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Antibiotic use in animal husbandry and
resistance development in human infections
Wolfgang Witte, PhD
Robert Koch Institute, Wernigerode, Germany
Two important factors impact on the emergence and spread of antibiotic resistance: transferable resistance genes
and selective pressure by use of antibiotics (1). Besides hospitals with a concentration of patients prone to infections
and corresponding antibiotic use, animal husbandry is a second considerable reservoir of heavy antibiotic use and
transferable antibiotic resistance. Industrial animal husbandry keeps large numbers of animals in comparably small
space and outbreaks of infections can easily spread. For technical reasons there is often mass medication of all
the animals of a particular flock. In Europe animals are also under transport stress when shipped from breeding
stations to farms for fattening. The consequence is a broad scale antibiotic prophylaxis.
For a number of decades antimicrobials have been used as growth promoters, especially in pig and poultry farming.
The use of growth promoters leads to 4 - 5 % more body weight for animals receiving them as compared to controls.
Much larger amounts of antibiotics are used in this manner than are used in medical applications: In Denmark in
1994, 24 kg of the glycopeptide vancomycin were used for human therapy, whereas 24,000 kg of a similar glycopeptide
avoparcin were used in animal feed. From 1992 to 1996, Australia imported an average of 582 kg of vancomycin per
year for medical purposes and 62,642 kg of avoparcin per year for animal husbandry. Vancomycin and avoparcin have
the same mode of action; resistance to one can confer resistance to the other.The biological bases of the growth
promoting effects are far from being understood; according to data from Sweden, this effect can be mainly demonstrated
under suboptimal conditions of animal performance (2).
That antibiotic use in agriculture will result in transfer of antibiotic resistant bacteria and transferable resistance
genes to humans was already discussed nearly 30 years ago, especially with regard to growth promoters. In 1969,
the Swann Committee of the United Kingdom concluded that there should be no use of antibiotics as growth promoters
if they are also used for human chemotherapy and/or if they select for cross resistance against antibiotics used
in humans (3). Criteria for legislation in countries of the European Communities responding to this recommendation
were published 16 years later (4). However these criteria had been applied only to substances admitted for legislation
and not to the "oldies" which are in long time use. Legislation authorities of the US never saw sufficient
evidence for prohibiting the use of penicillin or tetracycline as growth promotors. The glycopeptide avoparcin
was never registered in the US.
During the past 10 years methods of molecular fingerprinting bacterial pathogens and their resistance genes became
a powerful tool for epidemiological tracing and have provided much more conclusive evidence for the spread of antibiotic
resistance from animal husbandry to humans.Currently two issues are subject of discussions among the scientific
community, agriculture industry, regulatory boards and politicians: antimicrobial growth promoters and veterinary
fluoroquinolone use.
Growth promoters
That the comparably low concentrations of growth promoters select for transferable antibiotic resistance has often
been doubted. There is however convincing evidence from two sets of studies. Feeding of oxytetracycline to chickens
was shown to select for plasmid mediated tetracycline resistance in E.
coli in chickens. Transfer of the tetracycline resistant
E. coli
from chickens to farm personnel was demonstrated (5, 6).
In the former East Germany in 1983, oxytetracycline was replaced as feed additive by the streptothricin antibiotic
nourseothricin. This antibiotic was used country wide only for animal feeding. Resistance was negligible in 1983.
Two years later, resistance (mediated by a transposon-encoded streptothricin acetyltransferase gene) was found
in E. coli
from the gut of pigs and in meat products. By 1990, resistance to nourseothricin had spread to E. coli from the gut
flora of pig farmers, their families, citizens from municipal communities, and patients with urinary tract infections.
In 1987, the same resistance determinant was detected in other enteric pathogens, including Shigella which occurs only in humans (7, 8).
With the emergence and spread of glycopeptide resistance, enterococci became a subject of great interest (9). Enterococci
colonize the guts of humans and other animals, and easily acquire antibiotic resistance genes and transfer them.
During the last 5 years enterococci have been recorded among the top five of bacterial nosocomial pathogens. Although
less pathogenic than E. faecalis,
E. faecium
has drawn increased attention because of its development of resistance to glycopeptides (9).
In enterococci there are three known genotypes of transferable glycopeptide resistance with the vanA gene cluster
the most widely disseminated one (10). Studies demonstrating selection of transferable, vanA-mediated glycopeptide resistance in E. faecium by use of the glycopeptide
avoparcin as a growth promoter in animal husbandry, have again focused attention on the use of antibacterials as
growth promoters (11, 12). Glycopeptide resistant E. faecium (GREF) can easily reach humans via meat products (13) and consequently GREF
have been isolated from stool specimens from nonhospitalized humans (13). A common structure of the vanA gene cluster
has been found in a number of GREF of different ecological origin (human, food, animals; (14), indicating a frequent
dissemination of vanA
among different strains and also among different conjugative plasmids.
Ergotropic use of avoparcin was stopped Denmark in May 1995, in Germany in January 1996 and in all EU countries
in April 1997. When investigated for GREF by end of 1994, thawing liquid from all of the investigated poultry carcasses
was found heavily contaminated, by end of 1997 GREF were found in comparably low number in only 25 % of the investigated
samples [15]. In parallel a decrease of faecal carriage of GREF by humans in the community was seen: 12 % by end
of 1994 and 3.3 % by end of 1997 (15). These findings highlight the potential role of a reservoir of transferable
glycopeptide resistance in animal husbandry for spread to humans. With the availability of the streptogramin combination
quinupristin/dalfopristin streptogramins became an important alternative for treatment of infections with GREF
(not E.
faecalis!)
Until last year, there was no medical use of streptogramins in German hospitals. However streptogramine resistance
has been found in GREF from both patients and animals. The resistance is mediated by the satA gene coding for a streptogramin acetyltransferase. The dissemination of
satA
was probably driven by use of the streptogramin antibioticvirginiamycin as growth promoter for more than 20 years
(16).
Veterinary fluoroquinolone use
A decrease in fluoroquinolone sensitivity in S. typhimurium has been described which parallels the time of fluoroquinolone use in veterinary
medicine. This was especially observed in the United Kingdom for S.
typhimurium strain DT 104 (17). Although the MIC's of ciprofloxacin
for these isolates (0.25 - 1.0 mg/l) are still below clinical breakpoints for fluoroquinolones (for ciprofloxacin
resistance ( 4 mg/l according to NCCLS), the clinical failure of ciprofloxacin for treating infections with S. typhi exhibiting
elevated MIC's raises concern with regard to enteric Salmonella spp. In other countries like Germany, France, Australia, and the US S. typhimurium with
ciprofloxacin MIC's above 0.25 mg/l are still rare.
Fluoroquinolone resistance in bacteria is mainly due to mutations in the target enzymes (DNA gyrase, topoisomerase
IV; 18) and therefore spreads in a clonal way with particular bacterial strains affected.Enterics develop quinolone
resistance by stepwise acquisition of mutations at certain positions in the active center of the target enzymes
(19). Further accumulation of these mutations by enteric Salmonella spp. will very probably lead to high level quinolone resistance.
Another intestinal pathogen which has its reservoir in animals is Campylobacter spp. Fluroquinolone resistant Campylobacter
can be isolated from human infections from faecal samples
of chickens and from chicken meat (20). Different frequencies of quinolone resistant Campylobacter isolates from human cases of diarrhoe have been reported from several parts
of the world. The Campylobacter
spp. are obviously polyclonal (several strains harboured in the gut flora of man and animals), comparable to E. coli. Although
currently available molecular typing techniques are available to Campylobacter most probably because of polyclonalityquinolone resistant Campylobacter strains
have not been traced back to animal flocks.
Global situation for prevention and regulation
Use and licensing of these compounds varies tremendously worldwide. In developing countries, which are responsible
for about 25 % of world-meat production, policies regulating veterinary use of antibiotics are poorly developed
or absent. In China, raw mycelia are used as animal growth promoters. In Russia, chloramphenicol is still in veterinary
use. In Southeast Asia, use of antimicrobials in shrimp farming is unregulated. The problems caused by inappropriate
use of antibiotics reach beyond the country of origin. Meat products are traded worldwide, and bacterial populations
evolve independent of geographical boundaries.
The agriculture industry is now building large chicken farms in Brazil with the aim to ship the products to arabic
countries. The same can be observed for Thailand and shipping to central Europe. As long as global regulations
are not feasible, a control of imported meat products for contamination with particular multiresistant bacteria
(i.g. GREF) has to be taken into consideration.
The Swann'sCommittee's recommendations have been revived by WHO in 1994 and also concluded again from a workshop
in 1997 (21, 22). Nevertheless, when Finland applied for a stop of macrolide use of growth promotors (tylosin,
spiramycin) in EU countries, the scientific committee for animal nutrition which is advising the European Commission
came now to the conclusion that there is no convincing evidence for selection and spread of resistance. The international
dimensions of the spread of antibiotic resistance has been a topic of the last May's top level G8 conference and
the need for efficient surveillance has been underlined. Improved surveillance of the incidence and spread of antibiotic
resistance is an important prerequisite to regulatory measures. Unfortunately current surveillance projects do
not include a monitoring of antibiotic usage in order to see more directly the consequences of selective pressure.
Use of antibacterials as growth promoters includes an uncalculatable hazard. As evident from the emergence of streptogramin
resistance in enterococci, a compound or class of compounds that is used now as a growth promoter can, in the future,
become important for human chemotherapy. The debate whether animal husbandry can do without antibacterial growth
promoters continues. Sweden has demonstrated that procedural modifications can decrease the use of antibiotics,
the antibacterials are prohibited as growth promoters since 1986 (23). Learning from the Swedish experience, agricultural
science should define conditions for animal fattening without use of antibacterial growth promoters and without
sacrificing production.
The often heard argument that giving up these kinds of growth promoters will lead to a substantial increase of
the prices for meat products does not hold true. The Bavarian board for animal husbandry has performed a large
field trial on the economic impact of antibiotic use for growth promotion which included ~ 400,000 pigs fed with and ~ 400,000
pigs fed without
growth promoters. One kilogram of pork produced without these growth promoters is about 0.10 Deutsche Mark more
expensive [unpublished results].
It is further argued that a stop to the use of antibacterial growth promoters will endanger this world's nutrition.
It is well known that the total amount of grain currently produced is sufficient to feed the world's human population.
Hunger in parts of the world has mainly to do with social conditions and distribution of food. Furthermore, supporters
of antimicrobial growth promoters claim that their use protects animals from various kind of infections (24). Isn't
it also an ethical aspect to keep animals in such a way that they don't need this permanent prophylaxis? In the
long run investments into alternatives to antimicrobials for animal growth promotion and improvement of the conditions
of animal performance should pay off in more efficient production.
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