eMJA: Collignon, Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link?

eMJA The Medical Journal of Australia

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Vancomycin-resistant enterococci and use of avoparcin in animal feed: is there a link?

Australia is unique among Western countries in allowing animal use of this vancomycin-like antibiotic

Peter J Collignon

MJA 1999; 171: 144-146
See also Ferguson, Robertson et al & Grayson et al.

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Introduction - What is the evidence that avoparcin use in animals contributes to VRE in humans? - What other factors have a role in amplification and spread of VRE? - How much vancomycin resistance is there in Australia? - Recommendations - Acknowledgments - References - Authors' details
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Introduction

Antibiotics are used in animals to treat and to prevent infections.^1,2 They are also used extensively in subtherapeutic doses to promote growth by increasing weight gain and improving feed utilisation. In Australia (as in many other countries), more antibiotics are used on a tonnage basis in animals than in humans.²

One such antibiotic is the glycopeptide avoparcin. In Australia, it is registered for use as a growth promoter in chickens, pigs, calves, beef and dairy cattle.³ It is also approved for prophylaxis of necrotic enteritis (caused by Clostridium perfringens) in broiler chickens.³ Glycopeptide antibiotics are also used in human medicine, the two most important being vancomycin and teicoplanin.¹ Indeed, these glycopeptides are the only effective therapy currently available for some infections (eg, bacteraemia caused by multiresistant Staphylococcus aureus). They are also important in therapy of serious infections caused by enterococci, antibiotic-resistant pneumococci and coagulase-negative staphylococci.^1,4-6

The potential problem with use of avoparcin in animals is that it may lead to selection and amplification of vancomycin-resistant pathogens, such as enterococci. These resistant bacteria may be potentially transferred to humans via the food chain^4,6-8 and may cause human disease in appropriate circumstances (eg, abdominal sepsis). More often, the genes encoding vancomycin resistance (especially the transposon Tn1546 which encodes the resistance gene cluster known as "VanA") may be transferred to other strains of enterococci^4,9,10 or to other, far more virulent, organisms, such as S. aureus. However, to date, this latter transfer has been observed only in the laboratory.¹¹

Vancomycin-resistant enterococci (VRE) have been frequently reported in Europe and the United States.^4,9 Recently, strains of S. aureus with intermediate resistance to vancomycin have been isolated from patients in countries including Japan, France and the US,^12,13 although none have been described to date in Australia.¹² Vancomycin resistance is of major concern to medical practice, as there are no antibiotics currently approved to treat infections caused by most vancomycin-resistant bacteria, which may be life-threatening; a US study found that bacteraemia with VRE was associated with markedly higher death rates than bacteraemia with antibiotic-sensitive strains of enterococci.¹⁴

What is the evidence that avoparcin use in animals contributes to VRE in humans?

A likely direct link has been shown between avoparcin use in animals and VRE infection in a farm worker with a compound fracture.¹⁵ However, it is much more difficult to show that VRE strains are transmitted through the food chain and cause infection in the general population. The evidence comes from observational studies, as it is neither practicable nor ethical to carry out direct experiments in humans, as was the case in trying to demonstrate the link between lung cancer and smoking.¹⁶

A strong case that avoparcin use in animals is associated with development and amplification of VRE, and that these resistant bacteria may cause infection in humans, needs to show that:

VRE are present in animals receiving avoparcin;
VRE are more common in animals, farm areas and countries where avoparcin has been used (and rare or absent in areas where it has not been used);
VRE are detectable in food products from animals fed avoparcin; and
VRE are found in the general community in people who have, or are likely to have, consumed these products.

In Europe, unlike Australia, studies have addressed these issues, and all these conditions have been satisfied for VanA VRE, the most common European form. This has led the European Union to ban the use of avoparcin in animals.

Requirements 1 and 2: VRE have commonly been found in a wide range of animals on farms that have used avoparcin in Germany and Denmark. For example, VRE made up 0-59% of enterococcal isolates from animals on farms that had used avoparcin,^6-8 but were not found in animals on nearby farms not using avoparcin.⁷ In studies from the US (where avoparcin has never been approved for use) and from Sweden (where its use was discontinued 10 years ago), no VRE were isolated from farm animals.^6,8

Requirement 3: VRE have been isolated from many different food products from animals fed avoparcin. For example, in Germany, VRE have been found in 8% of minced beef and pork samples, and in the Netherlands in 79% of poultry products at the retail level.^10,17

Requirement 4: In Europe, VRE are widespread among people in the community who have had no association with hospitals. VRE were found in the bowel of 2% to 17% of the general community in countries including the United Kingdom, the Netherlands, Germany and Belgium.^7,9 However, when volunteers in Belgium were given oral glycopeptides, VRE were found in more than 60% of those tested.¹⁸ As mutation to vancomycin resistance is believed extremely rare -- it is encoded by a very complex cluster of genes^6,18 -- it is most likely that these volunteers were already harbouring VRE in very small numbers, which were amplified by the glycopeptides.

The most likely explanation for the widespread nature of VRE among people in the community with no association with hospitals is that the organism has been acquired from food.^4,7,9 The molecular evidence also strongly suggests that VRE are transmitted from animals to humans, not the reverse.¹⁹ Although VRE strains display many different phenotypes and genotypes, even in a single patient,^6,20 the transposon that encodes the VanA type of vancomycin resistance (Tn1546) is highly conserved. This transposon carries many genes,¹⁹ but only a few (vanA, vanH and vanX) are essential for resistance. Characterisation of the transposon from isolates from Europe, the US and the Middle East found only minor variations, and none in the essential genes, except a single base-pair variation (G or T) at one position in the vanX gene.¹⁹ All strains of VRE isolated from poultry had a G at this position and nearly all from pigs had a T, but strains from humans included both variants,¹⁹ implying that animals were the primary source of the human strains.

These findings amount to strong, albeit observational, evidence that animal use of avoparcin in Europe has resulted not only in selection of VRE but, more importantly, its major amplification in animals (particularly VanA strains of VRE).^4,6,7,9 These VRE strains may be present on food products distributed throughout Europe and overseas (possibly to the US and Australia). They may then colonise and persist in the human intestine, usually in small numbers, and possibly transfer their resistance to other, more human-adapted, enterococci.

What other factors have a role in amplification and spread of VRE?

Human medicine has undoubtedly contributed to spread of VRE. If VRE are present in the bowel of any patient, then their numbers will be potentially amplified by use of any glycopeptide or other antibiotics, especially broad-spectrum antibiotics, such as cephalosporins and fluoroquinolones.^4,21,22

Hospital use of vancomycin appears the major factor in development and spread of VRE in the US, where avoparcin has not been approved for use in animals, but where human use of vancomycin is far greater than in Europe or Australia (11 200 kg in the US, compared with 2200 kg in France, Germany and the UK combined in 1996²³). In contrast, in Europe, amounts of glycopeptides used in animals before the recent ban far exceeded amounts used in humans. For example, in Denmark, 24 000 kg of avoparcin were used annually in animals in 1994, compared with 24 kg of glycopeptides in humans; in Austria, corresponding figures were 20 000 kg versus 66 kg.^24,25 Given this difference and the evidence outlined above, it appears probable that, in Europe, animal use of avoparcin has been a major contributing factor to both development and widespread dissemination of VanA VRE in the community and hospitals.

In Australia, as until recently in Europe, animal use of avoparcin greatly exceeds human use of glycopeptides. Between 1991 and 1993, 125 000 kg of avoparcin were used annually, compared with 193 kg of vancomycin in humans.² Also, Australia has had no obvious centre of VRE development, in contrast to the US, where the first VRE isolates were found in New York and then spread.⁴ VRE isolates in Australia are sporadic, polyclonal and widely distributed throughout the country; they have been found even in smaller non-metropolitan hospitals, where extensive use of vancomycin is unlikely.²⁶ This suggests that spread of VRE in Australia is likely to be similar to spread in Europe -- through the food chain. Once VRE strains are introduced into a hospital, in a patient's bowel, they and the resistance genes they carry are amplified by antibiotic use, and their dissemination is facilitated by poor infection control.

How much vancomycin resistance is there in Australia?

Reports of infection caused by VRE are still relatively few in Australia compared with the US and Europe, but numbers appear to be rising.²⁶ VRE strains have appeared independently in diverse locations and are highly polyclonal.²⁶ To August 1998, at least 69 strains or clusters of strains had been detected in patients with VRE infection. However, nearly three times as many strains or clusters were detected by screening contacts or high risk groups.²⁶ The strains causing infection were found in 26 institutions in 10 widely separated cities or regions without any obvious temporal association. They comprised at least 20 distinct types of enterococci (based on species, antibiotic sensitivity and gel electrophoresis patterns). Most of the 69 strains were Enterococcus faecium, with the rest Enterococcus faecalis. In contrast to European VRE strains, most of the Australian strains were positive for the vanB gene rather than the vanA gene (51 vanB versus 15 vanA).

Virtually no data are available on how widespread VRE are in animals or the food chain in Australia. It is to be hoped that VRE numbers in animals are still low, as suggested by the only study available, involving 29 farms in New South Wales. Only two isolates of VRE with acquired resistance were found in 197 animals (one vanA and one vanB, both E. faecium).²⁷

Recommendations

Approval for use of an antibiotic as a growth promoter or in-feed antibiotic for animals in Australia is supposedly based on the criteria espoused in the 1969 Swann Report from the UK²⁸ (Box). These criteria were recommended after an outbreak of severe human infection caused by antibiotic-resistant salmonella strains derived from animals. Avoparcin does not appear to satisfy at least two of the three criteria, and the evidence that it satisfies the third -- providing economic benefit to Australian agriculture -- is unconvincing:

Avoparcin is similar to an important therapeutic antibiotic used in humans -- vancomycin.
Use of avoparcin is associated with development of antibiotic resistance that is of importance to humans -- development and spread of VRE.
While data indicate that avoparcin confers some benefits, through improved feed conversion and weight gain, these benefits appear greatest in animals that are stressed or subject to poor animal husbandry practices.⁶ It is hoped that, in Australia, higher standards are generally observed. To my knowledge no double-blind, placebo-controlled trials of the claimed economic and disease-prevention benefits have been published in peer-reviewed journals. Furthermore, many less critical antibiotics than avoparcin (eg, penicillin) would be equally efficacious in treating clostridial infections, for which avoparcin is promoted as prophylaxis. Moreover, these infections can be prevented by changes in animal husbandry practices and feed, without antibiotics.⁶

The European Union has now banned the use of avoparcin because of concerns about development and spread of VRE. In the US, avoparcin was never approved for use, as it was classified as a carcinogen.⁹ Australia appears unique in the Western world in still allowing use of avoparcin in animals.^4,9 At present, it is available without even a prescription from a veterinarian, but "over the counter"!

I believe that avoparcin and other glycopeptides should not be available for use in food-producing animals as either growth promoters or for therapy or prophylaxis. I also believe that avoparcin did not fulfil the necessary criteria for approval when first introduced in Australia more than two decades ago. Glycopeptides, which represent the "last line" of defence in treatment of many infections, should not be used at all in food-producing animals. It is time to ban the use of avoparcin in animals in Australia.

Acknowledgments

I would like to thank the many infectious diseases physicians, microbiologists and scientists who helped in preparation of this paper with their helpful advice and information, particularly Associate Professor Christopher Fairley, Alfred Hospital, Monash University, Melbourne, VIC.

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Authors' details

Departments of Infectious Diseases and Microbiology, Canberra Hospital, University of Sydney, Canberra, ACT.
Peter J Collignon, FRACP, FRCPA, Clinical Associate Professor, Canberra Clinical School.

Reprints will not be available from the author.
Correspondence: Professor P J Collignon, Departments of Infectious Diseases and Microbiology, Canberra Hospital, PO Box 11, Woden, ACT 2606.
Email: peter_collignonATdpa.act.gov.au

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