Introduction:
The access to anti-infectives is essential for veterinary surgeons to treat their patients, just like the medical profession. However just as in human medicine, if antimicrobials are used then there is a risk of resistance developing to them. It is therefore the responsibility of both veterinarians and doctors to use antimicrobials as prudently and carefully as possible so that the opportunity for resistance to develop is limited as much as possible without compromising the health and welfare of our patients. Fortunately not all antimicrobials cause resistance to develop quickly and not all bacteria develop resistance rapidly but both professions will have shared the same problems of treating recurring infections, especially in animals, Escherichia coli in cystitis, Pseudomonas aeruginosa in ear infections and Staphylococcus aureus infections of the skin and in man E. coli in urinary tract infections, P. aeruginosa in cystic fibrosis cases and S. aureus in hospital acquired wound infections.

In general terms treating companion animals, cats, dogs and horses, are similar to general medical practice, with individual cases and individual treatments but patients do not live so long and euthanasia is possible. There are veterinary hospitals and referral hospitals, which have some problems with refractory cases but in general resistance is not a severe problem. The main difference in veterinary medicine is the mass treatment or herds and flocks, which is much more complicated as it involves animal management, husbandry, environment, disease management, herd immunity production and associated economic implications. This is the area, which has attracted much criticism for the use of antimicrobials either as medicines or as growth promoters for disease suppression and production improvement.

Antimicrobial usage in animals in the UK:
The Veterinary Medicines Directorate (VMD) (2001), the equivalent of the Medicines Control Agency, has collected the data from animal health companies on the quantities of antimicrobials sold each year.

Graph 1. Antimicrobial usage in the UK- comparison of companion and farm animal use

(Source: DEFRA/VMD, 2001)

Food producing animals are given most antimicrobials approximately 437 tonnes for therapeutic use (prescription only medicines (POM) - veterinary control), 24 tonnes for growth promotion and approximately 150 tonnes as anticoccidials for use mainly in poultry production. The last two are not under veterinary control and are categorized as zootechnical feed additives. In contrast companion animals are given 29 tonnes for therapy (POM), mainly orally as tablets, creams and ear and eye ointments.

Graph 2. Comparison of antimicrobial usage by route of administration

(Source: DEFRA/VMD, 2001)

Medicated feedstuffs are the major route of administering antimicrobials mainly to pigs and poultry (approx 340 tonnes), oral medications are given mainly in the drinking water to poultry and less so to pigs (20-25 tonnes) and tablet/capsule forms to pets (25 tonnes). Solubles are normally about 10% of the medicated feed premix route, so I have suspicions about the accuracy of the VMD figures for year 2000, as sales in that sector have not increased that much. Injectables (27 tonnes) are relatively stable and are mainly split between cattle and pigs. Intramammary preparations (6 tonnes) are mainly for dairy cows and almost equally split between dry cow preventive therapy and lactating cow for mastitis treatment.

Sales by therapeutic group are also of interest. Tetracyclines dominate with about 200 tonnes sold. Medicated feed premixes (chlortetracycline) account for the majority of use followed by water medication. Oxytetracycline injection would also be significant in all food producing species. Doxycycline is currently restricted to pet use.

Graph 3. Comparison of use by therapeutic group

(Source: DEFRA/VMD, 2001)

Trimethoprim/Sulphas (94 tonnes) are also very popular in all species and formulations. Beta lactams (50 tonnes) are available as medicated feed premixes, penicillin V and amoxycillin, solubles are also available particularly for poultry. Amoxycillin/clavulanic acid is also very important as orals for pets (largest seller), injectables and also in mastitis products. The cephalosporins have been mainly developed for pet oral presentations, injectables for all species and especially for mastitis products, as have the other synthetic penicillins such as cloxacillin. They represent a relatively small volume in tonnage terms but very high value.

Distribution:
Unlike medical practice, where issuing a prescription is the normal and supply is by the pharmacist, in veterinary practice the vet dispenses the antimicrobial and it is only for medicated feed premixes that a MFS (medicated feedstuff) prescription is usually issued to a feed mill that produces the medicated feed. The supply of antimicrobials is therefore an important part of practice income at over £85 million. This situation is under review following the Marsh Report (2001) but in spite of the commercial interest, I feel it is better for the veterinarian to control the supply of these products, as the animals are under his care and he can coordinate all aspects of disease control and monitor the susceptibility of the bacteria.

Antimicrobial resistance - veterinary pathogens:
A number of veterinary pathogens are reviewed and the relative resistance compared. It is only recently that DEFRA has started to collate this information via its Veterinary Laboratories Agency, and the data for 1999 was released last year.

E.coli is a problem particularly in the young animal of all species. In poultry though it is a common secondary invader following a respiratory infection either caused by a virus or a mycoplasma. In cattle, sheep and pigs Pasteurella spp are a major problem either as primary pathogens in the former or as a secondary respiratory pathogen in pigs associated with Mycoplasma hyopneumoniae. Actinobacillus pleuropneumoniae is also a common primary respiratory pathogen in pigs, which on occasion is difficult to treat. The isolates submitted are from clinical cases that may have been treated before and may have proved refractory to treatment so may be considered a worse case scenario.

Table 4. Comparison of E.coli resistance (%) from various species to antimicrobials

Antimicrobial	Cattle	Sheep	Pig	Poultry	Dog	Cat
Ampicillin 10μg	51	36	45	36	36	23
Amox/clav 20/10μg	14	7	-	-	8	0
Tetracycline 10μg	57	53	83	56	25	22
Neomycin 10μg	29	21	18	13	-	4
Apramycin 15μg	5	3	15	3	-	0
TMP/S 25μg	29	20	49	29	17	9
Enrofloxacin 5μg	1	0	3	2	0	0

(Source: DEFRA/VLA, 2001a)

There is quite a high incidence of ampicillin resistance in all species, which is reduced for the combination product amoxycillin/clavulanic acid. Tetracycline resistance is high in the pig and quite high in the other food-producing animals. Enrofloxacin resistance is very low in all species of animal. It was also of interest that the piglet data was monitored by age and the resistance to fluoroquinolones was seen mainly in the young pig < 1 month of age (2%), where the piglet doser is used, but declined in the older pig.

Table 5. Comparison of respiratory pathogen resistance (%) to antimicrobials

	P. multocida	M. haemolytica	P. multocida	A. pleuropneumoniae
Antimicrobial	Cattle	Cattle	Pig	Pig
Ampicillin 10μg	1	2	2	4
Amox/clav 20/10μg	1	0	-	-
Cephalexin 30μg	2	0	-	-
Tetracycline 10μg	6	6	14	26
TMP/S 25μg	2	3	7	12
Enrofloxacin 5μg	0	0	0	0
Florfenicol 30μg	0	0	-	-
Ceftiofur 30μg	-	-	-	3

(Source: NOAH, 2001a)

There is a low level of resistance by the major respiratory pathogens to all antimicrobials for cattle with tetracycline the highest at only 6%. In pigs it was marginally higher for P. multocida with 14% for tetracycline but higher again for A. pleuropneumoniae at 26% but very low for ampicillin and the cephalosporins and none for the fluoroquinolones.

Mastitis in dairy cows is commonly treated with antimicrobials and it is here a range of specialised products and combinations are used especially in lactating cow formulations to enhance and broaden the spectrum of activity by using aminoglycosides and penicillins together. Lactating cow products should be quick acting, short duration of activity for short milk withdrawal periods whereas dry cow therapy should be long acting. An interesting variety of antimicrobials are used for both. There are distinct organisms associated with mastitis, Streptococcus dysgalactiae and Staphylococcus aureus are contagious in nature and Strep. uberis and E.coli are environmental in nature especially in the winter when the cows are housed.

Table 6. Comparison of mastitis bacterial resistance (%) to various antimicrobials
 

Antimicrobial	S. dysgalactiae	Staph. aureus	S. uberis	E. coli
Penicillin 10μg	0	28	0	-
Ampicillin 10μg	0	28	0	12
Amox/clav 20/10μg	0	5	1	4
Tetracycline 10μg	45	5	16	15
Erythromycin 5μg	3	4	6	-
Neomycin 30μg	57	1	71	6

(Source: DEFRA/VLA, 2001a)

The streptococci are basically sensitive to the penicillins but there is resistance shown by S. aureus but a good sensitivity to aminoglycosides, hence they are widely used in combinations. E.coli sensitivity is generally good.

E.coli from diarrhoeas, Staph. aureus from skin infections and pseudomonas spp, especially from ears infections, can be major causes of refractory treatment in dogs. The incidence of resistance at Glasgow University referral hospital was reported (Normand and others, 2000; Taylor, 2000, personal communication).

Table 7. Comparison of dog bacterial resistance (%) to various antimicrobials

Antimicrobial	Staphylococcus	E. coli	Pseudomonas	Pseudomonas ears
Amoxycillin 25μg	20	56	-	-
Ampicillin 25μg	23	54	97	-
Amox/clav 30μg	3	27	85	92
Cephalexin 30μg	20	-	-	-
Chloramphenicol 10μg	5	24	-	-
Enrofloxacin 5μg	4	2	12	58
Erythromycin 10μg	17	-	-	-
Lincomycin 2μg	16	-	-	-
Oxytetracycline 30μg	38	40	76	-
Penicillin 10μg	53	-	-	-
TMP/S 25μg	20	38	79	-
Carbenicillin 100μg	-	-	24	25
Gentamicin 10μg	-	0	6	8
Polymixin B 300iu	-	-	9	0

(Source: Normand and others, 2000; Taylor, 2000, personal communication)

As expected the levels of resistance are higher at the referral level as the animals have usually been treated before being sent to the hospital. Pseudomonas species do represent some of the most resistant organisms to treat, as in human medicine but usually surgery on the ear will cure the majority of cases.

Antimicrobial resistance - some zoonotic pathogens: Salmonella spp are probably the major cause for concern with regard to zoonotic pathogens. Many species are pathogenic to animals such as Salmonella enterica Typhimurium, but many are exotics and appear to cause few clinical problems in animals.

Table 8. Comparative resistance (%) of salmonella from different species to various antimicrobials

Antimicrobial	Cattle	Sheep	Pigs	Poultry
Streptomycin 25μg	17	15	42	11
Sulphonamide 300μg	18	16	63	25
Tetracycline 10μg	18	19	83	13
Neomycin10μg	0	1	4	2
Ampicillin 10μg	16	15	43	10
TMP/S 25μg	5	3	35	16
Chloramphenicol 10μg	16	15	31	9
Apramycin 15μg	-	-	6	0
Nalidixic acid 30μg	2	-	5	11

(Source: DEFRA/VLA, 2001b)

Resistance appears to be highest in pig isolates as S. Typhimurium accounts for 77% of the isolates. Quinolone resistance as judged by the nalidixic acid marker is highest in poultry, but actual fluoroquinolone resistance in the UK is usually reported as very low or only borderline (Teale, 2002). Turkey isolates of S. Typhimurium, in previous years, had the highest reported nalidixic acid resistance of about 75% but this appears to have changed in 2000.

Table 9. Comparison of S. Typhimurium DT104 resistance (%) to nalidixic acid by species and time

Year	Cattle	Sheep	Pigs	Chicken	Turkeys
1996	5	9	7	6	75
2000	10	0	2	14	0

(Source: DEFRA/VLA, 2001b)

There have been some dramatic changes in the incidence of salmonella isolations from poultry with the introduction of new vaccines especially for S. Enteritidis and the control of salmonella through the breeding pyramids.

Campylobacter spp are still the commonest form of food poisoning in man with C. jejuni accounting for nearly 89 % of cases and C. coli for 11% but by using an international database it can be demonstrated that they occur in different ratios in different species and with different resistance patterns (Burch, 2002).

Table 10. Comparison of campylobacter spp isolation (%) from different species

Species	Man	Chicken	Cattle	Pig
C. jejuni	89	85	98	7
C. coli	11	15	2	93

(Source: Burch, 2002)

Resistance development by campylobacter has been reported as a major concern for man. Erythromycin resistance has proven quite a useful marker for assessing the risk of transmission from one animal species to man.

Table 11. Comparison of erythromycin resistance (%) by campylobacter from various species

Species	Man	Chicken	Cattle	Pig (GB)
C. jejuni	1	4	0	47  (40)
C. coli	18	13	-	67  (85)

(Source: Burch, 2002; (GB) Teale, 2002)

Pigs have a very high level of erythromycin resistant campylobacter, which is in complete contrast to man and therefore it suggests that pigs are low risk transmitters either by meat or by environmental contamination from slurry. If resistance to fluoroquinolones are examined a different picture emerges.

Table 12. Comparison of fluoroquinolone resistance (%) by campylobacter from various species

Species	Man	Chicken	Cattle	Pig (GB)
C. jejuni	25	33	9	12  (0)
C. coli	36	37	-	25  (10)

(Source: Burch, unpublished data; (GB) Teale, 2002)

Fluoroquinolone resistance is lower in pigs (especially in GB) and may reflect a background or inherent resistance in C. coli from pigs in GB. Cattle resistance is also low but generally chicken's resistance levels are similar to man's levels. The resistance pattern reflects the antimicrobial usage pattern especially in GB.

Enterococci spp. are primarily commensals in animals but are considered potentially pathogenic in immuno-compromised man e.g. due to medication for transplants or cancer, inherited disorders and due to AIDS. E. faecium is predominant in man but both E. faecium and E. faecalis are found in animals.

Table 13. Comparison of enterococci spp isolation (%) from different species

Species	Man (GB1)	Chicken	Cattle	Pig
E. faecium	85	41	63	53
E. faecalis	15	59	37	47

(Source: GB1- House of Lords,1998; Danmap 2000, 2001)

The Danes have been carrying out monitoring for a number of years and probably have the most comprehensive data on resistance to these bacteria. They have tracked the effects of the removal of growth promoters from use as they were stopped in 1998. They have seen levels of resistance fall in both broilers and pigs and their meat products against the products such as virginiamycin and macrolides but have noticed a slight rise recently associated with macrolides in pigs and a more marked rise in penicillin resistance in poultry. This may be associated with the growth of tylosin use in pigs as a therapeutic and synthetic penicillins in chickens to control necrotic enteritis caused by Clostridium perfringens.

Table 14. Comparison of antimicrobial resistance (%) by E. faecium from various species

Antimicrobial (BP-μg/ml)	Broiler	Cattle	Pigs (GB)
Tetracycline (8)	6	46	68  (99)
Penicillin (8)	67	29	45  (6 – Ampicillin)
Erythromycin (4)	13	38	47  (93)
Gentamicin (512)	0	0	0    (0)
Streptomycin (1024)	3	23	27
Vancomycin (16)	6	0	6    (1)
Dalfopristin / Quinupristin (2)	37	42	24  (47)
Virginiamycin (4)	34	38	23  (11)

(Source: Danmap 2000, 2001; (GB) Teale, 2002) BP = Break Point

Table 15. Comparison of antimicrobial resistance (%) by E. faecalis from various species

Antimicrobial (BP-μg/ml)	Broiler	Cattle	Pigs
Tetracycline (8)	48	70	77
Penicillin (8)	1	3	0
Erythromycin (4)	26	18	28
Gentamicin (512)	0	0	2
Streptomycin (1024)	5	18	22
Vancomycin (16)	0	0	0

(Source: Danmap 2000, 2001) BP = Break Point

In general E. faecalis appears more sensitive to the antimicrobials than E. faecium. Both showed a high sensitivity to gentamicin and vancomycin.

Conclusions and possible ways forward:
Veterinary surgeons need antimicrobials to fight bacterial infectious diseases in their patients, whether in food-producing animals or companion animals, to maintain health and productivity on one side and health and welfare for all. It is a key professional obligation.

Guidelines on the prudent use of antimicrobials have been introduced by the WHO, OIE at an international level, to our own RUMA (Responsible Use of Medicines Alliance) guidelines issued by our own national veterinary association and species-specific societies. Included in these codes of good practice are quality assurance schemes, where details of antimicrobial use are recorded, herd-health surveillance programs, and education programs for vets and farmers to promote the responsible use of antibiotics. There is separate advice on the use of fluoroquinolones.

At a regulatory level, antimicrobials undergo extensive testing for safety similar to man. In addition, residue levels in edible tissues are assessed not only for toxicological effect (ADI tox - Acceptable Daily Intake) but also on the microbiological effect the residues might have on human gut flora (ADI micro) and the maximum residue limit (MRL) for an edible tissue is set for that substance at the lower level. Additional resistance development guidelines are currently being developed. The fate of residues in excreta is also examined in a very stringent ecotoxicological assessment, including possible effects on soil bacteria, fish, insects etc. This is not the case for human medicines at present.

A number of growth promoters were banned in 1999, all of which had some medicinal effect, which was not fully recognised at the time. There has been a rise in the use of antimicrobials to counter necrotic enteritis in poultry caused by C. perfringens, these are mainly penicillins but macrolides could also be developed for this indication. In pigs there was a switch of the use of tylosin, a macrolide, from a growth promoter to a therapeutic for the control of ileitis caused by Lawsonia intracellularis, which is endemic in the national pig herd. Diarrhoeas in the weaned pig would have increased but for the use of zinc oxide, hence resistance to E. coli has been reduced but there are some ecotoxicological questions. There has been seen a marked reduction in the incidence of resistance in Denmark to virginiamycin, avoparcin and macrolides in E. faecium, the significance of this, in a zoonotic way, needs to be determined. The banning of the rest of the growth promoters in 2006, is unlikely to have any impact on human health as none of the antimicrobials are related to products used in man and two, salinomycin and monensin, will continue to be used as anticoccidials in poultry. They are considered essential for the production of chicken meat under current production systems.

Surveillance and monitoring of bacterial resistance is essential for the future. In animal health, it has been carried out for salmonella spp for several years, and an extensive database has been established. The impact of salmonella controls on poultry and the introduction of S. Enteritidis vaccines in layers have caused the isolation figures to plummet in year 2000. Unfortunately DEFRA has only just started to coordinate this for the other bacterial species but it is a good start and plans are being made to develop the scheme. What is happening on the medical side? Are they able to coordinate the health authorities antimicrobial resistance patterns and relate them to antimicrobial usage and practice yet?

The epidemiology of the spread of many of the infections is still not clear. A proportion of infections will come from contaminated meat but it rarely accounts for all of the cases. Many other sources are contaminated, whether food of non-animal origin, water possibly inadequately treated, contaminated by human and animal waste or by wild birds e.g. Campylobacter jejuni from wildfowl. According to PHLS (Smerdon and others, 2001; Kessel and others, 2001) approximately 50% of incidents of infectious intestinal disease are associated with commercial catering and a significant number of cases are associated with poor hygiene, inadequate storage and also contamination by the food handlers, especially in the case of S. Enteritidis.

Future developments of new antimicrobial molecules for the food-producing animal side are considered unlikely. Existing molecules are being developed, for new indications or new species. New molecules derived from human research are likely to be too expensive even for companion animal use and the regulatory hurdles for food-producing animals prohibitive. Vaccines are an exciting opportunity for the reduction of antimicrobial usage, e.g. Mycoplasma hyopneumoniae vaccines have reduced the incidence of chronic pneumonia in fattening pigs and a live L. intracellularis vaccine in the US may also prove important for ileitis, reducing macrolide and tetracycline usage. A live S. Enteritidis vaccine has dramatically reduced the incidence in layers and eggs. Could a suitable live C. jejuni vaccine have the same effect?

Until much of the information can be developed or brought together and analysed, a qualitative assessment of the true risks involved with regard to antimicrobial usage and resistance, whether in man or animals, cannot be made. It is a complex situation and it is essential to bring together expertise not only from the veterinary and medical sides but also the food safety and environmental health sectors to try to clarify the cause and its scale and determine the best route forward and funding.

References:

1. Burch, D.G.S. (2000) In ‘Antibacterials - Products and Markets.’ Animal Pharm Reports SR197, Richmond, Surrey, UK, p 51.
2. Burch, D.G.S. (2002) Risk assessment - Campylobacter infection transmission from pigs to man using erythromycin resistance as a marker. Proceedings of the Antimicrobial Agents in Veterinary Medicine Conference, Helsinki, Finland, in press.
3. Danmap 2000 (2001) Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. Danish Veterinary Laboratory, Copenhagen, Denmark.
4. DEFRA/VLA (2001a) Antimicrobial Sensitivity Report 1999.
5. DEFRA/VLA (2001b) Salmonella in Livestock Production in GB, 2000.
6. DEFRA/VMD (2001) Sales of Antimicrobial Products used as Veterinary Medicines, growth Promoters and Coccidiostats in the UK in 2000.
7. House of Lords, Select Committee on Science and Technology (1998) Resistance to Antibiotics and Other Antimicrobial Agents, pp 61-62.
8. Kessel, A.S. and others (2001) General outbreaks of infectious intestinal disease linked with poultry, England and Wales, 1992-1999. Communicable Disease and Public Health, 4 3, 171-177.
9. Marsh, J. and others (MAFF) (2001) Report of the Independent Review of Dispensing by Veterinary Surgeons of Prescription Only Medicines.
10. National Office of Animal Health (NOAH) (2001) Compendium of Data Sheets for Veterinary Products. Enfield, United Kingdom. pp. 2001-2002.
11. National Office of Animal Health (NOAH) (2001) UK Sales Survey of Animal Health and Veterinary Products. Enfield, United Kingdom.
12. Normand, E.H. and others (2000) Trends of antimicrobial resistance in bacterial isolates from a small animal referral hospital. Veterinary Record, 146, 151-155.
13. Smerdon, W.J. and others (2001) General outbreaks of infectious intestinal disease linked with red meat, England and Wales, 1992-1999. Communicable Disease and Public Health, 4, 4, 259-267.
14. Teale, C.J. (2002) Antimicrobial resistance in porcine bacteria. The Pig Journal, 49, 52-69.

 

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