Select Committee on Science and Technology Seventh Report


CHAPTER 3 PRUDENT USE IN ANIMALS (continued)

Salmonella

  3.15     The recent history of Salmonella in the United Kingdom, as told by the PHLS (p 56), is closely related to the history of antibiotics for animals. The Swann enquiry of 1969 was precipitated by an epidemic of multi-resistant S. typhimurium DT 29 in cattle and man. Following the Swann report and the withdrawal of growth promoters related to human antibiotics such as chloramphenicol, levels of DT 29 rapidly subsided. A second wave of multi-resistant S. typhimurium (DT 204, DT 193 and DT 204c) ensued from 1975; this followed the introduction of some of the affected antimicrobials into calf husbandry, and provided "the first conclusive evidence" of a veterinary antibiotic (apramycin) giving rise to resistance to a human antibiotic (gentamicin). Since 1990 there has been a third wave of multi-resistant S. typhimurium (DT 104); since 1994 multi-drug resistance has also increased in S. virchow, less prevalent than S. typhimurium but more invasive in man, and in S. hadar.[35] Substantial increases in resistance to the fluoroquinolone ciprofloxacin in S. hadar and S. virchow, and in multi-resistance in S. typhimurium DT 104, followed the licensing for veterinary use of the fluoroquinolones enrofloxacin in 1993 and danofloxacin in 1996. PHLS concludes, "The use of fluoroquinolones and trimethoprim in food animals has contributed to the development of resistance to these antibiotics in zoonotic Salmonellas" (cp QQ 85-88).

  3.16     According to Dr Simmons, "The appearance of ciprofloxacin resistance in strains from man coincided with the approval of enrofloxacin for veterinary use in the United Kingdom, and some microbiologists feel strongly that it is a consequence of it" (p 220). Dr Janice Bates of Worthing Hospital is one of them (p 378; cp BMA p 382). The report of the WHO meeting concludes that there is "direct evidence" that antimicrobial use in animals selects for resistant Salmonella serotypes, which have been transmitted to man, and "particular concern" about fluoroquinolone-resistance. Experts at PHLS, and others both in the United Kingdom and in the USA, believe that the fluoroquinolones should be used exclusively for treating human disease.[36]

  3.17     Mr Peter Watson of Bayer, speaking for NOAH, offered us some evidence on the other side (Q 424). First, some of the strains recorded in the laboratory as being resistant were still susceptible to treatment in clinical conditions.[37] Second, a recent survey in Northern Ireland found no Salmonella of bovine origin resistant to fluoroquinolones, despite widespread use of fluoroquinolones in cattle in the Republic of Ireland since 1986. NOAH believes that fluoroquinolone resistance in Salmonella in the rest of the United Kingdom may be on the wane (p 212), and that the level of resistance to apramycin is "ultra-low" and "of no clinical significance" (p 211).

Campylobacter

  3.18     Campylobacters are the most common cause of food-poisoning in the United Kingdom. According to the WHO report, "Following the introduction of fluoroquinolones for use in poultry [notably enrofloxacin, licensed in the United Kingdom in 1993] there has been a dramatic rise in the prevalence of fluoroquinolone-resistant Campylobacter jejuni isolated in live poultry, poultry meat and from infected humans. Moreover, prior to any use in poultry, no resistant strains were reported in individuals with no previous exposure to quinolones. Fluoroquinolone-resistant C. jejuni has been associated with therapeutic failures in humans".

  3.19     Dr Bates, citing evidence from the Netherlands, claims that ciprofloxacin-resistance in Campylobacter is "secondary" to use of enrofloxacin in poultry (p 378; cp Piddock p 445). The BPMF acknowledge the evidence from the Netherlands to this effect, and also evidence from Spain (p 389); they blame the situation on a lack of control on the use of fluoroquinolones in poultry in those countries, and they acknowledge a lack of data on this problem in the United Kingdom.

Enterococci

  3.20     Enterococci have natural resistance to numerous antibiotics, and cause serious infections in hospitalised immune-impaired patients. Infection with enterococci resistant to the glycopeptide vancomycin (VRE) is almost untreatable (PHLS p 44). The report of the WHO meeting expresses concern at the possibility of "increased dissemination of glycopeptide resistance genes to Enterococcus faecalis and their spread to other gram-positive organisms, particularly to MRSA for which vancomycin is the drug of last resort". According to the PHLS, "The public health and economic consequences of [such spread] would be catastrophic".[38]

  3.21     Avoparcin is a glycopeptide, which has been used as a growth promoter since 1975. WHO bluntly state that the use of avoparcin as a growth promoter in animal husbandry "has contributed" to the reservoir of transferable resistance genes to glycopeptides, including vancomycin, in the commensal enterococci of animals, and that these can reach humans via the food chain. Whether resistant strains derived from animals are the same as the resistant strains which cause human disease is a matter of current scientific controversy.[39] The EU Scientific Committee for Animal Nutrition (SCAN) considered the matter in 1995, decided that the case was not proven, and recommended further research; but in 1996 the European Union decided to suspend use of avoparcin altogether.[40]

  3.22     The PHLS (p 44) tell us that there is "considerable evidence" that VRE may spread to humans via the food chain, and that "several studies have implicated" avoparcin. The new antibiotic Synercid[41] is the PHLS's best hope as a treatment for multi-resistant enterococci; but resistance to Synercid may have been induced already by use of the related growth promoter virginiamycin, used in pigs, poultry and cattle. PHLS recommend extensive further study of the relative contribution of clinical antibiotics and animal growth promoters to the selective pressure on enterococci, including (a) molecular typing, to establish whether resistant strains found in people and animals are the same, (b) characterisation of resistance genes, and of their capacity to transfer between enterococci in animals and those in man, and (c) investigation of the agents being used instead of avoparcin, to find out whether they are continuing to select for cross-resistance to glycopeptides. They call also for surveillance of VRE in the community and the food chain; at present what data there are come from hospitals.

  3.23     We put to NOAH the question of virginiamycin and Synercid. Dr Bywater replied that, though virginiamycin has been used in animals for thirty years, the enterococcus which is the target organism remains "almost entirely susceptible". However according to Dr Bates (p 379), "Evidence emerging from the United Kingdom, Germany and the Netherlands shows that resistance to Synercid in clinical strains already exists".

  3.24     Defenders of avoparcin (e.g. NOAH, p 200, Q 397, BPMF p 390) point out that VRE is common in the USA, despite the fact that avoparcin has never been permitted there as a growth promoter. Dr Bates (p 379) accepts that VRE in the USA is probably due to human use of vancomycin, which is greater there than in Europe. However, some experts whom we met in the USA believe that there is substantial illegal use of avoparcin in the livestock industry, and that because of the global nature of food transport and travel there are opportunities to import vancomycin-resistant organisms (cp Simmons Q 448, Soil Association p 506). NOAH also observe that VRE is found in horses, for which avoparcin is not used (QQ 396, 401); and the BPMF point out that in Denmark, where avoparcin was widely used, VRE in humans is "virtually unknown" (p 390).

E. coli

  3.25     Certain E. coli are food-borne pathogens but most are susceptible to antimicrobials at present. However, the development of antimicrobial resistance in E. coli is of concern since there is a high propensity to disseminate antimicrobial-resistant genes.

  3.26     Dr Laura Piddock of the University of Birmingham has studied acquisition of ciprofloxacin-resistance by E. coli; she believes, "The primary exposure is likely to be in an animal due to the veterinary use of fluoroquinolones" (p 444). According to Dr Simmons, some fluoroquinolone-resistant E. coli "seem to be associated with enrofloxacin usage in animals" (p 220).

Swedish experience

  3.27     Sweden banned the use of antimicrobials for in-feed use without prescription in 1986. On joining the EU, Sweden received a derogation to assess the acceptability and validity of the EU's animal production model and the use of approved in-feed antimicrobial additives for meat-producing animals. However, the ban has resulted in lower production efficiency and increased costs (NOAH p 201, QQ 406-421). In no single year has the pig industry made a profit and it is at present supported by Government subsidy.

  3.28     Absence of growth promoters was associated with an increase in post-weaning scour (Institute of Biology p 423), mortality and a longer growth rate. Disease control has been achieved by improved management, the licensed use of prescribed antimicrobials, and in-feed zinc oxide.[42] According to the BPMF, the Swedish experience suggests that a husbandry system without growth promoters may even use more antimicrobials in total than a conventional system, including more therapeutic agents directly related to antibiotics used in man (p 388; cp UKASTA p 531); but according to the Soil Association, overall use of antibiotics in Sweden fell by 30 per cent by 1988 and has remained low (p 504).

  3.29     Though the Swedish pig industry is recognised as inefficient, the Swedish government are seeking to persuade other EU countries to follow their lead on the basis of control of health hazards to humans and consumer concerns.

US experience

  3.30     In 1995 the US Food and Drug Administration (FDA) approved the prescription of the quinolone sarafloxacin for the prevention of pneumonia in poultry, subject to resistance monitoring up and down the food chain. Then, in 1997, a telephone call from the PHLS Laboratory of Enteric Pathogens alerted FDA to the emergence of ciprofloxacin resistance in S. typhimurium DT104 in the United Kingdom. Since then, FDA has issued no more approvals for fluoroquinolones for animals; meanwhile, resistance to fluoroquinolones has been found in Campylobacter, though none as yet in Salmonella. FDA are using DNA fingerprinting to see whether resistance in Campylobacter can be traced to poultry and sarafloxacin. In discussion at FDA, during our visit to the USA (see Appendix 6), we were taken aback to be asked why the United Kingdom continues to approve fluoroquinolones for animal use, when the USA has stopped doing so on information from the PHLS.

Licensing regime

  3.31     The Swann Report recommended that a single Government advisory committee "should have overall responsibility for the whole field of use of antibiotics and related substances whether in man, animals, food preservation, or for other purposes". This recommendation was implemented by the establishment of the Joint Committee on Antimicrobial Substances (JCAMS), as a sub-committee of the Committee for the Safety of Medicines and the Veterinary Products Committee; but JCAMS was wound up in 1980. The Soil Association (p 501) put it to us that JCAMS was not effective, and that Swann's original recommendation ought now to be implemented in full.[43]

  3.32     NOAH drew our attention to a potential gap in the licensing arrangements for feed additives in the United Kingdom (p 198, QQ 403-5). Both the United Kingdom and the European Union regimes are to change as from 1 April 1998. Directive 70/524 is to be amended so as to move from approval of substances to approval of individual branded products; meanwhile the United Kingdom licensing requirements under the Medicines Act are to be revoked altogether. It will be "a number of years" before the new EU regime is fully in place; during that period, according to NOAH, there will be "a free and uncontrolled market for antibiotic growth promoters in the United Kingdom".

Aquaculture

  3.33     Several of those whom we have met, in both the United Kingdom and the USA (e.g. PHLS Q 82), have suggested that we should take into account the use of antibiotics in aquaculture (fish-farming). Hitherto, fish farming has relied heavily on the use of antibiotics; and, for example, catfish farming has been associated with resistant Aeromonas and Vibrios. However, the development of a vaccine for furunculosis has resulted in a marked reduction in antibiotic use in the United Kingdom and other countries (NOAH pp 201, 212). Nevertheless, antibiotic use is substantial in Asia, and there is a resistance problem in ornamental fish (Simmons Q 461) and terrapins.

Uses of antimicrobial agents on plants

  3.34     Antibiotic-resistant organisms may be found on common fruits and vegetables following the use of antibiotic sprays to control bacterial and fungal growth (Institute of Biology p 425). While there is little direct danger from eating fruit and vegetables treated in this way, the organisms could transfer their resistance to more potent human pathogens.

  3.35     The bacterium Burkholderia cepacia is used widely for environmental purposes (biodegradation of landfill wastes), and also for enhancement of crop yields and prevention of post-harvest loss of fruit and vegetables through its antifungal properties. Dr Philip Murphy, Director of the Northern Ireland Public Health Laboratory, drew our attention to concern about its use, given its significance as a pathogen in cystic fibrosis and its resistance to all available antibiotics (p 435).

Sheep: worms and scab

  3.36     Dr Gerald Coles of Bristol University (p 250) expressed concern about two major parasitic infections of sheep: nematodes (worms) and sheep scab. These pose no threat to human health, but can have a serious impact on farming and on animal welfare. Nematodes resistant to all anthelmintic treatments have forced some farms to close in South Africa, and have been found in Australia and New Zealand, and in two herds of Angora goats in the United Kingdom. "The evidence is that most [United Kingdom] farmers are not yet taking the problem seriously. The problem is compounded by the fact that some of the recommendations [for controlling resistance] have never been validated in the field due to the lack of research funds." Dr Coles blames multi-resistance on over-use of anthelmintics; he considers it "most probable" that the worms have passed from goats to sheep. He recommends that all sheep grazed with Angora goats should be monitored, and that sheep carrying worms resistant to ivermectin should be banned from sale except for slaughter. The Ministry of Agriculture, Fisheries and Food (MAFF) acknowledge that the situation "merits some degree of concern" (p 551).

  3.37     Until 1992 sheep scab was kept at low levels in the United Kingdom by compulsory dipping (MAFF p 551). In 1992 these controls were lifted, and since then levels of scab have risen. What is worse, resistance has emerged to both pyrethroids and organophosphates (though not yet to both together), either through inappropriate use against scab, or through the effect on undiagnosed scab of correct use against other infestations. Dr Coles paints a gloomy picture: "It is quite probable that resistance to the third group [of insecticides, i.e. ivermectin] has already developed, or will do so shortly...It is quite probable that multi-resistant mites will occur within 3-5 years. On welfare grounds this would leave only the reintroduction of the organochlorine lindane, or slaughter of the affected flock(s). If organophosphates are banned, flock slaughter may have to start within two years".

  3.38     MAFF are less pessimistic (p 551). "MAFF is aware of reports on the limited existence of sheep scab mites in the United Kingdom flock which are resistant to either pyrethroid or organophosphate classes of treatment compounds. However, there is no evidence of such mites having a resistance to both pyrethroids and organophosphates. There are no recorded cases of resistance to ivermectin, the third class of treatment compound, in sheep scab mites anywhere in the world. We consider therefore that there are effective treatments currently available against sheep scab in the United Kingdom flock. The potential problem of the further development of acaricide resistance in sheep scab mites is nevertheless recognised and MAFF is funding research into the factors which are involved, together with surveillance methodology, and possible alternatives in sheep scab control."

  3.39     The previous Government went back somewhat on the deregulation of 1992, and made it compulsory to treat flocks visibly affected by scab and illegal to move them in the mean time (Sheep Scab Order 1997, S.I. 1997 No. 968). However, according to Dr Coles, this is not enough. "Firstly, sub-clinical scab cannot be diagnosed, so scab will still be spread. Secondly, without rapid sensitive tests for resistance, farmers will not know if they are using a fully effective product...Without diagnosis of the resistance status of outbreaks, incompletely effective treatments may be used, resulting in further sub-clinical scab and dissemination of the resistance mites."

  3.40     MAFF reply, "The objective of the Sheep Scab Order is not to eradicate the sheep scab mite but to facilitate the control of clinical disease by sheep farmers" (p 552). Sub-clinical disease, and the effectiveness of treatments, are not the concern of the Order.

  3.41     The British sheep industry is the biggest in the EU; and Dr Coles considers that resistance in nematodes and scab mites is imperilling its future. He calls for recognition of the problem by Government and farmers (Q 562); for surveillance (Q 535), and for research into how resistance arises, how to detect it and how to avoid it (QQ 541, 564; see MAFF p 551); for voluntary or compulsory certification of health when sheep are sold (QQ 545, 550); and for vigorous programmes of eradication while effective treatments remain.

Antibiotic-resistance marker genes in genetically-modified organisms

  3.42     When a genetic modification is made to an organism using techniques of bioengineering, it is usual to incorporate a "marker" to indicate whether the modification has been a success. One suitable form of marker is a gene which codes for resistance to an antibiotic: the modified organism can then be exposed to the antibiotic, and if it resists then the modification has worked.

  3.43     It has been suggested in some quarters that there is a risk that resistance genes incorporated into genetically-modified organisms as markers may somehow confer resistance on pathogens. This possibility has been considered by the Government's Advisory Committee on Novel Foods and Processes (ACNFP); the EU Scientific Committees for Food, and for Animal Nutrition (SCAN); and by the WHO and the FAO. The consensus is that the risk of transfer is very small, and that even if it were to happen the effect on the overall resistance picture would be marginal. There has been however a disagreement between the ACNFP and SCAN over a genetically-modified maize containing a marker gene for â-lactam resistance in E. coli; the story is told in the evidence of Dr Simmons, a member of the ACNFP, who considers that the EU set an unfortunate precedent by allowing the maize to be imported (p 221, Q 469; cp Monsanto p 434).

  3.44     Of the many witnesses who have expressed to us their grave concern about the issue of antibiotic resistance, none has pointed to biotechnology as a contributory factor[44]; therefore we have not gone into this matter in detail.


35   Resistant strains of the Salmonella responsible for most human food-poisoning in the United Kingdom, S. enteritidis, have throughout this period remained rare (BPMF p 389). Most cases of Salmonella do not require antibiotic treatment; but antibiotics are needed by vulnerable patients, and when Salmonella gives rise to bacteraemia. So resistance is of concern in human medicine; also, resistant strains are harder to eradicate in animals (Soil Association p 506). Back

36   We understand that the WHO and the FDA are to meet in June 1998 to discuss this. Back

37   "This may not be the case" (Piddock p 444). Back

38   Cp Amyes and Young, p 375, on VRE and VRSA. Back

39   One of those who believes that the strains are distinct is Professor Mark Casewell, whom we met at King's College Hospital: see Appendix 5. Back

40   Dr Johan Vanhemelrijk, Secretary-General of the European Federation of Animal Health (FEDESA), commented, "The Commission Directive is based on the absence of the disproof of risk; I think that is a strange way of making law" (Q 396). SKB support the ban, as "a precautionary and protective measure in the current climate of doubt" (p 475). NOAH considers the "precautionary principle" to be "ill-judged" (p 212); the BPMF acknowledge the force of the precautionary principle, but consider the ban unwarranted even on that basis (p 390). The only Member State to vote against the ban was the United Kingdom (Simmons p 219). Back

41   Trade name for a combination of the streptogramins quinupristin and dalfopristin, which may be licensed soon. Back

42   Zinc oxide is not favoured by environmentalists because of its ability as a heavy metal to stay in the soil. Back

43   Cp Dr R Hill (p 420), who recommends medical involvement in the licensing of veterinary drugs, and the Institute of Biology (p 422), who call for a "holistic" approach to the whole phenomenon of resistance. Back

44   Though the Institute of Biology express concern (p 424). Back


 
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