New Delhi Metallo-beta-lactamase (NDM-1) is an enzyme which makes bacteria resistant to a

broad range of beta-lactam antibiotics. This includes antibiotics of the carbapenem family, which
are a mainstay for the treatment of antibiotic-resistant bacteria. The gene for NDM-1 is one
member of a large gene family that encodes beta-lactamase enzymes called carbapenemases.
Bacteria which carry such genes are often referred to in the news media as “superbugs”, since
infections with these bacteria are very hard to treat successfully. Indeed, the United Kingdom
Health Protection Agency has stated that “most isolates with NDM-1 enzyme are resistant to all
standard intravenous antibiotics for treatment of severe infections.”

Structure of the carbapenem backbone.

NDM-1 was first identified in December 2009 in a patient hospitalised in New Delhi with a
Klebsiella pneumoniae infection. It has since been detected in bacteria in India, Pakistan, the
United Kingdom, the United States, and Canada. The most common organisms expressing this
enzyme are the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae, but the gene
for NDM-1 can spread from one strain of bacteria to another through horizontal gene
[Link] are a class of beta-lactam antibiotics which are capable of killing most
bacteria by inhibiting the synthesis of one of their cell wall layers. The carbapenems were
developed to overcome antibiotic resistance mediated by bacterial beta-lactamase enzymes.
However, the blaNDM-1 gene produces NDM-1, which is a carbapenemase beta-lactamase – an
enzyme that hydrolyzes and inactivates these carbapenem antibiotics.
Carbapenemases are particularly dangerous resistance mechanisms, since they can inactivate a
wide range of different [Link] NDM-1 enzyme is one of the class B metallo-beta-
lactamase; other types of carbapenemase are class A or class D beta-lactamases. (The class A
Klebsiella pneumoniae carbapenemase (KPC) is currently the most common carbapenemase,
which was first detected in North Carolina, USA, in 1996 and has since spread worldwide. A
later publication indicated that Enterobacteriaceae that produce KPC were becoming common in
the United States.)
The resistance conferred by this gene (blaNDM-1) therefore aids the expansion of bacteria that
carry it throughout a human host, since they will face less opposition/competition from
populations of antibiotic-sensitive bacteria, which will be diminished by the original antibacterial
treatment.
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive
exposure to an antibiotic. Genes can be transferred between bacteria in a horizontal fashion by
conjugation, transduction, or transformation. Thus a gene for antibiotic resistance which had
evolved via natural selection may be shared. Evolutionary stress such as exposure to antibiotics
then selects for the antibiotic resistant trait. Many antibiotic resistance genes reside on plasmids,
facilitating their transfer. If a bacterium carries several resistance genes, it is called multiresistant
or, informally, a superbug.
The primary cause of antibiotic resistance is antibiotic use both within medicine and veterinary
medicine. The greater the duration of exposure the greater the risk of the development of
resistance irrespective of the severity of the need for [Link] widespread use of
antibiotics both inside and outside of medicine is playing a significant role in the emergence of
resistant [Link] are often used in rearing animals for food and this use among others
leads to the creation of resistant strains of bacteria. In some countries antibiotics are sold over the
counter without a prescription which also leads to the creation of resistant strains. In supposedly
well-regulated human medicine the major problem of the emergence of resistant bacteria is due
to misuse and overuse of antibiotics by doctors as well as [Link] practices contributing
towards resistance include the addition of antibiotics to the feed of livestock. Household use of
antibacterials in soaps and other products, although not clearly contributing to resistance, is also
discouraged (as not being effective at infection control).Also unsound practices in the
pharmaceutical manufacturing industry can contribute towards the likelihood of creating
antibiotic resistant strains.
Certain antibiotic classes are highly associated with colonisation with superbugs compared to
other antibiotic classes. The risk for colonisation increases if there is a lack of sensitivity
(resistance) of the superbugs to the antibiotic used and high tissue penetration as well as broad
spectrum activity against “good bacteria”. In the case of MRSA, increased rates of MRSA
infections are seen with glycopeptides, cephalosporins and especially [Link] the case of
colonisation with C difficile the high risk antibiotics include cephalosporins and in particular
quinolones and clindamycin.
The volume of antibiotic prescribed is the major factor in increasing rates of bacterial resistance
rather than compliance with antibiotics. A single dose of antibiotics leads to a greater risk of
resistant organisms to that antibiotic in the person for up to a year.
Inappropriate prescribing of antibiotics has been attributed to a number of causes including:
people who insist on antibiotics, physicians simply prescribe them as they feel they do not have
time to explain why they are not necessary, physicians who do not know when to prescribe
antibiotics or else are overly cautious for medical legal reasons. A third of people for example
believe that antibiotics are effective for the common cold  and 22% of people do not finish a
course of antibiotics primarily due to that fact that they feel better (varying from 10% to 44%
depending on the country). Compliance with once daily antibiotics is better than with twice daily
[Link] optimum antibiotic concentrations in critically ill people increase the frequency
of antibiotic resistance organisms. While taking antibiotics doses less than those recommended
may increase rates of resistance, shortening the course of antibiotics may actually decrease rates
of resistance.
Role of other animals
Drugs are used in animals that are used as human food, such as cows, pigs, chickens, fish, etc.,
and these drugs can affect the safety of the meat, milk, and eggs produced from those animals
and can be the source of superbugs. For example, farm animals, particularly pigs, are believed to
be able to infect people with MRSA. The resistant bacteria in animals due to antibiotic exposure
can be transmitted to humans via three pathways, those being through the consumption of meat,
from close or direct contact with animals, or through the environment.
The World Health Organization concluded that antibiotics as growth promoters in animal feeds
should be prohibited (in the absence of risk assessments). In 1998, European Union health
ministers voted to ban four antibiotics widely used to promote animal growth (despite their
scientific panel’s recommendations). Regulation banning the use of antibiotics in European feed,
with the exception of two antibiotics in poultry feeds, became effective in 2006. In Scandinavia,
there is evidence that the ban has led to a lower prevalence of antimicrobial resistance in (non-
hazardous) animal bacterial populations. In the USA federal agencies do not collect data on
antibiotic use in animals but animal to human spread of drug resistant organisms has been
demonstrated in research studies. Antibiotics are still used in U.S. animal feed—along with other
ingredients which have safety concerns.
Growing U.S. consumer concern about using antibiotics in animal feed has led to a niche market
of “antibiotic-free” animal products, but this small market is unlikely to change entrenched
industry-wide practices.
In 2001, the Union of Concerned Scientists estimated that greater than 70% of the antibiotics
used in the US are given to food animals (e.g. chickens, pigs and cattle) in the absence of
[Link] 2000 the US Food and Drug Administration (FDA) announced their intention to
revoke approval of fluoroquinolone use in poultry production because of substantial evidence
linking it to the emergence of fluoroquinolone resistant campylobacter infections in humans. The
final decision to ban fluoroquinolones from use in poultry production was not made until five
years later because of challenges from the food animal and pharmaceutical [Link],
there are two federal bills S.549and H.R. 962 aimed at phasing out “non-therapeutic” antibiotics
in US food animal production.
Origin and spread
The NDM-1 enzyme was named after New Delhi, the capital city of India, as it was first
described by Yong et al. in December 2009 in a Swedish national who fell ill with an antibiotic-
resistant bacterial infection that he acquired in [Link] infection was unsuccessfully treated in
a New Delhi hospital and after the patient’s repatriation to Sweden, a carbapenem-resistant
Klebsiella pneumoniae strain bearing the novel gene was identified. The authors concluded that
the new resistance mechanism “clearly arose in India, but there are few data arising from India to
suggest how widespread it is.” In March 2010 a study in a hospital in Mumbai found that the
majority of carbapenem-resistant bacteria isolated from patients carried the blaNDM-1 gene.
In May 2010 a case of infection with E. coli expressing NDM-1 was reported in Coventry in the
United Kingdom. The patient was a man of Indian origin who had visited India 18 months
previously, where he had undergone dialysis. In initial assays the bacteria was fully resistant to
all antibiotics tested, while later tests found that it was susceptible to tigecycline and colistin.
The authors warned that international travel and patients’ use of multiple countries’ healthcare
systems could lead to the “rapid spread of NDM-1 with potentially serious consequences”.
As of June 2010, there were three reported cases of Enterobacteriaceae isolates bearing this
newly described resistance mechanism in the US, the CDC stated that “All three U.S. isolates
were from patients who received recent medical care in India.” However, US experts have stated
that it is unclear if this strain is any more dangerous than existing antibiotic-resistant bacteria
such as methicillin-resistant Staphylococcus aureus, which are already common in the USA.
Structure of colistin, one of the few antibiotics able to treat NDM-1 positive bacterial infections.
In July 2010 a team in New Deli reported a cluster of three cases of Acinetobacter baumannii
bearing blaNDM-1 that were found in the intensive care unit of a hospital in Chennai, India in
April 2010. As previously, the bacteria were fully resistant to all the aminoglycoside β-lactam
and quinolone antibiotics, but were susceptible to tigecycline and colistin. This particularly broad
spectrum of antibiotic resistance was heightened by the strain bearing expressing several
different resistance genes in addition to blaNDM-1.
A study by a multi-national team was published in the August 2010 issue of the journal The
Lancet Infectious Diseases. This examined the emergence and spread of bacteria carrying the
blaNDM-1 gene. This reported on 37 cases in the United Kingdom, 44 isolates with NDM-1 in
Chennai, 26 in Haryana and 73 in various other sites in Pakistan and India. The authors’ analysis
of the strains showed that many carried blaNDM-1 on plasmids, which will allow the gene to be
readily transferred between different strains of bacteria by horizontal gene transfer. All the
isolates were resistant to multiple different classes of antibiotics, including beta-lactam
antibiotics, fluoroquinolones, and aminoglycosides, but most were still susceptible to the
polymyxin antibiotic colistin.
The Origin of SuperBug
In early August 2010 a chemical compound GSK 299423, was found to significantly fight
against antibiotic-resistant bacteria by making such bacteria unable to reproduce, citing a likely
treatment to the NDM-1 strain.
On August 21, 2010 Ontario, Canada had it’s first confirmed case of the “superbug” in
Brampton. There have been other confirmed cases in British Columbia and Alberta.
Indian response
The Indian health ministry has disputed the conclusion of the August 2010 Lancet study that the
gene originated in India or Pakistan, describing this conclusion as “unfair” and stating that Indian
hospitals are perfectly safe for treatment. Indian politicians have described linking this new drug
resistance gene to India as “malicious propaganda” and blamed multinational corporations for
what they describe as selective malignancy. A Bharatiya Janata Party politician has instead
argued that the journal article is bogus and represented an attempt to scare medical tourists away
from India. The Indian Ministry of Health released a statement “strongly refut[ing]” naming the
enzyme “New Delhi”. The primary author of the 2010 Lancet study, who is based in the
University of Madras, has stated that he does not agree with the part of the article that advises
people to avoid elective surgeries in India.
In contrast, an editorial in the March 2010 issue of the Journal of Association of Physicians of
India blamed the emergence of this gene on the widespread misuse of antibiotics in the Indian
healthcare system, stating that Indian doctors have “not yet taken the issue of antibiotic
resistance seriously” and noting little control over the prescription of antibiotics by doctors and
even [Link] Times of India states that there is general agreement among experts that
India needs both an improved policy to control the use of antibiotics and a central registry of
antibiotic-resistant infections.
In August 2010, the first reported death due to a bacteria expressing the NDM-1 enzyme was
recorded as a Belgian man who had become infected, while being treated in a hospital in
Pakistan. He died despite being administered colistin, a powerful antibiotic. A doctor involved in
his treatment said, “He was involved in a car accident during a trip to Pakistan. He was
hospitalized with a major leg injury and then repatriated to Belgium, but he was already
infected”.
New Update
Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi
metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated
the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the
UK.
Methods
Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south
India), Haryana (north India)—and those referred to the UK’s national reference laboratory.
Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene
blaNDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of
XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR
typing. Case data for UK patients were reviewed for evidence of travel and recent admission to
hospitals in India or Pakistan.
Findings
We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other
sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and
Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline
and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the
UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids:
those from UK and Chennai were readily transferable whereas those from Haryana were not
conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within
the past year, or had links with these countries.
Interpretation
The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated
international surveillance is needed.
Updated as per New Research on NDM1. till aug 13 2010.
by
Gyandotcom