xd.

1. The emergence of pan-resistant Gram-negative pathogens merits
a rapid global political response
Timothy R. Walsh1,2* and Mark A. Toleman1
1
Section of Medical Microbiology, 6th Floor Main Building, IIB, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;
2
Clinical Centre for Research, University of Queensland, Royal Brisbane & Women’s Hospital, Herston QLD 4006, Australia
*Corresponding author. Tel: +44-2920-744725; Fax: +44-2920-742161; E-mail: t.r.walsh@uq.edu.au
Recent media coverage of New Delhi metallo-b-lactamase (NDM-1) put antibiotic resistance back on the pol-
itical map if only for the wrong reasons, mainly the reaction to the naming of NDM-1 and the incorrect assump-
tion that medical tourism was being deliberately targeted. However, work on NDM-1 has most certainly
highlighted the rapid dissemination of new antibiotic resistance mechanisms via economic globalization. The
example of NDM-1 has also magnified the desperate need for a publicly funded global antibiotic surveillance
system rather than just national or regional systems. Furthermore, there is a pressing need to establish a
global task force to enforce international transparency and accountability on antibiotic stewardship and the
implementation of measures to curb antibiotic resistance. An international antibiotic stewardship index
should be established that is related to each country’s gross domestic product (GDP) and assesses how
much of their GDP is committed to publically funded health initiatives aimed at controlling antibiotic resistance.
Keywords: global antibiotic resistance, NDM-1, New Delhi metallo-b-lactamase, India, southern Asia
There are few antibiotic resistance mechanisms that have cap-
tured the attention of scientists, as well as politicians and the
general public, more than New Delhi metallo-b-lactamase-1
(NDM-1). While methicillin-resistant Staphylococcus aureus
(MRSA) and Clostridium difficile have monopolized the media
headlines for some years, the advent of the ‘NDM-1 superbug’
(as it has been referred to in the media) heralds in a new era in anti-
biotic resistance both in the UK and abroad.1
The fact that this new
resistance was not primarily clonally spread but could disseminate
rapidly via plasmid transmission among the normal human Gram-
negativeintestinalflorawas an important finding.1,2
Humanscarry
10–100 trillion bacteria as normal flora, and the potential for the
NDM-1 gene pool to ‘hide’ in normal human Gram-negative flora is
enormous. Extrapolating the data from our recent NDM-1 environ-
mental study,3
and further supported by the recent article by Perry
et al.,4
we estimate that at least 100 million Indian residents carry
NDM-1-positive bacteria as normal gut flora; therefore the poten-
tial for endogenous infections such as untreatable cystitis is frigh-
tening.3 – 6
We suspect that this carriage rate is similar elsewhere in
southern Asia. As judged by the ‘WHO Global Strategy for Contain-
ment of Antibiotic Resistance’, the WHO has historically failed to
understand the indubitable link between antibiotic resistance
and lack of adequate sanitation.7
For India, this is a particularly
pressing issue, as approximately700 million people lackbasic sani-
tation and more people own mobile phones than toilets.8 – 10
In
short, India’s sanitation is woefully inadequate and is one of the
key reasons why so many Indians could be carrying Enterobacter-
iaceae expressing NDM-1. For this situation to arise in a country
that claimsto be akeyeconomic global powerand boasts more bil-
lionaires, millionaires and international offshore accounts than
most other countries is bitterly regrettable and, as evidenced by
NDM-1, also has profound international ramifications. Pound for
pound, or dollar for dollar, the greatest impact global stakeholders
could have on antibiotic resistance is to provide adequate sani-
tation and access to potable water—a basic human right that
has been seemingly forgotten.11
The key chronological events surrounding the NDM-1 story
and the political reaction are summarized in Table 1. The
response of the Indian government and officials to reports on
NDM-1 involved a damage limitation exercise driven by national
pride and a perceived need to protect their pharmaceutical
industry and their lucrative ‘medical tourism’ practice. Despite
this response, the naming of the enzyme as NDM-1 no doubt
forced the Indian government to finally initiate measures to
curtail the continuing spread of resistance, culminating in a
document on the ‘Indian strategy to tackle antibiotic resist-
ance’.12
Likewise, an article published in April 20113
forced the
government to admit the lack of uncontaminated potable
water and to subsequently distribute chlorine tablets 1 week
after the paper was published.13
India currently produces at least 30% of the world’s oral and
injectable antibiotics, and could rightly argue they are supporting
the WHO agenda of supplying the world with affordable medi-
cines. However, overuse of antibiotics that are excreted by
patients and find their way into hospital and community waste-
water systems provides an environmental selection pressure for
# The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother 2012; 67: 1–3
doi:10.1093/jac/dkr378 Advance Access publication 12 October 2011
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2. the emergence and persistence of multidrug-resistant (MDR) and
pan-drug-resistant (PDR) bacteria.14– 17
Perhaps, ironically, this
industry that we are so globally reliant on also spawns super-
bugs; other industries such as tourism or ‘medical tourism’
then export them around the world.1
The pipeline for new and promising antimicrobials against
NDM-1 producers looks equally lamentable. ACHN-490 [a novel
aminoglycoside (‘neoglycoside’)] is likely to have little or no activity
due to the plethora of 16S rRNA methylases (ArmA, RmtC, RmtD)
carried by NDM-1 producers.18
Leucyl tRNA synthetase inhibitors
look promising, but data on emerging resistance are still not
clear, and while b-lactam/b-lactamase inhibitors look encoura-
ging,19,20
NDM-1 producers can produce up to nine different
b-lactamases, thereby complicating the picture. However, unless
international patent issues are adhered to and enforced, in the
medium to long term it is irrelevant what the antibiotic pipeline
produces. For example, before tigecycline was marketed in
Europe, formulations were available in southern Asia, i.e. inter-
national patent applications were blatantly ignored. This is a
major disincentive for pharmaceutical companies to spend
$1 billion to develop novel antibiotics—an increasingly serious
issue currently being addressed by national working parties21,22
and desperately requiring prominent political intervention.
Equally, it is regrettable that at a crucial time when there is a des-
perate need for novel antibiotics, pharmaceutical companies are
constantly merging and re-merging, resulting in a loss of focus
and the shedding of vital expertise that is lost to other disciplines
such as cancer research. The UK is also guilty of short-
sightedness—in the last 10–15 years, university microbiology
departments throughout the UK and elsewhere have either been
merged into oblivion or abolished altogether, such that research-
ers with vital expertise (bacterial physiologists and geneticists)
are far too few in number to adequately support industry in this
epic battle. Thus, at a time when PDR Enterobacteriaceae are
fast becoming a global reality, both academia and industry are ill
equipped to respond.
So, how will it end? Since various countries have blatantly
ignored previous suggestions for 10 years, will the WHO
World Health Day23
that was held on 6 April 2011 have any
impact?—probably not! First, it could be argued that capitalism
has plunged the international community into this quagmire, so
it may be that capitalism in the form of litigation is a plausible sol-
ution. Countries that have been sensible and prudent will spend
$10–$100 thousand per patient dealing with serious long-term
MDR and PDR infections that have been imported from other
‘not-so-prudent’ countries. These ‘prudent’ countries may legally
pursue other countries through the international courts, forcing
them to yield and finally accept a modicum of international
responsibility and accountability.
Second, the name of NDM-1 alone managed to effect change
because it inadvertently embarrassed a nation and held it firmly
under the international spotlight, eventually resulting in a publi-
cation on antibiotic resistance in India.24
Thus, can it be that an
international antibiotic stewardship index scoring system might
cause the same dramatic effect? Such an index would focus atten-
tion on national activities of antimicrobial stewardship (both com-
munity and hospital), sales of non-prescription antibiotics, and
implementation of credible infection control policies and national
antibiotic surveillance programs. Accordingly, each country would
be ranked, as has been done previously for other areas, such as
theinternationaltransparencyindex.25
Thiscausecouldconceivably
be highlighted at the annual European Antibiotic Awareness Day on
18 November,26
but with an increasing emphasis on global resist-
ance. Such a ranking system should be established by an appointed
international group of experts that is publically funded and comple-
tely dissociated from any political influence. Perhaps like the carbon
tax, ‘negligent’ countries, and in particular wealthy ‘negligent’
countries, who do not commit a reasonable proportion of their
GDP24
levels to public health issues should have a substantial inter-
national antibiotic tax levied upon them. The revenue from such a
tax could be pooled through reputable international organizations
(WHO) and used to fund antimicrobial drug discovery and develop-
ment programmes. Critics of such a proposal should reflect on the
UK MRSA rates, which were publically reported, engaged both the
local and national press, and forced wide-ranging measures to
reduce MRSA rates throughout the UK.27
Third, it is clear that in the case of NDM-1, medical and non-
medical tourism have played a significant role in disseminating
Table 1. Key chronological events of the NDM-1 story
Date Event
10 August 2010 Lancet Infect Dis press release on NDM-1
12 August 2010 first Lancet Infect Dis article on NDM-1 published1
12–20 August 2010 Indian co-authors placed under immense pressure by Indian media7
Late August 2010 Indian researchers told not to work on NDM-1
September 2010 Indian scientists told it is illegal to send isolates out of India
October 2010 meeting in New Delhi to formalize status of work on NDM-1
October–November 2010 Indian government sets up ‘Task Force’ to tackle antibiotic resistance
March 2011 Indian strategy to tackle antibiotic resistance published12
March 2011 GARP report of antibiotic resistance in India published24
7 April 2011 second Lancet Infect Dis paper on NDM-1 published on WHO antibiotic resistance press day3
8–9 April 2011 Indian government criticism of second paper
13 April 2011 Indian government distributes chlorine tablets13
April 2011 Indian government announces grants to work on NDM-1
GARP, Global Antibiotic Resistance Partnership.
Leading article
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3. NDM-1 around the planet via air travel. Therefore, not only
should there be an air travel carbon dioxide emissions tax, but
also a dissemination of infectious disease (DID) tax of 1%.
Such revenues would be enormous, but must be designated
for research into bird flu, H1N1 and, of course, PDR bacterial
pathogens. Not only would this vastly increase research capacity
into PDR pathogens, but it would put the issue foremost in the
minds of the general public and politicians—exactly where it
belongs!
Funding
M. A. T. is funded by the European commission FP7 PAR initiative.
Transparency declarations
None to declare.
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