INTRODUCING THE VIRBAC RANGE OF DCT: GOOD THINGS COME IN INNOVATIVE PACKAGES.

INTRODUCING THE VIRBAC RANGE OF DCT: GOOD THINGS COME IN INNOVATIVE PACKAGES.

THE IMPORTANCE OF THE DRY PERIOD The dry period is a critical phase of the year for a dairy cow, as it represents the main opportunity for the udder to both recover from any damage or infection from the prior lactation, and prepare for the next. The dry period is actually a very active phase within the udder, initially with formation of a keratin plug to ensure closure of the teat canal, and then with the removal (involution) and regeneration (lactogenesis) of the milk-secreting alveolar cells 1. To fully complete this process requires a minimum of 6 weeks, and preferably at least 8 weeks. Shorter dry periods are associated with lower production in the following lactation due to insufficient generation of new alveolar tissue, particularly in heifers entering their second lactation. The importance of the dry period is perhaps best illustrated by the effects on production in cows with no dry period. Bachman and Schairer showed 25 30% reductions in milk yield in the subsequent lactation when cows were not dried off at all 2. These authors also demonstrated the effects of a short dry period, with 30 40 day dry periods resulting in 2 12% less production than 50 60 day dry periods. In New Zealand the dry period represents both an opportunity and a risk. Our seasonal calving pattern allows all cows to be dry (and potentially treated) at the same time, reducing the risk of contagious mastitis. However, exposure to the elements means there is a higher risk of environmental mastitis (chiefly Streptococcus uberis) at dry off and in early lactation than in many other dairy farming areas. These unique challenges have resulted in New Zealand dairy farmers, veterinarians and researchers being at the forefront of the development and implementation of many innovative techniques and products to control environmental mastitis. STRUCTURE OF THE BOVINE MAMMARY GLAND 1 2 3 4 Blood capillary Basal membrane Myoepithelial cells Epithelium of secretory cells 10 7 6 1 2 3 4 5 5 Alveolar lumen 6 Alveolous 8 7 Ducts 8 Gland cistern 9 Teat canal 10 Glandular tissue 9 2

INTRAMAMMARY INFECTION DURING THE DRY PERIOD In the early dry period closure of the teat canal with the keratin plug is incomplete, increasing the risk of environmental mastitis. However, in at least 20% of quarters the teat plug is still not present by 6 weeks after dry off 3, meaning that this risk is reduced but not eliminated in the mid-late dry period. In the late dry period and at calving the risk of mastitis is again substantially elevated by the combined effects of udder engorgement and stress-related immune suppression. New Zealand studies have shown that 9 13% 4,5 of uninfected quarters that are not treated at dry off have developed a new intramammary infection by calving. The effects of bacterial colonisation of the udder during the dry period can extend into the subsequent lactation, with over 50% of the clinical mastitis cases seen in the first 100 days of lactation originating from infections acquired during the dry period 6. As a result, effective preventative therapy either in the form of antibiotic dry cow therapy or an internal teat sealant will control mastitis through to calving and into early lactation. DRY COW THERAPY SMARTSAMM RECOMMENDATIONS SmartSAMM recommends that all cows are protected by some treatment during the dry period. This is likely to include antibiotic DCT in high SCC cows, and antibiotic DCT or ITS in low SCC cows. The use of dry cow therapy to treat existing infections in New Zealand dairy herds was widespread by the 1980 s, with a 1986 survey 7 reporting that 81% of farmers used dry cow therapy selectively, i.e. primarily for treatment rather than prophylaxis. More recently the focus of dry period treatment has shifted from an emphasis on curing cows with existing infections, to also preventing new intramammary infections in uninfected cows. A number of New Zealand studies 3,4,5,8 have shown that clinical mastitis can be reduced through to calving and into the subsequent lactation by using either long-acting cepalonium dry cow therapy or teat sealants, on their own or in combination. It is now well accepted that an efficacious treatment (or combination of treatment) at dry off can treat existing udder infections and prevent new infections throughout the whole dry period, at calving and into the early part of the next lactation. The shift in focus from primarily treatment to both treatment and prevention has been reflected in the recently released SmartSAMM industry recommendations 9. Short-acting dry cow therapy will provide cure of existing infections and reduction in mastitis in the early dry period, but has not been associated with these ongoing effects. 3

CEPHALONIUM IN DRY COW THERAPY Cephalonium has been in use in New Zealand since 1976, when Cepravin Dry Cow was launched in New Zealand. Cephalonium was developed by Glaxo Laboratories after the molecule was discarded from human use, as its poor solubility and very low absorption from the gastrointestinal tract made it unsuitable for oral administration. These very traits, along with a non-irritant nature within the udder, made it an ideal candidate for long-acting dry cow therapy. Cephalonium is a first generation cephalosporin, with a largely gram positive spectrum. It is highly efficacious against all of the major Gram positive mastitis pathogens, and is particularly potent against streptococci. At the concentrations achieved in the udder at insertion cephalonium is also above the MIC 90 for E. coli. These features combine to provide high cure rates, long-lasting prevention of environmental infections, and protection against accidental introduction of bacteria through poor hygiene at administration. The full potential of cephalonium in New Zealand conditions was demonstrated by Williamson in 1995 3. In this study, treated cows showed a reduction in the incidence of new infections through the dry period and at calving from 12.3% to 1.2%. There was 43% less mastitis in the next lactation (up until March), and reductions in SCC of 49% in cows that were infected at dry off and 30% in uninfected cows, when compared with untreated controls. Subsequent studies and field experience with cephalonium products have reaffirmed these results, including a study comparing cephalonium dry cow with cloxacillin in addition to an internal teat sealant, and the internal teat sealant on its own 4. All three groups showed similar and substantial reductions in mastitis during the dry period, at calving and into the next lactation. This reinforced that the SmartSAMM aims of reducing mastitis by protecting udders throughout the dry period can be achieved with cephalonium dry cow therapy, internal teat sealants or a combination of antibiotic and teat sealant. GOOD THINGS COME IN INNOVATIVE PACKAGES When you think of dry cow, numerous buckets, lots of cardboard, plenty of packaging waste, and awkward multiples of syringes (tubes) probably come to mind. That s why Virbac NZ has packaged our new internal teat sealant and cephalonium dry cow products in practical, resealable pouches that contain 40 tubes (to treat 10 cows). Much easier maths for clinic staff to dispense and farmers to use. Tubes are kept clean and dry. No large buckets and bins to clog vet clinics and dairy sheds. QUADRANT DC FEATURES AND BENEFITS FEATURES BENEFITS FIRST-GENERATION CEPHALOSPORIN: CEPHALONIUM NEW ZEALAND R & D First choice dry cow antibiotic. Long-acting nature improves cure rate. Made and trialled in NZ. Efficacy was established in a 2007 comparative study 10 with Cepravin Dry Cow, where both cure of existing infections (in 214 quarters) and prevention of new infections (242 quarters) were found to be non-inferior across all pathogens and for major pathogens. HIGH QUALITY, NZ MANUFACTURING Excellent manufacturing and safety record. 4

Quadrant DC is a long-acting, antibiotic dry cow therapy containing 250 mg of cephalonium, in each single-dose syringe. Treats existing and reduces new infections throughout the dry period and at calving. NZ trialled and made. Antibacterial teat wipes available on request. Contains an orange light antibiotic: Antimicrobials restricted to specific indications or used as second line therapy under therapeutic guidelines. USAGE Quadrant DC is a long acting, antibiotic dry cow containing 250 mg of Cephalonium, in each syringe. In conjunction with teat spraying and proper management of the cow during the drying off period, the careful administration of Quadrant DC at drying off: Reduces new infections at drying off and in the dry period. Treats subclinical mastitis that may be present at drying off. Helps reduce SCC s and mastitis in the subsequent lactation. Quadrant DC treatment can be followed by administration of intramammary teat sealants Boviseal (A11406) or Teatseal (A7294) for additional protection from new intramammary infections. DOSAGE AND ADMINISTRATION Treat each cow immediately following its final milking for the season. Administration must not be delayed. When using dry cow preparations, care must be taken not to introduce infection into the udder. INSTRUCTIONS After milking is complete, thoroughly clean and disinfect the end of the teat (e.g. with a Virbac Antibacterial Teat Wipe or cotton wool soaked in methylated spirit). Hold the barrel of the syringe firmly in one hand and remove the protective cap by gently twisting or bending. Take care not to contaminate the nozzle. PARTIALLY insert the nozzle into the teat canal and apply steady pressure on the syringe plunger until the full dose has been delivered. DO NOT MASSAGE the teat after application. Finally, spray teat carefully with an effective teat spray. PRECAUTIONS Use immediately after the last seasonal milking only. If mastitis develops during the dry period a milking cow preparation should be used for treatment. A dry cow therapy must not be used. Dry cow preparations must not be used in lactating cows. Penicillins and cephalosporins may cause hypersensitivity (allergy) following injection, inhalation, ingestion or skin contact. Do not handle this product if you know you are sensitised, or if you have been advised not to work with such preparations. Handle this product with great care to avoid exposure. WITHHOLDING PERIODS It is an offence for users of this product to cause residues exceeding the relevant MRL in the Food Notice: Maximum Residue Levels for Agricultural Covmpounds. MILK: If the cow calves 49 days or more after treatment: Withhold milk for 8 milkings after calving. If a cow calves within 49 days of treatment: Withhold milk for 49 days after treatment plus an additional 8 milkings. Please consult your veterinarian for further advice. MEAT: Animals producing meat and offal for human consumption must not be slaughtered during or within 30 days of the last treatment. PRESENTATION Presented in pouches of 40 syringes (10 cows). STORAGE Store protected from light below 25 C. KEEP OUT OF REACH OF CHILDREN. Quadrant DC is a Restricted Veterinary Medicine. Available only under Veterinary Authorisation. Registered pursuant to the ACVM Act 1997, No. A10107. See www.foodsafety.govt.nz for registration conditions. 5

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TEAT SEALANTS IN DRY COW THERAPY In the mid 1990 s researchers in NZ trialled a non-antimicrobial approach as an alternative to antibiotic DCT 4. This ITS product was composed of 4 grams of 65% w/w bismuth subnitrate in a paraffin base. When infused into the teat canal, the viscous paste sinks to the lower teat sinus and remains there, without hardening or setting, until removal by suckling calves or by manual stripping of the quarter. Internal teat sealants provide a barrier to ascending bacteria, reducing the incidence of mastitis after drying off. In cows which fail to form a complete keratin plug teat sealants also help to provide ongoing protection throughout the dry period, and immediately prior to calving when the natural keratin plug may be disrupted by udder engorgement. ITS have proven to be as effective as a long-acting antibiotic DCT in protecting cows from new Strep. uberis infections during the dry period and at calving. Local and overseas studies have continued to show that ITS are effective at protecting uninfected quarters from becoming infected in the dry period. 11,12,13 More recently, the protective effect of ITS for preventing Strep. uberis infections in heifers prior to their first calving, has also been convincingly demonstrated. 14,15 The use of ITS in heifers and in uninfected cows at dry off, as well as the added benefits an ITS can offer in cows already treated with antibiotic DCT, have led to ITS being recommended in many situations by SmartSAMM. CEPHALONIUM DRY COW AND TEAT SEALANT IN COMBINATION The use of antibiotic dry cow therapy in combination with ITS is well established, and is recommended by SmartSAMM for infected cows where environmental challenge is high. A number of studies have shown that the addition of an ITS to cephalonium DCT has an additive effect. Berry and Hillerton showed that this additional effect resulted in 50% less new infections at calving, while Bradley (2010) found a 30% reduction in mastitis at calving and in the first 100 days of lactation in infected cows given ITS in addition to cephalonium. The option of a combination of cephalonium with ITS remains the only drying off strategy that has been consistently shown in studies to be superior to the use of cephalonium DCT alone. BOVISEAL FEATURES AND BENEFITS FEATURES NON-ANTIBIOTIC TEAT SEALANT MANUFACTURED IN IRELAND BY BIMEDA ANIMAL HEALTH BENEFITS Reduces calving mastitis in heifers when administered 1 month pre-calving. Protects against new infections when administered to uninfected cows at dry off. Bimeda Animal Health are the pioneers of internal teat sealants and the largest manufacturers in the world. 7

TM Boviseal contains 2.6 g of bismuth subnitrate in each 4 g, single-dose syringe. Indicated for the prevention of mastitis in dairy cows during the non-lactating (dry) period and for the prevention of peri-calving mastitis in maiden heifers. Prevents new infections by providing a physical barrier immediately on insertion, blocking the entry of bacteria into the udder throughout the dry period and at calving. Made in Ireland by the pioneers of ITS, Bimeda Animal Health. Antibacterial teat wipes available on request. INDICATIONS DOSAGE: For intramammary use. For single use only. In lactating heifers (first calvers) and cows with somatic cell counts (SCC) of less than 120,000 and 150,000 respectively. In cows and heifers with higher SCC: immediately following treatment with a suitable dry cow antibiotic treatment to the affected quarter. Refer to leaflet for administration instructions. DO NOT USE in lactating cows. DO NOT USE in cows with clinical mastitis at drying off. ADMINISTRATION Care must be taken not to introduce pathogens into the teat in order to reduce the risk of post-infusion mastitis. 1. Thoroughly clean hands prior to administration and wear clean gloves during administration. 2. Immediately after the last milking at drying off, prior to administration of Boviseal, the udder should be stripped and each teat thoroughly cleaned and disinfected with surgical spirit or alcohol-impregnated wipes as the product possesses no antimicrobial activity. Allow the teat to dry prior to infusion. 3. Carefully insert nozzle into the teat canal with minimum penetration (up to 3 mm). 4. Apply gentle and continuous pressure while pinching the top of the teat until the paste is fully expressed. DO NOT MASSAGE or squeeze the teat or udder after infusion of the product as this may dislodge the seal. 5. Following infusion it is advisable to use an appropriate teat spray. WITHHOLDING PERIODS MILK: Milk intended for sale for human consumption must be discarded during treatment for not less than 8 milkings or approximately 96 hours after calving. MEAT: Nil. REMOVAL It is important to remove Boviseal from freshly calved cows to stop any particles entering the vat. Thoroughly hand strip 10 12 strips per quarter at the first milking after calving. Stripping should commence at the very top of the teat. Where possible, avoid removal of Boviseal by the milking machine. DANGER HANDLING PRECAUTIONS May intensify fire; oxidiser. Keep/store away from clothing and combustable materials. Take all necessary precaution to prevent mixing with combustible materials. Do not use or store near heat. In case of fire: Use a Class B Fire Extinguisher for extinction (e.g. CO 2 or Dry Powder). Wear eye and face protection. KEEP OUT OF REACH OF CHILDREN DISPOSAL Preferably dispose of product by use. Otherwise dispose of product, packaging and waste at an approved landfill or other equivalent facility. PRESENTATION Presented in pouches of 40 syringes (10 cows). STORAGE Store below 25⁰C (room temperature). Registered to: BIMEDA (NZ) LIMITED 22 Amersham Way, Manukau City, Auckland. Distributed by: VIRBAC NEW ZEALAND LTD 26-30 Maui Street, Pukete, Hamilton. Visit us at nz.virbac.com Boviseal is a Restricted Veterinary Medicine. Available only under Veterinary Authorisation. Registered pursuant to the ACVM Act 1997, No. A11406. See www.foodsafety.govt.nz for registration conditions. 8

ANTIMICROBIAL RESISTANCE AND DRY COW THERAPY The advent of the 21st century brought a growing awareness of the risk to public health of antimicrobial resistance, and of the potential that antimicrobial use in food-producing animals could generate resistance that may be transferred to human pathogens through the food chain. As a result, practices such as whole herd dry cow therapy have come under increasing public and regulatory scrutiny. While the risk of transfer of resistant bacteria to the public via milk is considered to be low (mainly due to pasteurisation of consumer products) and the most recent meeting of the Expert Panel on Antibiotic Resistance 16 concluded that dairy industry present policy settings are prudent and conservative, there is a responsibility for the whole industry to use antimicrobials as judiciously as possible. In 2016, the New Zealand Veterinary Association released a document entitled Antibiotic Judicious Use Guidelines for the New Zealand Veterinary Profession. 17 In this a traffic light system of classification for veterinary antimicrobials was introduced. Products categorised as green are considered to be first line therapy, yellow are restricted to specific indications or used as second line therapy, and red are considered important in treating refractory conditions in human and veterinary medicine, so should only be used following veterinary diagnosis and where a specific need is identified. Based on this classification, all four antimicrobials currently used in dry cow therapy in New Zealand (cephalonium, cephapirin, cloxacillin and ampicillin) are in the same yellow category. This reinforces that all dry cow therapy prescribing should adhere to prudent use guidelines. To date no resistance in mastitis pathogens to the antimicrobials in dry cow therapies has been identified in New Zealand, although a 2015 study 18 did find that: [T]he distribution of MIC for cloxacillin for S. uberis (but not S. dysgalactiae) was bimodal. This is an indication of presence of wild (non-resistant) and resistant strains. While not confirmation of resistance, this does suggest that cloxacillin resistance in S. uberis may be an emerging issue that could impact on prescribing decisions in the future. THE NZVA S RECOMMENDATIONS The NZVA, in consultation with the Society of Dairy Cattle Veterinarians (DCV) and Antimicrobial Resistance Leadership Group (AMRLG), proposes that: By 2020, DCT (Dry Cow Therapy) will only be used in the treatment of existing intramammary infections. 9

ANTIMICROBIAL CLASSIFICATION FIRST LINE SECOND LINE CASE BY CASE Procaine penicillin Penethamate hydroiodide Oxytetracycline Cloxacillin Semi-synthetic penicillins (ampicillin, amoxicillin, clavulanic acid) 1st and 2nd generation cephalosporins (cephalexin, cefuroxime) Aminoglycosides (neomycin, streptomycin) Potentiated sulphonamides etc. These will only be used following veterinary diagnosis with sufficient evidence to indicate need Fluoroquinolones 3rd and 4th generation cephalosporins (e.g.: ceftiofur) Macrolides (e.g.: oleandomycin, tylosin) FIRST LINE SECOND LINE CASE BY CASE Adapted from: Antibiotic Judicious Use Guidelines for the New Zealand Veterinary Profession, Dairy. NZVA publication, June 2016. This classification is based on, but differs from, the WHO classification, being less restrictive and intended to suit practical guidelines for veterinary practices in New Zealand conditions. Consideration should always be given to PK/PD properties to ensure enough of the appropriate antibiotic is available at the biophase. Narrow-spectrum antimicrobials should be used in preference to broad-spectrum antimicrobials whenever appropriate. Culture and susceptibility should be utilised, when clinically relevant, to aid in the selection of antimicrobials. REFERENCES 1. Capuco AV, Akers RM, Smith JJ. 1997. Mammary growth in Holstein cows during the dry period; quantification of nucleic acids and histology. J of Dairy Sci; 80, 477-487. 2. Bachman and Schairer, 2003. Invited Review: Bovine Studies on Optimal lengths of Dry Periods. J. Dairy Sci; 86: 3027-3037. 3. Williamson J.H. et al. (1995). The prophylactic effect of a dry cow antibiotic against Streptococcus uberis. NZVJ 43: 228-234. 4. Woolford M. W. et al.(1998). The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation. NZVJ 46: 12-19. 5. McDougall S. A randomised, non-inferiority study of a new cephalonium dry cow therapy. NZVJ 2010, 55: 161-170. 6. Bradley, A. J., and M. J. Green. 2000. A study of the incidence and significance of intramammary enterobacterial infections acquired during the dry period. J. Dairy Sci. 83:1957 1965. 7. Laycock CL, Duganzich D, Woolford MW, Wickham B. Mastitis control and teat preparation. Proceedings of the 1987 Ruakura Farmer s Conference, pp 62-64. 8. Parkinson TJ, Vermunt JJ, Merrall M. Comparative efficacy of three drycow antibiotic formulations in spring-calving New Zealand dairy cows. NZVJ 2000. 48: 129-135. 9. DairyNZ SmartSAMM Technotes May 2012, Technote 14: Decide dry cow management strategy. 10. Virbac Data on File. 11. Williamson, J.H. Strategies for protecting the teat at dry off. Proceedings of the National Mastitis Council Annual Meeting, 88-94 (2001). 12. Berry, E.A. & Hillerton, J.E. The effect of an intramammary teat seal on new intramammary teat seal on new intramammary infections. J Dairy Sci 85, 2512-20 (2002). 13. Huxley J.N., Green M.J., Green L.E. & Bradley A.J. Evaluation of the Efficacy of an Internal Teat Sealer During the Dry Period. J. Dairy Sci. 85:551 561 (2002). 14. Parker, K.I. et al. Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving. J Dairy Sci 90, 2017-18 (2007). 15. Parker, K.I., Compton, C.W., Anniss, F.M., F.M., Heuer, C. & McDougall, S. Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable, or both, precalving. J Dairy Sci 91, 169-81 (2008). 16. Beresford, R, T Blackmore, P Chambers, N French, D Holland, et al (2005) A review of the impact of the use of antimicrobials in animals and plants on the development of antimicrobial resistance in human bacterial pathogens: Report of the Expert Panel on Antibiotic Resistance. www.foodsafety.govt.nz/elibrary/industry/steering-group2004/review_ Impact-Prepared_Appointed.pdf (accessed 7 January 2014). 17. New Zealand Veterinary Association. Antibiotic judicious use guidelines for the New Zealand veterinary profession: Dairy, published June 2016. 18. McDougall S, Hussein H and Petrovski K. Antimicrobial resistance in Staphylococcus aureus, Streptococcus uberis and Streptococcus dysgalactiae from dairy cows with mastitis. NZVJ. 62:2, 68-76. Cepravin Dry Cow is a registered trademark of Intervet Inc. Cepravin Dry Cow is a Restricted Veterinary Medicine. Available only under Veterinary Authorisation. Registered pursuant to the ACVM Act 1997, No. A3322. 10

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For more information on Boviseal and Quadrant DC: Visit nz.virbac.com/dct Talk to your Virbac Area Sales Manager. Virbac New Zealand Limited. 26 30 Maui Street, Pukete Park, Hamilton 3200. Tel: 0800 VIRBAC (847 222).