CHAPTER 3 PRUDENT USE IN ANIMALS
3.1 It may be that
as much as half of all antimicrobial usage by volume takes place
outside human medicine (PHLS Q 82; SKB p 475); and we
were aware before we began our enquiry of the relevance to our
topic of the use of antibiotics as growth promoters, and for prophylactic
and therapeutic purposes, in animals and fish, and the use of
antibiotic resistance markers in genetically modified organisms.
The former is currently under consideration by a working group
of the Government's Advisory Committee on the Microbiological
Safety of Food (Georgala p 373, Simmons Q 437, Calman
Q 769), and the latter has recently been considered by the
Advisory Committee on Novel Foods and Processes (Q 437).
Therefore these questions have not been the main focus of this
enquiry. However, too many witnesses have brought the issue of
growth promoters to our attention, to allow us to disregard it.
3.2 Antimicrobial use
in livestock originated some 50 years ago when chlortetracycline
fermentation waste was found to enhance the growth of poultry,
pigs and other species. Intensification of livestock production
was an increasing practice of the time and the use of broad spectrum
antibiotics was shown to control the diseases, especially respiratory
and enteric conditions, attendant on intensive production. The
use of antibiotics in animals is now a significant part of the
armamentarium of veterinary medicine for all species. Their use
is now regulated both nationally (Medicines Act 1968) and at EU
level (Directive 70/524 for feed additives, 81/851 for medicines).
Animal medicines
3.3 Antimicrobials
are used in animals for the treatment of clinical disease, the
larger food species and companion animals being treated individually.
With intensive systems, such as poultry and pigs, individual treatment
may be, and usually is, not feasible and mass oral medication
is the only practical method of treatment. This may be administered
in the food or more usually in the drinking water.
3.4 Prophylactic antibiotic
use is applied with respect to predictable diseases or at the
outbreak of a disease in a herd or flock. This is usually applied
as mass medication ("metaphylaxis"). Examples are the
use of medicated feed or water to prevent the emergence of disease
in poultry when it is known that mycoplasma organisms are transmitted
vertically through the egg to cause disease in chicks, the occurrence
of respiratory problems when young animals are regrouped, colibacillosis
during the post-weaning period in pigs, and "shipping fever"
following transport. The case for group treatment, and for medication
via water rather than food, is put succinctly in the evidence
of the National Office of Animal Health (NOAH, Q 422, pp 199
and 214) and the British Poultry Meat Federation (BPMF, p 387);
but some observers consider that the borderline between mass prophylaxis
and growth promotion, which is crucial to the regulatory regime,
is poorly delineated (e.g. SKB p 475, Bates p 378, Simmons
Q 467, Soil Association p 508).
Growth promoters
3.5 The use of antimicrobial
agents as growth promoters[27]
has been practised for some thirty years. They improve the growth
rate and efficiency of feed in cattle, pigs and poultry. Their
mode of action is not fully understood; it is said to be by suppressing
commensal bacteria which would divert nutrition from the animal,
and by maintaining a more effective and absorptive gut lining
(NOAH Q 412, p 212; BPMF p 388; Simmons p 216).
Growth promoters are used at low concentrations (2.5 ppm
to 50 ppm according to compound). Their use increases average
daily growth and food conversion ratios by 3 per cent to
11 per cent depending on species; in financial terms, this
is considered to make the difference between profit and loss.
3.6 Though applied
in sub-therapeutic doses, growth promoters also appear to have
the effect of suppressing disease (Q 418). While antibiotics
for therapeutic use are available on a prescription-only basis
(POMs), growth promoters are generally available to livestock
producers from food manufacturers ("Pharmacy and Merchant's
List"—PML), without veterinary prescription.[28]
Human health concerns
3.7 The widespread
use of antimicrobial agents as growth promoters, and the public
health implications of their use, precipitated the appointment
of a Committee on the Use of Antibiotics in Animal Husbandry and
Veterinary Medicine (the Swann Committee: see Box 6) which in
1969 recommended banning the use of human therapeutic antibiotics
as growth promoters for animals. This led to legislation. However
no restriction was placed on the use of such antibiotics for therapy
or prophylaxis in animal use. In 1992, the Expert Group on Animal
Feedingstuffs (the Lamming Committee) recommended that prophylactic
use should be "reconsidered"; the Veterinary Products
Committee accordingly reconsidered it, and decided to "discourage"
it, while continuing to consider each case on its merits.
3.8 Despite the Swann
Report, the use of antimicrobial agents as growth promoters continues
to generate criticism that they are used for purely economic reasons
and as substitutes for good husbandry and hygiene, and that because
of the risk to human health they should be banned (e.g. SKB p 475,
Soil Association p 505), or at any rate restricted (e.g.
Simmons Q 451). According to the BPMF (p 388), "The
only antibacterials authorised as digestive enhancers are ones
that are not used, or related to those used, in human medicine.
Antibacterials which are known or suspected of causing resistance
in human bacteria are not used". However avoparcin and virginiamycin
would appear to be important exceptions: see below, Enterococci.
Moreover, an agent reserved for animals today may be discovered
tomorrow to have clinical applications in man; and resistance
by the particular mechanism of efflux can act on highly diverse
molecular classes, so that treatment with an animal agent might
well give rise to cross-resistance to an unrelated agent used
in man (SKB p 475).
| Box 6
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| THE SWANN REPORT
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| The Joint Committee on the use of Antibiotics in Animal Husbandry and Veterinary Medicine, chaired by Professor M M Swann, was appointed jointly by Health and Agriculture Ministers in July 1968. Its report (Cmnd 4190) was issued in November 1969.
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| The Swann Report concluded that "the administration of antibiotics to farm livestock, particularly at sub-therapeutic levels, poses certain hazards to human and animal health"; in particular it had led to resistance in enteric bacteria of animal origin. This resistance was transmissible to other bacteria (it had been the discovery that this might be so, followed by an epidemic of resistant S. typhimurium in 1963-65, which prompted Ministers to appoint the Committee); and enteric bacteria were transferable from animals to man.
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| It therefore recommended that only antibiotics which "have little or no application as therapeutic agents in man or animals and will not impair the efficacy of a prescribed therapeutic drug or drugs through the development of resistant strains of organisms" should be usable for growth promotion. The Report named the following antibiotics, which were then in use for growth promotion, as unsuitable for such use: chlortetracycline, oxytetracycline, penicillin, tylosin (a macrolide related to erythromycin) and the sulphonamides. The Government largely accepted these recommendations.
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| The Report recommended that a single advisory committee, constituted under the Medicines Act 1968, "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". It also recommended research into alternative means of growth promotion; and improved surveillance and epidemiology of diseases common to animals and man.
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3.9 In the course of
our inquiry, the WHO convened a major multidisciplinary meeting
on this subject.[29]
Its report concluded, "Antimicrobial use leads to the selection
of resistant forms of bacteria in the ecosystem of use. This will
occur with all uses including treatment, prophylaxis and growth
promotion...Low-level, long-term exposure to antimicrobials may
have a greater selective potential than short-term full-dose therapeutic
use". The meeting recommended prohibition of growth promoters
which are "used in human therapeutics, or known to select
for cross-resistance to antimicrobials used in human medicine";
and "a systematic approach towards replacing growth-promoting
antimicrobials with safer non-antimicrobial alternatives".
The Chief Medical Officer acknowledged the importance of the WHO
meeting, and said, "The area is one of significant concern"
(Q 769). Dr Robin Bywater of Pfizer, who attended the
WHO meeting, told us that the industry would be "fully supportive"
of reduced reliance on antimicrobial growth promoters, "if
such products can be replaced by effective alternatives"
such as probiotics[30]
(Q 395).
3.10 The animal health
and welfare and environmental benefits of growth promoters have
been clearly delineated by NOAH (QQ 406-421), the BPMF (p 388)
and UKASTA (p 533), and are illustrated by the experience
of Sweden in trying to do without them (see below). Antimicrobial
resistance in diseases affecting the animals themselves is of
welfare and economic concern in animal production, but NOAH does
not see it as a major problem in that context (p 212). What
matters for our purposes is the potential of animal-derived resistant
organisms and their genes passing to humans, either via direct
contact with animals[31]
or through the consumption of food or water.
3.11 Antimicrobial
residues in food of animal origin (regulated by acceptable maximum
residue levels—MRLs) are considered to be a low risk (NOAH
p 200, BPMF p 390, UKASTA p 530). The Soil Association
suggest that therefore the Veterinary Medicines Directorate (VMD)
and the Veterinary Laboratories Agency (VLA) should pay less attention
to residues, and more to resistance (p 501).
3.12 There is a marked
discrepancy of opinion about the link between antibiotic use in
animals and resistance in man. The argument is being conducted
in conditions of some heat[32]
and inadequate light. Dr Norman Simmons, a Consultant Microbiologist
and a member of both ACMSF and ACNFP, told us that United Kingdom
veterinary medicine does not look for resistance (Q 438).[33]
NOAH responded (p 212) that the pharmacovigilance section
of the VMD, and the VLA, are generally aware of the resistance
pattern in the United Kingdom; but they admitted that there is
"a shortage of data gathered in a consistent manner which
would allow thorough evaluation of changes in [animal] gut flora
over a period of years" and their relationship to human infection.
Surveillance in this area is generally agreed to be less than
optimal. The report of the WHO meeting stresses the need for international
action to produce better information as to the prevalence and
spread of resistance in zoonotic bacteria,[34]
using monitoring networks such as the EU's ENTERNET (formerly
SALM-NET, developed by PHLS).
3.13 It is important
to recognise what are the hazards presented by antimicrobial resistance
in animals to human health. The first is the transfer of resistant
zoonotic pathogens. The second is the selection of antimicrobial-resistant
bacteria which are not pathogenic for man, but which may transfer
their resistance via plasmids to human commensal and pathogenic
bacteria, which may later cause resistant disease.
3.14 As NOAH rightly
observe (p 199), many problem pathogens, e.g. MRSA,
have nothing to do with animals or food; and much of the food-poisoning
which is the cause of widespread concern both here and in the
USA is not caused by resistant organisms. However, animal antibiotics
are implicated in the rise of resistance in some strains of Salmonella,
Campylobacter, Enterococcus, and E. coli; we consider
each of these below.
27
The industry prefers the term "digestive enhancers",
which more accurately reflects what these substances do (BPMF
p 388); but "growth promoters" is the term in familiar
usage. The growth promoting antimicrobials in use include: Carbodox,
Olaquindox, Avilamycin, Avoparcin, Efrotomycin, Flavophospholipol,
Oleandamycin, Spiramycin, Tylosin and Virginiamycin. Back
28
The regulatory regime for animal feed is described in the evidence
of the Veterinary Medicines Directorate (p 565) and the UK
Agricultural Supply Trade Association (UKASTA, p 529). Back
29
Medical Impact of the Use of Antimicrobials in Food Animals, Berlin,
13-17 October 1997. Back
30
Probiotics work on the principle that harmful micro-organisms
in the alimentary tract may be kept at low levels by displacing
them with benign or beneficial organisms, as opposed to destroying
them with antibiotics. Back
31
Including companion animals, ie horses and pets (BPMF p 388). Back
32
See for example the tone of the supplementary memorandum from
NOAH, and the divergence between the WHO press release following
the Berlin meeting and the final report of the meeting (WHO Q 135,
NOAH p 213). Back
33
The British Veterinary Association call for epidemiological surveys
in this area as a "key priority" (p 393). Back
34
Bacteria found in animals and transmissible to man. Back
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