Regulatory control of antibiotics to manage antibiotic resistance: progress report december 2003
REGULATORY CONTROL OF ANTIBIOTICS TO MANAGE ANTIBIOTIC RESISTANCE: PROGRESS REPORT December 2003 INTRODUCTION
Antibiotic sales statistics have been collected and analysed for three years. There are stillsome errors in the data and many variables that make it imprudent to draw conclusions fromeven moderate shifts in total volumes sold from one year to the next. Sales statistics are theonly source of information at this stage, but the development of additional data sets andsignificant changes in the data (collected on an individual product basis rather than an activeingredient basis) that will be collected in the future will provide more information. ANTIBIOTIC SALES SURVEY AND COMMENTS ON USE
The following are the 2002 sales statistics for antibiotics for use in animals. The first threecolumns in the tables are the kilograms of active ingredient administered orally (i.e. in feed orwater). The fourth column shows the kilograms sold for parenteral administration. The salesin 2001(column 5) are compared to the sales in 2002 (column 6). Table 1: 2002 sales of antibiotics for cattle (age unspecified) In-feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
No virginiamycin or zinc bacitracin was sold for use in cattle, and only 5.2 kilograms ofparenterally administered flouroquinolones were sold for therapeutic use.
No dimetridazole, furizolidone or nitrofurazone was sold for use in cattle of unspecified age. Table 2: 2002 sales of antibiotics for cattle (calves) In-feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
No virginiamycin, zinc bacitracin, flouroquinolone, dimetridazole, furizolidone ornitrofurazone was sold for use in calves. Industry perspective on use in cattle There is little routine use of antibiotics in the beef industry, but there is no collective voice for that industry to provide a meaningful perspective on what use there is.
Antibiotics are more commonly used in the dairy industry, but not as mass medication in feedor water. While there is a significant therapeutic use of injectable antibiotic products, theprinciple use of antibiotics in the dairy industry is in the form of intramammary mastitistreatments. Most of the antibiotic families are used in intramammary treatment. However, likeother forms of parenteral antibiotics, intramammary treatments are not considered to be asignificant factor in the potential development of antibiotic resistance. In addition, virtually allmilk in New Zealand is pasteurised prior to its use. This all but eliminates the opportunity forresistance to be transferred to human enteric pathogens. Table 3: 2002 sales of antibiotics for pigs In feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
During 2002 there was an apparent overall increase of 51% sales of antibacterial substancesfor use in pigs but this increase relates mostly to:
• the sales of mecadox (not of human health significance because it is not used in humans);
• a correction in a sales statistical error in tertracyclines in 2001.
The industry advised that the 2001 sales statistic for tetracyclines was an obvious under-reporting, probably due to changes in the registrant companies. The 2002 sales figure is morelikely to reflect actual sales. There was a decrease in penicillin sales to zero, and a decrease ofmacrolide/lincosamine sales of 7%. Sales of aminoglycosides increased by 43%, but theactual amounts sold in 2001 and 2002 were relatively small.
The greatest increase in sales was in the ‘other’ category, mostly reflecting increased sales ofzinc bacitracin and carbodox. The antibiotics in the ‘other’ category that were consideredsignificant to the potential antibiotic resistance problem did not show a marked increase insales (see following paragraph). This was anticipated and is consistent with the strategy tomanage the potential antibiotic resistance problem.
For therapeutic use, 4.32 kilograms of orally administered virginiamycin were sold. Forprophylactic use in feed, 577 kilograms of zinc bacitracin were sold. No fluoroquinoloneswere sold for use in pigs. No furizolidone or nitrofuran was sold for use in pigs, but 19.15kilograms of dimetridazole to be administered in feed/water were sold for therapeutic use. There were also 676 kilograms of carbodox sold for prophylactic use.
In addition to the antibiotics that were specifically sold for use in pigs, table 6 shows the saleswhen the animal(s) to be treated were not specified. No zinc bacitracin, fluoroquinolones orvirginiamycin was sold for use when the animal was not specified; 7.6 kilograms ofdimetridazole, 110.7 kilograms of frazolidone and 1.5 kilograms of nitrofurazone were sold. 52 kilograms of trimethoprim were sold (7.9 in feed/water for therapeutic purposes and 44.6for parenteral administration).
Some of these antibiotics could have been used on pigs, but the total kilograms administeredin feed/water was small and would not significantly change the statistics in table 3 even if itwere unreasonably assumed that the total quantity was used in pigs. The quantities ofparenterally administered antibiotics in table 6 were significant but not relevant to thepotential antibiotic resistance problem because of the limited effect they could have onbacteria in the digestive tract. Pork industry perspective of antibiotic use during 2002 The pork industry is concerned by the conclusions drawn on the use of antibiotics during 2002. These include statements such as, ‘During 2002 there was an overall increase of 51% sales of antibacterial substances for use in pigs’. These conclusions are based on sales data voluntarily supplied by pharmaceutical companies and do not reflect actual usage.
It is the pork industry’s view that the data is flawed and that the total use of antibiotics in2002 was in fact lower than 2001. The New Zealand pork industry is a responsible user ofantibiotics and this is particularly so where off-label usage occurs.
The pork industry has agreed to supply actual antibiotic usage prescribed by veterinariansduring 2003 in an endeavour to remedy the current flaw in data collection. This will enable adirect comparison to be made between sales and usage for the 2003 year. This initiative willbe put into perspective under other initiatives below. Table 4: 2002 sales of antibiotics for poultry In feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
There was an apparent 25% increase in overall sales of antibiotics from 2001 to 2002. Thiswas primarily made up of increases in sales of zinc bacitracin (26002 kg) and the ionophores. This was anticipated and is consistent with the strategy to reduce dependence on antibiotics ofsignificance to human health.
However, there was an apparent increase in sales of macrolides (51%). These antibiotics areof human health significance and the rise is of concern. This will be monitored carefully tosee if this is related to an ongoing dependence on this family of antibiotics or is a coincidentalvariation brought about by increased disease challenges during the year. Given the personalcorrespondence with the pharmaceutical industry and the ACVM Group, the latter is morelikely to be the case.
No fluoroquinolones or virginiamycin was sold for use in poultry. Nineteen kilograms ofdimetridazole, 55 kilograms of furizolidone, and 453 kilograms of avilamycin were sold foruse in poultry. These were all sold for administration in feed or water.
It is unlikely that any of the antibiotic quantities listed in table 6 were administered to poultrybecause they are formulated in a way that would make that impractical. Poultry industry perspective of use of antibiotics during 2002 The statement is made that there was an apparent increase of overall sales of antibiotics. The apparent 25% increase in antibiotics from 2001 to 2002 was in the same time period as a 12.7% increase in tonnage of chicken produced. That level of tonnage growth is amongst the highest for a number of years. The poultry industry estimates 50% of the apparent increase in antibiotic sales is, therefore, due to growth in the size of the industry.
There is also the issue of whether the 2001 statistics were correct and at least part of theremaining increase is coming off an uncertain baseline statistic. Another potentialcomplicating factor in the figures is the phasing of antibiotic products. Purchases areundertaken on a quarterly basis and thus phasing issues could affect the figures. This is likelyto explain the increase in macrolide sales. Macrolide antibiotics are used on a rotation basiswith at least two other antibiotics.
There is also the issue of dose rates for different products with varying parts per millionpossibly affecting the statistics.
The poultry industry consider the rise in sales of tetracycline to be a reporting or data entryerror as the poultry production companies say they did not use tetracycline products. TheACVM Group notes discrepancies in tetracycline sales since 2000. The discrepancies arelikely to be eliminated when annual reports are provided on a product basis in the future.
Given the industry perspective on use compared to the sales statistics, it appears that therewas actually no change or less use of antibiotics in the poultry industry during 2002. Thispoints out the problem with depending on amalgamated sales statistics only. The industry isreviewing its use during the year and, to complement the sales statistics, is likely to provideother sources of data in the future as proposed by the pig industry. Table 5: 2002 sales of antibiotics for animals other than poultry, pigs, calves and cattle In feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
Antibiotic sales in table 5 relate to their use in companion animals (cats, dogs and small pets)and horses. It is also likely to include use in small ruminant animals such as sheep, goats andcamelids, but this use would be very limited and almost exclusively parenteral to individualanimals rather than mass medication of flocks.
No zinc bacitracin, fluoroquinolones, virginiamycin or dimetridazole was sold for use in thisgroup of animals; 264 kilograms of trimethoprim were sold. For parenteral administration fortherapeutic reasons, 0.19 and 0.38 kilograms of furizoladone and nitrofurazone respectivelywere sold. Table 6: 2002 sales of antibiotics for animal species unspecified In feed/water Other routes (kg active ingredient) (kg active ingredient) Antibiotic group Prophylactic Therapeutic Growth/feed conversion penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores
No zinc bacitracin, fluoroquinolones or virginiamycin was sold for use when the animal wasnot specified; 7.6 kilograms of dimetridazole, 110.7 kilograms of frazolidone and 1.5kilograms of nitrofurazone were sold. Fifty-two kilograms of trimethoprim were sold (7.9 infeed/water for therapeutic purposes and 44.6 kg for parenteral administration). Summary comments on sales statistics Table 7 total 2002 sales of antibiotics Antibiotic group Cattle, pigs Unspecified and poultry penicillins cephalosporins aminoglycosides macrolides lincosamides tetracyclines sulphonamides ionophores Total 2002
As can be seen in the sales statistics, there is an apparent increase (1700 kilograms) in 2002sales of antibiotics over the 2001 statistics. Sales for other animals (for the most part pets andhorses) are not significantly different. Sales for food animals are up by 10,000 kilograms,while sales for unspecified animals were down by 8500 kilograms. The size of the nationalflock has increased and there was an increase in disease challenges for pigs and poultryduring the year. There was an increase in dosage rate as new prophylactic treatment regimeshave been developed. In addition, it is standard practice to rotate products, some with activeingredients with markedly different activity by weight.
The patterns of sales for the last three years have been erratic. They show marked fluctuationsover the three to four years that the statistics have been collected. The livestock industriesbelieve that actual use, corrected for all of the variables mentioned above, is less than in 2001. Because statistics were not collected to confirm this impression, the industries are planning togenerate alternative data sources that would put the sales statistics into better perspective.
The changes and variables make it difficult to compare the returns across the years. Inaddition, sales statistics in isolation may not correlate well with actual use. At the same time,
the statistics to date still seem to contain reporting errors that relate to a number of factorssuch as:
• uncertain estimations of quantities of sales relating to species when actual use is dictated
by prescribing veterinarians rather than the pharmaceutical companies;
• misreporting quantities in products with multiple antibiotic ingredients;
• changes in the pharmaceutical companies during the year; and
• human error in recording and reporting.
While these factors may reduce the accuracy of the statistics, it is considered that the statisticsare still sufficiently representative to show the relative magnitude of sales and the importanceof the different antibiotic families. Although companies are becoming more proficient inreporting and that reporting, in the future, will be tied to a statutory obligation to report on anindividual product basis, there is likely to be a continuing (even if decreasing) potential forerror.
It is clear that sales statistics on their own are not sufficiently tied to actual use patterns toprovide meaningful information. Consequently, other sources of data are being developed tosupplement the sales statistics in the future (see other initiatives below). ANTIBIOTIC USE IN THE HORTICULTURAL INDUSTRY
The aminoglycoside streptomycin is used in the horticultural industry for treatment of pip andstone fruit and tomatoes for bacterial infestations such as fireblight in apples. During 2002359 kilograms of active ingredient were sold for that purpose. Sales in 2001 were 391kilograms.
No other antibiotics are used in the horticultural industry in New Zealand. DEVELOPMENT OF ANTIBIOTIC RESISTANCE IN ANIMALS IN NEW ZEALAND
During the year there has been no further evidence that the use of antibiotics in animals iscontributing to the development of antibiotic resistance in New Zealand. In countries wherethere is considerably more reliance on antibiotics than in this country the evidence implicatingthat use to the development of resistance is still inconclusive.
What resistance has been noted in New Zealand still seems to be associated with use ofantibiotics in humans. There is no evidence that continued exposure of the general populationto produce from animals that have been treated with antibiotics in New Zealand has resultedin a shift in the prevalence of antibiotic resistant bacteria. REGULATORY CHANGES
The regulatory changes that were initiated in 2001 are only now having an effect. This isaltering the sale and use patterns of antibiotics in New Zealand and contributing to theprudent use of antibiotics in animals. However, because there is no obvious correlationbetween the use of antibiotics in animals and the actual prevalence of resistant strains ofbacteria in the general public in New Zealand, it will be difficult to measure the public healtheffect of the prudent use of antibiotics in animals.
There are no further regulatory changes planned at this time. OTHER INITIATIVES
The last three years of collecting and analysing sales statistics have highlighted the limitationof this single source of data. Consequently, the two major intensive livestock industries (pigand poultry) and the feed manufacturing industry are exploring two other sources of data:
• estimates of level of prescribing from veterinarians; and
• reporting on quantities of medicated feed manufactured.
These data sets could be related to the sales statistics and to the descriptions of antibiotic usepatterns being developed by the industry sectors to provide a more complete picture of howthe principles of prudent use of antibiotics are being applied in New Zealand. CONCLUSION
While there has been an increase in sales of antibiotics in 2002, there may not have been anyincrease in actual use. The level of increase may not be significant when the variables aretaken into consideration.
The statistics in this report provide a view of potential exposure of livestock to antibioticsonly. Collection of data on the prevalence of resistant strains of bacteria in the animalpopulation will be expensive with little confidence that the presence of resistant strains isinfluenced by use of antibiotics in those herds or flocks. It may be equally likely that thestains could be introduced via contact with other animals, birds or people.
The livestock industries, having gone to the expense of making changes to facilitate theprudent use of antibiotics, are resistant to carrying out extensive trials and monitoring toidentify resistant strains of bacteria when there appears to be little effort to clarify the picturein the human population. They have agreed in principle to assist in a comprehensive studythat is well planned and epidemiologically sound, given all the interacting populations. However, they have indicated that they are not prepared to lead such a study or provide datathat is likely to be used out of context for questionable speculation.
While it was proposed to initiate a pilot project to clarify the relationship between sales anduse, progress has been limited to defining the alternative data sets that could be collected. There is still insufficient focus to guide any change in existing surveillance and monitoringprogrammes.
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