Results showed that 68.5% of the antimicrobials surveyed were administered as in-feed medications. 17.5% of the total volume of antimicrobials utilised were parenteral antimicrobials, whereas antimicrobials for water medication constituted 12% of the total and ’other‘ dosage forms, for example the topical and aural dosage forms, constituted 1.5% of the total. Intramammary antimicrobials represented 0.04% of the total. The surveillance systems for veterinary antimicrobials used by other countries were scrutinised and compared. It was concluded that a combination of the surveillance systems applied by Australia and the United Kingdom is the best model (with modifications) to apply to the animal health industry in South Africa. Such a surveillance system, of the volumes of veterinary antimicrobials consumed, should ideally be implemented in conjunction with a veterinary antimicrobial resistance surveillance and monitoring programme. This will generate meaningful data that will contribute to the rational administration of antimicrobials in order to preserve the efficacy of the existing antimicrobials in South Africa.

Veterinary requirements for the treatment of established infections with antimicrobials, for reasons of animal disease control and welfare, are similar to those of human medicine. The use of antimicrobials for treatment, prophylaxis, metaphylaxis and as growth promoters in food-producing animals is essential for a sustainable and economically viable animal industry.^4,5 However, the application of antimicrobials in animals, particularly in food animals, may lead to a selection of resistant strains of bacteria, which in turn may proceed to infect both animals and man.⁶ It is a well-established fact that the application of antimicrobials in the field of animal health impacts on the development of antimicrobial resistant diseases in the human medical field. However, data on the actual supply and consumption of volumes of antimicrobials utilised in animal health are very scanty in South Africa and there is a lack of information about the volumes and patterns of antimicrobial usage in food animals.⁵

This study was an attempt to move in the direction of partially addressing some of the gaps in our knowledge, and covered the period from 2002 to 2004. Various aspects of antimicrobial consumption were covered in this study, such as the antimicrobials authorised for use in South Africa, volumes of antimicrobials consumed during 2002 to 2004, volumes of antimicrobials included in-feed and the national sales value of antimicrobials. The objectives of this survey were therefore to set a benchmark for a monitoring and surveillance programme of the volumes of antimicrobials available and consumed by food animals in South Africa. With this benchmark policy decision makers will be better informed to address concerns regarding antimicrobial resistance, such that the efficacy of antimicrobials may be preserved for use for future generations of humans and animals.^{5,6,7,8,9,10,11}

• The Fertilizers, Farm Feeds, Agricultural Remedies and Stock Remedies Act (Act No. 36 of 1947), administered by the National Department of Agriculture and which represent over-the-counter (OTC) stock remedies.
• Medicines and Related Substances Control Act (Act No. 101 of 1965) administered by the National Department of Health and for which a veterinary prescription is required.

• class of antimicrobial
• trade name of antimicrobial
• active pharmaceutical ingredient (API)
• dosage form and strength
• indication (i.e. species of food animals and whether or not for treatment, prophylaxis or growth promotion)
• the Act under which the antimicrobial is administered
• withdrawal period.

• class of antimicrobial
• active pharmaceutical ingredient (API)
• kg active ingredient
• dosage form
• indication (i.e. species of food animals and whether or not for treatment, prophylaxis or growth promotion).

• class of antimicrobial
• active pharmaceutical ingredient (API)
• kg active ingredient
• registration as a stock remedy or veterinary medicine.

FIGURE 1: Percentages of volume (kg) for sales of classes of antimicrobials for the period 2002�2004.

FIGURE 2: Percentages of volume (kg) for sales of in-feed antimicrobials for the period 2002�2004.

FIGURE 3: Percentages of volume (kg) antimicrobials sold for water medication during 2002�2004.

FIGURE 4: Percentages of volume (kg) of parenteral antimicrobials sold during 2002�2004.

FIGURE 5: Percentages of dosage forms of antimicrobials sold during 2002�2004.

Figure 3 indicates the percentages of volume (kg) of antimicrobials sold for water medication.

Internal validity: The study was undertaken in accordance with the approved protocol and the measurements were consistently taken in the same way from the information supplied. The only information that could not be measured was the information on the sales of antimicrobials sourced from SAAHA, because the statistics supplied were in monetary value as opposed to kg of active pharmaceutical ingredient.

Only eight veterinary pharmaceutical companies responded to the survey. The data obtained in this survey are, therefore, unfortunately not representative of the total volume of veterinary antimicrobials consumed by food animals in South Africa during the 2002 to 2004 period. The volumes consumed by food animals were projected at considerably more than 1 538 443 kg during the three year period from 2002 to 2004. The data collected may be skewed as the pharmaceutical companies that contributed to the survey had more of certain classes and dosage forms of antimicrobials authorised for use than other pharmaceutical companies. Data also did not include antimicrobials imported under special conditions, such as Section 21 (of Act No. 101 of 1965) applications, although the latter should have been negligible. Nevertheless, this study provided useful information on trends of antimicrobial usage in food animals.

In comparing this survey with other surveillance systems undertaken by other countries, certain observations were made: The data recorded by the surveillance systems in Sweden, Denmark, the United Kingdom (UK) and Australia are more accurate representations of the volumes of antimicrobials consumed in food animals. In Sweden all antimicrobials are dispensed through pharmacies. The annual reports include figures for both food and companion animals. The total figures indicate trends of usage. Products used under special license are also included in the figures.^18,19 The Danish Ministry of Food, Agriculture and Fisheries funds a monitoring system based on drug usage information collected at the herd level, known as VETSTAT. The data input for VETSTAT is very detailed and includes farm identification, animal species, age group, date of administration, antimicrobial identification, volumes of antimicrobials, the disease category and the identification of the prescriber.¹ The Veterinary Medicines Directorate (VMD) in the UK obtains antimicrobial use data from the pharmaceutical companies on a voluntary basis, and the data also includes any antimicrobials imported under special conditions. The volumes are expressed in tons (kg x 10³) of active ingredient and include information for food animals and non-food animal usage, as well as these volumes being broken into sales for each food animal species.²⁰

The Therapeutic Goods Administration (TGA) in Australia requires that all importers of antimicrobials declare the volume of the antimicrobial, the type of antimicrobial, indicate if they are for veterinary or human application and whether they are intended for treatment or growth promotion or not. Food animal species information cannot be obtained from this permit.²¹ The information obtained in South Africa was based on the class, type of antimicrobial, kg active ingredient, as well as dosage form and indication for species (treatment or prevention of disease or growth promotion). A major deficiency in the data obtained from the eight companies was that it often could not be established whether or not the product had been sold for treatment or prevention of disease or growth promotion, and patterns of use at the level of food animal species also could not be ascertained. The data derived are more detailed and are consequently more useful in the surveillance systems established by the Swedish Veterinary Antimicrobial Resistance Monitoring, (SVARM), VETSTAT and the VMD.

The antimicrobial groups showing the largest sales, in terms of weight, namely the macrolides and pleuromutilins (42.4% of the total volume), with reference specifically to tiamulin and tylosin, are used for the treatment and prevention of diseases such as mycoplasmosis in poultry and pigs and as growth promoters in food animals.¹⁵ Tylosin was the most extensively sold antimicrobial in this study, yet it was one of four growth promoters banned in the EU following recommendations by a World Health Organisation (WHO) meeting in Geneva, in 1997. These four growth promoters namely tylosin, spiramycin, bacitracin and virginiamycin were banned because of their structural relatedness to therapeutic antimicrobials used in humans. The extensive sales of tylosin in South Africa provide cause for great concern because its main route of administration is through the feed and at sub-therapeutic levels as a registered growth promoter. This form of administration thereby promulgates the potential for resistance to similarly related antimicrobials administered in human medicine. All registered tylosin products are available in South Africa as over-the-counter (OTC) stock remedies under Act 36 of 1947 with the exception of one Act 101/1965 tylosin-sulpha combination.

The second largest group of antimicrobials sold, the tetracyclines (16.7% of the total volume sold), are broad-spectrum antimicrobials, active against Mycoplasma spp. and Chlamydophila spp. and are also effective against erhlichias, rickettsias, anaplasmas and some protozoa.²² The third largest group, the sulphonamides (12.4% of the total volume), are also readily available, due to the number of products registered in terms of Act 36 of 1947, and also have a wide spectrum of antimicrobial activity.^14,23,24 The antimicrobials with the fourth largest sales, the penicillins (10.7% of the volume), are mainly applied in the treatment of Gram-positive bacterial infections, and are also effective against anaerobes.²⁵ Cephalosporins also belong to the same class of antimicrobials, the beta-lactams and are prescribed by veterinarians in South Africa for the treatment and prevention of disease. They have the same mechanism of action as the penicillins and may therefore be selected for an extended spectrum of beta-lactamase resistance. This extended spectrum of resistance has resulted in Gram-negative bacteria such as Escherichia coli strains, expressing extended-spectrum beta-lactamases (ESBLs) or plasmidic C beta-lactamases in food animals, emerging globally and has limited the treatment strategies available for bacterial infections.^1,4,21 There are many analogues of the tetracyclines, sulphonamides and beta-lactams used in treating people.²⁶ These antimicrobials are very important in human health⁷ and have the potential to add to the development of cross-resistance to antimicrobials administered in human health.

Although quinolones only constituted 0.2% of the volume of antimicrobials sold, there is increasing concern with the emergence of quinolone resistant strains in zoonotic Salmonella, and of Campylobacter bacteria having been reported in Denmark, the United States and the United Kingdom. Quinolones are also an important group of antimicrobials administered in human medicine and resistance to this group leaves few treatment options available, as multiple cross-resistance to other antibiotics is now commonplace. Quinolones are approved for therapeutic and preventative medication in animal health in many countries, including South Africa, and it is suspected that such use contributes to the emergence of resistant bacteria in humans.³ There are also other public health concerns in administering certain antimicrobials, such as the potential genotoxic effects of some growth promoters and the potential cardiotoxic effects of the ionophores.²⁷

The observation, that the in-feed dosage forms constituted 68.5% of the total of antimicrobial dosage forms sold in South Africa, (with tylosin the predominant antimicrobial sold in-feed at 61% of the volume), is significant for the following reasons. There is a big difference in the way in which medicines are administered to humans and animals. In humans, treatment is directed at the individual patient, but for animals entire groups of animals may be treated with the administration of medicated feed. Moreover, as mentioned earlier, the dosages included for growth promotion are usually at low concentrations for extended time periods. Both of these practices, in combination, have the potential to accelerate the emergence of resistant bacteria in the animals concerned, that can then infect humans, through contact or via the food chain. Oxytetracycline had the second highest sales for in-feed antimicrobials at 10.7% of the volume. Oxytetracycline is well-known to result in resistant genes in bacteria, following exposure of these bacteria to low doses of this drug over an extended period of time. This resistance can develop quickly and extend from a single individual to other members of its species as well as to people living and working in that environment, through direct contact. However, it is difficult to determine the impact of in-feed application on bacterial resistance in food animals because it is simultaneously being administered for therapy and prophylaxis.^28,29 Due to the concerns expressed above, antimicrobial growth promoters in South Africa should be reviewed by the regulatory authorities. These should be reviewed in order of priority, relating to the documented evidence for their ability to increase antimicrobial resistance in other groups of antimicrobials, or because of their structural relatedness to antimicrobials in human medicine.

Concern is not as great for antimicrobials administered through water, as for in-feed medications, the majority of which are registered as antimicrobial growth promoters (AGPs). This is because the concentrations administered through water are adequate for the treatment or prevention of bacterial diseases, and are administered over three to seven days, as opposed to continuous administration over weeks of the animals’ lifespan.

Penicillins constituted the majority of parenteral dosage forms sold. The penicillins are broad-spectrum and the longer-acting salts facilitate convenient and once-off administration. One of the main concerns about the parenteral administration of penicillins is the withdrawal period, as, any significant residues that arrive in the food chain could cause overgrowth and invasion of pathogenic bacteria.^30,31

In the light of the fact that the most common mastitis-causing bacteria are Streptococcus agalactiae and Staphylococcus aureus, both of which are Gram-positive organisms susceptible to penicillins, the result is that the greatest majority of intramammaries sold were penicillins or penicillin dihydrostreptomycin combinations, which was to be expected.³² In terms of the problem of resistance to antimicrobials in the national dairy herds, resistant S. aureus mastitis is a problem in South Africa and it is necessary to holistically assess this type of resistance problem according to its management and treatment.³³

In terms of the correlation of volumes of antimicrobials sold compared with values of sales of antimicrobials, the only significant finding from the sales figures was that there were increased sales of AGPs from 2002 through to 2004.³⁴ The local status of antimicrobial resistance in South Africa has also been compared to the global health phenomenon of antimicrobial resistance. The results of the first report of SANVAD, in 2007, has also confirmed that antimicrobial resistance is a serious problem in South Africa.⁵ This can be shown, for example, in the summarised results, by SANVAD, of a study measuring the antimicrobial susceptibility of potentially human pathogenic bacteria isolates versus those of healthy farm animals. It was noted that both E. coli and Enterococcus species showed increased antimicrobial resistance, equivalent to that of comparative profiles from European counterparts in both human and animal samples. The highest resistance was reported for tetracyclines and sulphonamides and the lowest resistance was for ceftiofur (a third-generation cephalosporin). Highlighted also in the report was the evidence of E. coli isolates obtained from abattoir chickens, which showed higher resistance for tetracyclines, fluoroquinolones and sulphonamides, in particular, than for isolates obtained from clinically ill chickens.⁵

In discussing the best surveillance system to administer in South Africa, concerning antimicrobials, the different types of surveillance systems available in Denmark, Sweden, United Kingdom and Australia were reviewed and compared. To establish and sustain such data systems, as found in Scandinavia, in a country like South Africa, is currently impractical as legislation controlling veterinary products is currently very fragmented. Additionally, the interests of the relevant stakeholders in animal health are very diverse, not to mention the human, financial and technical logistics of initiating and sustaining such an exercise.

In assessing the animal health situation in South Africa it would be of value to obtain import statistics of veterinary antimicrobials from the South African Revenue Service (SARS). The tariff codes established by SARS would have to be revisited and made much more specific for the different classes of veterinary antimicrobials. As in Australia, importers of veterinary antimicrobials, in South Africa, should also declare the indicated application of such antimicrobials, whether or not for therapy, prophylaxis or growth promotion. In scrutinising the feasibility of data that could be submitted by the veterinary pharmaceutical companies, as well as the information that was established from this survey, the most applicable type of information systems could be adapted from the VMD surveillance reports and would include the following information for food animals, namely annual sales volumes (kg) of antimicrobials by:

• chemical grouping
• dosage form
• therapeutic and prophylactic antimicrobials
• antimicrobial growth promoters
• ionophoric coccidiostats
• non-ionophoric coccidiostats
• annual sales volumes (kg) of antimicrobials under Section 21 (a special permission permit by Act No. 101 of 1965) importation or Act 36 of 1947 permit importation and sales of antimicrobials with indication of therapy
• prophylaxis or growth promotion for each food animal species.

In establishing patterns of application for each species, each company would be able to give the trade name of the antimicrobial sold, which in turn would give the authorised indications for use in South Africa and at least give some idea of patterns of application.

It is of course recognised that a surveillance system is a dynamic information system that, on an ongoing basis, will need to be changed to better adapt to changing trends of antimicrobial consumption and resistance patterns. It is very important that this surveillance system, of consumption of antimicrobials, is paired with an antimicrobial resistance surveillance and monitoring programme in order to better facilitate the slowing down of resistance and the problems associated with resistance. This can be achieved by recognising trends of antimicrobial resistance and applying rational use of antimicrobials accordingly.

2. Van den Bogaard AE, Stobberingh EE. Epidemiology of resistance to antibiotics – Links between animals and humans. Int JAntimicrob Ag. 2000;14:327–335. http://dx.doi.org/10.1016/S0924-8579(00)00145-X

3. White DG, Acar J, Anthony F, et al. Antimicrobial resistance: standardization and harmonization of laboratory methodologies for the detection and quantification of antimicrobial resistance. OIE Rev Sci Tech. 2001;20:849–858.

4. Acar J, Röstel B. Antimicrobial resistance: An overview OIE Rev. Sci Tech. 2001;20(3):797–810. PMid:11732423

5. South African National Veterinary Surveillance and Monitoring Programme for Resistance to Antimicrobial Drugs (SANVAD), 2007. University of Pretoria and ARC-Onderstepoort Veterinary Institute. Pretoria.

6. Mellon M, Benbrook C, Benbrook KL. Hogging It! Estimates of antimicrobial abuse in livestock. Cambridge: Union of Concerned Scientists Publications; 2001.

7. Mitema ES, Kikuvi GM, Wegener HC, Stohr, K. An assessment of antimicrobial consumption in food producing animals in Kenya. J Vet Pharmacol Ther. 2001;24:385–390. http://dx.doi.org/10.1046/j.1365-2885.2001.00360.x

8. Nel H, Van Vuuren M, Swan GE. Towards the establishment and standardization of a veterinary antimicrobial resistance surveillance and monitoring programme in South Africa. Onderstepoort J Vet Res. 2004;71:239–246. PMid:15580774

9. Nicholls T, Acar J, Anthony F, et al. Antimicrobial resistance: monitoring the quantities of antimicrobials used in animal husbandry. OIE Rev Sci Tech. 2001;20:841–847.

10. World Health Organization (WHO). Global principles for the containment of antimicrobial resistance in animals intended for food. Geneva: WHO; 2000.

11. World Health Organization (WHO). Monitoring antimicrobial usage in food animals for the protection of human health. Geneva: WHO; 2001.

12. Grave K, Greko C, Nilsson L, et al. The usage of veterinary antibacterial drugs for mastitis in cattle in Sweden and Norway during 1990–1997. Prev Vet Med. 2000;42:45–55. http://dx.doi.org/10.1016/S0167-5877(99)00057-4

13. Jensen F, Jacobsen E, Bager F. Veterinary antimicrobial usage statistics based on standardized measures of dosage. Prev Vet Med. 2004;64:201–215. http://dx.doi.org/10.1016/j.prevetmed.2004.04.001, PMid:15325773

14. Fertilizers, Farm Feeds, Agricultural Remedies and Stock Remedies Act (Act No. 36 of 1947), South Africa, Available from: Government Gazette, [statute on the internet]. c2005 [cited 2005 Feb 19].

15. Swan GE, Carrington C, Du Plessis A, Wellington A, editors. IVS Desk Reference (IDR) 2003/2004. Johannesburg: MIMS, a division of Johnnic Publishing Limited, 2002; p. 5–657.

16. Swan GE, managing editor. Specialty Index. MIMS IVS: Johannesburg: MIMS, a division of Johnnic Publishing Limited, 2004; p. 23–35.

17. Witte W. Selective pressure by antibiotic use in livestock. Int J Antimicrob Ag. 2000;16:S19–24. http://dx.doi.org/10.1016/S0924-8579(00)00301-0

18. Swedish Veterinary Antimicrobial Resistance Monitoring (SVARM), National Veterinary Institute. Uppsala, 2003; p. 5-41.

19. Swedish Veterinary Antimicrobial Resistance Monitoring (SVARM), National Veterinary Institute. Uppsala, 2007; p. 3-55.

20. Veterinary Medicines Directorate (VMD). Sales of antimicrobial products authorised for use as veterinary medicines, antiprotozoals, antifungals, growth promoters and coccidiostats, in the UK. [homepage on the internet]. c2009 [cited 2009 Feb 11]. Available from http://www.vmd.gov.uk/publications/annreps/annreps.htm

21. Joint Expert Technical Advisory Committee on Antibiotic Resistance (JETACAR). The use of antibiotics in food-producing animals: Antibiotic-resistant bacteria in animals and humans. JETACAR, 1999; p. 17–169.

22. Prescott JF. Tetracyclines. In: Prescott JF, Baggot JD, Walker RD, editors. Antimicrobial therapy in veterinary therapy. 3rd ed. Ames: Iowa State University Press, 2000; p. 215–289.

23. Medicines and Related Substances Act (Act 101 of 1965), South Africa, Available from: Government Gazette, [statute on the internet]. c2005 [cited 2005 Feb 19].

24. Prescott JF. Sulphonamides, diaminopyrimidines and their combinations. In: Prescott JF, Baggot JD, Walker RD, editors. Antimicrobial therapy in veterinary therapy. 3rd ed. Ames: Iowa State University Press, 2000; p. 290–314.

25. Prescott JF. Beta-lactam antibiotics: penam penicillins. In: Prescott JF, Baggot JD, Walker RD, editors. Antimicrobial therapy in veterinary therapy. 3rd ed. Ames: Iowa State University Press, 2000; p. 105–119.

26. Snyman J editor. MDR MIMS Desk reference. Vol. 41. Johannesburg: MIMS, a division of Johnnic Publishing Ltd,2006; 41.

27. Young R, Craig A. Residues of dangerous drugs in intensively produced chicken meat and eggs. In: Young R, editor. The Use and Misuse of Antibiotics in UK Agriculture – Part 3 Bristol: Bristol House, 2001; p. 25–42.

28. Wegener HC. Antibiotics in animal feed and their role in resistance development. Curr Opin Microbiol. 2003;6:439. http://dx.doi.org/10.1016/j.mib.2003.09.009, PMid:14572534

29. Wegener HL, Costarrica ML. Antimicrobial resistance: risk analysis methodology for the potential impact on public health of antimicrobial resistant bacteria of animal origin. OIE Rev Sci Tech. 2001;20(3):811–827.

30. Gustafson RH, Bowen RE. Antibiotic use in animal agriculture. J. Appl Microbiol. 1997;83:531–541. http://dx.doi.org/10.1046/j.1365-2672.1997.00280.x, PMid:9418018