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6. Discussion
It is generally accepted that the use of antimicrobial agents for treatment of infections is the major driving force in the selection for resistance. Even though there are no major differences in the concentrations used, whether the use of antimicrobial agents for growth promotion selects for resistance remains a subject of controversy.
When the Swann Committee’s recommendations were released, their strategies were mainly directed against the use of tetracycline. By and large their recommendations were implemented in the European countries, whereas countries such as USA continued to use tetracycline and penicillin as growth promoters. However, despite the general acceptance of the recommendation from the Swann Committee, macrolides such as spiramycin and tylosin were approved for use in the mid 1970’s. It can be questioned how large an impact this use has had on human health, because resistance to macrolides was at that time already widespread among human pathogens. However, in the case of macrolide resistant zoonotic bacteria such as Campylobacter the use of tylosin and/or spiramycin may have had consequences for human health.
Before 1986 enterococci were in general considered susceptible to glycopeptides, but soon after the first observations of VRE this resistance spread rapidly world-wide. Thus, like in several other cases antimicrobial resistance can emerge very rapidly in bacteria in response to the selective pressure. The only way to limit the spread of antimicrobial resistance and thereby extend the usefulness of antimicrobials is through a restricted use of antimicrobials (WHO, 1997).
It has been recommended that antibiotics that select for resistance against antibiotics used for human therapy should no longer be allowed in animal husbandry. Especially the use of growth promoters should be limited to agents that are of no interest for therapeutic use (WHO, 1997). For instance, when avilamycin, avoparcin and virginiamycin were approved for use as growth promoters in animals, these groups of antibiotics were not seen as potentially important human antibiotics. Due to resistancy problems with other antibiotics this is no longer the view. However, the resistance that has already been created by the use of avoparcin and virginiamycin as growth promoters will most likely reduce the efficacy and shorten the lifespan of vancomycin and quinupristin/dalfopristin as therapeutics in humans. The only way to avoid or limit the consequences of such Frank Møller Aarestrup
situations is to avoid the usage of antimicrobial agents for food animals as much as possible and more in particular the use of those classes that are considered of major importance for treatment of infections in humans.
The Danish programme for monitoring and control of antimicrobial resistance has shown that it is possible at least to some degree to limit the occurrence of resistance by removing the selective pressure (Bager et al. 1999, Aarestrup et al., 2000, Aarestrup et al.
submitted). It is, however, not known whether the occurrence of resistance will ever reach the same low level as before the antimicrobials were introduced. Most probably a low frequency of resistant bacteria will persist and make up a reservoir from where resistance problems easily can be selected if antibiotics are introduced again.
Furthermore, it has generally been expected that the presence of resistance mechanisms would reduce the fitness of the bacteria and that resistance, thus, would decline if the selective pressure were removed. However, recent studies have indicated that resistant bacteria might adapt and thereby uphold the same fitness as susceptible bacteria (Schrag et al., 1997; Andersson et al., 1999).
7. Conclusions
To control the development of resistance to antimicrobial agents, the safest way seems to be to limit their use as much as possible. Thus, all unnecessary use of antimicrobial agents should be strongly discouraged. This includes usage to increase production or as prophylactics. However, it is and will also in the future be necessary to use antimicrobial agents for treatment of infectious diseases in food animals and we will also in the future observe the selection of antimicrobial resistance among bacteria from food animals.
It is not known which resistance problems we may face in the future. However, to implement timely actions, to limit the emergence of antimicrobial resistance and the consequences for human and animal health, it is necessary to obtain and maintain scientific knowledge regarding factors affecting the occurrence, emergence and spread of resistance. Some suggestions for programmes that could be implemented are given in Table 3.
At present, knowledge of antimicrobial resistance in food animals is incomplete in most countries. An organised monitoring of antimicrobial resistance carried out by an international network of laboratories should be implemented in order to be able to identify and report emerging resistance problems at the earliest possible stage. In this way we might be able to implement interventions before emerging resistance causes major problems.
Knowledge regarding the consumption of antimicrobial agents for different food animal species is generally unavailable in most countries. Such knowledge is needed for assessing its impact on the occurrence of resistance and for determining where and for which infections most antimicrobials are used. Programmes to collect data on the consumption of antimicrobial agents are therefore also strongly needed.
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It appears that one of the mechanisms that may contribute to slow down the emergence of antimicrobial resistance is a more limited and prudent use of antimicrobial agents. It should be stressed that antimicrobial agents are extremely valuable drugs in the treatment of infections and they should only be used when needed and in an appropriate way. Some antimicrobial agents are more important than others for treatment of infections in humans.
Furthermore, some antimicrobial agents are probably more prone to select for resistance than others.
It is recommended that those responsible for medical treatment of food animals adopt a policy for prudent use of antimicrobial agents for food animals. This policy should take into account the need to treat infections in animals, but also the potential negative consequences for human health. The policy should also be based on knowledge regarding the normal susceptibility patterns of the different causative agents. Furthermore, genes encoding resistance can be located on the same mobile DNA-elements and the potential co-selection by use of different antimicrobial agents should be taken into account when implementing an antibiotic policy.
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Table 3. Suggestions for programmes to implement in all countries producing food animals.
Suggestion Content and benefit
Monitoring of antimicrobial •Data on the occurrence of antimicrobial resistance
resistance •Used to guide the veterinary antibiotic policy and to follow the effects of changes of usage of antimicrobial agents
•Used as an early warning system for emergence or changes in the occurrence of resistance that requires further studies or interventions
Monitoring of usage of •Used to follow the association between usage and resistance
antimicrobial agents •Gives information regarding which infections that require most antimicrobial agents
Veterinary antibiotic policy •Must take into account the need to treat animals, but also potential negative consequences for human health
•Should be based on the resistance monitoring and scientific data
•Should give concrete guidelines and not overall statements
Research •Research should be used to form the veterinary antibiotic policy and should use data and bacterial strains from the monitoring systems
•Research could for example be performed within the following areas:
• The effect of treatment strategies on resistance
• The genetic background for resistance
• The spread of resistance and resistance genes between reservoirs
• The evolution and adaptation of resistance
Much knowledge regarding the most appropriate treatment regime in terms of achieving cure of infections are available. However, virtually no knowledge regarding the most appropriate treatment in relation to limiting the development of resistance is at hand.
Research in this area is highly needed.
The impact on human and animal health of the selection for antimicrobial resistance in the animal reservoir is not sufficiently known. Large-scale epidemiological and experimental studies including all relevant information on the use of antimicrobial agents, modes of administration, occurrence of resistance and spread of resistant clones and resistance genes in all relevant bacterial reservoirs exposed to antimicrobial agents or that might act as reservoirs, are strongly encouraged.
In Denmark a continuous monitoring of the occurrence of antimicrobial resistance among food animals was implemented in 1995 (Aarestrup et al., 1998a). Furthermore, a programme monitoring the consumption of antimicrobial agents at the farm level was implemented during 2000. A veterinary antibiotic policy has recently been described in Denmark (Pedersen et al., 1999). This includes concrete guidelines for use of specific antimicrobial agents for infections with specific infectious bacterial agents and furthermore, guidelines on which antimicrobial agents should be reserved for special cases only.
These programmes and guidelines are at present not fully operational and the long-term effects must await future studies. However, the emergence of antimicrobial resistance has to be limited. Thus, to avoid further deterioration of available and future antimicrobial agents we need to implement timely interventions based on scientific knowledge before it is too late.
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