JAC Advance Access originally published online on May 12, 2008
Journal of Antimicrobial Chemotherapy 2008 62(2):229-233; doi:10.1093/jac/dkn183
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Garrod Lecture |
The 2008 Garrod Lecture: Antimicrobial resistance—animals and the environment
House of Lords, London SW1A 0PW, UK
* E-mail: soulsbyl{at}parliament.uk
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Abstract |
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Top
Abstract
IntroductionThe evolution of resistance to microbes is one of the most significant problems in modern medicine, posing serious threats to human and animal health. The early work on the use of antibiotics to bacterial infections gave much hope that infectious diseases were no longer a problem, especially in the human field. However, as their use, indeed over-use, progressed, resistance (both monoresistance and multiresistance), which was often transferable between different strains and species of bacteria, emerged. In addition, the situation is increasingly complex, as various mechanisms of resistance, including a wide range of β-lactamases, are now complicating the issue.
The use of antibiotics in animals, especially those used for growth promotion, has come in for serious criticism, especially those where their use should be reserved for difficult human infections. To lend control, certain antibiotic growth promoters have been banned from use in the EU and the UK.
Antimicrobial resistance is not confined to bacteria but occurs in viruses, protozoa and helminths. In many of these, the mechanism of resistance is unknown, and hence their control is still in question. It is likely, however, that the mechanisms are no less complicated than those pertaining to bacteria.
Keywords: resistance mechanisms , food animals , growth promoters
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Introduction |
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It was with the greatest of pleasure that I received the letter from the President of the British Society for Antimicrobial Chemotherapy, Professor Peter Davey, inviting me to present the Garrod Lecture at the spring meeting of the Society. This pleasure was tinged with a fear that the fast-moving field of molecular biology in antimicrobial therapy and antimicrobial resistance could leave my comprehension of the issues far behind the present knowledge and the understandings that have been evident in the present meeting of the British Society for Antimicrobial Chemotherapy. So I have decided, initially at least, to rely on the old man's trick of using history as a starting point, possibly appropriately as this is the 80th year since the discovery of penicillin by Fleming at St Mary's Hospital in London. My early memories of penicillin were as a veterinary surgeon in practice in the Lake District in the mid 1940s, when very limited supplies of aqueous penicillin became available after the Second World War to vets in practice. Staphylococcal and streptococcal mastitis, often acute, were serious problems in high-yielding dairy cows but could be treated miraculously by an intramammary infusion or subcutaneous injection of aqueous penicillin. Previously, oral sulphonamides were the order of the day, often with limited success. The remarkable power of antibiotics such as penicillin caused L. P. Garrod to comment in 1968 that ‘no-one recently qualified, even with the liveliest imagination, can picture the ravages of bacterial infection which continued until little more than 30 years ago’. Now 30 years on, the phenomenon of resistance is widespread, a cause of serious concern in hospital wards [e.g. methicillin-resistant Staphylococcus aureus (MRSA)] affecting not only bacteria but also viruses and metazoan organisms such as helminths and other parasites.
Though later I went on to become a parasitologist, this was almost by default, as in the 1940s I was keen to take up bacteriology as a PhD subject. Unfortunately my Supervisor-to-be died and the search for a new supervisor took me to the late Professor J. T. Mackie, Professor of Bacteriology in Edinburgh. This in turn led me to the intriguing possibility of a study of the immunology of parasitic infections, a field unexplored and thought by the majority of parasitologists to be totally without a future! It proved not to be the case and I have spent many happy and productive years looking at the immunoresponses to helminths, such that a vaccine against them is a distinct possibility. Sabbatical leave in Giessen, Germany, led me to look into the immunological aspects of the treatment of filarial infections, where strange immunological responses occurred following treatment with antifilarial compounds. It was at the nearby University of Marburg that I heard and met Ernst Chain in 1975 as he delivered a guest lecture at the University, which included references to antibiotic resistance in bacteria. A few years earlier in 1969, the Surgeon General of the United States, William H. Steward, testified before Congress that ‘it was time to close the book on infectious diseases and to declare the war against this pestilence over’. This optimism is now widely accepted as not only mistaken but also damaging to the research effort in the control and prevention of infectious disease, since up to 60% of all ill-health is due to infectious disease and the magic bullets of antibiotics have lost their magic while exotic diseases threaten our shores.
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Return to bacteriology and antimicrobials |
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My interest in bacteriology and antibiotics was rekindled, and when several years later I was asked if I would Chair an inquiry into antimicrobial resistance by the Select Committee of the House of Lords Science and Technology Committee, I gladly accepted. This Committee reported in 1998.1 The investigation covered a wide range of issues and made a number of recommendations to which in large part the Government responded well. These included guidelines to medical practitioners supported by cartoons and school educational programmes (e.g. the ‘Andybiotic’)2 to promote sensible antibiotic use from the school level and upwards. The press conference on the Report warned in no uncertain terms that antibiotic resistance was a major threat to public health and urgent action was necessary to avoid a return to the pre-antibiotic era referred to by Garrod. This was, however, not the first warning of antibiotic resistance, as a series of conferences, reports and advisory bodies prior to the House of Lords inquiry expressed concern at the widespread use of antibiotics in medicine, veterinary medicine and horticulture. These included the Swann Committee, set up to report on antimicrobial use in man and animals. Swann concluded in 19693 that there was a significant problem in antibiotic use and particularly in its use in animal feed as a growth promoter. This was especially pertinent to antibiotics also used in human medicine. Swann also recommended that a committee with authority to review and recommend antibiotic use in man, animals and horticulture be set up. Such a committee was not established until the House of Lords Science and Technology Committee on Resistance to Antibiotics and other Antimicrobial Agents in 1998 reminded the Government of the serious situation and pressed for the long awaited ‘Swann Committee’.3 The Scientific Advisory Committee on Antibiotic Resistance (SACAR) was the result.4
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Use of antibiotics in animals |
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A major concern of the use of antimicrobials in food-producing animals has been the transfer of resistance via the food chain to humans. This has particularly generated strong debate on the use of antibiotics as growth promoters in young animals such as chickens, piglets and calves, where the addition of small quantities of antibiotics, well below the normal therapeutic doses, will greatly enhance growth, a fact discovered in the USA in the 1940s when chickens were fed fermentation by-products of chlortetracycline. Since then antibiotic growth promoters have been used extensively in livestock production, often being relied upon not only to enhance growth but to substitute in part for poor husbandry practices.
Therapeutic antibiotic use in animals showed the same dramatic increase as in humans, and on the therapeutic side, many serious infections of farm livestock were amenable to treatment and cure. Examples are mastitis due to staphylococci and streptococci, pneumonia due to Pasteurella and the various enteritides due to Salmonella and other Gram-negative organisms. With the increased use of therapeutic antibiotics in livestock and the expansion of antibiotic growth promoter use, animal use of antibiotics had come to dominate the antibiotic field. Added to such use has been their widespread administration in companion animals, including fish, and their use in horticulture for the control of fungal and other infections of fruit and trees. Concern about antibiotic resistance, especially associated with antibiotics that were used both in human patients and as growth promoters in livestock, led to the Swann Report (mentioned above).
A particularly worrying feature of resistance to antibiotics is the development of multiresistance and the ability to transfer this resistance to other organisms. The concern over the transfer of multiresistance derived from growth promoters via the food chain to human patients has occasioned much debate and though clear evidence of multidrug resistance in enteric organisms leading to antibiotic-resistant human infections is sparse, all authorities believe the prudent use of antibiotics in food-producing animals should have high priority.3 To this end on 1 July 1989, an EU-wide ban on the use of four growth-promoting antibiotics came into effect. These were spiramycin, tylosin, bacitracin zinc and virginiamycin. This was later ratified by the UK. The result of this ban was a dramatic fall in the sales of antimicrobial growth-promoting products in the UK. Thus, in 1998, 141 tonnes of active growth-promoting ingredients were sold and by 2005 this had reduced to 14. Remaining antibiotic growth promoters (monensin, avilamycin, salinomycin and flavomycin) came under an EU-wide ban in January 2006 and it is projected that a further dramatic decrease in sales of growth promoters will occur. Of sales of antimicrobials in 2005 for use in food-producing animals, 97% were for therapeutic purposes and only 3% were for growth promotion.
Whereas the important concern of antibiotic use in growth promotion has been attended to by banning certain antibiotics as growth promoters, the overall sales of therapeutic antimicrobials for food animals have remained much the same over the last 8 year period, between 371 and 402 tonnes of active ingredient, and sales for use in non-food-producing animals varied between 19 and 34 tonnes of active ingredient.5 The demand for antibiotics in food-processing animals varies with respect to diseases to be controlled. In pigs, for example, the occurrence of porcine dermatitis and nephropathy syndrome and post-weaning multisystemic wasting syndrome often leads to secondary infections requiring antimicrobial usage.
Whereas concern is centred on animal-derived bacteria causing problems in humans (zoonoses), there are occasions when infections pass the other way, as is the case with multidrug-resistant Salmonella Newport, which can cause severe clinical disease in cattle and horses and is increasingly common in humans. Apart from its pathology, Salmonella Newport readily transfers resistance to other organisms. The most likely route by which multidrug-resistant strains of Salmonella Newport may enter the UK are via animal feed ingredients, human travellers and horses. While sales of antibiotics for use in non-food-producing animals (e.g. companion animals) are much lower than in food animals, nevertheless they are widely used in veterinary care for companion animals and while the concerns to human health via the food chain do not apply, resistance due to over use is much the same as in human use. Some resistances pose the same problems as in human patients; in animal surgery, MRSA is an increasing issue in dogs and possibly also in horses. It is still unclear whether the source of these organisms is animal or human, but because of the apparently widespread occurrence of MRSA as a colonizing organism in man, it is likely that human sources are responsible for some of the problems in animal surgery and medicine at least.
The concept of the overuse of fluoroquinolones in human and veterinary medicine and the production of resistance was pointed out by Piddock in 1998.6 These antibiotics, which are highly active and broad-spectrum, have many uses in human and veterinary medicine. Piddock pointed out that highly resistant strains had recently emerged, resistance being chromosomally mediated so the spread of resistant bacteria contributed to the high numbers of resistant strains reported by some institutions.
A feature of antibiotic resistance in several species of bacteria is that of multidrug resistance and the transfer of this resistance to related and unrelated organisms. In some species of bacteria, resistance extends across several antibiotics. Cross-resistance to injectable antibiotics, such as third- and fourth-generation cephalosporins, may be particularly serious as these injectables are often the last line of defence in the treatment of life-threatening infections. Hence, the unexpected and increasing appearance of extended-spectrum β-lactamases (ESBLs) in isolates of E. coli and other bacteria is of major clinical concern, but also in the spread in food-associated infections.
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Extended-spectrum β-lactamases |
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Resistance to broad-spectrum penicillins quickly followed their use in the 1960s, with most of this resistance being due to β-lactamases. Multiple β-lactamase types have now been recognized, and a classification based on hydrolytic profiles has been developed. Livermore,7 in defining an ESBL, traces the evolution of these enzymes and their nomenclature. In the introduction to ESBLs, Forever? by Cornaglia et al.8 published on behalf of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), it is mentioned that the β-lactams are the most flexible antibiotic class, being versatile and diverse in terms of chemical properties, antibacterial spectra and administration requirements. The authors argue that the major threat for these compounds is the ever-growing diversification and proliferation of β-lactamases. Among the 350 different β-lactamases identified, almost one-third are able to hydrolyse broad-spectrum cephalosporins. It is clear that over the last 20 years, a variety of definitions have arisen and that proposed at ESCMID by Livermore7 is particularly useful: ‘an ESBL is any β-lactamase, ordinarily acquired and not inherent to a species, that can rapidly hydrolyse or confer resistance to oxyimino-cephalosporins (not carbapenems) or any β-lactamase mutant, within a family, that has an enhanced ability to do so’.
Since the recognition of ESBLs, the new, additional, concern is the CTX-M enzymes, including CTX-M-15 type β-lactamase, which is particularly widespread in the UK and other countries. The occurrence of ESBLs largely, initially, was recognized in hospital environments. However, little attention has been directed to the spread of antibiotic-resistant bacteria via food and other routes, such as water effluent. These drug-resistant bacteria and their genes, which include those encoding CTX-M and CMY β-lactamases, are now widespread. Third-generation cephalosporins, such as ceftiofur, are widely used in many different food animals as there are often minimal restrictions in place on their use. Recently, too, a fourth-generation cephalosporin (cefquinome) was approved for use in the EU and it is likely to be approved soon by the US Food and Drug Administration without label restrictions. An example of the potential for animal spread is the report of imported chicken meat as a potential source of quinolone-resistant E. coli producing ESBLs in the UK by Warren et al.9
How CTX-M has changed the face of ESBLs, especially in Europe, has been reviewed by Livermore et al.10 This review largely deals with nosocomial isolates, often Klebsiella spp. or Enterobacter spp., but identifies greater penetration into E. coli. In studies reported on the detection through monitoring of ESBLs in the UK, all ESBLs detected in E. coli from clinical diagnostic samples have originated from cattle. The Veterinary Laboratory Agency has identified ESBL-producing E. coli in horses and sheep on a farm investigated during a follow-up visit associated with the prior isolation of E. coli producing CTX-M-15 from cattle. The majority of E. coli isolates with ESBL-mediated resistance are from calves, the majority being under 2 weeks of age.11 The isolates of E. coli carrying ESBLs recovered recently have come from different counties of the UK so these enzymes are widespread.
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Responsible use of medicines in agriculture (RUMA) |
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Criticism has been directed to the use of antibiotics in livestock production, particularly as growth promoters in young animals, chickens, pigs, lambs and calves. The concern as expressed in several reports is that such use could lead to resistance to antibiotics, particularly those in general use for human infections. However, the livestock sector of agriculture has responded to the criticism by the formation of RUMA, this being a consortium of veterinarians, agriculturists and pharmaceutical organizations. As well as the collection and analysis of data referring to antimicrobial sales and usage, it produces guidelines and advice on antimicrobial use. This is a welcome illustration of private sector concern and action, addressing the nexus between animal and humans use of antibiotics.
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Committee for medicinal products for veterinary use |
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This Committee of the European Medicines Agency has produced a reflective paper on the use of third- and fourth-generation cephalosporins in food-producing animals in the EU with reference to the development of resistance and impact on human and animal health. This paper discusses cephalosporins with a focus on substances of the third- and fourth-generation and food-producing animals but excludes these compounds in aquaculture. The paper gives a good account of the mechanism in action, classification and spectrum of activity. It gives a useful list of the various generative cephalosporins (first through fourth) and the resistance of various organisms to cephalosporins.
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Reservoirs of antibiotic resistance (ROAR) network |
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This network (ROAR) was born out of the Alliance for the Prudent Use of Antibiotics (AUPA), being a realization of the misuse of antibiotics in medicine, veterinary medicine and agriculture, as growth promoters in animal feed, but also their use in non-medical areas such as cleaning agents and use in horticulture for the control of fungal and bacterial attacks on fruit and vegetables. But in addition to the above is the flow of antibiotics after clinical use in animal and human waste and thence into the environment with the acquisition of resistance by commensal organisms, the exchange of resistance genes between commensals and eventually back to pathogenic forms. Resistant enteric bacteria have been found in wild life (wild rodents) where no contact with domestic livestock or medicants is evident. Whether such infections are manifestations of environmental contamination as envisaged by ROAR or are natural resistant populations existing independent of antibiotic usage in man and animals is unclear at present.
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Resistance in other microorganisms |
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Earlier, I mentioned my interest in parasitology, particularly in parasitic helminths. At that time, some 50 years ago, resistance of sheep nematodes to phenothiazine was recognized, but over the intervening years anthelmintics of broad spectrum have come and gone due to the development of anthelmintic resistance. The two compound groups now concerned in this are the benzimidazoles and ivermectin. The situation has been so severe that livestock farming (sheep) is impossible in parts of South Africa and Australia and may jeopardize horse farming. Despite the highly effective antiparasitic compounds, resistance has developed largely due to poor grazing management and little or no assessment of the need for antiparasitic treatment, such as the performance of a faecal egg count. In fact, the overall picture of resistance of nematodes to anthelmintics is not too dissimilar to that of antibiotic resistance to bacteria.
Resistance on the part of helminths, strongyles and flukes received scant attention in the House of Lords Science and Technology Select Committee Report, partly because there was little or no human health concern with such resistance but also because little was known of the mechanism of resistance, though the overall cause, as with antibiotics, is the overuse of anthelmintics. Resistance is now widespread to the majority of anthelmintics by the majority of pathogenic strongyles of cattle, sheep and horses; even the liver fluke (Fasciola hepatica) is resistant to the commonly used compounds such as triclabendazole and closantel. As this is also a parasite of man, infection with resistant forms may have serious human health consequences.
The other concept of parasite control that is generally not recognized is that in a parasitic population, those developmental stages outside a host greatly outnumber the parasitic stages within the host. The fate of the developmental stages outside the host is determined by environmental factors such as temperature, moisture and desiccation, and the ‘infectivity’ of a pasture is determined by the input of developmental stages to it, such as the eggs in faeces, exposure to environmental factors and the return of the hosts to the pasture. Various management techniques have been used with horses to reduce this burden of infectivity and include the collection of faeces either manually or by vacuum sweeper, by grazing with alternate hosts (usually sheep) or by cropping, e.g. silage or hay. What is not fully understood are the microclimate and microsurvival requirements of such developmental stages outside the host and their relationships to free-living nematodes and other microorganisms, such as bacteria and fungi. In the case of bacteria, there is increasing evidence that antibiotic resistance may be transmitted by commensal soil and other environmental bacteria (ROAR—as above). We do not know whether there might be a similar situation occurring with metazoan organisms on pasture, but it is unlikely that genes are unable to move amongst species of animal parasitic nematodes, bearing in mind the genetic capabilities of plant parasitic nematodes.
The developmental stages of animal strongyles that are not exposed to anthelmintics during treatment are described as being ‘in refugia’. Many factors determine the rate at which resistance develops but levels ‘in refugia’ are considered to be the most important as they are not selected by treatment and so provide a pool of sensitive genes in the population. Modern thinking concludes that refugia are overlooked as perhaps the most important factor concerning the development of anthelmintic resistance.
Refugia in horse strongyles consist of the proportion of a parasitic population that is not exposed to a drug at the time of treatment. Free-living stages on pasture constitute a major part of the refugium but also included are parasites in untreated animals and certain developmental stages that do not come into contact with the drugs, such as the encysted larval stages of the cyathostomins (the small strongyles). Maintenance of adequate parasite refugia can slow development of anthelmintic resistance, a point confirmed experimentally in sheep in Australia. Therefore, avoidance or reduction of treatments at times when parasite refugia are small is important to sustain anthelmintic efficacy. It follows that a thorough knowledge of the distribution of the parasite population in horses is important.
Intensive anthelmintic use over several decades has caused dramatic changes in parasite prevalence and disease, a similar situation to the imprudent use of antibiotics for bacterial infections. The concept of a ‘Wormy World’, as is the bacterial world, is still with us. Effective anthelmintics and antibiotics need to be viewed as important resources that must be used with care as they are not readily renewable.
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Conclusions |
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The evolution of resistance to microbes is one of the significant problems in modern medicine, possessing serious threats to human and animal health. This article has dealt with but a small sample of resistances of bacteria but has included a selection of resistance in parasitic helminths. It has not dealt with the array of disease-producing protozoa, such as malaria and trypanosomes nor the transmitting arthropods, all of which have important overtures to human and animal health.
The role of the environment in the transmission of resistance from food-borne resistance or by contamination of crops and water are topics yet to be thoroughly investigated and understood.
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Transparency declarations |
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None to declare.
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References |
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1 House of Lords Select Committee on Science and Technology. Session 1997–98. Seventh Report. Resistance to Antibiotics and other Antimicrobial agents. London: The Stationary Office.
2
Woodhead M, Finch R. Public education—a progress report. J Antimicrob Chemother (2007) 60(Suppl 1):i53–5.
3 Swann MM, Baxter KL, Field HI, et al. Report of the Joint Committee on the use of Antibiotics in Animal Husbandry and Veterinary Medicine. Published by HMSO. London, 1969.
4
Wise R. An overview of the Specialist Advisory Committee on Antimicrobial Resistance. J Antimicrob Chemother (2007) 60(Suppl 1):i5–7.
5 Veterinary Medicines Directorate. Sales of Antimicrobial Products Authorised For Use As Veterinary Medicines, Antiprotozoals, Antifungals, Growth Promoters and Coccidiostats in the UK in 2005. http://www.vmd.gov.uk/Publications/Antibiotic/salesanti05.pdf(13 March 2008, date last accessed).
6
Piddock LJV. Fluoroquinolone resistance. BMJ (1998) 317:1029–30.
7 Livermore DM. Defining an extended-spectrum β-lactamase. Clin Microbiol Infect (2008) 14(Suppl 1):3–10.
8 Cornaglia G, Garau J, Livermore DM. Living with ESBLs. Clin Microbiol Infect (2008) 14(Suppl 1):1–2.
9
Warren RE, Ensor VM, O'Neill P, et al. Imported chicken meat as a potential source of quinolone-resistant Escherichia coli producing extended-spectrum β-lactamases in the UK. J Antimicrob Chemother (2008) 61:504–8.
10
Livermore DM, Canton R, Gniadkowsk M, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother (2007) 59:165–74.
11 Teale CJ, Barker L, Foster AP, et al. Extended-spectrum β-lactamases detected in E. coli recovered from calves in Wales. Vet Rec (2005) 156:186–7.[ISI][Medline]
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