Mastitis Therapeutics PDF

Mastitis therapeutics Rob Smith Up date to the cascade • After Brexit “Table 1” has been replaced by a list on VMD website of products with MRL. • https://www.gov.uk/guidance/the-cascade-prescribing-una uthorised-medicines • https://assets.publishing.service.gov.uk/government/upload s/system/uploa...

Mastitis therapeutics Rob Smith Up date to the cascade • After Brexit “Table 1” has been replaced by a list on VMD website of products with MRL. • https://www.gov.uk/guidance/the-cascade-prescribing-una uthorised-medicines • https://assets.publishing.service.gov.uk/government/upload s/system/uploads/attachment_data/file/959434/MRLs_in_ GB.pdf • Northern Ireland still with the EU law for food producing animals! (table 1 in the Annex to Regulation (EU) No. 37/2010) To tube or not to tube? • Is that the question? • or only to tube or also inject? • or what to tube? • Develop a farm policy Do they self cure? • Depends on type of bacteria • Not treating mild cases due to gram negative organisms now being advocated • 50%+ cases are in quarters infected before • Is udder mint better? – No, but it smells nice! • Oxytocin does reduce bacterial counts – Not only because of stripping out • Antibiotics reduce bacterial counts Mastitis Therapy • Dry Cow Therapy • Therapy Failure • Milking Cow Therapy Sales of Antibiotics Source: Tab 1.1; p. 15 VARSS REPORT 2018 Sales of Antibiotics Sales of Antibiotics 8 Sales of Antibiotics 9 The Dry Cow • • • • Has traditionally been neglected Does not make farmers money Can set the farmer up to lose money Dry period is the time to set the cow up for a successful lactation • Traditionally 60 days but consider shorter particularly if worried about drying off at high yields Dry Cow Therapy Quiz • What is Xtra in Bovaclox Xtra that isn't in Bovaclox ? • 600 mg Cloxacillin vs 500 mg • 300 mg Ampicillin vs 250 mg Dry Cow Therapy Quiz • Is this the same “Xtra” that is in Orbenin Xtra but not in Orbenin ? Dry Cow Therapy Quiz • Is this the same “Xtra” that is in Orbenin Xtra but not in Orbenin ? • NO –no Ampicillin in either Orbenin • But 600 mg Cloxacillin vs 500 mg Dry Cow Therapy Quiz • Not that simple • Maximum duration of activity increases from 30 to 70 days • How ? Dry Cow Therapy Quiz • Not that simple • Maximum duration of activity increases from 30 to 70 days • How ? • Due to formulation and base Dry Cow Therapy – Why ? • Clear persistent infections – Sub-clinical – Staph. Aureus – intracellular location – High cell count cows • could think of mastitis in terms of cell count rather than clinical disease • penalty docked from milk cheque Source of Mastitis Cases Protect against new infection • Acute enterobacteriacae infection postpartum (E. coli, Klebsiella, Serratia etc) – 50% of clinical cases in 1st 100 day acquired during dry period – Details of study – next slide Enterobacterial Mastitis Study Protect against new infection • Acute enterobacteriacae infection post-partum (E. coli, Klebsiella, Serratia etc) – 50% of clinical cases in 1st 100 day acquired during dry period – 70 % if include those infected at drying off – UBRO Red (similar to available Ubrostar Red) – Other products – Cephaguard DC, Cepravin – Low cell count herds Bradley and Green (2000) J. Dairy Science 83 1957-1965 Dry Cow Therapy – Why ? • Protect against new infection – Summer mastitis - • Arcanobacter pyogenes - necrosis • Peptococcus indolicus - foul smell • Strep. dysgalactia - 1o infection ? • Others in other countries • Protection for Heifers ? • Management - flies - Pyrethrin pour on Disadvantages • Lower cell count – more likely to get acute mastitis? • Hygiene during application - new infections • Spectrum of product to protect against enterobacteriacae infections acquired during dry period • Treat 100 % of quarters to protect 15 % Disadvantages • Antibiotics resistance – evidence ? – Cloxacillin and Staph. Aureus • Cost - 4 quarters and all cows – £1.80 - £ 3.00 / tube • Societal / Consumer pressure ? – Inappropriate prophylactic use of antibiotics? – Perceived milk quality • Farm Assurance schemes – Organic - “natural” ideal Selective dry cow therapy • Teat sealant only to some cows • Can also be used in combination with antibiotic tubes • 4 g of suspension containing 65% bismuth subnitrate • @ £1.40+ / tube to farmer • 3 actual products world wide? • Orbeseal (Zoetis) • Boviseal (Bimeda?), Ubroseal blue (Boehringer Ingelheim) includes a blue dye • Noroseal (Norbrook), Cepralock (MSD) includes Povidone iodine How does OrbeSeal work? Remains as a paste within the base of the teat cistern and teat canal until stripped out at calving Remain in situ for the entire length of the dry period even in dry periods of up to 100 days Selective Dry Cow Therapy • Cows not treated with a sealant get 50% more mastitis • Which cows to select ? – Bacteriology – expensive & Staph intermittently shed – SCC < 200,000 cell/ml in cows • • • • • • • < 125,000 cell/ml in 1st lactation heifers? AND no clinical case in this lactation (or last x months) Lower limit under which cows given AB for protection? CMT before drying off if SCC not measured recently Check teat ends to ensure not damaged =>AB? Start with 25% of eligible cows and gain confidence Hidden cost – management & risk If not sterile then cows will get sick (and could die!) a few days after infusion. Sealant problems • Black spots in cheese – Bismuth subnitrate + hydrogen sulphide from maturing cheese = bismuth sulphide – Farmer trained to apply sealant and not massage the udder – Removal of sealant residues by centrifuging milk • Risk of infection if not instilled in a “surgically” sterile fashion • Newer “me too” products have limited clinical efficacy data prior to authorisation • Ubroseal being reformulated with blue dye so can see if it has been stripped out Farm advice we gave to Tesco farmers • 80+% of cows are not infected before drying off. • Do you protect them with antibiotic or only teat sealant (Selective Dry Cow Therapy (SDCT)? • Surgical levels of cleanliness are needed. • Selection: a low threshold of last somatic cell count, no recent history of mastitis, good health and no teat damage. • Milk can be tested the day before drying off with a California mastitis test to ensure the cow has not become infected since the last recording. • A proportion of the possible cows can initially be recruited for SDCT, e.g. one in four for the first six month, then results can be reviewed and increased. Arlagarden – Phase 2 Intra-mammary tube application • Hygiene vital • Protocol from Vale Vets on Canvas – Do after milking and cleaning of parlour – Clean gloves, washed between cows – Pre-dip and allow kill time of 30 secs+ – Loads of surgical spirit and cotton wool – Clean teat end until no more comes off – Get a new bit of cotton wool and do it again! • AHDB booklet and YouTube video clips Intra-mammary tube application • Teat order? – Back then front then treat front to back? – One at a time? • Nozzle design - teat penetration may damage canal seal – short nozzle only in tip of teat? • • • • • • – (Recent study at Liverpool suggests not difference in mastitis or SCC in next lactation) Post dip - some repeat dip daily Barrier external teat sealant? Loafing for 30 min Re-check daily Feed restriction to reduce milk production Dry cow management – do not neglect Formulation - aim of products • Short duration products – short dry period or repeat treatments – MC tubes (Ampiclox DC off market) – 35 days now minimum • Standard • Extended protection - Xtra's How achieved ? • Type of antibiotic • Salt of antibiotic • Particle size – Micronisation delays dissolution and absorption esp. Cloxacillin and Ampicillin (Dyna Mill) – (also used in injectables) • Base - as little as 0.5g of 3 g tube is antibiotic – oils, emulsions e.g. Aluminium monosterate First look at Antibiotic - target Staph. then broaden out • Cloxacillin + /- Ampicillin Cloxacillin only (as benzathine salt 500-600 mg) Noroclox DC, Orbenin + Orbenin extra (600mg) Cloxacillin + Ampicillin (as trihydrate 250-300 mg) Boviclox + Boviclox Extra Persistence of Cloxacillin Persistence of Ampicillin Duration against E. coli ? Antibiotic • Penicillin as procaine salt 300 mg + Framycetin + Penethamate = UbroStar Red = Multishield DC Persistence of Framycetin Cephalosporins • Cefalonium (250 mg) = Cepravin, = Cepritect • Cefquinome (150mg) = Cephaguard DC Duration of activity – Strep. Uberis Incidence of Clinical Mastitis in st 1 100 days of lactation UbroStar Red Bradley and Green 2001 n=440 cows /group. Total 21 % vs 29 % of cows had a case of mastitis Can we justify CIA dry cow therapy? • One type of the antimicrobial dry cow tube available is a CIA (Cefquinome; Cephaguard dry cow tubes). • From Jan 2017 Tesco require culture and sensitivity data showing that animals that have a high cell count at the end of lactation and at the first recording of the next lactation are infected with an organism that is only sensitive to this antimicrobial • From Oct 2019 Red Tractor Standards requires similar • If for acute mastitis after calving and you want to use this product for protection then data will need to indicate that it is the only antibiotic available in a dry cow tube to which the organism causing mastitis after calving is sensitive. • Considered as a short term measure whilst plans to reduce the risk factors for mastitis are implemented. Milk use times after injection • Need to predict calving date correctly ! • Too SHORT a duration product – risk of re-infection - summer • Too LONG a duration product – if calve early discard milk or bulk milk fail • Not the same for products of same active ingredient – 7 days vs 49 days for Amp & Clox products Milk use times after calving • Usually 96 hour post calving milk withhold • Some now extended 156 hours • Some down to 24 hours • Influence of other conditions – Milking frequency – Milk fever – Cepravin, Boviclox • Meat withhold 10 - 30 days - most 28 days Milk use times after calving Administration to Calving withhold Post-calving withhold Calving Calving Management of drying off • Set dry period – management decision – early / late • Batch dry off – get organised, identify cow, less mistakes • Abrupt – intermittent milking - cell counts increase • Cow should not go through parlour again – milk let down = risk of antibiotic in milk Other treatment at drying off • Tylosin (Tylan) • Tilmicosin (Micotil) – licenced for Staph aureus in sheep not cattle • Subcutaneous – now vet administration only • Milk withhold 36 days (Sept 09) • Intramammary - see EMEA site? • Other longer acting Macrolides – All licenced for pneumonia in beef cattle only – Tulathromycin (Draxxin) – Gamithromycin (Zactran) – Tildipirosin (Zuprevo) • Published data using Micotil suggests this approach not very effective against Staph/ Aureus. Milk and Blood Pharmacokinetics of Tylosin and Tilmicosin following Parenteral Administrations to Cows Avci and Elmas https://doi.org/10.1155/2014/869096 Comparison of Tilmicosin and Cephapirin as Therapeutics for Staphylococcus aureus Mastitis at Dry-off. Nickerson et al Cures for IMI caused by Staph. aureus at 28 d postcalving based on individual mammary quarters: Cephapirin benzathine 78.1% Tilmicosin infused 74.2% Tilmicosin injected 9.1% https://doi.org/10.3168/jds.S0022-0302(9 9)75286-0 Dry cow performance – has it worked? Cell count pattern classification Dry cow performance over last 300 day Do you need to treat all mastitis cases? • • • • Some culture negative Some due to yeast Some will self-cure Some farms using on farm culture systems and not treating mild gram –ve infections during lactation – e.g. Vetorapid, AccuMast • Developing area – keep an eye on it Mastitis Treatment Failure • Can I have something “stronger” • To obtain licence efficacy has been proven using the treatment protocol outlined on the data sheet only • Better than no treatment at all • Do not need to prove new treatment is better than existing treatments (yet) Mastitis Treatment Failure • Antibiotic resistance • Bacterial dormancy (treatment duration = 10 life cycles) • L-forms - naked so insensitive to beta-lactams • • • • – formation suppressed by novobiocin Biofilms Reduced host response – steroids, stress Reduced phagocytosis (novobiocin) Re-infections – from un-cleared udder infections – from teat-canal infections (nozzles) – from external sources (five point plan) Sandholm et al J. Vet. Pharmacol. Therap. (1990) 13 248-260 Mastitis Treatment Failure • AB's do not reach the site of infection in adequate concentrations due to – too low a dose – too long a dose interval – too short a treatment period Mastitis Treatment Failure • pharmacokinetic limitations – absorption, disposition, elimination – sequestration due to ionisation (pH trap) – diffusion barriers in intramammary treatment • (oedema, blocked ducts, abscesses, fibrosis) – poor delivery of AB across blood/milk barrier in parenteral treatment – binding of AB to milk or serum protein – intracellular parasitism Milking Cow Therapy • • • • • Intramammary Systemic Both Case Selection Cost vs Benefit Does it E. Coli mastitis warrant antibiotic therapy? • • • • 228 cows with coliform mastitis in Israel Treated with potentiated sulphonamide +/- Ketoprofen Recovery 74.6 % if organism AB resistant Recovery 89.1 % if organism AB sensitive Odds Ratio for cow recovery 95% confidence interval Antibiotic sensitive 2.75 1.29 – 5.85 NSAID treated 2.76 1.12 – 6.79 Shpigel et al Veterinary Record (1998) 142 ANTIMICROBIAL PRESCRIBING PRACTICE IN CATTLE IN THE UK RESULTS Clinical scenario 1 – Acute E. coli mastitis 97% would use antimicrobial, 3% would not. 7% Tetracyclines Potentiated Amoxycillin 3rd/4th Gen Cephalosporin Potentiated Sulphonamide Fluoroquinolones 0% 8% 9% 14% 54% 10% 20% 30% 40% 50% 60% % first choice 26% would leave the antimicrobial on the farm for similar cases 9% said they would not Does it E. Coli mastitis warrant a Fluoroquinolones? • 132 cows with acute clinical mastitis • Confirmed growth of E. coli in a pre-treatment milk Enrofloxacin + Ketoprofen Ketoprofen alone Bacteriological cure 91%* 87% Clinical cure 47% 57%* Cow survival 95% 93% Cows remaining in the herd after 6 months 72% 81% Suojala et al. J Dairy Science (2010) 93 1960 Does mild /acute E. Coli mastitis warrant antibiotic therapy? • Some vets and farmers culturing and only treating gram positive cultures • Tri-plates on-farm culture or Petrifilm? • No treatment , 2 or 8 days ceftiofur intramammary tubes • No difference in E.Coli bacteriological cure (96-98%) • Klebsiella a problem – AB helpful but poor cure for all treatments. AB treatment duration No 2 day 8 day Quarter level recurrence Culling Voluntary dry off quarter Days to normal milk 32% 18% 20% 4.2 days 34% 12% 30% 4.8 days 32% 11% 27% 4.5 days Fuenzalida and Ruegg 2019 doi: 10.3168/jds.2018-16156. Clinical Surveillance of AMR Resistance to non-HP-CIAs (A) and HP-CIAs (B) of Escherichia coli isolated from mastitis samples from cattle in England and Wales. Note scale differs between graphs. (A) (B) 50 3.0 40 AG 2.0 0.0 BL BL TC TS BL QU Key  2018  2019  2020 Enrofloxacin 1.0 Cefpodoxime Enrofloxacin Cefpodoxime Trim/sulph Tetracycline Ampicillin clavulanic acid Amoxicillin/ 0 Streptomycin 10 Resistant isolates (%) 20 Neomycin Resistant isolates (%) 30 QU © 2021 VMD HP-CIAs: Highest Priority Critically Important Antibiotics AG: aminoglycosides, BL: beta-lactams, QU: quinolones, TC: tetracyclines, TS: trimethoprim/ sulphonamides Source: Fig. 4.6; p. 92 VARSS REPORT 2020 © 2021 VMD 64 Clinical Surveillance of AMR AG Sulphonamides Trimethoprim/ Oxytetracycline Cefapirin Ampicillin clavulanic acid Amoxicillin/ Neomycin Resistant isolates (%) 35 30 (A) 25 20 15 10 5 0 Spectinomycin Non-susceptibility of (A) Escherichia coli (n=559); isolated from bovine mastitis samples submitted to Vale Veterinary Laboratories in 2020. BL TC TS © 2021 VMD AG: aminoglycosides, BL: beta-lactams, TC: tetracyclines, TS: trimethoprim/sulphonamides Note: The Private Laboratory Initiative is a new public-private data-sharing project, currently in proof-ofconcept stage. Due to methodological differences, results are not directly comparable to those generated by government labs, but they demonstrate the potential of this data to enhance AMR surveillance. Source: Fig. 4.10; p. 97 VARSS REPORT 2020 © 2021 VMD 65 E. Coli mastitis sensitivity “coliforms”mastitis sensitivity Clinical Surveillance of AMR Antibiotic resistance of Streptococcus uberis isolated from mastitis samples from cattle in England and Wales. 50 45 40 35 25 20 15 10 Tetracycline Novobiocin Penicillin Cefalexin* lanic acid Ampicillin BL Tylosin AG Amoxicillin/ 0 clavu- 5 Neomycin Resistant isolates (%) 30 ML TC Other © 2021 VMD Key:  2018  2019  2020 * No data available for 2018 AG: aminoglycosides, BL: beta-lactams, ML: macrolides TC: tetracyclines Source: Fig. 4.8; p. 94 VARSS REPORT 2020 © 2021 VMD 68 Clinical Surveillance of AMR Non-susceptibility of (B) Streptococcus uberis (n=555) isolated from bovine mastitis samples submitted to Vale Veterinary Laboratories in 2020. 40 (B) 35 Resistant isolates (%) 30 25 20 15 10 5 0 Neomycin AG Ampicillin Cefapirin BL Cloxacillin Penicillin © 2021 VMD AG: aminoglycosides, BL: beta-lactams, TC: tetracyclines, TS: trimethoprim/sulphonamides Note: The Private Laboratory Initiative is a new public-private data-sharing project, currently in proof-ofconcept stage. Due to methodological differences, results are not directly comparable to those generated by government labs, but they demonstrate the potential of this data to enhance AMR surveillance. Source: Fig. 4.10; p. 97 VARSS REPORT 2020 © 2021 VMD 69 Strep. Uberis mastitis sensitivity Strep. mastitis sensitivity Strep. Dysgalactiae mastitis sensitivity Clinical Surveillance of AMR Non-susceptibility of S dysgalactiae (n=97); isolated from bovine mastitis samples submitted to Vale Veterinary Laboratories in 2020. (A) Note: The Private Laboratory Initiative is a new public-private data-sharing project, currently in proof-ofconcept stage. Due to methodological differences, results are not directly comparable to those generated by government labs, but they demonstrate the potential of this data to enhance AMR surveillance. Source: Fig. 4.10; p. 97 VARSS REPORT 2020 © 2021 VMD 73 Strep. mastitis sensitivity Staph. aureus mastitis sensitivity Clinical Surveillance of AMR Non-susceptibility of Staph. Aureus (n=153); isolated from bovine mastitis samples submitted to Vale Veterinary Laboratories in 2020. Note: The Private Laboratory Initiative is a new public-private data-sharing project, currently in proof-ofconcept stage. Due to methodological differences, results are not directly comparable to those generated by government labs, but they demonstrate the potential of this data to enhance AMR surveillance. Source: Fig. 4.10; p. 97 VARSS REPORT 2020 © 2021 VMD 76 Staph. mastitis sensitivity MRSA? • • • • • • • East Germany – Pigs on farm as reservoir? Novel strain for the UK – LESS resistant Why was it a big issue? PCR missed new strain! Cross infection between humans and cattle Must monitor phenotype as well as genotype Long term importance still to be confirmed Gram+ve S. Aureus, Streps Gram –ve E. Coli Penicillin G +++ - + Streptomycin +++ ++ Pot. Amoxycillin +++ +++ Cloxacillin +++ - Cephalosporins +++ ++ Pot. Sulphonamide +++ +++ Tetracyclines + +++ Novobiocin ++ - Macrolides +++ - Neomycin + +++ Combinations to broaden spectrum Combinations may act synergistically Combinations to broaden spectrum Why have both Penicillin and Novobiocin with similar spectrum ? Combinations to Reduce Resistance Novobiocin prevents resistance to penicillin – how clinically significant ? What else is in the product ? Where do you want the antibiotic to get to? Does it get there ? Via the teat Well Limited Poor Macrolids Sulphonamides Streptomycin Phenicols Cephalosporins Framycetin Fluoroquinolones Tetracyclines (Neomycin) Penethamate Penicillin G Aminopenicillins Novobiocin Trimethoprim Penicillin / Streptomycin + others Streptopen MC Procaine Penicillin 1,000,000i.u. (1 g) Dihydrostreptomycin Sulphate 500 mg Multiject IMM Procaine Penicillin 100 mg Prednisolone (spring 2022?) Streptomycin 100 mg 10 mg Neomycin Sulphate 100 mg UBRO Yellow Penethamate 150 mg Prednisolone (Leo) 5 mg Dihydrostreptomycin 150 mg Framomycin 50 mg Tetra-Delta Procaine Penicillin 100 mg Prednisolone Dihydrostreptomycin 100 mg 10 mg Neomycin Sulphate 105 mg + Novobiocin 100 mg UBRO Pen Benzyl Penicillin 340.8 mg Procapen Benzyl Penicillin 1.7 g (not in NOAH) Synthetic Penicillins Orbenin LA Cloxacillin 200 mg Lactaclox + Ampicillin 75 mg Synulox LC Amoxycillin 200mg Combiclav Clavulanic acid 50 mg (Autumn 2022?) Prednisolone 10 mg Cephalosporins Pathocef Cefoperazone 250 mg Cobactan Cefquinome 75 mg Ceffect Cefimam LC Mastiplan LC Cefapirin 300mg Ubrolexin Cefalexin 200mg Kanamycin 100,000 I.U. Prednisolone 20mg Others Albiotic Lincomycin HCl 330mg Neomycin Sulphate 100 mg Lactatrim Trimethoprim 40 mg Duofast Sulfadiazine 200 mg Pirsue Pirlimycin 50mg What do we want to do? • Get milk back in the tank? • May get clinical cure • If infection not cleared mastitis will recur • High bacteriological cure rate = longer treatment less recurrence and spread = more milk long term • Treat long and hard – less likely to go chronic especially in heifers to secure future lactations What’s the price ? or total cost ? Therapeutic Strategies - during lactation • Typical label – 12 hours intervals for 3 consecutive milkings? – every 24 hours for 3 occasions • Multiject, UBRO Pen, – every 48 hours for 3 occasions – Orbenin LA – Once – Pathocef Therapeutic Strategies - during lactation • Off-label • Extended course • Pulse therapy course + withhold + course + withhold + course + withhold • Blitz – whole herd treated - Strep. agalactiae only • Mini blitz – whole group treated - any grumbling problem • Reassessment - records, CMT, ICSCC, bacteriology? Duration of treatment Duration Bacteriological Cure None 0% 2 days 44% 5 days 61% 8 days 95% Pirlimycin (Pirsue) to treat Staph. Aureus and Strep. Uberis Gillespie et al, (2002) Veterinary Therapeutics, 3, 373-380 Similar data for other products Intramammary vs Systemic Quicker return to milk production Intramammary vs Systemic More Milk Production - but more antibiotic used Does it get there ? Via the Blood Well Limited Poor Macrolides Sulphonamides Ceftiofur Phenicol Penicillins Streptomycin Tetracyclines i.v. Cefaquinome Framycetin Fluoroquinolones Trimethoprim Ziv, G. JAVMA (1980) 176 No 10 (2) 1109-1115 (Neomycin) 6 Benzyl penicillin (mcg/ml) 5 4 Serum 3 Milk 2 1 0 0 1 2 4 Time (h) 6 8 10 Benzyl penicillin in serum and milk after i.m. injection 6 g/cow 5 Serum Tetracycline(mcg/ml) 4 Milk 3 2 1 0 0 1 2 4 Time (h) 6 8 10 12 Tetracycline in serum and milk after i.m. injection 10 mg/kg b.w. T lo s in ( c l) T ylo sy in ( m cg /m m lg )/m 10 8 10 6 8 46 24 02 0 Serum Milk Serum Milk 00 11 22 44 66 88 Time Time (h) (h) 1010 1111 1313 Tylosin levels in serum and milk after i.m injection of 10 mg/kg b.w. Penicillin in serum and milk after i.m. injection of daily 15-7.57.5mg/kg Penethamate cow • (Not ionized at blood pH, as it is a weak basis (pKa=8.4) and lipid soluble so can cross membranes => hydrolysed to penicillin • 10% better cure rate than Pen/strep? • Mamyzin - make up in water at time of injection • Revozyn in oil so ready to use Route and time over MIC (1-8 mg/l for SDZ) (UK dose 12.5 mg/Kg sulphadiazine (SDZ) this used 40 mg/Kg)) Kaartinen et al Acta Vet Scand (1999) 40 271-278 Percentage of dose recovered from milk Normal Milk Mastitic milk Amoxycillin 0.06 % 0.15 % Oxytetracycline 0.07 % 0.08 % Tylosin 2.60% 1.40 % Prescott and Baggot: Antimicrobial Therapy in Veterinary Medicine 2 nd Ed 1993 Intramammary vs Systemic • Licensed Combinations – injection and tubes – Cobactan – Synulox • Unlicensed Combinations – Pen/strep injection and Pen/strep type tubes – Penethamate injection +/- and Pen or Pen/strep type tubes – Potentiated Sulphonamide injection +/- any tube Other things to consider • Oxytocin 100 i.u. daily for 1 week • • • • – £ 3.50 / day. Vitamin E 1000 IU / Selenium 50 mg per day Copper? Great care needed Zinc – teat keratin Startvac Vaccine – Escherichia coli (J5) inactivated – Staphylococcus aureus (SP140) inactivated, expressing Slime Associated Antigenic Complex (SAAC) – UK study showed reduced odds of mastitis (OR 0.58, CI 0.35-0.98) and increased yield in first 120 days Strep Uberis Vaccine • UBAC – Lipoteichoic acid from biofilm adhesion component of Strep Uberis – Authorised in UK, but limited availability direct from company Strep Uberis Vaccine 0.4 L/day higher in the UBAC® group than in the Placebo group (36.4 vs 36.8 L/day, respectively; P=0.183) Mastitis is painful! Pain Relief • increased sensitivity to touch, hyperalgesia, increased kicking, increased heart, respiratory rate, and rectal temp • NSAIDS also anti-endotoxic • Available products will be further discussed in one of next years therapeutics problems • Eat more, milk more, recover better • Metacam New Zealand study – lower culling for fertility Current NSAID options in cattle – Flunixin meglamine (Finadyne etc) 2-2.2mg/kg daily for 5 days i.v. (transdermal, i.m.?), 12 – 48 hour milk withhold – Ketoprofen (Ketofen) 3mg/kg daily for 3-5 days i.m. or i.v., nil milk withhold – Tolfenamic acid (Tolfine) 4mg/kg i.v. once, discard 1st milking – Meloxicam (Metacam) 0.5 mg/kg s.c. or i.v. once, 5 days milk withhold – Carprofen (Rimadyl) 1.5 mg/kg s.c. or i.v. nil milk withhold – Aspirin (Solacyl) 100% powder 40mg/kg oral. Not for use in animals producing milk for human consumption – Phenylbutazone Current NSAID options in cattle/600 Kg cow Finadyne solution Transdermal £35.40/100 ml £66.76/100 ml £ 4.72/day £ 26.71/day Meflosyl (“me too brand”) £30.79/100 ml £ 4.11/day Allevinix (i.m. flunixin) £40.02/100 ml £ 4.80/day Ketofen £36.94/100 ml £ 6.72/day Metacam days? £94.00/100 ml £ 10.57/ 2 Rimadyl £37.20/50 ml £ 12.75/day? Case Selection • Does it need treating? • Chances of success – How chronic? • History – cases this lactation, quarter SSC, palpation • Organism isolated – Age of animal – Stage of lactation – Concurrent diseases • udder - multiple quarters or teat lesions • systemic – BVD, rumenal acidosis Andy Biggs, Proceedings of the British Mastitis Conference (2002) Case Selection • Young, first case this lactation, high SCC previous month – IM (+ systemic) • End of lactation, high SCC – dry off and treat with dry cow therapy (+/- systemic) • Old and 3rd case this lactation, chronic high SCC – Cull • Young, first case, low SCC previous month – No treatment - watchful waiting What is your plan A? • Have a protocol for ALL to follow • Use 1 type of tube for most cases • Sample EVERY case before treating • Freeze and send in if not cured by 1 course • (including across dry period H=>H or L=>H SCC) • Change only if culture results support this • Change to what culture results indicate • If you NEED a big gun go back to a first line product once the problem has gone so you still have a Plan B for next time PREVENTION • Remove predisposing factors – Milking machine – Environment for lactating and dry cows – or re-infection is inevitable • Sources of infection – Environment – Cows • Quarantine / test new stock • records = cull / treatment policy – Quarter cell counts – Clinical cases per lactation • ADF, automated dipping and flushing of cluster Velactis • Velactis (cabergoline from CEVA Animal Health) • D2 dopamine receptor agonist inhibition of prolactin (PRL) secretion • an aid in the abrupt drying-off by reducing milk production to reduce milk leakage at drying off, the risk of new intramammary infections during the dry period and discomfort • The day following dry-off, treated cows lied 1.5h/d more than control cows – (J Dairy Sci. 2015 Oct;98(10):7097-101. doi: 10.3168/jds.2015-9751. Short communication: The effects of cabergoline administration at dry-off of lactating cows on udder engorgement, milk leakages, and lying behavior. Bach A, De-Prado A, Aris A) • Studies on use with DCT and teat sealant not yet published Velactis • Recent high quality research still showing good efficacy of 21% reduction in IMI – Hop GE et al. J Dairy Sci. 2019 Sep 11. pii: S0022-0302(19)30795-7. doi: 10.3168/jds.2019-16281. • So why was it withdrawn? And is it coming back? – Serious adverse events – recumbency and death – https://www.ema.europa.eu/en/news/ema-recommends-suspendingveterinary-medicine-velactis-used-dairy-cows-time-drying • CVMP think CEVA do not know enough about why this happened or that vets and farms should be expected to follow protocols suggested to reduce the likelihood of it. – Unlikely as of Sept 2019 CVMP recommendation – https://www.ema.europa.eu/en/documents/smop/cvmp-postauthorisation-summary-negative-opinion-velactis-ii/0004_en.pdf Imrestor • Pegbovigrastim (Imrestor by Elanco) • Cytokine bovine granulocyte colony stimulating factor (bGCSF). • 20 μg/kg subcut injection approximately 7 days prior to calving and on the day of calving. • Restores the “normal” neutrophil function to cattle during the periparturient period • Reduces susceptibility to clinical mastitis infections. • Pegfilgrastim is human product – look up uses Am J Vet Res. 2015 Mar;76(3):231-8. doi: 10.2460/ajvr.76.3.231. Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers. Hassfurther RL, TerHune TN, Canning PC Imrestor • • • • Withdrawn from the market What went wrong? What else do neutrophils do? Increase in metritis by 17% in one study although the metritic cows treated did give more milk • No increase in endometritis in another study Fig 3. Barca J, Schukken YH, Meikle A (2021) Increase in white blood cell counts by pegbovigrastim in primiparous and multiparous grazing dairy cows and the interaction with prepartum body condition score and non-esterified fatty acids concentration. PLOS ONE 16(1): e0245149. https://doi.org/10.1371/journal.pone.0245149 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245149 Imrestor • • • • • • • • Withdrawn from the market What went wrong? What else do neutrophils do? Increase in metritis by 17% in one study although the metritic cows treated did give more milk No increase in endometritis in another study EMA renewed marketing authorisation Sept 2020 What is it’s place? Will it increase metritis on your clients farms – do we understand what happened?