AGP  PART I

Emergence of a Debate: AGPs and Public Health

Human Health and Antibiotic Growth Promoters (AGPs): Reassessing the Risk

A. Bezoen, W. van Haren, J. C. Hanekamp

1 The Issue

1.1 Introduction

1.1.1. General

Resistance of bacteria against antibiotics, meaning that antibiotics do not have a bactericidal or bacteriostatic effect due to the rise or inherent capability to withstand the antibiotics in question, used in human medical treatment can be a serious public health risk. It is known that the use of antibiotics can lead to the origination/emergence of antibiotics resistant bacteria (Levy, 1997). Examples of bacteria that have become resistant to human antibiotics are:

• Methicillin-resistant Staphylococcus aureus (MRSA)
• Penicillin-resistant pneumococci
• Vancomycin-resistant enterococci (VRE)

It seems that there is hitherto no well-founded consistent scientific basis for the suggestion that these resistances -in part- originate from the several decades of animal feed additives use (the so-called Antimicrobial Growth Promoters (AGPs)), with a possible exception of the VREs. There is, however, extensive evidence and clinical experience that links these bacterial resistances with the human use of medicinal antibiotics both in hospitals and the local community. In spite of all this, bacterial resistance originating from animal use of antibiotics has become a subject of extensive political and scientific debate within the European Community.

Antibiotics, when added to the feed, decrease the time and the amount of feed needed to reach slaughter weight (Nefato, 1997). It has been shown that the use of antibiotics for this goal selects for resistant bacteria in animals (Hummel et al., 1986; Bager et al., 1997; Klare et al., 1995; Van den Bogaard et al., 1996, 1997b; Aarestrup et al., 1997, 1998). Some of the growth promoters used in feed are structurally related to antibiotics used in human medicine. Their mode of action on bacterial cells can then be identical (or highly comparable). Resistant bacteria found in animals might in this way be resistant to antibiotics used in human medicine. This is called cross-resistance. The concern now is that resistance, as found in animals, might spread to humans. This spread might add to the already widespread existence of bacterial resistance within humans resulting from human use of antibiotics. The reasoning behind this is simple and straightforward, albeit tentative:

Bacteria in the animal gut and faeces contain resistant bacteria, caused by the use of antibiotics as growth promoters in livestock feed, which might be transferred to humans in one way or the other. Those resistant bacteria might themselves be a human health threat or they might transfer their resistance to other bacteria capable of colonising the human gut. Virulent resistant strains might cause illness not easily treated by known antibiotics.

Scheme 1.1.1.1. Risk scheme concerning AGPs and human health.

In other words the human gut might be colonised by resistant bacteria previously present in animals. The second possibility is the transfer of resistance determinants from bacteria previously present in animals to human bacteria commonly present in the gut or to human pathogens. If resistance in the animal is due to the use of antibiotics in the feed, mixing antimicrobials with feed could in theory contribute to the emergence of serious infections in man.

It should be noted that most AGPs are active against Gram-positive bacteria and not against Gram-negative bacteria.2 Antibiotics that are active against Gram-negative bacteria are usually not active against Gram-positive bacteria and vice versa. Examples of Gram-negative bacteria are Escherichia coli and Salmonella typhimurium. An example of a Gram-positive bacterium is Staphylococcus aureus. The antibiotics discussed in this report are active against the Gram-positive bacteria group. The bacteria considered in this report belong to the Gram-positive group. The antibiotics resistance transfer issue is thus limited to the Gram-positive bacteria group when discussing the relevant AGPs.

1.1.2 Overview

Vancomycin (an antibiotic) resistant enterococci (VRE) were first detected in hospital patients in Europe in the late 1980s. Since then these bacteria have been isolated frequently in all parts of the world (Bates, 1997). VRE can be a problem for immuno-compromised patients, who have a severe disease or have been surgically operated. Also people who are wounded by an accident or carry medical devices like catheters have shown to suffer infections caused by VRE (Weinstein, 1998; Bogle and Bogle, 1997). In hospitals, the majority of VRE are isolated from patients in intensive care units and other specialised wards (Bates, 1997).

Later it appeared that not only patients with clear symptoms of infection carried VRE, but also other patients in the hospital and people on admission to the hospital (Jordens et al., 1994; Gordts et al., 1995; Klare et al., 1995). This indicated that the problem was not solely a hospital matter.

It was found that within community people VRE was also quite widespread. These bacteria were also detected in sewage, waste water, animals and meat. Where these VRE originated is not always clear.

It is necessary to elucidate how VRE emerge and to find the source of VRE in community and hospitalised people. Do these bacteria arise in humans or are bacteria or resistance genes transferred from other sources to humans adding to the resistance of human bacteria?

Glycopeptide antibiotics, like avoparcin, vancomycin and teicoplanin, can cause emergence/selection of resistant bacteria. This has been show in humans who received vancomycin or teicoplanin (Van der Auwera et al., 1997), as well as in animals which received avoparcin as growth promoter (Bager et al., 1997; Klare et al., 1995, Van den Bogaard et al., 1996). As glycopeptide antibiotics are rarely used to treat patients in Europe, the use of avoparcin as growth promoter in feed was suggested as source for resistant bacteria present in humans (due to cross-resistance).

Avoparcin has been used in Europe in animal feed until 1997. At the moment up to ten other antimicrobials are allowed as growth promoter in animal feed. So avoparcin is not the only feed additive that may have an effect on the prevalence of resistant bacteria in humans. In the USA avoparcin is not used as a growth promoter in animal feed. When comparing European and USA data about the prevalence and relatedness of VRE a better insight in the epidemiology (emergence and spread) of VRE might be obtained.

1.2 Objectives and Methods

1.2.1 Objectives

The main objective of this report is to reassess the risk to human health caused by antimicrobial growth promoters (AGP) used as feed additives. To be able to do this, several sub-questions have to be answered.

• Does the use of antimicrobial growth promoters (antibiotics) lead to the spread of AGP resistance beyond the sphere of livestock production? There is strong evidence for the presence and emergence of bacteria in animals resistant to antibiotics present in the feed. This is not a point of controversy at the moment. It is useful to know which antibiotics are used to promote animal growth. Then it will be made clear which of them possibly form a threat to human health. The prevalence of resistance to these antibiotics (and their structural analogues used in human medicine) will be listed.
• Are there documented cases that show the spread of antimicrobial resistant bacteria from livestock to humans? Resistance to avoparcin-vancomycin (used in feed and to treat humans respectively) is quite wide spread among pigs and poultry (less in cows). Articles that describe the spread of VRE or other resistant bacteria from livestock to humans, if present, will be evaluated.
• What is the risk of the use of antibiotics in feed to human beings and how does this relate to other risk factors? Risk factors for humans concerning antibiotic resistance will be discussed. The use of antibiotics in feed as a risk factor will be evaluated.
• Can these data be generalised to all AGPs? Not only avoparcin and its relation with resistance to vancomycin will be studied, also other antibiotics used in feed and showing cross-resistance with antibiotics used in human health care will be included.

1.2.2 Methods

Literature of the last decade containing data about resistant bacteria in animals and humans will be analysed. First, factors leading to the emergence of resistant bacteria will be studied. It is important to know whether resistant bacteria are a threat for all humans or whether certain risk groups can be distinguished. Subsequently, we will focus on the resistant bacteria originated in animals due to the use of antibiotics in feed. Do they cause a threat to human health? Especially claims describing the transfer of resistant bacteria or resistance genes from animals to humans will be studied thoroughly. To be able to compare data obtained in different research groups, laboratory methods to isolate, identify and compare resistant bacteria will be reviewed.

Quite a few hurdles concerning scientific studies into resistance transfer from animals to humans have to be taken before unambiguous answers can be given. Proper comparison of data is difficult. Can resistance percentages found in animals, humans and water samples be compared or be related to each other? The following should be noted:

• Data collection and comparison should contain a thorough description of the history of the samples taken.
• Relating the use of antibiotics to the prevalence of antibiotic resistance, the history of antibiotics used in the feed and as therapy (humans and animals) has to be known.
• Different methods are used to isolate and identify resistant bacteria making data analysis and comparison complicated.
• Testing resistance to multiple antibiotics is useful in comparing strains and resistance plasmids. However, when it concerns e.g. VRE, usually only resistance to vancomycin is tested. Phenotypic and genotypic methods have to be combined when strains are compared (antibiotic susceptibility, PCR of resistance genes, PFGE of the genome).3

Interviews with people in the field-feed producing organisations, laboratory scientists, clinical microbiologists- will be arranged. These interviews will contribute to a good overview of amounts of antibiotics used, important literature, laboratory methods and problems occurring in hospitals.

We will not discuss the precise action of antimicrobial growth promoters on feed conversion and growth of the animal nor will we discuss environmental issues related to the use of AGPs. Also economic aspects of continued or decreased use or even a total ban of AGPs will be excluded from this study. Moreover, it is imperative that the economic, commercial and ethical aspects surrounding this issue be separated from the human health risks in relation to the use of AGPs in animal rearing. Finally, the burden of proof within the scientific arena requires a tremendous experimental effort, a thorough scientific and philosophical rigour, and a transparent presentation of results contributing to a more lucid scientific discussion.