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

Review Article
An update on newer -lactamases
Varsha Gupta
Department of Microbiology, Government Medical College & Hospital, Chandigarh, India
Received July 11, 2006
The resistance to -lactam antibiotics is an increasing problem worldwide and lactamases production
is the most common mechanism of drug resistance. Both global and Indian figures showed a marked
increase in the number of -lactamases producing organisms. These enzymes extended spectrum -
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 -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 -lactamases. Amp C- -lactamases are clinically significant, as these confer resistance
to cephalosporins in the oxyimino group, 7 -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 -lactam/ -lactamases inhibitor combinations,
carbepenems and piperacillin tazobactam plus aminoglycoside combination. Proper infection control
practices and barrier precautions are essential to contain the organisms producing -lactamases.
Key words -lactamases - ESBL - MBL - resistance - SHV - TEM
The first -lactamase was identified in Escherichia
coli prior to the release of penicillin for use in medical
practice
1
. In Gram negative pathogens, -lactamase
production remains the most important contributing
factor to -lactam resistance
2
.
The four major groups of -lactams penicillin,
cephalosporins, monobactams and carbapenems have
a -lactam ring which can be hydrolysed by -
lactamases resulting in microbiologically ineffective
compounds
3
. The persistent exposure of bacterial strains
to a multitude of -lactams has led to overproduction
and mutation of -lactamases. These -lactamases are
now capable of hydrolyzing penicillins, broad-spectrum
cephalosporins and monobactams. Thus these are new
-lactamases and are called as extended spectrum beta
lactamases (ESBLs)
4
. In Gram negative bacteria these
enzymes remain in the periplasmic space, where they
attack the antibiotic before it can reach its receptor site
5
.
The first plasmid mediated -lactamase was described
in early 1960
6
. ESBLs have been isolated from a wide
variety of Enterobacteriaceae, Pseudomonas
aeruginosa and Capnocytophaga ochracea
7- 9
.
417
On the basis of mechanism of action, most common
-lactamases are divided into three major classes (A,C
& D) depending on amino acid sequences. These
enzymes act on many penicillins, cephalosporins and
monobactams. Class B -lactamases called as metallo
beta lactamases (MBLs), act on penicillins,
cephalosporins and carbapenems but not on
monobactams
10
. MBLs differ from other -lactamases
in using metal ion zinc, linked to a histidine or cysteine
residue to react with the carbonyl group of the amide
bond of most penicillins, cephalosporins and
carbapenems
11
. Another class, Amp C- -lactamases are
also clinically significant, since they confer resistance
to cephalosporins in the oxyimino group, 7-methoxy
cephalosporins and are not affected by available -
lactamase inhibitors
12
. Amp C -lactamases have been
reported in E. coli, Klebsiella pneumoniae, Salmonella
spp., Citrobacter freundii, Enterobacter aerogenes and
Proteus mirabilis
13-15
.
Origin & spread
Many Gram negative bacteria possess a naturally
occurring, chromosomally mediated -lactamase. These
enzymes may have evolved from penicillin binding
proteins with which they show some sequence
homology. This development was likely due to selective
pressure exerted by -lactam producing soil organisms
found in the environment
16
. The TEM 1 enzyme was
originally found in E. coli isolated from a patient named
Temoniera hence named as TEM
17
. Being plasmid and
transposon mediated has facilitated the spread of TEM
1 to other species of bacteria. The second common
plasmid mediated -lactamase found in K. pneumoniae
and E. coli is SHV 1 (sulphydryl variable). The SHV1
-lactamase is chromosomally encoded in the majority
of isolates of K. pneumoniae but is usually plasmid
mediated in E. coli
18
. The first real ESBL to be described
in 1983 was TEM 3, and now over 100 additional TEMs
have been isolated
7
. Unlike the TEM type -lactamases,
there are fewer derivatives of SHV 1. However, a multi-
resistant transferable plasmid encoding the SHV 5 -
lactamase causing unusually high resistance to
ceftazidime and aztreonam and combination of
acetylating enzymes producing resistance to all
clinically available aminoglycosides was identified in
K. pneumoniae
19
. K. pneumoniae has been considered
as the main agent producing ESBL. This may be
attributed to presence of large mult-iresistant plasmids
and presence of ESBL genes on these plasmids. Also
Klebsiella is more adapted to hospital environment and
longer survival of this organism on hands,
environmental surfaces facilitates cross infection within
hospitals
20
.
An individual acquires an ESBL strain either due to
contact with the colonized health care worker or
contaminated fomites. After this, the isolate emerges as
a result of selective effect of antibiotic use
21
. Removal of
selective pressure by drug class restriction leads to the
disappearance of ESBL producing strains
22
. Some
important factors related to acquisition and infection with
ESBL producing organisms are seriously ill patients with
prolonged hospital stays, in whom invasive medical
devices are present
23-25
. Heavy antibiotic use is also a
risk factor for acquisition of an ESBL producing
organism
26
. Use of many third generation cephalosporins,
ceftazidime, quinolones, and aminoglycosides has been
shown to be associated with emergence of ESBLs
27-30
.
Patient to patient transmission has also been described
23
.
However, same ESBLs in a particular unit of a hospital
may be mediated by different plasmids and many different
ESBLs may be found in the same unit at a same time
31
.
Intensive care units are usually the epicenters of ESBLs
production. Transfer of genotypically related ESBLs may
occur from hospital to hospital
32
, from city to city
33
,
country to country
34
and even intercontinental transfer
has been described
35
. Community acquired infection with
ESBLs have also been found
36
.
Classification
-lactamases are increasing in number and
diversification of the group of enzymes is occurring that
inactivates -lactam type of antibacterials. These can
be classified based on two major approaches. One is
based on the biochemical and functional characteristics
of the enzymes and the second is based on the molecular
structure of the enzyme.
Functional classification of the -lactamases is
based on spectrum of antimicrobial substrate profile,
enzyme inhibition profile, enzyme net charge,
hydrolysis rate and other parameters. Bush et al
37
presented the classification based on 4 major groups
(1-4) and subgroups (a-f)
37
. According to this
classification, most ESBLs belong to group 2 B e, which
is -lactamases inhibited by clavulanic acid, which can
hydrolyze penicillins, narrow and extended spectrum
cephalosporins and monobactams.
Characterization and types of ESBLs
Classical ESBLs have evolved from the widespread
plasmid-encoded enzymes families TEM, SHV,
cefotaxime (CTX-M) and oxacillin (OXA).
418 INDIAN J MED RES, NOVEMBER 2007
TEM (Class A): TEM 1 is capable of hydrolyzing
penicillins and first generation cephalosporins but is
unable to attack the oxyimino cephalosporin. The first
TEM variant with increased activity against extended
spectrum cephalosporins was TEM 3
38,39
. To date, there
are > 130 TEM type and > 50 SHV type -lactamases,
and it appears that new ones are being found every week.
They are mainly found in E.coli, K.pneumoniae and P.
mirabilis
7
but can occur in other members of the
Enterobacteriaceae family and in some non-enteric
organisms such as Acinetobacter species.
SHV (Class A): The progenitor of the SHV class of
enzymes, SHV-1, is universally found in K. pneumoniae.
SHV 1 confers resistance to broad spectrum penicillins
such as ampicillin, ticarcillin and piperacillin but not
to oxyimino substituted cephalosporins
14
. In 1983, a new
SHV derived from a mutation in SHV 1 which is called
plasmidic SHV 2, was isolated from three isolates of
K. pneumoniae which demonstrated, transferable
resistance to cefotaxime as well as to other newer
cephalosporins
40
. To date, more than 50 SHV type -
lactamases have been described
7
.
CTX-M (Class A): A new family of -lactamases that
preferentially hydrolyzes cefotaxime has arisen. It has
been found in isolates of Salmonella enterica serovar.
Typhimurium and E.coli mainly and some other species
of Enterobacteriaceae
40-41
. These are not very closely
related to TEM or SHV -lactamases
43
. In addition to
the rapid hydrolysis of cefotaxime, another unique
feature of these enzymes is that they are better inhibited
by the -lactamase inhibitor tazobactam than by
sulbactam and clavulanate
44,45
.
Recently CTX -M enzymes have been recognized
in a number of focal outbreaks from many parts of the
world, e.g. in Japan (Toho-2)
45
, India (CTX-M-15)
46
and
UK
47
suggesting their wide dispersal.
OXA (Class D): The OXA type oxacillin hydrolyzing
enzymes are another family of -lactamases and have
been found mainly in P. aeruginosa
47
. OXA -
lactamases belong to Ambler class D
48
. These enzymes
confer resistance to ampicillin and cephalothin and are
characterized by their high hydrolytic activity against
oxacillin and cloxacillin and are poorly inhibited by
clavulanic acid
37
. Many of the newer members of the
OXA -lactamase family have been found in bacterial
isolates originating in Turkey and in France.
Other unusual enzymes having ESBL have also
been described (e.g., BES-1, CME-1, VE-B-1, PER,
SFO-1, GES-1)
7
. These novel enzymes are found
infrequently.
Genetics
The spread of -lactamases may be chromosomal
or plasmid mediated. The genes encoding some -
lactamases are carried by transposons
49
. Many genes
may be found in integrons. Sometimes, -lactamase
resistance markers are a part of the integron that has
gene cassettes encoding resistance genes for other
classes of antibiotics as well
50
. Decreased porin
production and overproduction of -lactamases can also
result in enhanced resistance, e.g. in K. pneumoniae K
6 strain there is novel ESBL - SHV 18 and it also
exhibits the loss of two outer membrane porins
51
. In
this case although the enzyme hydrolyzed cephotaxime
more than the ceftazidime but K6 strain was more
resistant to ceftazidime because of possible increased
penetration of cefotaxime or increased efflux of
ceftazidime
52
. This combination of mechanisms for
resistance have been described in group 1
cephalosporinases as well
53
.
The gene for TEM 1 and TEM 2 are carried by
transposons
54
. The gene encoding SHV 1 is found on
the chromosome of most isolates of K. pneumoniae
55,56
.
SHV genes may also occur on transmissible plasmids
57
.
Genes for the remaining new types of -lactamases
are usually found incorporated into integrons. Integrons
are involved in the acquisition of AmpC type -
lactamases by plasmids
58
. Carbapenemases of the
Imimenem (IMP) and Verona integrons encoded (VIM)
families are also found within integrons. Conjugational
transfer of wide host range R plasmids bearing blaIMP
gene is the mechanism of dissemination of blaIMP

gene
cassettes onto various Gram negative bacterial species
59
.
Another mode of resistance is that impenem and
meropenem resistant mutants of Enterobacter cloacae
and Proteus rettgeri lack porins
60
.
Epidemiology
Due to difficulties in detecting ESBL producers and
inconsistencies in reporting it is difficult to determine
the true prevalence of ESBL producing organisms.
However, the ESBL producing organisms are distributed
worldwide and their prevalence is increasing. The
incidence of ESBL varies depending on the area of the
world the isolates belong to. The first ESBL producing
organism was detected in Europe. Although, the initial
reports were from Germany and England
40,61
, later on
many reports came from France
39,62
. The proliferation
GUPTA: NEWER -LACTAMASES 419
of ESBLs in France was quite dramatic. Up to 35 per
cent of hospital acquired K. pneumoniae were found to
be ESBL producers by early 1990s
63
. Strict infection
control interventions led to the decline in the incidence
of ESBL producers. However, ESBL producing K.
pneumoniae are rising in Eastern Europe, in addition
30.2 per cent of Enterobacter are showing ESBL
production
64
. In USA, the first report occurred in 1988
65
.
National Nosocomial Infections Surveillance (NNIS)
figures revealed 6.1 per cent of K. pneumoniae isolates
from ICU while only 1.8 per cent of outpatient isolates
of K. pneumoniae to be ESBL producers
66
. CTX-M type
ESBL has recently been described in USA and Canada
67-69
.
Various ESBL types reported from South America are
SHV 2, SHV 5, CTX-M 2, GES-1 and BES 1
70-73
. As
high as 32 to 60 per cent of Klebsiellae isolates from
ICU in Brazil, Columbia and Venezuela have been found
to be ESBL producers
74-77
. From Africa and Middle East,
the ESBL production has been reported in 6.1 per cent
of K. pneumoniae isolates in a single South African
Hospital
78
. CTX-M-12 has been found in Kenya
79
. TEM
and SHV types of ESBLs have been characterized from
South Africa
80,81
. GES-2 has also been reported from P.
aeruginosa
82
. In Australian hospitals the proportion of
ESBL GES-2 producing K. pneumoniae isolates was
about 5 per cent
76
. From China, the figures of ESBL
producers varies between 25-40 per cent
83
. SHV-2 has
also been found in China
84
. About 12-24 per cent of
isolates from Thailand, Taiwan, Philippines and
Indonesia have been described by national surveys to
be ESBL producers
7
. In Japan, 5 per cent of K.
pneumoniae are ESBL producers
85
. The various lineage
of SHV viz., SHV 2, SHV 5, SHV 12 and others have
been described from Japan
86
. Recently, CTX-M types
have been reported from China, Japan, Korea and
Taiwan
87-90
. The SENTRY Surveillance Program
covered the period 1997-1999 and MYSTIC covered
1997-2003
91
also the latter included a greater number
of Intensive Care Units, the figure of MYSTIC program
showed an overall increase over SENTRY Surveillance
Program
92
. Apart from K. pneumoniae, E. coli, K.
oxytoca, ESBLs have become common in P. mirabilis.
ESBLs in Salmonella spp. are also growing
93
.
A latest study from US reported 4.9 per cent of all
Enterobacteriacae to be ESBL producers. These isolates
occurred at 74 per cent of the ICU and 43 per cent of
the non ICU sites. Transferable Amp C beta lactamases
were detected in 3.3 per cent of K. pneumoniae
isolates
94
.
Carbapenem resistant Serratia marcescens and P.
aeruginosa emerged in Japan nearly 10 years ago
95,96
.
These strains produced IMP 1 which is plasmid
mediated. Strains carrying bla (IMP-1) with a class 1
integron are the most prevalent types in Japan
97
.
However, now these have also been identified in Europe
and Singapore
98,99
.
In the last 4-5 yr, new transferable MBLs have
spread rapidly. In some countries, P. aeruginosa
possessing MBLs constitute nearly 20 per cent of all
nosocomial isolates, whereas in other countries the
number is comparatively low
100,101
. The spread of MBL
genes is likely to rise further highlights the importance
of reporting and studying the epidemic spread of these
enzymes by various surveillance projects like SENTRY,
MYSTIC, Alexander and EARSS
102
.
Many bacterial species like Enterobacter, S.
marcescens, E. coli, P. aeruginosa and C. freundii
possess -lactamases of the Amp C type
103
. The product
of Amp C gene is an enzyme that is broadly active
against cephalosporins but is not inhibited by
clavulanate. This differentiated Amp C enzymes from
ESBLs. Further, migration of chromosomal Amp C
genes into plasmids poses a serious threat. Usually, the
plasmid encoded Amp C -lactamases are present in
species that do not possess a chromosome encoded
version of the enzymes
104
. CTX-M types of ESBLs are
regarded as emerging pathogens. A recent study from
Spain showed 70 per cent of the ESBL producing E.
coli from bacteraemia cases to be of CTX-M types
105
.
Indian scenario
In India, ESBL producing strains of
Enterobacteriaceae have emerged as a challenge in
hospitalized as well as community based patients. In
1997, from Nagpur 17 out of 66 Klebsiella isolates
showed ESBL production
106
. In 2002, 68 per cent of
Gram negative bacteria were found to be ESBL
producers in a study from New Delhi in which 80 per
cent of Klebsiella were ESBL
107
. In 2004 two other
studies from Delhi showed 70.6 and 12.6 per cent
Klebsiella isolates to be ESBL producers
respectively
108,109
. Another comparatively recent study
in 2005 from New Delhi, showed 68.78 per cent of the
strains of Gram negative bacteria to be ESBL
producers
110
. ESBLs have been reported from
community isolates from north India as well
111
. A study
from Coimbatore, Tamil Nadu, showed the presence of
ESBL to be 40 per cent while from Nagpur this figure
was 50 per cent in urinary isolates
112,113
. In a study from
420 INDIAN J MED RES, NOVEMBER 2007
Chennai, ESBL production was detected in 6 out of 90
isolates of K. pneumoniae in children under five with
intestinal infections
114
. Further a study from Karnataka
showed the frequency of ESBLs in neonatal septicaemic
cases to be 22.7 per cent
115
. A similar study from
Lucknow showed high levels of ESBL production (63.6-
86.6 %)
116
. Amp C enzyme has also been described in
3.3 per cent of isolates from Karnataka
117
. Metallo-beta-
lactamase production is a significant problem especially
in hospital isolates of P. aeruginosa and Acinetobacter
species. Reports have described the prevalence of MBLs
in P. aeruginosa
118,119
and Acinetobacters species as well
from India
120
.
The results of the initial studies for the MYSTIC
programme in India confirmed the high levels of
resistance and ESBL production in Gram-negative
bacilli including Salmonella
121
. The latest report from
National Institute of Communicable Diseases (NICD),
New Delhi, India, shows PCR as a reliable method for
detection of ESBLs as well as the rise of resistance to
cefepime - a fourth generation cephalosporin
122
. CTX-
M-15 has also been found in Indian E. coli and K.
pneumoniae strains
123
.
Methods of detection
Different ESBL enzymes depict variable levels of
resistance to third generation cephalosporins. According
to National Committee for Clinical Laboratory
Standards (NCCLS) now Clinical and Laboratory
Standards (CLSI) interpretive definitions, ESBLs do not
always increase MICs to levels characterized as
resistant
124,125.
Now, it is mandatory that the routine
clinical microbiology laboratory employs ESBL
detection methods which are sensitive enough to
recognize the level of resistance that would be achieved
by the situation given in vivo.
Screening tests: Initial screening for reduced
susceptibility to cefpodoxime, cefotaxime, ceftriaxone,
ceftazidime or aztreonam and then performing
phenotypic confirmatory test is recommended. As
proposed by the CLSI, M100-S-16 document, the use
of more than one of the five indicator cephalosporins
suggested will improve the sensitivity of detection
126
.
But, if it is necessary to rely on a single screening
substance, ceftazidime or cefpodoxime would be the
best choice
127
.
Confirmatory tests
127
: (i) The double disk approximation
test: A susceptibility disk containing amoxicillin-
clavulanate and a disk containing one of the oximino
-lactam antibiotics is used. Enhancement of the zone
of ceftazidime disk on the side facing the amoxicillin-
clavulanate disk is interpreted as a positive test
129
. (ii)
Combined disk method - Commercialized disks
containing clavulanate plus ceftazidime or cefotaxime
(10 g plus 30 g respectively) are used in this
method
130
. (iii) E test ESBL strip- In this method the
zone of inhibition is read from two halves of the strip.
A decrease in the MIC of ceftazidime of more than three
dilutions in the presence of clavulanate is interpreted
as a positive test. Sometime due to weak enzyme
production, indeterminate results may be obtained. (iv)
Three dimensional test- This method is very sensitive,
but is technically difficult and labour-intensive requiring
experienced clinical microbiologist to interpret the
result
131
.

(v) The automated ESBL microbial
susceptibility test system- This method utilizes either
ceftazidime or cefotaxime alone and in combination
with clavulanic acid (4 g/ml). A predetermined
reduction in growth in wells containing clavulanate
compared with those containing each single drug
indicates the presence of an ESBL. Vitek ESBL test
system has shown variable results
132
. (vi) Recently CLSI
has recommended initial screening by testing for growth
in a broth medium containing 1 g/ml of one of five
extended spectrum -lactam antibiotics
128
. For
identification of specific ESBL expressed in a clinical
isolate, the following molecular detection methods can
be applied: Specific DNA probes, PCR with
oligonucleotide primers oligotyping, PCR followed by
restriction fragment length polymorphism analysis,
ligase chain reaction and nucleotide sequencing. These
techniques are available only in research centres and
are beyond the scope of routine clinical microbiology
laboratories.
Regarding the reporting of ESBL producing
isolates, the microbiology laboratory report should state
that the strain produced ESBL and should be considered
resistant to all penicillins, cephalosporins and
aztreonam.
For clinical laboratories to adapt a method for
screening for metallo beta-lactamases, the suggested
methodology is as follows; firstly, the isolates are
targeted based on ceftazidime and carbapenem MIC,
e.g. P. aeruginosa with an imipenem MIC> 16 g/ml
and Acinetobacter spp. isolates with an MIC >2 g/ml
is appropriate. For ease of application, the E test MBL
strip is recommended
133
. To increase the sensitivity of
MBL detection, several substrates (imipenem,
ceftazidime and meropenem) should be used preferably
GUPTA: NEWER -LACTAMASES 421
with more than one inhibitor (EDTA and
mercaptopropionic acid)
134
. It should be of help if
clinical laboratories are able to detect organisms
producing plasmid mediated Amp-C -lactamases with
a method, which is simple as well as inexpensive. CLSI
has no recommendations available for detection of these
organisms. A number of reports have been published
based on different methodologies used
135-137
.
Treatment
ESBL producing members of Enterobacteriaceae
are, as a rule, resistant to all cephalosporins and
extended spectrum penicillins, including the
monobactam, aztreonam, while resistance to
trimethoprim-sulfamethoxazole and aminoglycosides is
frequently co-transferred on the same plasmid
138
. Third
and fourth generation cephalosporins should not be used
even in the presence of apparent susceptibility.
Cephamycins such as cefoxitin, cefotetan and
moxalactam may be used for ESBL producing E.coli
and Klebsiella spp. However, cephamycin therapy leads
to emergence of plasmid mediated Amp C resistance.
These enzymes are phylogenetically very distinct from
the ESBL families and confer resistance to third
generation cephalosporins as well as cephamycins
139,140
.
ESBLs are usually susceptible to -lactam / -lactamase
inhibitor combinations, but these drugs can usually be
overwhelmed by particularly large amounts of enzyme
and thus show in vivo resistance. Treatment with -
lactam/ -lactamase inhibitor combination was shown
to be inferior to treatment with imipenem or piperacillin/
tazobactam plus aminoglycoside combination in an
animal model
140
. Currently the carbapenems, are
regarded as the drugs of choice against ESBL producing
organisms
7
. Carbapenem treatment however, is not
without its own complication because MBL producers
which are carbapenem resistant, have already spread in
various parts of the world
98,99
. The only therapeutic
option available for MBL producers is polymyxin
141
.
These molecules should not be used as monotherapy
but may be combined with some aminoglycoside
molecule. Also rifampin may be an interesting agent
for treating multi-drug resistant P. aeruginosa
infections. Thus, there is a need for developing novel
agents in the near future otherwise these organisms may
lead to therapeutic dead ends.
Control measures
Proper infection control practices and barriers are
essential to prevent spread and outbreaks of ESBL
producing bacteria. The reservoir for these bacteria
seems to be gastrointestinal tract
142
, oropharynx,
colonized wounds and urine.
The colonized hands, equipment could help in
spreading infection between patients. So, mandatory
infection control practices would be hand washing,
barrier precautions, isolation of colonized/infected
patients. Surveillance of patients of ICUs will help in
early detection and control practices related to ESBL
production. Antibiotic restriction and antibiotic cycling
especially the empirical use of higher generation
cephalosporins and carbepenems are other measures
which if monitored properly, could help in control of
the emergence and spread of ESBL producing bacteria.
Conclusion
The incidence of infections due to organisms
resistant to -lactam agents due to production of various
enzymes has increased in recent years. Detection of
ESBL production is of paramount importance both in
hospital and community isolates. Firstly, these strains
are probably more prevalent than currently recognized.
Secondly, ESBLs constitute a serious threat to currently
available antibiotics. Thirdly, institutional outbreaks are
increasing because of selective pressure due to heavy
use of expanded spectrum cephalosporins and lapses
in effective control measures. So vigilance and timely
recognition of infection with resistant bacteria and
appropriate antibiotic therapy, is the only answer to the
current multi drug resistant bacterial population. Careful
attention to barrier precautions and hand hygiene can
help in preventing the spread of these, multi drug
resistant Gram-negative microorganisms.
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Reprint requests: Dr Varsha Gupta, Professor, H.No.3109, Sector 48-D, Chandigarh 160047, India
e-mail: varshagupta_99@yahoo.com
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