Antibiotics In Agriculture
- From: rpautrey2 <rpautrey2@xxxxxxxxx>
- Date: Sun, 3 Feb 2008 00:26:06 -0800 (PST)
Antibiotics In Agriculture
PNAS | April 30, 2002 | vol. 99 | no. 9 | 5752-575
PubMed Citation
by Lipsitch, M.
by Levin, B. R.
Commentary
Article
Everybody knows that bacterial resistance to antibiotics is a bad
thing, at least for humans and animals, if not for bacteria. Drugs
that were effective for treating community- and hospital-acquired
infections are no longer so because the target bacteria are resistant
to their action. To be sure, it may be some time before we really
enter the predicted "postantibiotic era" in which common infections
are frequently untreatable. Even now, however, the consequences of
resistance in some bacteria can be measured as increases in the term
and magnitude of morbidity, higher rates of mortality, and greater
costs of hospitalization for patients infected with resistant bacteria
relative to those infected with sensitive strains (1). Dozens of new
antimicrobial compounds have been licensed in the U.S. during the last
half century, but almost all "new antibiotics" introduced in the last
40 years have been relatively minor chemical variants of compounds to
which bacteria have already developed resistance. As a result,
bacteria have rapidly adapted existing resistance mechanisms to evade
the new compounds. Indeed, only a single chemically novel class of
antibacterial agents, the oxazolidinones, has been introduced into
clinical use since the 1970s.
There is no question that the resistance problem is of our own making,
a direct consequence of the appropriate as well as the inappropriate
use of these "wonder drugs" by humans. The abundant calls for the more
prudent use of antibiotics (http://www.healthsci.tufts.edu/apua/
apua.html) are well justified, if seemingly unnecessary. Who would
admit to being against the prudent use of anything? Although it is not
clear that by reducing our use of these drugs alone we will be able to
reverse the growing tide of resistance (2-5), we can certainly slow
and maybe even stop that tide. But how do we reduce antibiotic use?
Although many antibiotic-prescribing decisions in human medicine may
be black or white (clearly medically necessary or clearly not
indicated), there is a large gray area in which they provide a small
but significant clinical benefit to the individual (for example, more
rapid cure of acute otitis media) or psychological benefit to the
patient (for example, a placebo effect) and/or the physician (for
example, to facilitate the closure of a consultation). These gray-area
applications of antibiotics must be weighed against the incremental
harm to the population as a whole caused by the additional selective
pressure for antimicrobial resistance. In such contexts, determining
what is an appropriate use of an antibiotic is a judgment call in
which cultural, social, psychological, and economic factors play at
least as great a role as clinical and epidemiological considerations.
Over half of the antibiotics that are produced in the U.S. are used
for agricultural purposes.
The article in this issue by Smith et al. (6) focuses on the theater
of antibiotic use that for more than three decades (7) has been the
major target of those campaigning to reduce antibiotic use: their use
for growth promotion and treatment of food animals. Over half of the
antibiotics that are produced in the U.S. are used for agricultural
purposes, according to a recent estimate (8), and there is no question
that this application of these drugs has contributed to the generally
high frequency of resistant bacteria in the gut flora of chickens,
swine, and other food animals. However, regulation of agricultural
uses of antibiotics has been controversial, largely because
policymakers have been urged to weigh the clear benefits to animal
health as well as the economic benefits of antibiotic use to food
producers, pharmaceutical companies, and possibly also to consumers
against a threat to human health that is often difficult to quantify
precisely. Antibiotic use in animals has at least four potential
effects on human health, each of which presents separate challenges to
unambiguous documentation and quantitative measurement.
The most readily demonstrable and quantifiable effect of antibiotic
use in animals and resistance in animal flora on human health is
through zoonotic infections that are rarely transmitted between
humans. By ingesting contaminated meat (or other foods that have been
cross-contaminated by animal manure or by meat-borne bacteria during
preparation), people can become infected by bacteria that can be
pathogenic to humans and are resistant to one or more of the drugs
that could be used to treat these infections. An example that has
engendered much recent discussion is gastroenteritis (food poisoning)
caused by Campylobacter jejuni resistant to fluoroquinolones
(ciprofloxacin and related compounds). Among their many uses,
fluoroquinolones are used to treat chickens for bacterial infections,
and fluoroquinolone-resistant Campylobacter have been found in raw
chicken. Thus, it would seem that consumption of chickens would be a
risk factor for the acquisition of a fluoroquinolone-resistant
Campylobacter infection, and some studies, although not all, have
supported this proposition. A recent risk assessment study
commissioned by the U.S. Food and Drug Administration (FDA) has
estimated that about 8,000-10,000 persons in the U.S. each year
acquire fluoroquinolone-resistant Campylobacter infections from
chicken and attempt to treat those infections with a fluoroquinolone
(9). Molecular epidemiological studies provide further support for the
causal link between chicken consumption and fluoroquinolone-resistant
Campylobacter infections. The strains of Campylobacter found in the
meat of chickens seem to be identical to those responsible for human
infections (10).
Nevertheless, even in this seemingly straightforward situation,
unequivocally documenting and quantifying the effects of antibiotic
use in food animals on human health has caveats. First, the presence
of identical strains of fluoroquinolone-resistant Campylobacter in
chickens and in humans does not causally link the use of
fluoroquinolones in the chickens to the resistant strains. There is
ample evidence to suggest that bacteria, including resistant strains,
enter the poultry environment from many different sources (11), and
that transmission of resistant bacteria on a farm may occur in the
absence of antibiotic-mediated selection (12). Thus, humans may
acquire resistant infections from food animals even if antibiotics are
not used by those animals. Second, epidemiological studies have
identified other risk factors for Campylobacter infection in humans,
including contact with companion animals, like dogs and cats. These
animals may be treated with fluoroquinolones but are rarely tested as
potential sources of the human infection.
Unfortunately, the other three ways in which antibiotic use and
resistance in food animals can impinge on human health are even more
difficult to document unambiguously, much less to quantify. The first
of these possible contributions is as a breeding ground for resistance
genes and operons, for the accumulation of these genes on integrons
and their movement to plasmids and other accessory elements. That is,
animal use could in principle be a selective force responsible for the
assembly of resistance gene clusters [like that postulated for the
vancomycin-resistance operons in Enterococcus or the multiple-
resistance island in Salmonella DT104 (13)] and movement of those
genes and clusters from their ancestral bacteria into the commensal
and pathogenic bacteria of mammals. Second, once the genetic machinery
for resistance or multiple resistance is assembled, commensal bacteria
inhabiting food animals may serve as a reservoir for resistance-
encoding plasmids and other accessory elements, and the size of this
reservoir will be enhanced by antibiotic use in agriculture. When
humans ingest these animal commensals, they may transfer their
resistance elements to other strains or species that are pathogenic to
humans. In this case, bacteria from zoonotic sources serve as vectors
that transmit resistance genes to the human bacterial flora. Finally,
there is the contribution of antibiotic use in food animals to
resistance in bacteria that are shared by food animals and humans and
infectiously transmitted among humans. Among the more notorious of
these examples are vancomycin-resistant strains of Enterococcus that
plague the intensive care units of hospitals. In this situation, it is
clear that resistant organisms can enter human flora from contact with
farm animals, but the majority of human exposure occurs through
transmission from one human to another (largely in hospitals), rather
than from direct exposure to animal sources and is amplified by the
extensive use of vancomycin in these settings.
Although these last three contributions of antibiotic use in food
animals to human health are hard to directly document and quantify
empirically, the Smith et al. (6) article in this issue of PNAS offers
a way to quantitatively evaluate the last of these possible
contributions (and to some extent the penultimate). They address and
provide answers to questions that should be of considerable interest
to policymakers formulating regulations for the use of antibiotics in
food animals: If human exposure to antibiotic-resistant commensal
bacteria from food animals could be limited or prevented, how much
difference would it make to the impact of these bacteria (and
resistance-encoding accessory elements) on human health, and what
factors affect the magnitude of this difference?
Smith et al. (6) use a simple but realistic mathematical model in
which there is a constant influx of resistant bacteria via food to the
human population. Based on the analysis of the properties of this
model, they conclude that for bacteria like Enterococci that are
frequently transmitted among humans, "input" of resistant strains from
the food chain will make only a small difference in the eventual
equilibrium prevalence of resistant strains in the human population.
The reason for this conclusion is intuitively appealing; the rate of
input of resistant bacteria from animal sources is small relative to
the amplification achieved by the human use of antibiotics and the
transmission of resistant strains among humans. More colloquially,
their theoretical results support the adage that once the horse has
fled the barn, it is too late to close the door. On the other side,
their results also point to the role antibiotic use in food animals
may have had in unlocking if not fully opening that door. The use of
antibiotics in food animals may have little effect on the eventual
prevalence of resistance in human commensals, but if extensive animal
use precedes extensive human use of drugs, the animal use may well
shorten the time before resistance becomes problematic in the human
flora.
The regulations they implement may come too late to prevent the spread
of resistance to that drug in the commensal and pathogenic bacteria of
humans.
The finding by Smith et al. (6) suggests that once evidence of the
medical impact of antimicrobial use is apparent (as measurable
frequencies of resistant infections of humans by commensal bacteria
resistant to clinically important drugs), regulation of the animal use
of those drug classes would have little or no effect. If valid and
general, this finding creates a difficulty for regulators. Faced with
industry and political pressure to show a "scientific basis" for
restrictions on antimicrobial use, the regulations they implement may
come too late to do anything to prevent the spread of resistance to
that drug in the commensal and pathogenic bacteria of humans. This
dilemma is not unique to the use of antibiotics in animals. In
designing policies that affect infectious diseases (14), global
climate (15), or other systems with their own internal dynamics,
waiting until there is evidence of conclusive harm may result in a
missed opportunity to prevent damage, because the effects of a policy
change once the damage is done may be weak or delayed. In such
situations, the desire for a scientific basis for regulatory action
must be weighed against the potential risks of inaction. Defining
these potential risks, as Smith et al. have done, then becomes an
important role for scientific studies, alongside more conventional
efforts to document existing harms.
The other side of this finding by Smith et al. (6) also has the
potential for being controversial. In essence, they suggest that
regulators should have little concern about the use of drugs in
animals for which resistant commensals are already problematic in
humans. This suggestion contrasts with the traditional recommendation
of permitting animal use only for those drugs that are rarely used in
human medicine. As Smith et al. conclude, "the agricultural use of
antibiotics in new resistance classes should be delayed until the
period of maximum medical utility has passed."
Their conclusion could be, and doubtless will be, seen as support for
the continued use of antibiotics in food animals. If a drug used to
treat or promote the growth of food animals has little or no impact on
human health, is beneficial to the health of the animals, and reduces
the cost of food production, why not use it? However, as Smith et al.
(6) caution, there are caveats associated with this interpretation of
their findings. One is that their conclusion applies to resistance in
bacteria that are transmitted among humans for which most of the human
resistance can be attributed to the human use of those drugs. Their
conclusion does not apply to purely zoonotic infections of humans
where resistance could preclude effective treatment, like the
antibiotic-resistant Campylobacter or Salmonella infections acquired
from meat (10, 16). Finally, their model and analysis does not address
the problem of associated linkage selection in bacterial strains or
plasmids that carry multiple genes for resistance to different
antibiotic classes. For example, the use of tetracycline in food
animals may have little or no effect on the utility of tetracycline
for human use, because it is rarely used for the treatment of food-
borne infections or of commensals acquired from food. However, animal
tetracycline use could well increase the frequency of multiple
antibiotic-resistance plasmids, which, in addition to tetracycline
resistance, carry genes for resistance to antibiotics for which
resistance in human pathogens and commensals would be more
problematic. The same principles apply to multiply resistant bacterial
strains, regardless of whether resistance is plasmid-borne or
chromosomal.
The controversy about the contribution of agricultural antibiotic use
to clinically important resistance in human medicine is fueled and
sustained by the problem of obtaining direct, quantitative information
about the magnitude and nature of that contribution. The article by
Smith et al. (6) offers an alternative way to evaluate this
contribution through the use of mathematical models of the processes
involved in the spread of resistance from food animals to humans. As
Smith et al. emphasize, their model should not be taken as a precise
risk assessment or a quantitative prediction but rather as an
illustration of possible mechanisms. Nonetheless, they have taken
pains to make assumptions that are consistent with what is known and
that make biological sense. Further investigations are certainly
required to document and measure many of these biological processes.
More immediately, however, Smith et al. make the case that
restrictions of antibiotic use in animals cannot always wait for
incontrovertible evidence of harm and that, indeed, such delays may
result in a lost opportunity to preserve the usefulness of classes of
antibiotics in human medicine. They also raise the point that under
some conditions, there may be little or no harm to human health if the
antibiotics used for animal use are those for which resistance is
already common in bacteria that are commensal inhabitants and
opportunistic pathogens of humans.
Acknowledgements
We thank Fernando Baquero for helpful comments on the manuscript. M.L.
is supported by National Institutes of Health Grant AI48935 and by a
Research Starter grant from the Pharmaceutical Research and
Manufacturers of America Foundation. R.S.S. is supported by U.S.
Department of Agriculture Cooperative State Research, Education, and
Extension Service Grant 00-35212-9398. B.R.L. is supported by National
Institutes of Health Grants GM33782 and AI40662 and by the Wellcome
Trust.
Note Added in Proof
Since this commentary was written, market forces have begun to move
the debate over antibiotic use in agriculture in new ways. It was
recently reported that several major poultry producers had decided to
stop using fluoroquinolones to treat chickens (17). Most recently,
Russia banned imports of chicken from the U.S., citing concern about
antibiotic residues in the meat (18).
Footnotes
See companion article on page 6434.
E-mail: mlipsitc@xxxxxxxxxxxxxxxxx
References
1. Rubin, R. J. , Harrington, C. A. , Poon, A. , Dietrich, K. ,
Greene, J. A. & Moiduddin, A. (1999) Emerg. Infect. Dis. 5, 9-17[ISI]
[Medline] .
2. Levin, B. R. , Lipsitch, M. , Perrot, V. , Schrag, S. , Antia,
R. , Simonsen, L. , Walker, N. M. & Stewart, F. M. (1997) Clin.
Infect. Dis. 24, S9-S16.
3. Stewart, F. M. , Antia, R. , Levin, B. R. , Lipsitch, M. &
Mittler, J. E. (1998) Theor. Popul. Biol. 53, 152-165[CrossRef]
[Medline] .
4. Lipsitch, M. (2001) Trends Microbiol. 9, 438-444[CrossRef][ISI]
[Medline] .
5. Levin, B. R. (2001) Clin. Infect. Dis. 33, Suppl. 3, S161-S169.
6. Smith, D. L. , Harris, A. D. , Johnson, J. A. , Silbergeld, E. K.
& Morris, J. G. (2002) Proc. Natl. Acad. Sci. USA 99,
6434-6439[Abstract/Free Full Text].
7. Swann, M. M. (1969) Report of the Joint Committee on the Use of
Antibiotics in Animal Husbandry and Veterinary Medicine (Her Majesty's
Stationery Office, London).
8. Mellon, M. , Benbrook, C. & Benbrook, K. L. (2001) Hogging It:
Estimates of Antimicrobial Abuse in Livestock (Union of Concerned
Scientists, Washington, DC).
9. Food and Drug Administration. Center for Veterinary Medicine.
(2001) The Human Health Impact of Fluoroquinolone-Resistant
Campylobacter Attributed to the Consumption of Chicken (Food Drug
Admin., Washington, DC).
10. Smith, K. E. , Besser, J. M. , Hedberg, C. W. , Leano, F. T. ,
Bender, J. B. , Wicklund, J. H. , Johnson, B. P. , Moore, K. A. &
Osterholm, M. T. (1999) N. Engl. J. Med. 340, 1525-1532[Abstract/Free
Full Text].
11. Kinde, H. , Read, D. H. , Ardans, A. , Breitmeyer, R. E. ,
Willoughby, D. , Little, H. E. , Kerr, D. , Gireesh, R. & Nagaraja, K.
V. (1996) Avian Dis. 40, 672-676[CrossRef][ISI][Medline] .
12. Marshall, B. , Petrowski, D. & Levy, S. B. (1990) Proc. Natl.
Acad. Sci. USA 87, 6609-6613[Abstract/Free Full Text].
13. Boyd, D. , Peters, G. A. , Cloeckaert, A. , Boumedine, K. S. ,
Chaslus-Dancla, E. , Imberechts, H. & Mulvey, M. R. (2001) J.
Bacteriol. 183, 5725-5732[Abstract/Free Full Text].
14. Trichopoulos, D. & Adami, H. O. (2001) N. Engl. J. Med. 344,
133-134[Free Full Text].
15. Michaelowa, A. & Rolfe, C. (2001) Environ. Manage. 28,
281-292[Medline] .
16. Fey, P. D. , Safranek, T. J. , Rupp, M. E. , Dunne, E. F. ,
Ribot, E. , Iwen, P. C. , Bradford, P. A. , Angulo, F. J. & Hinrichs,
S. H. (2000) N. Engl. J. Med. 342, 1242-1249[Abstract/Free Full
Text].
17. Burros, M. (2002) NY Times (Print) Sect, 1, col. 6.
18. Peralte, P. C. (2002) Altanta J. Const. , p. H.1.
www.pnas.org/cgi/doi/10.1073/pnas.092142499
Companion article to this Commentary:
Animal antibiotic use has an early but important impact on the
emergence of antibiotic resistance in human commensal bacteria
David L. Smith, Anthony D. Harris, Judith A. Johnson, Ellen K.
Silbergeld, and J. Glenn Morris, Jr.
PNAS 2002 99: 6434-6439. [Abstract] [Full Text]
This article has been cited by other articles in HighWire Press-hosted
journals:
L. Macovei and L. Zurek
Influx of Enterococci and Associated Antibiotic Resistance and
Virulence Genes from Ready-To-Eat Food to the Human Digestive Tract
Appl. Envir. Microbiol., November 1, 2007; 73(21): 6740 - 6747.
[Abstract] [Full Text] [PDF]
M. S. Smith, R. K. Yang, C. W. Knapp, Y. Niu, N. Peak, M. M. Hanfelt,
J. C. Galland, and D. W. Graham
Quantification of Tetracycline Resistance Genes in Feedlot Lagoons by
Real-Time PCR
Appl. Envir. Microbiol., December 1, 2004; 70(12): 7372 - 7377.
[Abstract] [Full Text] [PDF]
P. Ebner, K. Garner, and A. Mathew
Class 1 integrons in various Salmonella enterica serovars isolated
from animals and identification of genomic island SGI1 in Salmonella
enterica var. Meleagridis
J. Antimicrob. Chemother., June 1, 2004; 53(6): 1004 - 1009.
[Abstract] [Full Text] [PDF]
Copyright © 2002 by the National Academy of Sciences
.
- Prev by Date: Fermented Foods
- Next by Date: Bacteriotherapy To Displace Pathogenic Organismsis
- Previous by thread: Fermented Foods
- Next by thread: Bacteriotherapy To Displace Pathogenic Organismsis
- Index(es):
Relevant Pages
|
Loading
