well as community based patients. In
Taiwan 87-90 . The SENTRY Surveillance Program 1997, from Nagpur 17 out of 66 Klebsiella isolates
covered the period 1997-1999 and MYSTIC covered showed ESBL production106. In 2002, 68 per cent of
1997-200391 also the latter included a greater number Gram negative bacteria were found to be ESBL
of Intensive Care Units, the figure of MYSTIC program producers in a study from New Delhi in which 80 per
showed an overall increase over SENTRY Surveillance cent of Klebsiella were ESBL107. In 2004 two other
Program 92. Apart from K. pneumoniae, E. coli, K. studies from Delhi showed 70.6 and 12.6 per cent
oxytoca, ESBLs have become common in P. mirabilis. Klebsiella isolates to be ESBL producers
ESBLs in Salmonella spp. are also growing93. respectively108,109. Another comparatively recent study
in 2005 from New Delhi, showed 68.78 per cent of the
A latest study from US reported 4.9 per cent of all strains of Gram negative bacteria to be ESBL
Enterobacteriacae to be ESBL producers. These isolates producers 110 . ESBLs have been reported from
occurred at 74 per cent of the ICU and 43 per cent of community isolates from north India as well111. A study
the non ICU sites. Transferable Amp C beta lactamases from Coimbatore, Tamil Nadu, showed the presence of
were detected in 3.3 per cent of K. pneumoniae ESBL to be 40 per cent while from Nagpur this figure
isolates94. was 50 per cent in urinary isolates112,113. In a study from

Chennai, ESBL production was detected in 6 out of 90 β-lactam antibiotics is used. Enhancement of the zone
isolates of K. pneumoniae in children under five with of ceftazidime disk on the side facing the amoxicillin-
intestinal infections114. Further a study from Karnataka clavulanate disk is interpreted as a positive test129. (ii)
showed the frequency of ESBLs in neonatal septicaemic Combined disk method - Commercialized disks
cases to be 22.7 per cent 115. A similar study from containing clavulanate plus ceftazidime or cefotaxime
Lucknow showed high levels of ESBL production (63.6- (10 µg plus 30 µg respectively) are used in this
86.6 %)116. Amp C enzyme has also been described in method130. (iii) E test ESBL strip- In this method the
3.3 per cent of isolates from Karnataka117. Metallo-beta- zone of inhibition is read from two halves of the strip.
lactamase production is a significant problem especially A decrease in the MIC of ceftazidime of more than three
in hospital isolates of P. aeruginosa and Acinetobacter dilutions in the presence of clavulanate is interpreted
species. Reports have described the prevalence of MBLs as a positive test. Sometime due to weak enzyme
in P. aeruginosa118,119 and Acinetobacters species as well production, indeterminate results may be obtained. (iv)
from India120. Three dimensional test- This method is very sensitive,
but is technically difficult and labour-intensive requiring
The results of the initial studies for the MYSTIC experienced clinical microbiologist to interpret the
programme in India confirmed the high levels of result 131 . (v) The automated ESBL microbial
resistance and ESBL production in Gram-negative susceptibility test system- This method utilizes either
bacilli including Salmonella121. The latest report from ceftazidime or cefotaxime alone and in combination
National Institute of Communicable Diseases (NICD), with clavulanic acid (4 µg/ml). A predetermined
New Delhi, India, shows PCR as a reliable method for reduction in growth in wells containing clavulanate
detection of ESBLs as well as the rise of resistance to compared with those containing each single drug
cefepime - a fourth generation cephalosporin122. CTX- indicates the presence of an ESBL. Vitek ESBL test
M-15 has also been found in Indian E. coli and K. system has shown variable results132. (vi) Recently CLSI
pneumoniae strains123. has recommended initial screening by testing for growth
Methods of detection in a broth medium containing 1 µg/ml of one of five
extended spectrum β-lactam antibiotics 128 . For
Different ESBL enzymes depict variable levels of identification of specific ESBL expressed in a clinical
resistance to third generation cephalosporins. According isolate, the following molecular detection methods can
to National Committee for Clinical Laboratory be applied: Specific DNA probes, PCR with
Standards (NCCLS) now Clinical and Laboratory oligonucleotide primers oligotyping, PCR followed by
Standards (CLSI) interpretive definitions, ESBLs do not restriction fragment length polymorphism analysis,
always increase MICs to levels characterized as ligase chain reaction and nucleotide sequencing. These
resistant124,125. Now, it is mandatory that the routine techniques are available only in research centres and
clinical microbiology laboratory employs ESBL are beyond the scope of routine clinical microbiology
detection methods which are sensitive enough to laboratories.
recognize the level of resistance that would be achieved
Regarding the reporting of ESBL producing
by the situation given in vivo.
isolates, the microbiology laboratory report should state
Screening tests: Initial screening for reduced that the strain produced ESBL and should be considered
susceptibility to cefpodoxime, cefotaxime, ceftriaxone, resistant to all penicillins, cephalosporins and
ceftazidime or aztreonam and then performing aztreonam.
phenotypic confirmatory test is recommended. As For clinical laboratories to adapt a method for
proposed by the CLSI, M100-S-16 document, the use screening for metallo beta-lactamases, the suggested
of more than one of the five indicator cephalosporins methodology is as follows; firstly, the isolates are
suggested will improve the sensitivity of detection126. targeted based on ceftazidime and carbapenem MIC,
But, if it is necessary to rely on a single screening e.g. P. aeruginosa with an imipenem MIC> 16 µg/ml
substance, ceftazidime or cefpodoxime would be the and Acinetobacter spp. isolates with an MIC >2 µg/ml
best choice127. is appropriate. For ease of application, the E test MBL
Confirmatory tests127: (i) The double disk approximation strip is recommended133. To increase the sensitivity of
test: A susceptibility disk containing amoxicillin- MBL detection, several substrates (imipenem,
clavulanate and a disk containing one of the oximino ceftazidime and meropenem) should be used preferably

with more than one inhibitor (EDTA and seems to be gastrointestinal tract 142 , oropharynx,
mercaptopropionic acid) 134. It should be of help if colonized wounds and urine.
clinical laboratories are able to detect organisms
The colonized hands, equipment could help in
producing plasmid mediated Amp-C β-lactamases with
spreading infection between patients. So, mandatory
a method, which is simple as well as inexpensive. CLSI
infection control practices would be hand washing,
has no recommendations available for detection of these
organisms. A number of reports have been published barrier precautions, isolation of colonized/infected
based on different methodologies used135-137. patients. Surveillance of patients of ICUs will help in
early detection and control practices related to ESBL
Treatment production. Antibiotic restriction and antibiotic cycling
ESBL producing members of Enterobacteriaceae especially the empirical use of higher generation
are, as a rule, resistant to all cephalosporins and cephalosporins and carbepenems are other measures
extended spectrum penicillins, including the which if monitored properly, could help in control of
monobactam, aztreonam, while resistance to the emergence and spread of ESBL producing bacteria.
trimethoprim-sulfamethoxazole and aminoglycosides is Conclusion
frequently co-transferred on the same plasmid138. Third
and fourth generation cephalosporins should not be used The incidence of infections due to organisms
even in the presence of apparent susceptibility. resistant to β-lactam agents due to production of various
Cephamycins such as cefoxitin, cefotetan and enzymes has increased in recent years. Detection of
moxalactam may be used for ESBL producing E.coli ESBL production is of paramount importance both in
and Klebsiella spp. However, cephamycin therapy leads hospital and community isolates. Firstly, these strains
to emergence of plasmid mediated Amp C resistance. are probably more prevalent than currently recognized.
These enzymes are phylogenetically very distinct from Secondly, ESBLs constitute a serious threat to currently
the ESBL families and confer resistance to third available antibiotics. Thirdly, institutional outbreaks are
generation cephalosporins as well as cephamycins139,140. increasing because of selective pressure due to heavy
ESBLs are usually susceptible to β-lactam / β-lactamase use of expanded spectrum cephalosporins and lapses
inhibitor combinations, but these drugs can usually be in effective control measures. So vigilance and timely
overwhelmed by particularly large amounts of enzyme recognition of infection with resistant bacteria and
and thus show in vivo resistance. Treatment with β- appropriate antibiotic therapy, is the only answer to the
lactam/ β-lactamase inhibitor combination was shown current multi drug resistant bacterial population. Careful
to be inferior to treatment with imipenem or piperacillin/ attention to barrier precautions and hand hygiene can
tazobactam plus aminoglycoside combination in an help in preventing the spread of these, multi drug
animal model 140 . Currently the carbapenems, are resistant Gram-negative microorganisms.
regarded as the drugs of choice against ESBL producing
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