Tools for Tracking Antibiotic Resistance
Naomi Lubick
Authors and
Disclosures
Posted: 05/23/2011; Environmental Health Perspectives.
2011;119(5):a214-a217. © 2011 National Institute of Environmental Health
Sciences
以下這篇只是摘錄:
Introduction
When a team of researchers from Sweden first started
measuring chemicals in a river near
Patancheru, India, they found shocking
concentrations of drugs flowing downstream—for example, levels of the potent
antibiotic ciprofloxacin greater than those found in the blood of humans
taking the drug. A major source of these drugs was treated wastewater
from pharmaceutical manufacturing plants that was discharged into the river
and surrounding environs, as Joakim Larsson and his colleagues from the
University of Gothenburg reported several years ago.[1] An
update published in PLoS ONE[2] now
links the drugs with downstream
development of microbes with genetic resistance to multiple antibiotics
typically used to treat human illness.
The researchers found snippets
of genetic material in bacteria from river sediments downstream of the treatment
plant that conferred resistance not only to ciprofloxacin, a fluoroquinolone,
but also to betalactams, aminoglycosides, sulfonamides, and other classes of
antibiotics. Several genes that provide resistance to ciprofloxacin
and have the ability to transfer between different bacteria were extremely
common at some of the sampling sites.[2]
What if the bacteria in Patancheru could develop ways to
survive the daily onslaught of ciprofloxacin, most likely over the course of
years in their river environment, and ended up passing on their new genetic
resistance to pathogenic bacteria that could be a threat to human health?
Although Larsson's team has yet to catalog antibiotic resistance in the local
population, people in the region are continually exposed to resistant
microbes as they use the river water for agriculture and everyday home life.
"This is a huge scary
experiment in nature," Larsson says.
Just how isolated these kinds of drug "hot spots"
are remains unknown, although researchers have pressed for global monitoring
of antibiotic use and resistance for the past several decades, across
disciplines as diverse as clinical medicine and ecotoxicity. Bringing together these fields reflects the breadth
of challenges in tracking antibiotic resistance, but new technologies and
ideas hold promise for the near future.
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Overcoming
a Lack of Coordination
"Misuse of antibiotics is obviously what creates
the basic factors that produce drug resistance," says Mario Raviglione,
director of the World Health Organization (WHO) department charged with
tuberculosis control; this is true in both the developing and developed worlds.
And despite educational campaigns by the U.S. Centers for Disease Control and Prevention
(CDC)[3]
and others aimed at improving clinicians' use of antibiotics, overprescribing remains a problem for
multiple reasons.[4]
Moreover, patient compliance—for
example, taking the full course of prescribed antibiotics—can be lax, which
leads to the evolution of more antibiotic-resistant pathogens.
Agricultural
use of human drugs adds to the threat of drug resistance. After World War II, antibiotics started to be used
for purposes such as growth promotion in livestock. Since then, antibiotics—and in some cases, the genes for
resistance to multiple drugs—have been found on industrial cattle, swine, and
shrimp farms,[5,6,7,8]
measured on chicken skins in grocery stores,[9] and even
detected in apple orchards sprayed with drugs originally intended for human
use.[10]
For World Health Day in April 2011 the WHO chose the
theme of the global spread of antibiotic resistance, marking a little over a
decade since the organization first called for patient and doctor guidelines to
protect antibiotics from becoming obsolete.[11] A
document issued by the WHO in 2001 put forth a series of recommendations for
patients and the general community, prescribers and dispensers, hospitals,
agricultural enterprises, national governments and health systems, and drug
developers and promoters.[12]
However, in general "very few countries, if any, have made a comprehensive
effort to do any of the measures included in the older guidelines," says
Raviglione, who led preparations for World Health Day 2011. "Why are
countries not picking them up? Lack of resources? Their health systems are not
strong enough? The cost of drugs?"
On 7 April 2011 the organization released updated
policy guidance for countries to curb the spread of antibiotic resistance in
health care settings.[13] Some of
this guidance is aimed at doctors and hospitals, while some is geared toward
policy makers and legislators. The simple package of policy recommendations is
intended to be easy for countries to adopt, Raviglione says. The WHO-level
focus on antibiotic resistance issues also gives health ministers around the
world a platform from which to call for funding and research attention at home.
Kink
in the Pipeline
Another worry underlying the issue of resistance is
the fact that pharmaceutical
companies are not discovering new antibiotics. At least three reasons
explain why the pipeline is so empty, says Ingrid Petersson, director of
science relations at pharmaceutical company AstraZeneca. First, finding new pathways in microbes or pinpointing proteins to
create new antibiotics is difficult, in part because of what could be
considered an embarrassment of possibilities with too many unknowns. Second,
she says, the regulatory environment is complicated: getting a drug through
approval processes takes a long time and costs a lot of money, among other
factors. And third, low prices for existing antibiotics—many of which are
generics—do not encourage companies to invest in new drugs.
"Existing, older antibiotics are cheaper, which
makes it difficult to achieve realistic prices for new antibiotics—prices which
would provide a viable return on investment," explains Colin Mackay,
director of communication and partnerships for the European Federation of the
Pharmaceutical Industries and Associations, a trade organization.
"Furthermore, antibiotics are only used acutely, perhaps only for a week
to ten days at a time. This adds to the difficulty in making a return on
investment. By comparison, treatments for chronic illnesses, say for
cardiovascular or musculoskeletal conditions, are used long term, perhaps for
the rest of the patient's life."
Nevertheless, some major companies are looking into
new antibiotics. For example, AstraZeneca is looking for solutions for
multidrug-resistant tuberculosis.[35,36]
Companies are investing money, sometimes by acquiring smaller companies that
have begun the research or joining in efforts with nonprofits[37] and
academic researchers. Petersson notes that the Trans Atlantic Task Force on
Antimicrobial Resistance,[38] formed
between the European Union and the United States as part of the 2009 EU–US
Summit Declaration,[39] will
present suggestions at this year's summit meeting for areas of cooperation,
including incentives for industry to pursue new drug development.
The WHO, the CDC, and other national, international,
and nonprofit organizations are pursuing alternative business models.
Government funding, as when a federal agency invests in vaccine research, may
be one option, Cars suggests. So-called advanced market commitments—where
governments pledge to purchase drugs, thus guaranteeing a market—is another
option. In its new policy guidance,[13] the WHO
calls for global and national commitments to develop drugs and share
information on the national costs of inaction, as well as "push" and
"pull" incentives to reduce the inherent risks in the initial phases
of research and development and to offset the risks of an uncertain market,
respectively.
Crossing
Boundaries
Heeding calls[40-42] for
better management of the drugs currently available to doctors will require much
more attention to trends of resistance. In particular, monitoring is now
lacking. "If anything, we don't know enough about developing countries to
understand the situation—what resistant bacteria are there? In Europe and the
U.S., systems of surveillance are in place, but not in most of Africa or
Asia," Raviglione says, referring to health systems, although the same
holds true for environmental surveys.
Europe and the United States use far more antibiotics
by volume as well as newer antibiotics compared with less affluent countries
that typically use fewer and older generations of drugs, Raviglione says. That
would indicate such countries might not yet have resistance to
latest-generation drugs the same way Europe and the United States do. But there
remains concern about the outsourcing of drug production to developing countries,
especially India and China, where lax enforcement of regulations could increase
the likelihood of unchecked environmental releases of active pharmaceutical
ingredients—hence studies such as Larsson's work in Patancheru. The potential
for impacts of manufacturing newer antibiotics in developing countries, with
possible unwanted environmental releases, has not yet been studied, say the
scientists contacted for this story.
Making data internationally available so that teams
are tracking the same genes and species in different countries may be one
avenue of attack on the issue of antibiotic resistance. Julian Davies, a
professor emeritus of microbiology and immunology at the University of British
Columbia, and David Graham, an environmental engineer at Newcastle University,
have been working on a proposal to bring together members of the medical,
environmental, and microbial research communities to address antibiotic
resistance issues. If funded, their efforts could result in local centers on
every continent working to monitor antibiotic resistance, look for simple
solutions to preventing the spread of antibiotic-resistant microbes inside
hospitals, and communicate about antibiotic resistance issues at an
international scale.
The interdisciplinary breadth needed to address the
many issues at hand have led to miscommunications stemming from vocabulary,
Graham says. Take the word transmission, he
explains: "To a physician or engineer, transmission means migration
between individuals at larger scales, whereas to a microbiologist transmission
is something at the micro-scale between the bacteria themselves. It took us
[the diverse members of the team working on the proposal] awhile to agree upon
a common language."
But microbes have few such communication barriers, and
they quickly find ways to communicate resistance, as plane transit brings
countries—and antibiotic resistance hot spots—closer together. Some of the
global aspects of the problem can be illustrated by last year's description of
NDM-1, a protein present on plasmids that confers antibiotic resistance to
multiple antibiotics.[43] The
mechanism of resistance traveled from hospitals in India to the United Kingdom
via patients who had visited the subcontinent, presumably for cheap medical
treatments, and then returned home. Furthermore, NDM-1 has appeared in tap
water and wastewater outside of hospital settings in New Delhi, according to
another recent report in The Lancet Infectious
Diseases,[44]
heightening concerns for local transmission in an urban environment
