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The effect of internal teat sealant products (Teatseal and Orbeseal) on intramammary infection, clinical mastitis, and somatic cell counts in lactating dairy cows: A meta-analysis

Open ArchivePublished:September 23, 2013DOI:https://doi.org/10.3168/jds.2013-6544

      Abstract

      The objective of this study was to assess the efficacy of internal teat sealant products containing bismuth subnitrate (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) when used alone, or in the presence of antibiotic dry cow therapy (ADCT), before or at drying off on the incidence of new intramammary infections (IMI), clinical mastitis, and milk somatic cell count (SCC) during lactation. The literature search identified 18 English-language publications on the use of Teatseal in dairy cattle. A total of 12 studies with 17 subtrials or comparisons including 13 positive control subtrials (internal teat sealant and ADCT vs. ADCT) and 4 negative control subtrials (internal teat sealant vs. untreated) examining IMI were included in the analysis. Internal teat sealants, alone or in the presence of ADCT, reduced the risk of acquiring new IMI after calving by 25% [risk ratio (RR) = 0.75; 95% confidence interval (CI): 0.67 to 0.83]. Internal teat sealants reduced the risk of IMI by 73% compared with untreated cows (RR = 0.27; 95% CI: 0.13 to 0.55). The results of both meta-analyses of IMI, with positive and negative controls, were heterogeneous [I2 (a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity) = 65.4 and 92.1%]. No farm or cow factors studied significantly contributed to the heterogeneity of the results. A total of 16 studies (21 subtrials), including 14 positive control subtrials and 7 negative control subtrials, examining clinical mastitis were included in the analysis. Internal teat sealants alone and in the presence of ADCT reduced the risk of clinical mastitis after calving in lactating cows by 29% (RR = 0.71; 95% CI: 0.62 to 0.82), and 48% (RR = 0.52; 95% CI: 0.37 to 0.75), respectively. The results of the meta-analysis on clinical mastitis with positive controls were homogeneous (I2 = 33.6%), whereas the results of studies with negative controls were heterogeneous (I2 = 60.4%). No farm or cow factors studied that had sufficient data to evaluate significantly contributed to the heterogeneity of the results. The estimated linear score (LS) of milk SCC after calving in published studies (n = 3) and for studies that provided raw data (n = 2), was significantly lower for cattle treated with internal teat sealants and ADCT in 3 studies than for cattle treated with internal teat sealants only. The estimated LS of pooled raw data of 3 studies from 32 herds showed that the LS of cows treated with internal teat sealant and ADCT was not significantly different than those treated with ADCT only. This study found that the application of internal teat sealants in the presence of ADCT or the use of internal teat sealants alone at dry off significantly reduced the incidence of IMI and clinical mastitis in lactating dairy cows compared with respective control groups. Further studies are needed to investigate the effect of internal teat sealants on postpartum milk SCC in lactating dairy cows.

      Key words

      Introduction

      Clinical and subclinical mastitis are major concerns for dairy producers and cause significant economic losses to the dairy industry. The losses include antibiotic treatment, lower milk yield, decreased fertility, and increased culling or death (
      • Bradley A.J.
      Bovine mastitis: An evolving disease.
      ). Although environmental and host factors are critical to the pathogenesis of mastitis, more than 137 different organisms have been identified as causes of clinical mastitis (
      • Watts J.L.
      Etiological agents of bovine mastitis.
      ). This diversity of agents is reflected in treatment difficulties and limits the efficacy of prevention programs. Interventions that provide means of reducing the risk of infection and the sequelae to infection, such as elevated SCC, independent of causal organisms, are of great potential benefit.
      Treatment of cows with long-acting antibiotics at dry off has been an important element of therapeutic and preventive measures in dairy farms (
      • Bramley A.J.
      • Dodd F.H.
      Reviews of the progress of dairy science: Mastitis control—Progress and prospects.
      ). Dry cow therapy has been used successfully for the treatment of subclinical mastitis at drying off and to protect the udder against new infections during the early dry period (
      • Browning J.W.
      • Mein G.A.
      • Barton M.
      • Nicholls T.J.
      • Brightling P.
      Effects of antibiotic therapy at drying off on mastitis in the dry period and early lactation.
      ;
      • Williamson J.H.
      • Woolford M.W.
      • Day A.M.
      The prophylactic effect of a dry cow antibiotic against Streptococcus uberis.
      ). However, milk loss as a result of withholding periods and concerns over the use of antibiotics that may contribute to an increased risk of antibiotic residues and bacterial resistance (
      WHO (World Health Organization)
      ;
      • Berry E.A.
      • Hillerton J.E.
      The effect of selective dry cow treatment on new intramamamry infections.
      ;
      • Oliver S.P.
      • Murinda S.E.
      Antimicrobial resistance of mastitis pathogens.
      ;
      • Ruegg P.L.
      Mastitis in dairy cows.
      ) are matters that suggest the need for alternate approaches to mastitis control.
      The use of internal teat sealants as a preventive measure provides an alternate approach to traditional antibiotic programs. The use of internal teat sealants at drying off mimics the physiological mechanisms that close the teat canal (
      • Meaney W.J.
      Effect of a dry period teat seal on bovine udder infection.
      ). After drying off, a keratin plug forms naturally in the teat canal and acts as an important defense mechanism against IMI. However, the rate of closure of teat canal varies among cows, and it has been suggested that 50% of teats may still be open 10 d after drying off (
      • Williamson J.H.
      • Woolford M.W.
      • Day A.M.
      The prophylactic effect of a dry cow antibiotic against Streptococcus uberis.
      ). Methods of achieving an artificial closure have been examined for the prevention of IMI during the past 30 yr (
      • Meaney W.J.
      Effect of a dry period teat seal on bovine udder infection.
      ;
      • Williamson J.H.
      • Woolford M.W.
      • Day A.M.
      The prophylactic effect of a dry cow antibiotic against Streptococcus uberis.
      ;
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      ). A new teat sealant containing bismuth subnitrate was developed by
      • Meaney W.J.
      Effect of a dry period teat seal on bovine udder infection.
      , who showed that this was effective at preventing new dry period infections in an artificial challenge study. A commercial form of a bismuth subnitrate-based product with the presence of short-acting antibiotic was further developed in Ireland (Osmonds Teat Seal; Cross Vetpharm Group Ltd., Dublin, Ireland). Subsequently,
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      experimented with a reformulated version of the teat sealant (Teatseal; Bimeda Ltd., Auckland, New Zealand) to assess its potential for the prevention of new IMI and clinical mastitis during the dry period and subsequent lactation.
      Both challenge (
      • Meaney W.J.
      Effect of a dry period teat seal on bovine udder infection.
      ) and field (
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      ) studies reported a significant reduction in the incidence of IMI and clinical mastitis in cows treated with internal teat sealant products containing bismuth subnitrate and in the presence of antibiotic dry cow therapy (ADCT) during dry off and lactation (
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      ). Similar studies in the United Kingdom (
      • 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.
      ), Australia (
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      ), New Zealand (
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      ,
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      ;
      • Laven R.A.
      • Lawrence K.E.
      Efficacy of blanket treatment of cow and heifers with internal teat sealant reducing the risk of mastitis in dairy cattle calving on pasture.
      ), United States (
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      ;
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      ), and Canada (
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ) demonstrated that the use of internal teat sealants at dry off can be effective in preventing IMI or new IMI and clinical mastitis in the subsequent lactation.
      • Crispie F.
      • Flynn J.
      • Ross R.P.
      • Hill C.
      • Meaney W.J.
      Dry cow therapy with a non-antibiotic intramammary teat seal—A review.
      stated that if internal teat sealants are not used hygienically and according to the manufacturer’s instructions, this could lead to mastitis. Therefore, the incorporation of antibiotics into internal teat sealants may prevent inadvertent contamination during infusion and improves product safety.
      The objectives of this study were to assess the efficacy of an internal teat sealant containing bismuth subnitrate, sold as Orbeseal and Teatseal (Pfizer Animal Health, West Ryde, Australia), when used alone or in the presence of ADCT before or at drying off on the incidence of the cumulative number of new IMI and clinical mastitis cases from the time of dry off to 100 to 150 d of lactation, and milk SCC in a period from calving to the first 3 wk of lactation. The term internal teat sealant refers to Orbeseal and Teatseal throughout this paper.

      Materials and Methods

       Literature Search

      The literature search used PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Google Scholar (http://scholar.google.com/), ScienceDirect (http://www.sciencedirect.com/), and CAB (http://www.cabi.org), contact with workers in the field, records of Pfizer Animal Health, and investigation of references in papers that were identified. The search strategy was to identify papers that contained data on prospective, randomized, controlled experiments examining effects of internal teat sealants, either alone or in the presence of ADCT on the incidence of new IMI and clinical mastitis during the dry period and lactation. Papers identified included 18 English-language publications on the use of internal teat sealants (Teatseal Bimeda, NZ; and Teatseal and Orbeseal, Pfizer Animal Health) in dairy cattle.
      The following key words were used in different combinations for our search: internal teat sealant, teat sealer, Teat seal, Teatseal, Orbeseal, intramammary infection, clinical mastitis, postpartum milk SCC, subclinical mastitis, cattle, and cow. The most commonly reported outcomes were IMI and clinical mastitis during the lactation. The definitions used in these studies are listed in Appendix Table A1. In almost all cases, clinical mastitis was diagnosed by dairy managers. Subsequently milk samples were collected by the farm staff or study personnel for bacteriological examination.

       Inclusion and Exclusion Criteria

      Studies were included or excluded based on criteria developed by the authors. Quality assessment criteria included randomization of study groups and comparability of treatment groups at entry to each trial. Experiments were included in the analysis if they reported that the cattle used were lactating dairy cows and they reported the data required on IMI and clinical mastitis (i.e., number of cases in each group) to determine the relative risk. Only 3 studies (
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ;
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      ) reported measures of milk SCC [i.e., linear score (LS) of SCC]. We were also able to obtain the raw data for milk SCC from 4 investigators.
      A total of 21 studies and comparisons were excluded from the analysis. Studies that failed to meet the selection criteria included reviews (n = 2), experimentally infected cows (n = 6), studies that compared internal teat sealant with lacticin 3147 or a combination of teat sealant with lacticin 3147 (n = 3), and studies published in non-English journals (n = 6). Comparisons and trials within studies that treated cows systemically with antibiotics (
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      ; experiments 1, 3, and 4) or when internal teat sealant was used in both treatment and control groups (
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      The use of a cephalonium containing dry cow therapy and an internal teat sealant, both alone and in combination.
      ; experiment 2) were also excluded from analysis.

       Data Extraction

      A total of 18 field studies with 22 IMI and 27 clinical mastitis subtrials and comparisons were reviewed. Of this, 17 IMI and 21 clinical mastitis subtrials and comparisons met the eligibility criteria for meta-analysis. Data recorded included authors, year of publication, country, number of farms, breed, parity, unit of observation for treatment allocation and analysis, DIM, dry period, type of ADCT used, diagnostic methods of IMI and clinical mastitis, and farming systems. A summary of studies and variables that were measured is provided in Table 1 and Appendix Table A2). Information on the type and name of ADCT and teat sealant, number of cows and quarters, and number of cows with IMI and clinical mastitis in the control and treatment groups is provided in Table 2.
      Table 1Studies that investigated the effect of teat sealant products (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) on the incidence of IMI and clinical mastitis during the dry period and after calving
      StudyBreedParityUnit of

      treatment
      Unit of

      analysis
      DIMDry period
      CDC=cephalosporin cefquinome; COMBO=combination treatment comprising narrow-spectrum cloxacillin and an internal teat sealant; OEDC=narrow-spectrum antibiotic treatment comprising cloxacillin alone.
      (d)
      SCC at enrollment
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      The use of a cephalonium containing dry cow therapy and an internal teat sealant, both alone and in combination.
      Guernsey

      Holstein-Friesian
      MultiparousQuarter,

      within cow
      Quarter10061 (uninfected);

      70 (infected)
      Uninfected: clinical history and SCC <200 of the last 3 mo; infected: SCC >200
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      Holstein-FriesianMultiparousCow, quarters

      between cows
      Quarter10062.3 (CDC);

      64.3 (COMBO);

      62.7 (OEDC)
      Bulk milk SCC <300
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      MultiparousCow, quarters

      between cows
      Cow98.5; 98.663.6; 64.4SCC <250; SCC >250
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      Holstein-Friesian

      and Friesian × Jersey
      Multiparous

      and primiparous
      Quarter,

      within cow
      Quarter150SCC <200
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      MultiparousQuarter,

      within cow
      Quarter6028 to 100
      • Berry E.A.
      • Hillerton J.E.
      The effect of an intramammary teat seal on new intramammary infections.
      Cow, quarters

      between cows
      Quarter

      and cow
      100SCC <200
      • Berry E.A.
      • Johnston W.T.
      • Hillerton J.E.
      Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.
      Cow, quarters

      between cows
      Quarter

      and cow
      10056 to 70
      • Newton H.T.
      • Green M.J.
      • Benchaoui H.
      • Cracknell V.
      • Rowan T.
      • Bradley A.J.
      Comparison of the efficacy of cloxacillin alone and cloxacillin combined with an internal teat sealant for dry-cow therapy.
      Quarter,

      within cow
      Quarter100SCC >200
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      Cow, quarters

      between cows
      Quarter100
      • 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.
      Cow, quarters

      between cows
      Quarter

      and cow
      100>51Herd selection: bulk SCC < 200; cow selection: SCC< 200
      • Laven R.A.
      • Lawrence K.E.
      Efficacy of blanket treatment of cow and heifers with internal teat sealant reducing the risk of mastitis in dairy cattle calving on pasture.
      Friesian and Friesian

      × Jersey
      Cow and heiferCow

      and heifer
      85SCC >150; SCC <150
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      Friesian, cross-bred,

      and Jersey
      PrimiparousQuarter,

      within heifer
      Heifer14
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      PrimiparousHeiferHeifer14
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      Holstein-FriesianMultiparousQuarter,

      within cow
      Quarter6030 to 90

      Izak, E., E. Castello, and G. Veneranda. 2011. Efficacy and economic benefit of an internal teat sealant during drought and rainy weather dry period on incidence of clinical mastitis. In 3rd International Symposium on Mastitis and Milk Quality, St. Louis, MO. American Association of Bovine Practitioners, Auburn, AL; and National Mastitis Council, Verona, WI.

      ; abstract)
      MultiparousCowCow100At least 45 dSCC <250 and no clinical mastitis
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      Holstein-FriesianMultiparousCowCow10528 to 120 d

      (mean: 62)
      1 CDC = cephalosporin cefquinome; COMBO = combination treatment comprising narrow-spectrum cloxacillin and an internal teat sealant; OEDC = narrow-spectrum antibiotic treatment comprising cloxacillin alone.
      Table 2Number of herds, animals and quarters, products used in control and treatment groups, and number of cases with IMI and clinical mastitis
      StudyNo. of

      herds
      No. of

      animals
      No. of

      quarters
      CriteriaControlTreatmentIMI at quarter

      or cow levels
      New IMI after calving includes number of acquired IMI during the dry period and at or after calving and diagnosed after calving.
      Clinical mastitis

      after calving

      (quarter/cows)
      Number of clinical quarters over total number of quarters; number of clinical quarters over total number of cows; number of clinical cows over total number of cows.
      ControlTreatmentControlTreatment
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      The use of a cephalonium containing dry cow therapy and an internal teat sealant, both alone and in combination.
      64191,604High SCC infected (>250)250 mg of cephalonium
      Cepravin Dry Cow (Intervet Schering-Plough Animal Health, Milton Keynes, UK).
      250 mg of cephalonium + Orbeseal
      Orbeseal (Pfizer Animal Health, Sandwich, UK).
      330/830271/83184/86259/862
      3911,632Low SCC uninfected (<250)250 mg of cephalonium + OrbesealOrbeseal256/779288/77741/81644/816
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      83051,220Bulk milk SCC <300150 mg of cephalosporin cefquinome
      Cephaguard Dry Cow (Virbac Ltd., Bury St. Edmunds, UK).
      600 mg of cloxacillin
      Orbenin Extra Dry Cow (Pfizer Animal Health, Sandwich, UK).
      + Orbeseal
      207/577187/61325/15131/154
      3061,236600 mg of cloxacillin600 mg of cloxacillin + Orbeseal232/588187/61337/15531/154
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      Environmental pathogens.
      6886SSC >250600 mg of cloxacillinTeatseal
      Teatseal (Pfizer Animal Health).
      + 600 mg of cloxacillin
      156/2,14779/2,069129/29981/265
      1,127SSC <250600 mg of cloxacillinTeatseal82/33154/312
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      35281,033Negative controlTeatseal
      Teatseal [Bimeda (NZ) Ltd., Auckland, New Zealand].
      85/52813/50522/1436/121
      250 mg of cephaloniumTeatseal14/52813/50510/1436/121
      Negative control600 mg of cloxacillin Teatseal +85/52810/50522/14311/121
      250 mg of cephalonium600 mg of cloxacillin Teatseal14/52810/50510/14311/121
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      2419Dry period600 mg of cloxacillin600 mg of cloxacillin + Orbeseal
      1 to 3 DIM600 mg of cloxacillin600 mg of cloxacillin + Orbeseal236/812187/821
      6 and 8 DIM600 mg of cloxacillin600 mg of cloxacillin + Orbeseal210/811167/809
      60 DIM600 mg of cloxacillin600 mg of cloxacillin + Orbeseal66/86251/862
      • Berry E.A.
      • Hillerton J.E.
      The effect of an intramammary teat seal on new intramammary infections.
      74011,596Dry periodNegative controlOsmonds Teat Seal
      Osmonds Teat Seal (Cross Vetpharm Group, Tallaght, Dublin, Ireland).
      3981,583At calvingNegative controlOsmonds Teat Seal
      Osmonds Teat Seal (Cross Vetpharm Group, Tallaght, Dublin, Ireland).
      93/799;27/784;
      62/20121/197
      • Berry E.A.
      • Hillerton J.E.
      Effect of an intramammary teat seal and dry cow antibiotic in relation to dry period length on postpartum mastitis.
      11,127At calvingCephaloniumCephalonium + Orbeseal39/53122/59615/1334/150
      • Newton H.T.
      • Green M.J.
      • Benchaoui H.
      • Cracknell V.
      • Rowan T.
      • Bradley A.J.
      Comparison of the efficacy of cloxacillin alone and cloxacillin combined with an internal teat sealant for dry-cow therapy.
      10283Total: 1,924; enrolled: 313After calving600 mg of cloxacillin600 mg of cloxacillin + Orbeseal181/566152/56650/14123/142
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      35282,1121–3 DIMPenicillin-dihydrostreptomycin
      Quartermaster (Pfizer Animal Health).
      Orbeseal penicillin- dihydrostreptomycin160/97181/1,009
      • 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.
      16IMI: 467; mastitis: 4792,016After calving250 mg of cephaloniumTeatseal369/940321/92331/24225/237
      • Laven R.A.
      • Lawrence K.E.
      Efficacy of blanket treatment of cow and heifers with internal teat sealant reducing the risk of mastitis in dairy cattle calving on pasture.
      1249 InfectedAfter calving (first 11 wk after calving)600 mg of cloxacillinTeatseal17/11411/135
      217 NoninfectedNegative controlTeatseal11/1087/109
      206 HeifersNegative controlTeatseal18/1026/104
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      5255 Heifers1,020IMI within 4 DIMNegative controlTeatseal66/50549/50134/50121/501
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      301,0674,146IMI within 5 DIMTylosin
      Tylan (Elanco Animal Health, Manukau City, New Zealand).
      (i.m.)
      Teatseal259/1,02877/1,02874/26860/268
      Negative controlTeatseal255/1,03677/1,02869/26560/268
      Tylosin (i.m.)Tylosin (i.m.) + Teatseal259/1,02897/1,05274/268104/266
      Negative controlTylosin (i.m.) + Teatseal255/1,03697/1,05269/268104/266
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      16408 cows with negative milk culture1,562Negative milk culture 14 d before dry off500 mg of cloxacillinOrbeseal54/78848/774
      326 cows with positive milk culture1,209Positive milk culture 14 d before dry off500 mg of cloxacillin500 mg of cloxacillin + Orbeseal49/60528/604

      Izak, E., E. Castello, and G. Veneranda. 2011. Efficacy and economic benefit of an internal teat sealant during drought and rainy weather dry period on incidence of clinical mastitis. In 3rd International Symposium on Mastitis and Milk Quality, St. Louis, MO. American Association of Bovine Practitioners, Auburn, AL; and National Mastitis Council, Verona, WI.

      278SCC <250 and with no previous IMI600 mg of cloxacillinTeatseal2/3610/42
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      121,334Antimicrobial dry-cow therapy (ADCT)Orbeseal + ADCT125/66997/665
      1 New IMI after calving includes number of acquired IMI during the dry period and at or after calving and diagnosed after calving.
      2 Number of clinical quarters over total number of quarters; number of clinical quarters over total number of cows; number of clinical cows over total number of cows.
      3 Cepravin Dry Cow (Intervet Schering-Plough Animal Health, Milton Keynes, UK).
      4 Orbeseal (Pfizer Animal Health, Sandwich, UK).
      5 Cephaguard Dry Cow (Virbac Ltd., Bury St. Edmunds, UK).
      6 Orbenin Extra Dry Cow (Pfizer Animal Health, Sandwich, UK).
      7 Environmental pathogens.
      8 Teatseal (Pfizer Animal Health).
      9 Teatseal [Bimeda (NZ) Ltd., Auckland, New Zealand].
      10 Osmonds Teat Seal (Cross Vetpharm Group, Tallaght, Dublin, Ireland).
      11 Quartermaster (Pfizer Animal Health).
      12 Tylan (Elanco Animal Health, Manukau City, New Zealand).

       Statistical Analysis

      A meta-analysis was conducted on the incidence of IMI and clinical mastitis using Stata (Intercooled Stata v.12;

      StataCorp. 2011. Stata Statistical Software: Release 12. StataCorp LP, College Station, TX.

      ). Fixed effect (
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ) and random effects (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ) models were used to assess the efficacy of internal treat sealants on the risk of IMI and clinical mastitis. In this study, risk ratio (RR) is the risk of IMI or clinical mastitis in cows that were treated with internal teat sealant commercial products or in the presence of ADCT (e.g., cloxacillin or cephalonium) compared with cows in control groups: either negative controls (untreated controls) or positive controls that were treated with ADCT. A total of 17 IMI and 21 clinical mastitis trials and comparisons were eligible for the meta-analyses. Studies conducted to assess the effect of therapeutic dry cow treatments on mastitis in dairy cattle needed to have adequate randomization among mammary quarters or cows.
      The statistical methods of meta-analytic procedures that were used in this paper have been previously published (
      • Lean I.J.
      • Celi P.
      • Raadsma H.
      • McNamara J.P.
      • Rabiee A.R.
      Effects of dietary crude protein on fertility: Meta-analysis and meta-regression.
      ;
      • Rabiee A.R.
      • Breinhild K.
      • Scott W.
      • Golder H.M.
      • Block E.
      • Lean I.J.
      Effect of fat additions to diets of dairy cattle on milk production and components: A meta-analysis and meta-regression.
      ). Briefly, a fixed-effect model is based on the assumption that every study evaluates a common treatment effect. Specifically, the fixed-effect assumption means that the hypothetical effect of treatment is the same in all studies. The summary treatment effect estimate resulting from this method of meta-analysis is a fixed treatment effect, and the confidence interval provided describes how certain we are about the pooled estimate.
      A Mantel-Haenszel risk ratio (RRM-H) is calculated using the following formula (
      • Rothman K.J.
      ), which is generated from a contingency 2 × 2 table:
      RRM-H=ajN0j/TjbjN1j/Tj,
      [1]


      where aj is the number of IMI or clinical mastitis cases (cow or quarter) in the treatment group for trial j, bj is the number of IMI or clinical mastitis cases (cow or quarter) in the control group for trial j, and N0j and N1j represent the number of cows in the treated and control groups, respectively. The numerator and denominator are summed over j, the number of trials.
      The random effects model assumes that the true treatment effects in individual studies may differ from each other. The true treatment difference in each trial is also assumed to be a realization of the random variable. The random variable is usually assumed to be normally distributed. The standard error of each trial estimate is increased and reflects the within- and between-trial variation. A pooled
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      risk ratio (RRD+L) is calculated with the following formula:
      RRD+L=WiRRiWi;
      [2a]


      95%CI=θ1.96×SEθtoθ+1.96×SEθ;
      [2b]


      Predictive interval=tdf×SE2+τ2,
      [2c]


      where Wi is the weight (inverse variance) of individual studies and RRi is the risk ratio of each subtrial or comparison (i). The 95% confidence interval for the overall estimate θ was estimated using Equation 2b, where θ is the log RR and SE is the standard error of log RR (

      Egger, M., G. D. Davey Smith, and D. G. Altman. 2001. Systematic Reviews in Health Care: Meta-Analysis in Context. British Medical Journal Books, London, UK.

      ). The confidence interval of the approximate predictive distribution of a future trial was estimated based on the extent of heterogeneity. This incorporated uncertainty in the location and spread of the random effects distribution used Equation 2c, where t is the t-distribution with k − 2 degrees of freedom (where k is the number of experiments), SE2 is the squared standard error, and τ2 is the heterogeneity statistic (
      • Bradburn M.J.
      • Deeks J.J.
      • Altman D.G.
      sbe24. metan—An alternative meta-analysis command.
      ).
      The number needed to treat (NNT) is the number of individuals that need to be treated to expect that 1 case of mastitis would be prevented (http://handbook.cochrane.org/). The NNT is equal to 1/(control group event risk − treatment group event risk) (

      Bradburn, M. J. 2003. Updated and new commands for meta-analysis in Stata. Accessed March 2013. http://wenku.baidu.com/view/8dcb3aa20029bd64783e2c1c.html

      ). The NNT was calculated in this study to provide several cows that needed to be treated with internal teat sealant to prevent 1 additional IMI or clinical case of mastitis after calving in lactating dairy cows is provided in Table 3. The NNT was calculated with Stata using the methods of

      Bradburn, M. J. 2003. Updated and new commands for meta-analysis in Stata. Accessed March 2013. http://wenku.baidu.com/view/8dcb3aa20029bd64783e2c1c.html

      .
      Table 3Relative risk and probability of IMI and clinical mastitis in dairy cows treated with internal teat sealants (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) alone or in the presence of antibiotic dry cow treatments (ADCT), number needed to treat (NNT), and heterogeneity among trials
      VariableSubgroup

      (no. of comparisons)
      Relative risk and 95% CIP-valueNNTHeterogeneity
      I2=a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity.
      Random effect

      (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      )
      Q statistics

      (chi-squared)
      I2 [% (95% CI)]P-value
      IMIPositive control (n = 13)0.75 (0.67, 0.83)<0.0012034.7165.4 (38, 81)<0.001
      Negative control (n = 4)0.27 (0.13, 0.55)<0.001737.7992.1 (83, 96)<0.001
      Clinical mastitisPositive control (n = 14)0.71 (0.62, 0.82)<0.0012119.5833.6 (0, 65)0.11
      Negative control (n = 7)0.52 (0.37, 0.75)<0.0011315.1560.4 (9, 83)0.019
      1 I2 = a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity.

       Forest Plots

      The effects of internal teat sealant on the risk of IMI and clinical mastitis in lactating dairy cows are provided in the forest plots (Figures 1 and 2). Points to the left of the line at RR = 1 represent a reduction in the risk of IMI or clinical mastitis, whereas points to the right of the line indicate an increase in the risk of IMI or clinical mastitis. Each square represents the RR for that study or subtrial. The upper and lower limit of the line connected to the square represents the upper and lower 95% confidence interval for the RR. The size of the square reflects the relative weighting of the study to the overall RR estimate with larger squares representing greater weight. The dotted vertical line represents the overall RR estimate. The diamonds at the bottom represent the 95% confidence interval for the overall estimates of fixed effect (
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ) and random effects (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ) models. The lines that are horizontally stretched on D+L diamond shapes are the predicted intervals and represent a conservative estimate of a predicted response to future treatment. The solid vertical line with RR of 1 is provided to indicate no net effect of intervention.
      The SCC data for cows after calving in 3 studies (
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      ;
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ) containing 32 herds were extracted and analyzed to compare the effect of internal teat sealant in the presence of ADCT versus ADCT treatment alone. The LS of postpartum milk SCC were analyzed using a mixed-effects linear model in which treatment, parity, and LS at drying off were the fixed effect terms and herd was the random effects term:
      yij=β0+β1X1ij+β2X2ij+β3X3ij+μj+ϵij,
      [3]


      where yij is the response variable (LS in lactation), β0 (intercept) is the overall mean of LS, and β1 to β3 are the fixed-effect coefficients of internal teat sealant, parity, and LS at drying off, respectively. In this model, X1ij to X3ij are the fixed-effect terms (internal teat sealant, parity, and LS at drying off), μj is the random-effect of herd, and εij is the residuals (error term). The interaction between internal teat sealant and herd was also examined.

       Assessment of Heterogeneity

      Heterogeneity among the estimated RR for studies included in the meta-analysis were assessed using a chi-squared (χ2) test of heterogeneity. In this case, the null hypothesis was that the effect of treatment was the same across j trials and the null hypothesis was rejected if the heterogeneity test statistic was greater than a critical value that separated the upper 10% of a χ2 distribution with (j − 1) degrees of freedom. We used an α level of 0.10 because of the relatively poor power of the χ2 test to detect heterogeneity among a small number of experiments (
      • Egger M.
      • Davey Smith G.
      Principles of and procedures for systematic reviews.
      ). Heterogeneity of results among experiments was quantified using the I2 statistic (
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ;
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analysis.
      ), which describes the proportion of total variation in study effect estimates that is due to heterogeneity.
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      developed measures of the impact of heterogeneity in a meta-analysis from mathematical criteria that are independent of the number of studies and the treatment effect metric. The I2 is described as a percentage of the total variation that is due to heterogeneity rather than chance:
      I2%=Qk1Q×100;
      [4a]


      95%UI=1k1Q±1.96VarQ,
      [4b]


      where Q is the chi-squared (χ2) heterogeneity statistic, k is the number of experiments, and I2 was calculated according to
      • Thompson S.G.
      • Sharp S.J.
      Explaining heterogeneity in meta-analysis: A comparison of the methods.
      and
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analysis.
      . Uncertainty intervals (UI) for I2 (dependent on Q and k) were calculated using the method described by
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      using Equation 4b. Negative values of I2 are equal to zero; consequently, I2 lies between 0 and 100%. A value higher than 50% may be considered substantial heterogeneity (
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analysis.
      ).

       Meta-Regression

      Meta-regression analyses were used to explore the source of heterogeneity of response using the logarithm of individual RR (log RR) for each experiment as the outcome and the associated standard error as the measure of variance. We have previously described the meta-regression procedures (
      • Lean I.J.
      • Celi P.
      • Raadsma H.
      • McNamara J.P.
      • Rabiee A.R.
      Effects of dietary crude protein on fertility: Meta-analysis and meta-regression.
      ;
      • Rabiee A.R.
      • Breinhild K.
      • Scott W.
      • Golder H.M.
      • Block E.
      • Lean I.J.
      Effect of fat additions to diets of dairy cattle on milk production and components: A meta-analysis and meta-regression.
      ).

       Publication Bias

      No definitive means exists to assess the presence of publication bias in meta-analysis (http://handbook.cochrane.org). Several statistical tests exist for detecting funnel plot asymmetry [for example, the rank correlation test of
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      and the linear regression test of
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ], but these do not have considerable power and are rarely used. Funnel plots can be used visually to demonstrate the presence or absence of small-study effect as publication bias.
      A funnel plot (as shown in Figures 3 and 4) is a simple scatter plot of the intervention effect estimates from individual studies against a measure of each study’s size or precision. It is commonly presented as a plot of the effect estimates on the horizontal scale, and the measure of variance on the vertical axis. The name funnel plot arises because the precision of the estimated intervention effect increases as the size of the experiment increases. Effect estimates from small experiments will, therefore, scatter more widely at the bottom of the graph, with the spread narrowing among larger experiments. In the absence of bias, the plot should approximately resemble a symmetrical (inverted) funnel. If bias exists (for example, because smaller experiments without statistically significant effects remain unpublished), this will lead to an asymmetrical appearance of the funnel plot, with observations (trials and subtrials) missing from the bottom corners of the graph. In this situation, the effect calculated in a meta-analysis will tend to overestimate the intervention effect (
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ). The more pronounced the asymmetry, the more likely it is that the bias will be substantial. The dashed lines provide the pseudo-confidence intervals for the RR estimates within the funnel plot. The vertical line is where the RR = 1.

       Contour-Enhanced Funnel Plots

      Contour-enhanced funnel plots have been proposed by
      • Peters J.L.
      • Sutton A.J.
      • Jones D.R.
      • Abrams K.R.
      • Rushton L.
      Contour enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry.
      to include contour lines corresponding to the statistical significance (P = 0.01, 0.05, and 0.1). This approach allows reviewers to differentiate among the trials that are highly significant from trials that are perceived to be missing. The contour-enhanced funnel plots may help to differentiate asymmetry caused by publication bias from that due to other factors. For example, if experiments appear to be missing in areas of statistical nonsignificance, then this adds credence to the possibility that the asymmetry is caused by publication bias. Conversely, if putative missing studies are in areas of higher statistical significance, this suggests that the observed asymmetry may more likely be due to factors other than publication bias.

       Milk SCC

      We were able to obtain the raw milk SCC data from 4 investigators (
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      ;
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      ;
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ) and estimated the LS of milk SCC after calving. Data from
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      were not used in this report because these samples were collected immediately after calving and may have contained colostrum (K. I. Parker, Animal Health Centre, Morrinsville, New Zealand, personal communication). We analyzed data that were provided by
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      and
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      , but not published in the original papers, and estimated the LS of milk SCC after calving for each study separately (Table 4). The results were not significant, but the internal teat sealants + ADCT reduced the LS of milk SCC in 2 trials, but not in
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      ; experiment 2). The LS of postpartum milk SCC data of 3 studies (
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      ;
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ) were then pooled as 1 data set and analyzed using a mixed-effects linear model, in which herds within studies were used as a random effects term, to explore the effect of internal teat sealant in the presence of ADCT on LS (Table 5).
      Table 4Milk SCC (linear score) of cows treated with internal teat sealants (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) and antibiotic dry cow treatments (ADCT) during the first 3 wk after calving
      StudyExperiment/

      period
      SourceDIMControlTreatmentStatistical model

      and variables

      accounted for
      Linear score of SCC; no. of cows

      (mean ± SE)
      P-value
      ControlTreatment
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      ; United States)
      Period 1Paper1–3600 mg of cloxacillin600 mg of cloxacillin + OrbesealMultivariate linear regression (PROC MIXED
      SAS Institute Inc., Cary, NC.
      ; not specified)
      NA
      NA=not available.
      ; 5.40 ± 0.17
      NA; 5.10 ± 0.17<0.001
      Period 26 and 8NA; 3.10 ± 0.18NA; 2.80 ± 0.18
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      ; Australia)
      Paper7600 mg of cloxacillinTeatseal + 600 mg of cloxacillinMultivariate linear regression (accounted for age, milk yield, SCC in previous lactation, herd)NA; 4.72 ± 0.05NA; 4.41 ± 0.05<0.001
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ; Canada)
      Paper>5ADCTOrbeseal + ADCTMixed linear regression [accounted for parity, season of calving and herd (random)]1,3340.11
      2.50 ± 0.182.44 ± 0.18
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      Data15–18Penicillin- dihydrostreptomycinOrbeseal + penicillin- dihydrostreptomycinMixed linear regression [accounted for age, FCM, SCC in previous lactation and herd (random)]306; 2.71 ± 0.10292; 2.32 ± 0.100.004
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      Experiment 1Data7500 mg of cloxacillinOrbesealMixed linear regression [accounted for age, SCC in previous lactation and herd (random)]1,510; 2.59 ± 0.10815; 2.53 ± 0.120.57
      Experiment 2500 mg of cloxacillin + Orbeseal1,510; 2.59 ± 0.10679; 2.74 ± 0.130.18
      1 SAS Institute Inc., Cary, NC.
      2 NA = not available.
      Table 5Analysis of linear score (LS) of individual cows in early lactation using a mixed effects linear regression model after adjusting for herd effects (random effects), parity, and LS at dry off (fixed effects)
      Predicted means are detailed.
      ItemWithout LS at dry off (n = 4,023)With LS at dry off (n = 2,506)
      Coefficient ± SEP-valueCoefficient ± SEP-value
      Treatment−0.086 ± 0.0700.22−0.034 ± 0.0900.72
      Parity
       20.175 ± 0.09<0.0580.0309 ± 0.110.78
       30.747 ± 0.11<0.0010.684 ± 0.15<0.001
       40.817 ± 0.13<0.0010.844 ± 0.18<0.001
       ≥51.270 ± 0.13<0.0011.222 ± 0.18<0.001
      LS at dry offNANA0.058 ± 0.0210.005
      Variance and 95% CILog-likelihoodVariance and 95% CILog-likelihood
      Random effect (herd)0.129 (0.062, 0.269)−8,776.3170.052 (0.010, 0.254)−5,528.2007
      Predicted mean for LS

      (mean ± SE)
      Predicted mean for LS

      (mean ± SE)
      ADCT
      ADCT=antibiotic dry cow treatments.
      2.75 ± 0.082.63 ± 0.08
      Teatseal
      Pfizer Animal Health, West Ryde, Australia.
      + ADCT
      2.67 ± 0.092.60 ± 0.10
      1 Predicted means are detailed.
      2 ADCT = antibiotic dry cow treatments.
      3 Pfizer Animal Health, West Ryde, Australia.

      Results and Discussion

      Sufficient studies of suitable quality were identified to allow a meta-analysis to be conducted (Tables 1 and 2). Most experiments included in the published papers were conducted in multiple herds and several factors that could act to confound estimates of the effect of treatment were investigated by qualitative review and meta-regression to determine if the outcomes of these studies (IMI and clinical mastitis) may have been influenced by some of these factors.

       Random Allocation of Treatment Among Front and Rear Quarters Within Cow

      The probability of risk of infection among front and rear glands should be considered during the random allocation of treatments to different quarters within cow, as
      • Adkinson R.W.
      • Ingawa K.H.
      • Blouin D.C.
      • Nickerson S.C.
      Distribution of clinical mastitis among quarters of the bovine udder.
      and
      • Barkema H.W.
      • Schukken Y.H.
      • Lam T.J.
      • Galligan D.T.
      • Beiboer M.L.
      • Brand A.
      Estimation of interdependence among quarters of the bovine udder with subclinical mastitis and implications for analysis.
      suggested that the risk of clinical mastitis is higher in the rear than front glands. If treatments were not applied equally across the front and rear glands or not accounted for, this could lead to a bias in assessing the efficacy of treatments.
      • Berry E.A.
      • Johnston W.T.
      • Hillerton J.E.
      Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.
      , however, found no statistical differences in infection status at calving with respect to front or rear, or left or right quarters when cows were treated with ADCT or internal teat sealant (Orbeseal; Pfizer Ltd., Tadworth, UK). In all studies (n = 6) that quarter within cows were the unit of observation and each quarter was treated with a different treatment regimen, the treatments were randomly allocated among the front and rear glands to avoid a potential bias.

       Between-Quarter Interdependence Within Cows

      Several studies (n = 6) existed in which the quarters within a cow were allocated to different treatment regimens, such as ADCT, untreated (control), and treated with internal teat sealants with or without ADCT (Table 2). Concerns existed about the interdependence of quarters in studies that used different treatments at the quarter level within cow, as failure to account for interdependence of quarters within a cow may lead to inaccurate variance estimates and errors in assessing treatment effects.
      • Berry E.A.
      • Johnston W.T.
      • Hillerton J.E.
      Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.
      demonstrated that quarters that were untreated during the dry period were independent from treated quarters of the same cow with respect to the risk of an IMI at calving.
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows.
      studied whether intramammary half-udder infusion of cloxacillin resulted in transfer of cloxacillin from treated to untreated mammary gland quarters within nonlactating cows. This study also investigated the concentrations of antibiotic in quarters, and whether selection of ipsilateral versus diagonal-contralateral quarters for treatment affected cloxacillin transfer among quarters. Cloxacillin was detected in 25% of all untreated mammary gland quarters (
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows.
      ), but concentrations of cloxacillin in untreated quarters were below MIC for targeted mastitis pathogens. Their study also found significant differences in cloxacillin concentrations in the ipsilateral or diagonal treatment groups. The results of their study suggest that within-cow half-udder comparison trials are valid for antimicrobial trials in nonlactating cows, although transfer of antimicrobials does occur in trace concentrations (
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows.
      ).
      Based on understandings derived from
      • Berry E.A.
      • Johnston W.T.
      • Hillerton J.E.
      Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.
      and
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows.
      regarding the random allocation and interdependence of quarters, we believe that the papers included in this meta-analysis have adequately addressed factors that may influence the validity of study designs.

       IMI

      A total of 12 studies with 17 subtrials, including 13 positive control subtrials and 4 negative control subtrials, on IMI were included in the analysis (Figure 1). Based on the considerations outlined above, the results are presented at the quarter level. The incidence of IMI reported includes the infected quarters that may have occurred during the dry period as well as those arising during and after calving. The use of internal teat sealants alone and in the presence of ADCT reduced the risk of acquiring new IMI after calving in lactating cows by 25% compared with the ADCT alone (RR = 0.75; 95% CI: 0.67 to 0.83).
      Figure thumbnail gr1
      Figure 1Forest plot of studies examining the risk of acquiring new IMI at the quarter level in lactating dairy cows treated with internal teat sealant compared with positive control (top) and negative control (bottom). Box sizes are proportional to the inverse variance of the estimates. Summary estimates of treatment effects (diamond shapes) are shown using (1) a fixed effects approach [M-H specifies a fixed effect model using the
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      method], (2) a random effects approach [D+L specifies a random effects model using the method of
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ], and (3) the predicted interval of a future trial, with the estimate of heterogeneity being taken from the inverse variance fixed effect model. RR = risk ratio; I2 = a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity. Color version available in the online PDF.
      Treatment of cows with internal teat sealant alone [except in the study of
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      , which was a combined treatment] reduced the risk of IMI by 73% of those in the untreated (negative control) cows (RR = 0.23; 95% CI: 0.13 to 0.55). The predictive interval estimates included 1.0 for the negative control studies (Figure 1), indicating that some null or negative responses to treatment with teat sealants may be observed in future studies.
      Overall pooling of the study approaches (i.e., use of internal teat sealants alone or in the presence of ADCT) reduced the risk of IMI by 39% compared with cows treated with ADCT (positive control) and untreated (negative control) cows (RR = 0.61; 95% CI: 0.51 to 0.72). However, given the marked differences in the pooled RR estimates between studies using teat sealants in the presence of ADCT and those without, we consider that the estimates of effect used in estimates of efficacy should be specific to whether teat sealant treatment is combined with ADCT or not.
      The results of both meta-analyses of IMI, with positive and negative controls, were heterogeneous (I2 = 65.4% and 92.1%; P < 0.001; Table 3). The sources of heterogeneity were explored, using the methods of
      • Knapp G.
      • Hartung J.
      Improved tests for a random-effects meta-regression with a single covariate.
      and
      • Harbord R.M.
      • Higgins J.P.T.
      Meta-regression in Stata.
      , using variables for which we had sufficient data, including presence or absence of antibiotic in the control group, type of antibiotics used in control groups, infection status of cows before treatment, and location (country) of study. None of these factors significantly contributed to the heterogeneity of the results. We were unable to explore the effect of housing and farming systems on the IMI outcomes because the individual studies that were included in the analysis had pooled data from different farming and feeding systems into a single point estimate. The heterogeneity of results is not of great concern because all these studies showed the same direction toward a reduction in IMI (RR <1). It is likely that differences in treatment protocols and the procedures used to detect the presence of IMI among studies contributed to the heterogeneity.
      The NNT for each cow to benefit from the intervention is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. For every 20 cows that were treated with the internal teat sealants in the presence of ADCT, 1 additional cow responded positively (i.e., did not have an IMI) to the combined treatment compared with ADCT treatment alone, whereas for every 7 cows that were treated with internal teat sealant in the presence of ADCT, the occurrence of 1 IMI was prevented compared with the untreated (negative control) cows.

       Clinical Mastitis

      A total of 16 studies with 21 subtrials, including 14 positive control subtrials and 7 negative control subtrials, on clinical mastitis up to 150 DIM were included in the analysis (Figure 2). The results were presented at both the quarter and cow levels. The incidence of clinical mastitis includes clinical cases that occurred at calving and during the first 100 to 150 DIM.
      Figure thumbnail gr2
      Figure 2Forest plot of studies examining the risk of clinical mastitis up to 150 DIM at the cow and quarter levels in lactating dairy cows treated with internal teat sealant compared with positive control (top) and negative control (bottom). Box sizes are proportional to the inverse variance of the estimates. Summary estimates of treatment effects (diamond shapes) are shown using (1) a fixed effects approach [M-H specifies a fixed effect model using the
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      method], (2) a random effects approach [D+L specifies a random effects model using the method of
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ], and (3) the predicted interval of a future trial, with the estimate of heterogeneity being taken from the inverse variance fixed effect model. RR = risk ratio; I2 = a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity. Color version available in the online PDF.
      The application of internal teat sealant products alone and in the presence of ADCT significantly reduced the risk of clinical mastitis after calving in lactating dairy cows (Table 3; P < 0.001). The use of internal teat sealants alone and in the presence of ADCT reduced the risk of clinical mastitis after calving in lactating cows by 29% compared with cows treated with ADCT alone (RR = 0.71; 95% CI: 0.62 to 0.82). Treatment of cows with internal teat sealants alone (Figure 3) reduced the risk of clinical mastitis by 48% (RR = 0.52; 95% CI: 0.37 to 0.75) compared with the untreated cows (negative control). Overall, the use of internal teat sealants alone or in the presence of ADCT reduced the risk of clinical mastitis after calving by 34% (RR = 0.66; 95% CI: 0.58 to 0.76; Table 3). Again, marked differences existed in the pooled RR estimates between studies using teat sealants in the presence of ADCT and those without. Therefore, estimates of effect used should be specific to whether teat sealant treatment is combined with ADCT or not. Both analyses (i.e., the negative and the studies combined with ADCT) of the effects of teat sealants on clinical mastitis had the predictive intervals that included 1.0 (Figure 2), indicating that some null or negative responses to treatment with teat sealants may be observed in future studies.
      Figure thumbnail gr3
      Figure 3Contour-enhanced funnel plots of risk of IMI for lactating dairy cows treated with internal teat sealants with and without antibiotic. Legend: levels of significance for studies (•) within the broken lines are 0.01, 0.05, and 0.10; FE = fixed effect.
      The results of meta-analysis on clinical mastitis with positive controls were homogeneous (I2 = 33.6%; P < 0.106), whereas the results of studies with negative controls were heterogeneous (I2 = 60.4%; P < 0.019), but the overall results were heterogeneous (I2 = 46.5%; P < 0.001). We explored the source of heterogeneity, using the methods of
      • Knapp G.
      • Hartung J.
      Improved tests for a random-effects meta-regression with a single covariate.
      and
      • Harbord R.M.
      • Higgins J.P.T.
      Meta-regression in Stata.
      , with the variables for which we had adequate data, including DIM, presence or absence of antibiotic in the control group, unit of treatment (quarters within cow vs. quarters between cows), type of antibiotic used in control groups, infection status of cows before treatment, and the location (country) where the study was conducted. None of these factors significantly contributed to the heterogeneity of the results.
      Two studies (
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      ;
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      ) differed from other studies in the direction of effect. These studies compared the internal teat sealants in the presence of cloxacillin versus cows treated with cefquinome or cloxacillin (
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      ) and the risk of clinical mastitis in the internal teat sealants in the presence of cloxacillin was greater than the cefquinome (Figure 3).
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      suggested that cows in the cefquinome group were less likely to develop clinical mastitis than those in the cloxacillin-treated group. In
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      , the unit of treatment was quarter within cow and the infected quarters within cows were allocated to the ADCT and combination of internal teat sealants and ADCT groups, whereas healthy quarters were allocated to negative and positive controls or internal teat sealants in the presence of ADCT. This difference in study design may explain the differences between the outcomes of their study compared with other studies. A sensitivity analysis was conducted by removing subtrial 2 of
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      , but little change occurred in the overall point estimate (RR = 0.65; 95% CI: 0.57, 0.75) and the results remained heterogeneous (I2 = 45.9%; P = 0.014).
      The NNT analysis indicated that we need to treat 21 cows with internal teat sealant + ADCT to prevent 1 case of clinical mastitis compared with ADCT alone. When comparing the internal teat sealants + ADCT versus negative control (untreated), 13 cows needed to be treated to prevent an additional case of mastitis.
      Sources of heterogeneity in these studies may include differences in the definition and diagnostic methods used for identifying clinical mastitis. Again, we could not explore the effects of housing and farming systems on clinical mastitis, because individual studies pooled data from different farming and feeding systems into a single point estimate.
      Although no robust statistical test exists to precisely quantify the presence or absence of publication bias in a meta-analysis, funnel plots are used to evaluate the presence or absence of publication bias. We used contour-enhanced plots to differentiate between the highly significant trails and the other studies as proposed by
      • Peters J.L.
      • Sutton A.J.
      • Jones D.R.
      • Abrams K.R.
      • Rushton L.
      Contour enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry.
      . The contour-enhanced funnel plots of IMI and clinical mastitis showed some evidence of publication bias (Figures 3 and 4). The probability of publication of studies with results showing a reduction in the number clinical mastitis cows in treatment group was greater than studies that reported an increase in the number of clinically mastitic cows. The point estimates on the very left side of the funnel plot may indicate highly significant reductions (P < 0.01) in the probability of IMI and clinical mastitis in dairy cows treated with teat sealant, rather than publication bias.
      Figure thumbnail gr4
      Figure 4Contour-enhanced funnel plots of risk of clinical mastitis for lactating dairy cows treated with internal teat sealants with and without antibiotic. Legend: levels of significant for studies (•) within the broken lines are 0.01, 0.05, and 0.10; FE = fixed effect.

       Milk SCC

      Three studies reported LS of milk SCC data after calving (
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      ;
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      ;
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      ).
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      demonstrated that quarters treated with Orbeseal and cloxacillin had a significantly lower mean LS at both 1 to 3 DIM and 6 to 8 DIM than control, cloxacillin only, quarters (Table 4; P < 0.001). An Australian study (
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      ) also showed that the mean LS for the cows treated with Teatseal and cloxacillin was significantly lower compared with cows treated with cloxacillin (Table 5; P < 0.001) after accounting for herd, age, milk production and SCC status in previous lactation. However,
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      found no significant reduction between ADCT and Teatseal and ADCT combined groups (Table 4; P = 0.11) across several herds.
      The analysis of pooled LS data, before and after controlling for LS at drying off, showed that no significant differences in LS existed between cows treated with internal teat sealants + ADCT versus ADCT alone. The interaction between LS at drying off and treatments was also not statistically significant. These limited data suggest that the effect of internal teat sealants + ADCT on postpartum milk SCC deserves further study.

      Conclusions

      The application of internal teat sealants with or without ADCT at dry off significantly reduced the incidence of IMI and clinical mastitis in lactating dairy cows. Further studies are needed to investigate the effect of internal teat sealants on milk SCC in lactating dairy cows after calving. Further clinical trials may provide further evidence of effects of treatment on this outcome.

      Acknowledgments

      This study was funded and supported by Zoetis (formerly Pfizer Animal Health, West Ryde, Australia) . We thank the authors of papers who generously provided their raw data and helped with the analysis of milk SCC data. The technical advice on the statistical analysis of SCC that was provided by Ian Dohoo (University of Prince Edward Island, Charlottetown, PE, Canada) is greatly appreciated.

      Appendix

      Table A1Definitions of IMI and clinical mastitis (CM) used by the study investigators
      ReferenceDefinitions of IMI and CM
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      The use of a cephalonium containing dry cow therapy and an internal teat sealant, both alone and in combination.
      ,
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      IMI: isolation of an organism was considered indicative of an IMI
      CM: farm personnel trained in the detection and sampling of CM throughout the study period (≤150 DIM)
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      IMI: new IMI was defined as the presence of a pathogen in the postcalving sample that had not been present at sampling at drying off
      CM: farm personnel trained in the detection and sampling of CM throughout the study period (≤150 DIM)
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      IMI: presence of clotted or discolored milk beyond the first 3 squirts of milk when the suspected quarter was hand stripped, or a hot or swollen quarter, or both
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      IMI: during the lactation (last 7 d) and after calving, milk samples were collected for bacteriological examination and detection of IMI
      CM: during the dry period, udder examination was conducted, which involved palpation of individual quarters to detect any difference in tissue firmness between adjacent quarters and hence the presence of clinical IMI; quarters determined to be clinically infected by palpation were sampled for bacteriological culture up to 150 DIM
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      Not provided
      • Berry E.A.
      • Hillerton J.E.
      The effect of an intramammary teat seal on new intramammary infections.
      ,
      • Berry E.A.
      • Hillerton J.E.
      Effect of an intramammary teat seal and dry cow antibiotic in relation to dry period length on postpartum mastitis.
      IMI: pathogen is isolated in 2 consecutive samples (2 out of 3 samples), or a pathogen obtained from 1 milk sample with elevated SCC in comparison with other quarter SCC
      CM: CM cases were detected by farm staff or at routine sampling time. These were defined when visible changes in the milk, such as watery milk, clots or flakes, or changes in the udder such as swelling or heat, were observed
      • Newton H.T.
      • Green M.J.
      • Benchaoui H.
      • Cracknell V.
      • Rowan T.
      • Bradley A.J.
      Comparison of the efficacy of cloxacillin alone and cloxacillin combined with an internal teat sealant for dry-cow therapy.
      CM: CM was defined as the presence of an abnormal secretion or udder changes, or both (heat pain or swelling, or both) as diagnosed by the herdsperson
      Clinical cases of mastitis were identified by herdspersons and milk samples were collected for bacteriological examination
      A minor pathogen was defined as either a coagulase-negative Staphylococcus species or a Corynebacterium species
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      IMI: new dry period infection: a significant isolate of an organism found in a quarter at the 1 to 3 DIM sample that was not present in the quarter sample at dry off
      Dry period cure: absence of an organism in a quarter at the 1 to 3 DIM sample that was present at dry off
      CM: quarter case of mastitis: a mastitis event in a single quarter; repeat cases occurring in the same quarter were considered a new clinical quarter case if the interval between events exceeded 7 d
      CM: cow case of mastitis: a cow suffering mastitis in 1 or more quarters at the same time; repeat cow cases were considered a new cow case if the interval between events exceeded 7 d
      • 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.
      Diagnosis, grading, and sampling of CM was conducted by trained herdspersons
      CM: CM quarter case: a single recorded occurrence of CM in a quarter, including all multiple quarter and recurrent cases; recurrent cases were classified as cases recurring in the same quarter greater than 5 d after the end of the last clinical episode and caused by the same pathogen
      CM: CM cow case: a cow experiencing a mastitis event, regardless of the number of quarters affected or the number of times each quarter was affected (if caused by the same pathogen)
      • Laven R.A.
      • Lawrence K.E.
      Efficacy of blanket treatment of cow and heifers with internal teat sealant reducing the risk of mastitis in dairy cattle calving on pasture.
      CM: diagnosis of CM was performed by a farmer and was based on the presence of clots in the milk, or of swelling, heat, or pain of the udder
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      CM: CM was defined as the presence of grossly visible changes (e.g., clots or blood) in the milk composition or swelling, pain, or both, in the gland; herd owners collected duplicate milk samples from glands diagnosed with CM
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      CM: CM was diagnosed by the herd owner based on the presence of visible changes (e.g., clots or discoloration) in the milk or swelling/pain in the gland
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      IMI: IMI was defined as isolation of any major mastitis-causing organism in conjunction with an SCC >200,000 cells/mL, or isolation of CNS (>10 cfu/0.01 mL of milk) in conjunction with an SCC >200,000 cells/mL
      CM: CM was defined as abnormal milk with or without signs of heat, redness, or swelling in the quarter and with or without clinical signs of systemic disease

      Izak, E., E. Castello, and G. Veneranda. 2011. Efficacy and economic benefit of an internal teat sealant during drought and rainy weather dry period on incidence of clinical mastitis. In 3rd International Symposium on Mastitis and Milk Quality, St. Louis, MO. American Association of Bovine Practitioners, Auburn, AL; and National Mastitis Council, Verona, WI.

      CM: CM was defined as the presence of visibly abnormal milk and (or) abnormal quarter or signs of systemic illness; isolates were identified according to the procedures of the National Mastitis Council (
      • Izak E.
      • Ackermann S.
      Prevalence and incidence of clinical mastitis at early lactation in dairy farms with low bulk tank somatic cell count in Argentina.
      )
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      CM: CM was defined as the presence of visibly abnormal milk (e.g., presence of clots, watery secretion) beyond the third forestripping, with or without signs of abnormality in the quarter or signs of systemic disease; following the clinical diagnosis, milk samples from the affected quarters were collected by producers
      Table A2Studies that investigated the effect of internal teat sealants (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) on the incidence of IMI and clinical mastitis during the dry period and after calving
      StudyCountryMilk sampling intervalDiagnosis description

      and procedures
      Housing/farming
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      The use of a cephalonium containing dry cow therapy and an internal teat sealant, both alone and in combination.
      United KingdomPrior to final milking and postcalvingBacteriological examination postcalving; clinical cases until 150 DIMFreestalls, covered straw yards, pasture
      • Bradley A.J.
      • Breen J.E.
      • Payne B.
      • Williams P.
      • Green M.J.
      A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant.
      United KingdomPrior to final milking and postcalvingBacteriological examination 2 wk precalving; clinical cases until 150 DIMFreestalls, covered straw yards, pasture (combination of all)
      • Runciman D.J.
      • Malmo J.
      • Deighton M.
      The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows.
      AustraliaPostcalving milk samples (d 21, 30, and 100)Clinical examination and then bacteriological tests of quartersPasture (n = 6)
      • Woolford M.W.
      • Williamson J.H.
      • Day A.M.
      • Copeman P.J.A.
      The prophylactic effect of a teat sealer on bovine mastitis during the dry period and the following lactation.
      New ZealandWithin 7 d of last lactation and within 24 h after calvingClinical examination and bacteriological testsPasture (n = 3)
      • Godden S.
      • Rapnicki P.
      • Stewart S.
      • Fetrow A.
      • Johnson A.
      • Bey R.
      • Farnsworth R.
      Effectiveness of an internal teat seal in the prevention of new intramammary infections during the dry and early-lactation periods in dairy cows when used with a dry cow intramammary antibiotic.
      United StatesImmediately before final milking, 1 to 3 DIM and 6 to 8 DIMBacteriological tests at dry off, dry off and 1 to 3 DIM, dry off and 6 and 8 DIM, and then up to 60 DIMPaddock (grazing) before dry off, and then freestall during experiment (n = 2)
      • Berry E.A.
      • Hillerton J.E.
      The effect of an intramammary teat seal on new intramammary infections.
      United KingdomOne week before drying off, at drying off, at calving, and 1 wk after calvingBacteriological tests at 1 wk before dry off, at dry off, at calving, 7 DIM, and clinical observation by farm staff until 150 DIMOrganic farms (n = 2) and research farms (n = 2)
      • Berry E.A.
      • Johnston W.T.
      • Hillerton J.E.
      Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.
      United KingdomOne week before drying off, at drying off, at calving, and 1 wk after calvingBacteriological tests at 1 wk before dry off, at dry off, at calving, 7 DIM, and clinical observation by farm staff until 150 DIMResearch farm (n = 1)
      • Newton H.T.
      • Green M.J.
      • Benchaoui H.
      • Cracknell V.
      • Rowan T.
      • Bradley A.J.
      Comparison of the efficacy of cloxacillin alone and cloxacillin combined with an internal teat sealant for dry-cow therapy.
      United KingdomTwo days before drying off, 1 d before drying off, at drying off, 4 d after calving, and 8 to 11 d after calvingBacteriological tests at 2 d before drying off, 1 d before drying off, on the day of drying off, 4 DIM, and between 8 and 10 DIM
      • Cook N.B.
      • Pionek D.A.
      • Sharp P.
      An assessment of the benefits of Orbeseal® when used in combination with dry cow antibiotic therapy in three commercial dairy herds.
      USAPrior to drying off and within 3 d of calvingBacteriological tests at dry off, within 3 d of calving, and on clinical cases up to 150 DIMFreestall (rubber matt = 1; sand bedded = 1; straw bedded = 1)
      • 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.
      United KingdomPrior to drying off and after calving before the first machine milkingBacteriological tests at dry off, after calving, and before first milkingPasture (summer) and covered stalls (winter)
      • Laven R.A.
      • Lawrence K.E.
      Efficacy of blanket treatment of cow and heifers with internal teat sealant reducing the risk of mastitis in dairy cattle calving on pasture.
      New ZealandNot providedClinical diagnosis by farmerGrazing (n = 1)
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougall S.
      Subclinical and clinical mastitis in heifers following the use of a teat sealant precalving.
      New ZealandPrior to treatment and within 4 d of calvingBacteriological tests at 31 d before calving start date, 4 DIM, and clinical diagnosis from calving to 14 DIMGrazing (n = 5)
      • Parker K.I.
      • Compton C.
      • Anniss F.M.
      • Weir A.
      • Heuer C.
      • McDougll S.
      Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.
      New ZealandPrior to treatment and within 5 d of calvingBacteriological tests at 31 d before calving start date, and clinical diagnosis from calving to 14 DIMGrazing (n = 30)
      • Sanford C.J.
      • Keefe G.P.
      • Dohoo I.R.
      • Leslie K.E.
      • Dingwell R.T.
      • DesCôteaux L.
      • Barkema H.W.
      Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle.
      CanadaTwo weeks before calving and within 8 d after calvingBacteriological tests at 14 d before dry off, end of lactation, within 8 DIM, and 60 DIM on cows with clinical signsFreestall (n = 8); tie-stall (n = 8)

      Izak, E., E. Castello, and G. Veneranda. 2011. Efficacy and economic benefit of an internal teat sealant during drought and rainy weather dry period on incidence of clinical mastitis. In 3rd International Symposium on Mastitis and Milk Quality, St. Louis, MO. American Association of Bovine Practitioners, Auburn, AL; and National Mastitis Council, Verona, WI.

      ; abstract)
      ArgentinaNot providedBacteriological tests from calving to 10 DIM and at 150 DIM
      • Baillargeon P.
      • LeBlanc S.J.
      Clinical and economic effects of an internal teat sealant at dry-off on the incidence of clinical mastitis in early lactation.
      CanadaPostcalving mastitic cows were sampledBacteriological tests on clinical mastitis cases up to 105 DIMFreestall (n = 7); tie-stall (n = 5)

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