Use of Antimicrobials in Food Animal Production
Frank M. Aarestrup and Lars B. Jenser
Abstract
The usage of antimicrobial for therapy, metaphylactic, prophylactic and as growth promoters is described. Already in the end of the 1960’ties the usage of antimicrobial for other purposes than therapy promotion was questioned and with the increased consumption of antimicrobial in food animal production higher prevalence of antimicrobial resistant bacteria have been observed. Figures for usage are hard to obtained but published numbers indicate very different patterns of usage with room for improvement and prudent usage in several countries. High usage of antimicrobial have led to banning of the usage of growth promoters in the European Union while several compound are still used for growth promotion and therapy in United States. Resistant bacteria selected for could via the farm to fork the transmitted from the animal reservoir to humans causing reduced treatment possibilities and prolonged hospitalization. Indication of spread of antimicrobial resistance between the animal and human reservoir is given.
Key Words: Antimicrobials; growth promoters; antimicrobial usage; and epidemiology of antimicrobial resistance; interventions and ban of growth promoters.
1. INTRODUCTION
Antimicrobials are substances of natural, semisynthetic, or synthetic origin that kill or inhibit the growth of a microorganism but cause little or no damage to the host (1).
This broader term than antibiotic, which refers to substances that are produced by microorganisms, will be used to include compounds with antibacterial effects used in modern animal production.
Antimicrobials have been used for treatment of animals and for growth promotion since the late 1940s. With the discovery of a large numbers of antimicrobials, these were introduced for routine therapeutic treatment of animals in the 1950s and soon after these compounds were shown to have a growth-promoting effect if fed to animals. One of the first-identified growth promoters, aureomycin, belongs to the tetracyclines (2–6). Anti- microbials have been commonly used for growth promotion since 1949 in the Unites States and since 1953 in the United Kingdom (7).
Modern agricultural production is very intensive with optimization of every step in the production and minimizing labor. Today most food animals in industrialized countries are reared in large groups on small areas with up to thousand animals living together and with an attempt to achieve quick weight gains.
As a consequence of this, a large number of substances with antimicrobial activity are used in modern food production. These include antimicrobials used for therapy, antimicrobial growth promoters, disinfectants, and metals. The most
From: Infectious Disease: Foodborne Diseases Edited by: S. Simjee © Humana Press Inc., Totowa, NJ
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commonly used ones are antimicrobials for therapy and growth promotion. In the following sections, a description of the usage of antimicrobials are given and the possible consequences hereof.
2. CLASSIFICATION OF DRUGS USED IN ANIMAL PRODUCTION
2.1. Therapeutic Antimicrobial
Several antimicrobials are used for the treatment of infections in animals. Among these are penicillins, cephalosporins, tetracyclines, chloramphenicols, aminoglycosides, spectinomycin, lincosamide, macrolides, nitrofurans, nitroimidazoles, sulfonamides, trimethoprim, polymyxin, and quinolones (1). Most antimicrobials are used to treat enteric and pulmonary infections, skin and organ abscesses, and mastitis (8).
2.2. Coccidiostats
Coccidiostats are substances, some with antimicrobial effects, used to prevent and treat coccidiosis in poultry. In Europe, antimicrobials used as coccidiostats must be approved by the European Union. Those currently authorized include decoquinate, diclazuril, halofuginone, robenidine, narazan, narazan/nicarbazine, lasalocid-sodium, and maduramicin-ammonium. They are mostly used in broilers, but also to some extent in turkeys and laying hens. In Denmark, mainly ionophores, such as salinomycin and monensin, are used as coccidiostats and the usage inclined to 25,493 kg active compounds during 1994–1999 but has since declined to a total of 11,133 kg active compounds in 2003 (9).
2.3. Growth Promoters
Several classes of antimicrobials have been used for growth promotion. In the European Union, 11 different compounds from eight structural different classes were approved until 1995 (Table 1). Some of these compounds are structurally closely related to the antimicrobial used in the therapy of humans and animals (see Table 1), and some have been used both for growth promotion and therapy (tylosin). Usage of antimicrobials as growth promoters belonging to the same antimicrobial group as the therapeutic-used antimicrobials will diminish the potential of the therapeutic antimicrobial in human therapy because of the selection of antimicrobial resistance that can be transferred through the food chain to humans. In 1969, the Swann committee (7) suggested not to use antimicrobials that were used for therapy as growth promoters. Since 1998, the European Union has banned several compounds and, has phased out the use of antimicro- bial growth promoters by 2005.
In the United States, compounds belonging to the same antimicrobial group, as previously were used as in Europe, are still used, whereas others like glycopeptides have never been used for growth promotion. Contradictory to the usage in Europe, several compounds, such as tetracycline, penicillin, and sulphonamides, are used both for growth promotion and for therapeutic treatment (10). Antimicrobials used are evaluated for safety to human health and are classified as critically important, highly important, important, or not important according to a published guidance (11,12).
Several organizations have developed principles for prudent usage of antimicrobials
(13,14) and organizations such as the Alliance for the Prudent Usage of Antibiotics
(APUA) and Union of Concerned Scientists (UCS) have created an awareness of the potential problem in using antimicrobials for growth promotion that could reduce the potential of therapeutic antimicrobials.
3. REASONS FOR USAGE AND CONSUMPTION OF ANTIMICROBIALS 3.1. Usage
In modern food animal production, antimicrobials are normally used in one of the four different ways. (1) Therapy: treatment of infections in clinical-sick animals, prefer- ably with a bacteriological diagnostic. (2) Metaphylactics: treatment of clinical-healthy animals belonging to the same flock or pen as animals with clinical signs. In this way,
Table 1Antimicrobial Used for Growth Promotion in Europe and United States
Related to antibiotic
Antimicrobial Antimicrobial used in human
group growth promoter United States
aEurope treatment
Polypeptides Bacitracin In use Banned (1999) Bacitracin
b(swine, poultry)
Flavofosfolipid Flavomycin/ In use (broilers) Banned None
Bambermycin (2006)
Glycopeptides Avoparcin Not used Banned (2006) Vancomycin, Teicoplanin
Ionophores Monensin Not used Banned None
(2006)
Salinomycin Not used Banned None
(2006)
Macrolides Tylosin In use (swine) Banned (1999) Macrolides (erythromycin) Spiramycin Not used Banned (1999) Macrolides
(erythromycin) Oligosaccharides Avilamycin Not used Banned Evernimicin
c(2006)
Quinoxalines Carbadox In use (swine) Until 1999
dNone
Olaquindox Not used Until 1999
dNone
Streptogramins Virginiamycin In use (broilers) Banned (1999) Quinupristin/
Dalfopristin, Pristinamycin Sulfonamides Sulfathiazole In use
d(swine) Not used Sulfonamides Tetracyclines Tetracyclines In use (swine)
eNot used Tetracyclines Penicillin Penicillin In use (swine)
eNot used Penicillin Pleuromuttilin Tiamulin In use (swine) Prophylactic None
usage
aAdopted from GAO-04-490, April 2004 (10).
bSkin infections.
cRedrawn before released for human treatment due to side effects.
dRedrawn due to carcinogenic effects.
eUsed in chlortetracycline/penicillin/sulfathiazole combinations.
infections may be treated before they become clinically visible and the entire treatment period may thereby be shortened. In addition, this can, because of the modern production systems, often be the only way to treat large broiler flocks with water medication. (3) Prophylactics: treatment of healthy animals in a period where they are stressed to prevent disease. Examples include medicated early weaning. This use of antimicrobials can be a sign of management problems and, in most countries, is not considered legal or imprudent. (4) Growth promotion: inclusion of antimicrobials continuously in animal feed to improve growth. The antimicrobials are used in subtherapeutic concentrations.
How this beneficial effect is achieved is not well established and this usage has been seriously questioned in several countries in recent years. The European Union has banned the usage of specific antimicrobials for growth promotion, and the quantities of antimicrobials used for growth promotion have been reduced.
3.2. Consumption
It is difficult to obtain solid data on the consumption of antimicrobials in the production of food animals. Exact figures are very rare and only estimates are available for a few countries.
In the United States, the consumption of antimicrobials increased tremendously throughout the 1950s to 1970s (Fig. 1). In 1951, a total of 110 mt were produced for additional to animal feed and other application, whereas 580 mt were produced for medical use in humans and animals (15). In 1978, 5580 mt were produced as feed additives, whereas 6080 mt were produced for treatment of humans and animals. Thus, an increase of 50 and 10 times, respectively, for growth promotion and treatment was observed. Recently, the UCS (16) estimated the total usage of antimicrobials in food animal production in United States to be 11,150 mt, whereas the usage for treatment of humans was estimated to be 1361 mt.
Fig. 1. Antimicrobial production from 1950 to 1978 (in millions of kg) in the United States (15).
In the United Kingdom, the estimated usage of antimicrobials in 1996 was 650 mt for therapy and 100 mt for growth promotion (17). For human treatment, approx 470 mt were used in 1997 (17).
In Denmark, Norway, and Sweden, monitoring programs estimate the usage of antimicrobials in production animals. In Sweden, estimates of antimicrobials used for therapy as coccidiostats and for feed medication are given and have been monitored yearly since 1998 (18). In Norway, estimates of antimicrobials used for therapy and for growth promotion are given and have been monitored since 1995 (19). Finally, in Denmark, estimates of antimicrobials used for therapy, growth promotion, and as coccidiostats are given and have been monitored yearly since 1996 (9). In Denmark, based on the VETSTAT program, usage can be monitored down to farm level.
The European Agency for the Evaluation of Medical Products (20) has estimated the amount of antimicrobials used for treatment and growth promotion for food animals in the different EU countries in 1997. The estimate for the production of animals from 1996 was included for comparison. In Fig. 2, the usage of antimicrobials to produce 1 kg of meat in different EU countries is presented. Even though problems exist in validating the estimated figures and production methods are different in individual countries, major differences in the amount of antimicrobials used were identified for the production of the same amount of meat. This provides room for major reductions in some countries.
Fig. 2. Milligrams of antimicrobial agents used in 1997 per kilogram of produced meat in the
different countries in the European Union (EMEA).
4. BANNING ANTIMICROBIALS USED IN ANIMAL PRODUCTION An association between usage of antimicrobials for growth promotion and occurrence of resistance was established before 1969 (7). The Swann report recommended that antimicrobials could be used for growth promotion under the limitations that the used antimicrobials had no economical values otherwise in production, had little or no application as therapeutic agents in humans or animals, and would not impair the efficacy of a prescribed therapeutic antibiotic or antibiotics through the development of resistant bacteria.
5. EFFECT OF BANNING AND OTHER INTERVENTION OF USAGE OF ANTIMICROBIALS
In Sweden, antimicrobials used for growth promotion were banned in 1986. All antimicrobials for veterinary use were then classified as medicine and were available only by veterinary prescription (21). It was also required that antimicrobial feed additives given to poultry should be proven not to increase colonization and shedding of Salmonella. No negative clinical or economical effect of the ban was detected in the Swedish slaughter pig production, whereas in poultry production the usage of antimicro- bials for growth promotion had a verified protective effect against necrotic enteritis.
Introducing better hygiene and management routines circumvented the effect of banning in the use of antimicrobials for growth promotion. In the piglet production, significant problems with weaning diarrhea were observed, resulting in an increase in the usage of antimicrobials for therapy. The termination of antimicrobials used for growth promotion resulted in a 35% reduction in the overall consumption of antimicrobials for animal production, and by other means of intervention, the used amount of antimicrobials for animals was reduced by a total of 50% (21). From the last year (1985) when the antimicrobial was used for growth promotion and until 1999, more than a 50% reduction was archived in the overall usage of antimicrobials for food animal production in Sweden (22). Similar results have been obtained in Norway (23) and Finland (24).
In Denmark, larger quantities of antimicrobials were used until 1998 in animal feed for growth promotion than for therapy (25,26). As provided by Danish regulation, all sales of veterinary medicines must take place by prescription from a veterinarian. The usage of antimicrobials were increased from 1986 to 1994 (Fig. 3). This correlated with a simultaneous increase in pig production, but the increased production could not only be justified by this increase in antimicrobial usage and could not be related to significant animal health problems.
In the mid-1990s, large amounts of tetracycline were used prophylactically. From
1995, a new regulation removed the economical incitement for the veterinarians to sell
antimicrobials to the farmers resulting in a decrease in the consumption of antimicro-
bials. In 1995, the Danish authorities observed an increase in the use of antimicrobials
for treatment of animals. Furthermore, the use of antimicrobials for growth promotion
came under increased scrutiny because of quantities used and possible co-selection for
resistance to therapeutic antimicrobials. The glycopeptide avoparcin was banned in
Denmark in 1995 based on the selection of resistance to glycopeptide-resistant entero-
cocci that, through the food chain, could be transferred to humans. For human treatment,
the glycopeptide vancomycin was used as a last resort against methicillin-resistant
Staphylococcus aureus and multi-resistant Gram-positive bacteria. During 1996 and 1997, the total consumption of antimicrobials was increased reflecting the increase in the food animal production. In 1997, avoparcin was banned in all EU countries based on a precautionary action.
In January 1998, the streptogramin virginiamycin was banned in Denmark based on crossresistance to Quinupristin–Dalfopristin (Synercid), an antimicrobial released for human treatment (27). In December 1998, the European Commission decided to ban the use of bacitracin (a polypeptide), spiramycin (a macrolide), tylosin (a macrolide), and virginiamycin (a streptogramin) for growth promotion starting on July 1, 1999.
Furthermore, the Danish food animal industries decided to voluntarily stop all usage of antimicrobial for growth promotion from the end of 1999. Consequently, the usage of growth promoters has decreased significantly during 1998 and 1999 and has now been terminated. These initiatives follow recommendations by the World Health Organization (28). By banning the use of growth promoters, the overall usage of antimicro- bials for production animals was reduced from 205,448 kg active compounds in 1994 to 101,900 kg active compounds in 2003. Following the voluntary ban on antimicrobials as growth promoters, the amount of antimicrobials used for therapy increased 178%
from 1998 to 2003, mostly based on usage of macrolides, tetracycline, and penicillin (9).
No negative effect of termination in the usage of antimicrobials as growth promoters on poultry products was observed (29), whereas the removal of antimicrobials as growth promoters from weaned pigs resulted in an increase of antimicrobial consumption for therapy (30).
6. RESISTANCE EPIDEMIOLOGY: SPREAD OF RESISTANCE FROM ANIMALS TO HUMANS
Spread of antimicrobial resistance from animals to humans has mainly been docu- mented for zoonotic bacteria. A zoonosis is an infection or infectious disease that are
Fig. 3. Estimate consumption of antimicrobials in Denmark from 1900 to 2003 (9).
transmissible under normal condition from vertebrate animals to humans (31). Well-known foodborne zoonotic agents are Salmonella, Campylobacter, Yersinia, Listeria, and enterohemorrhagic Escherichia coli. Several studies have shown that zoonotic bacteria will acquire resistance among food animals, after which they transfer to and cause infections in humans.
One of the most pronounced examples in recent years is the appearance of fluoro- quinolone resistance among food animals subsequently followed by spread of resistant zoonotic bacteria to humans. Fluoroquinolones are, in several countries, the drug of choice for treatment of gastrointestinal infections in humans, and an emergence of resistance among zoonotic organisms such as Salmonella and Campylobacter is a matter of increasing concern.
The first observations came from the Netherlands where water medication with the fluoroquinolone enrofloxacin in the poultry production was followed by an emergence of fluoroquinolone-resistant Campylobacter species among both poultry and humans (32).
Since then, several studies have documented an increase in the occurrence of resistance to fluoroquinolones among Campylobacter from food animals and humans following the introduction of fluoroquinolones for treatment of infections in food animals (33).
In Germany, an increase in the occurrence of fluoroquinolone resistance among Salmonella Typhimurium DT204c was observed after the introduction of enrofloxacin for veterinary use in 1989 (34). Most recently in the United Kingdom, substantial increases in resistance to fluoroquinolone in Salmonella Hadar and Salmonella Virchow, and in multiresistant Salmonella Typhimurium DT104 have followed the licensing for veterinary usage of the fluoroquinolone enrofloxacin in 1993 and danofloxacin in 1996 (35).
Resistant genes are transmissible and can be transferred both intra- and interspecies.
Bacteria of animal origin may act as reservoirs for resistant genes that can be transferred to the human reservoir. However, because antimicrobials belonging to same classes are used in veterinary and human medicine, it may be very difficult to determine the direction of transfer. Thus, when studying the spread of antimicrobial resistance from animals to humans, the best cases are often found while introducing new antimicrobials for the usage only in animals. The usages of other nonstructural related antimicrobials or even nonantimicrobials such as metals and disinfectants can make it difficult to establish a clear linkage between prevalence of antimicrobial resistance and usage of specific antimicrobials.
A number of observations of horizontal spread of resistance from bacteria in food animals to bacteria in humans have been reported.
The streptothricin antimicrobial nourseothricin was introduced in animal husbandry for
growth promotion in the former German Democratic Republic in 1983. No similar com-
pounds have been used prior to the introduction, and resistance was only observed at very
low frequencies. After the introduction, E. coli isolates with transferable resistant plasmids
emerged among pigs (36). This plasmid was subsequently found in isolates from the pigs,
farmers and their families, and was furthermore found in E. coli isolates of the gut flora
or causing urinary tract infections among humans living in the same geographic region
(37). Streptothricin resistance has also been found in Shigella isolates (38) and among
Campylobacter isolates (39) as well as in staphylococci linked to aminoglycoside resist-
ance (40) and enterococci here genetically linked to aminoglycoside and macrolides (41).
After the introduction of the aminoglycoside apramycin for veterinary use in the beginning of the 1980s, resistance to apramycin emerged among E. coli isolates found in cattle and pigs in France and in the United Kingdom (42,43). Apramycin has never been used for the treatment of infections in humans. The resistant gene (AAC(3)IV) encoding apramycin resistance co-selects for tobramycin, gentamicin, kanamycin, and neomycin resistance, but presence of this gene was first observed after the introduction of apramycin usage (44). This gene and similar resistant plasmids were subsequently found in S. enterica from animals and human clinical isolates of E. coli, S. enterica, and Klebsiella pneumoniae (45–51). These observations strongly indicate that this resistant gene primarily emerged among food animals selected by the usage of apramycin and then spread horizontal to bacteria of human origin where the usage of gentamicin for human treatment selected for its presence.
The glycopeptide avoparcin has been used for several decades as a growth promoter in Europe. A high prevalence of glycopeptide resistance was found among enterococci isolated from production animals in several European countries (52–54). Unique identical isolates were identified among isolates of human and animal origin when standard typing methods were used (55,56), whereas typing of strains indicated different clones in the human and animal reservoirs (57,58). Genetic studies showed that predominantly the vanA gene cluster encoded glycopeptides resistance among bacteria isolates from animals (59–61). These studies together with genetic characterization of glycopeptide resistant isolates from humans (62) detected genetic variations in the vanA gene cluster that could be used for determining ways of transmission. Especially prevalence of a single base-pair variant in the vanX gene of the vanA gene cluster in the different animal and human reservoirs indicated that glycopeptide resistance had spread from animals to humans (63).
Studies from Germany (64), the Netherlands (65), and Belgium (66) have indicated that banning of the growth promoter avoparcin has reduced the presence of glycopeptide resistant among enterococci of human origin. Especially in the study from Belgium (66), in which the prevalence of VanA, the dominant resistant determinant in animals, was reduced among patients after the ban of avoparcin.
7. SUMMARY AND CONCLUSIONS
Any usage of antimicrobials, even in subtherapeutic doses, will select for antimicro- bial resistance. Studies have shown that humans and animals are not distinct reservoirs, but that antimicrobial-resistant bacteria and antimicrobial-resistant genes are exchanged between the two reservoirs. The frequency by which this happens is difficult to deter- mine, and different environmental factors could select for different clones in the human and animal reservoirs. Transfer of resistance between the reservoirs can happen even if the resistant bacteria is only transient, as when consuming animal products, hence the prevalence of resistant bacteria in production animals and their products should be reduced as much as possible.
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