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Selection of ESBL-resistance in calves fed waste milk containing antibiotic residues - OD2031

Description
In recent years bacteria, particularly E. coli, have emerged with resistance to 3rd and 4th generation cephalosporin antibiotics. These antibiotics are widely used as front line treatments in human medicine and the development and dissemination of bacteria resistant to these medicines is a serious medical problem. This resistance is mainly conferred by the production of enzymes and there are large numbers of different enzymes which may be involved, but one large group of important enzymes comprises the Extended Spectrum Beta Lactamases (ESBLs). CTX-M enzymes are a specific type of ESBL which are able to degrade and inactivate these cephalosporin antibiotics. Ongoing surveillance studies at the Veterinary Laboratories Agency have revealed a number of farms where ESBL E. coli are present and on those farms, resistance is particularly common in young calves. However, cephalosporin antibiotics are often less commonly used to treat calves (although related aminopenicillins may be used) and this has led to the suggestion that exposure to these medicines may occur through indirect routes. Calves are often fed waste milk which may contain antibiotic residues. Waste milk is unfit for human consumption and is discarded at milking; waste milk may contain colostrum, milk from animals with mastitis or milk containing antibiotic residues. Cattle may be treated with antibiotics for a wide range of infections but mastitis is a very common problem in the dairy industry.
Bovine mastitis is defined as 'inflammation of the mammary gland' and continues to be the most economically important disease of dairy cattle. The most common causative agents of bovine mastitis in the UK are E. coli and Streptococcus uberis (Bradley, 2002). There are over 170 licensed medicinal products (source K. Goodyear, Veterinary Medicines Directorate) for the treatment of bovine mastitis. A wide range of antibiotics are used in these medicinal products, and some do contain 3rd and 4th generation cephalosporin antibiotics. They may be used prophylactically when milking ceases (a process termed "drying off") to prevent any infection developing during the dry period and clear residual infection. Others are used during lactation. Products used for the treatment of mastitis are often administered by infusion into the mammary gland. The concentration of antibiotics in waste milk is unknown but potentially could be very high as intra-mammary medicines can contain large quantities (in some cases hundreds of milligrams see appendix 1 section 7) of antibiotic, much of which would be excreted at the first milking after treatment. Antibiotic residues can also be excreted in milk after parenteral treatment of other infections and withholding times for milk are provided for veterinary medicinal products. In this project we will test the hypothesis that the feeding of waste milk containing antibiotic residues to calves, particularly the third and fourth generation cephalosporins, is associated with the selection of Extended Spectrum Beta Lactamase resistance.

Although all medicinal products for the treatment of mastitis are licensed, there is little information regarding those which are most popular, their frequency of use, particularly those containing 3rd and 4th generation cephalosporins and those practices used by farmers relating to the disposal of waste milk and feeding to calves. Without this basic information it is very difficult to assess the contribution of antibiotic residues to ESBL selection in calves. This study will examine the current situation relating to antibiotic use in the dairy industry which might lead to residues in waste milk and practices associated with the feeding of this by-product to calves. Waste milk will be collected and the identity and concentration of antibiotic residues determined. Certain cephalosporin antibiotics are unstable at high and low pH and fermentation has been suggested as a mechanism to remove such residues. Scientific evidence is required to demonstrate that alkalination/acidification or fermentation may provide practical methods for farmers to degrade antibiotic residues in waste milk. The occurence of ESBL E. coli in waste milk will be determined and further investigated on farm. In the USA extension advice provided with veterinary medicinal products warns against the feeding of waste milk to calves but there is no scientific evidence to support selection of ESBLs by antibiotic residues. Calves colonised with ESBL E. coli will be fed milk containing antibiotic residues and selection before, during and after exposure will be investigated, by examination of feaeces. Should ESBL selection be demonstrated in calves fed waste milk containing antibiotic residues in this experimental situation we will conduct appropriate epidemiological investigations on farms to deteremine whether such selection actually occurs in the field where the exposure to antibiotic residues may be far more variable.
The information from these studies will be collated and presented within a risk model to identify those key determinants which may select for ESBLs and form the basis of recommendations to Defra. The following deliverables will enable science based recommendations for the dairy industry to prevent ESBL selection :-
1. Current farming practices relating to the use of antimicrobials in dairy cattle and feeding of waste milk.
2. Assessment of the risk of antibiotic residues in waste milk promoting ESBL selection.
3. Concentrations of antibiotics likely to be found in waste milk.
4. Practical and economic recommendations for farmers to substantially reduce the risk of development of
ESBL resistance arising from the feeding of waste milk to calves.
Objective
This project will test the hypothesis "That the feeding of waste milk containing antibiotic residues to calves, particularly those of third and fourth generation cephalosporins, is associated with the selection of Extended Spectrum Beta Lactamase resistance in gut commensal bacteria such as E. coli."

1) Assessment of the current situation relating to the treatment of mastitis in cattle on a cross section of GB farms. If possible for specific mastitis products. The frequency of different therapeutic regimens and usage of veterinary medicinal products will be surveyed particularly with regard to 3rd/4th generation cephalosporins to determine the most common medications and treatment practices. We will also survey the use of antimicrobials, other than for the treatment of mastitis that might result in antimicrobial residues in milk. Also, what waste milk is fed to dairy bred calves and how, frequency of fermentation and pasteurisation prior to feeding. Details of other routes of waste milk disposal will be obtained.

2) Determine the identity and concentration of antibiotic residues in waste milk with a focus on 3rd and 4th generation cephalosporins and those most commonly used (from 1).

3) Assess the stability of antibiotic residues in waste milk under different storage conditions with a focus on 3rd and 4th generation cephalosporins and those most commonly used (from 1).

4) Analyse waste milk for ESBL bacteria, particularly with regard to E. coli.

5) Determine whether the feeding of milk to calves supplemented with a 3rd/4th generation cephalosporin can select for ESBL E. coli.

6) Determine ESBL/ resistance prevalence in E. coli at farms using antibiotics compared to those using other therapeutic options.

7) Quantitative risk analysis for the feeding calves waste milk containing antibiotic residue on the development of ESBL resistance.


Project Documents
• FRP - Final Report : Final Report OD2031 Assessment of the risk of selection of ESBL resistance in calves   (759k)
Time-Scale and Cost
From: 2010

To: 2013

Cost: £911,006
Contractor / Funded Organisations
Veterinary Laboratories Agency
Keywords
Animal Health              
Antimicrobial Resistance              
Cattle              
Dairy              
E.coli              
ESBLs              
Plants and Animals              
Zoonoses              
Fields of Study
Animal Health