CHAPTER 3 PRUDENT USE IN ANIMALS
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.
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.
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.
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).
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
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".
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.
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.
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
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).
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).
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
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
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.
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.
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".
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)
Uses of antimicrobial
agents on plants
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
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
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
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
therefore we have not gone into this matter in detail.
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
We understand that the WHO and the FDA are to meet in June 1998
to discuss this. Back
"This may not be the case" (Piddock p 444). Back
Cp Amyes and Young, p 375, on VRE and VRSA. Back
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
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
Trade name for a combination of the streptogramins quinupristin
and dalfopristin, which may be licensed soon. Back
Zinc oxide is not favoured by environmentalists because of its
ability as a heavy metal to stay in the soil. Back
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
Though the Institute of Biology express concern (p 424). Back