Carrie K. McMullen - UG ETD Template - University of Guelph

Antimicrobial dry cow therapy and modifiable management in dry dairy cows

to cure existing intramammary infections and improve udder health

by

Carrie K. McMullen

A Thesis

presented to

The University of Guelph

In partial fulfilment of requirements

for the degree of

Master of Science

in

Population Medicine

Guelph, Ontario, Canada

© Carrie K. McMullen, September 2020

ABSTRACT

ANITMICROBIAL DRY COW THERAPY AND MODIFIABLE MANAGEMENT IN

DRY DAIRY COWS TO CURE EXISTING INTRAMAMMARY INFECTIONS AND

IMPROVE UDDER HEALTH

Carrie K. McMullen Advisors:

University of Guelph, 2020 Professor C. B. Winder

Professor J. M. Sargeant

Proper management of dry cows is essential to promote good udder health during the dry

period following lactation. The most common form of dry cow management is administration of

antimicrobials at dry off to cure existing intramammary infections (IMI) and prevent the

occurrence of new IMI. We conducted a systematic literature review and network meta-analysis

to compare multiple antimicrobial options at dry-off for effectiveness to cure existing

intramammary infections in dairy cattle. Further, we utilized scoping review methods to identify

and describe modifiable dry cow management factors that potentially may be used in replacement

of, or in addition to, antimicrobial dry cow therapy. Findings suggest improved reporting of

studies, along with consistency in the selection of risk periods for outcome assessment in dairy

trials, would enable more useful synthesis work. Potential management areas for future knowledge

synthesis methods include mastitis vaccines, dry cow nutrition, and dry period lengths.

iii

ACKNOWLEDGEMENTS

The African proverb “It takes a village to raise a child” is a fitting quote to begin to

acknowledge the guidance I’ve received throughout my master’s degree – because it truly does

take a village to write a thesis. Thank you to my advisors, Drs. Charlotte Winder and Jan Sargeant,

for your support. You have both shared your wealth of knowledge with me, for which I am truly

grateful. To my committee member, Dr. David Kelton, for your support and expertise throughout

the many navigations of this research and manuscript drafts. Special thanks to the other professors

and students at the University of Guelph, Iowa State University, and Michigan State University

for making this experience so memorable and my thesis a product of which I am so proud.

To my roommates, Clara Sankey and Dima Ayache, for the endless cheerleading when the

end did not feel so near. You’ve reminded me that getting through graduate school in the midst of

a pandemic is about doing my best for that day, even if that did not compare to my most proficient

of days. To my book club gals and other friends at the University of Guelph, who have kept the

laughs coming and the good times rolling. So thankful graduate school brought me all of you.

To my family for always being in my corner. You have always been proud of me, and the

support you have given through all, successes and failures, has allowed me to pave my way and I

strongly believe my success as a graduate student can be owed to that.

“Intelligence plus character – that is the goal of true education.”

– Martin Luther King Jr.

Being a part of the Department of Population Medicine has deepened my understanding as

an epidemiologist and has most certainly molded my character in such a positive way. I am truly

richer as a person, student, and professional because of those who have crossed my path over the

past two years.

iv

STATEMENT OF WORK

Stipend funding support was obtained from the Ontario Veterinary College and the

Ministry of Training, Colleges and Universities, and graciously provided by the donors of the Dr.

Francis H. S. Newbould Scholarship, the Dr. Casey Buizert Memorial Award, the Dr. R. A.

McIntosh Graduate Award (OVC ’45), and the Barbara Kell Gonsalves Memorial Scholarship.

Research studies were designed by Charlotte B. Winder, Jan M. Sargeant, David F. Kelton, and

Carrie K. McMullen. Literature search strategies were developed and utilized by Julie Glanville

and Hannah Wood (Chapter 2) and Carrie K. McMullen (Chapter 3). Data screening, data

extraction, and risk of bias assessment were conducted by Carrie K. McMullen, Charlotte B.

Winder, Jan M. Sargeant, and Cassie N. Reedman (Chapter 2), and by Carrie K. McMullen,

Charlotte B. Winder, Kineta Cousins, and Katheryn J. Churchill (Chapter 3). The statistical

analysis R code was developed by Dapeng Hu (Chapter 2), and all statistical analyses were

conducted by Carrie K. McMullen. Annette M. O’Connor provided her expertise and support in

the analyses of Chapter 2. This thesis was prepared by Carrie K. McMullen, with comments and

approval from Charlotte B. Winder, Jan M. Sargeant, and David F. Kelton.

v

TABLE OF CONTENTS

Abstract .......................................................................................................................................... ii

Acknowledgements ...................................................................................................................... iii

Statement of Work ....................................................................................................................... iv

Table of Contents .......................................................................................................................... v

List of Tables ................................................................................................................................. x

List of Figures ............................................................................................................................. xiii

List of Abbreviations ................................................................................................................. xvi

List of Appendices ..................................................................................................................... xvii

1 CHAPTER 1: INTRODUCTION, LITERATURE REVIEW, STUDY RATIONALE . 1

1.0 INTRODUCTION .......................................................................................................... 1

1.1 PRODUCTION, ECONOMIC, AND WELFARE CONCERNS................................... 3

1.2 ANTIMICROBIAL DRY COW THERAPY ................................................................. 5

1.3 DRY COW MANAGEMENT ........................................................................................ 7

1.4 KNOWLEDGE SYNTHESIS ........................................................................................ 8

1.5 THESIS OVERVIEW, PURPOSE, AND OBJECTIVES ............................................ 13

1.6 REFERENCES ............................................................................................................. 14

2 CHAPTER 2: RELATIVE EFFICACY OF ANTIMICROBIAL DRY COW

THERAPY TO CURE EXISTING INTRAMAMMARY INFECTIONS DURING THE

DRY PERIOD: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS ........ 24

2.1 ABSTRACT .................................................................................................................. 24

2.2 INTRODUCTION ........................................................................................................ 25

2.2.1 Rationale ............................................................................................................... 25

2.2.2 Objectives ............................................................................................................. 26

vi

2.3 METHODS ................................................................................................................... 26

2.3.1 Protocol and registration ....................................................................................... 26

2.3.2 Eligibility criteria .................................................................................................. 27

2.3.3 Information Sources .............................................................................................. 27

2.3.4 Search .................................................................................................................... 28

2.3.5 Study selection ...................................................................................................... 28

2.3.6 Data collection process ......................................................................................... 29

2.3.7 Data items ............................................................................................................. 29

2.3.8 Geometry of the network ...................................................................................... 30

2.3.9 Risk of bias within individual studies ................................................................... 31

2.3.10 Summary measures ............................................................................................... 32

2.3.11 Network meta-analysis.......................................................................................... 32

2.3.12 Assessment of consistency .................................................................................... 34

2.3.13 Risk of bias in overall network ............................................................................. 34

2.3.14 Additional analyses ............................................................................................... 35

2.4 RESULTS ..................................................................................................................... 36

2.4.1 Study selection ...................................................................................................... 36

2.4.2 Study characteristics ............................................................................................. 36

2.4.3 Risk of bias within individual studies – cure of IMI from dry-off to calving ...... 37

2.4.4 Results of individual studies ................................................................................. 38

2.4.5 Quantitative summary ........................................................................................... 38

2.4.6 Network meta-analysis: all-cause cure of existing IMI from dry-off to calving .. 39

2.4.7 Summary of network geometry ............................................................................ 39

2.4.8 Assessment of consistency .................................................................................... 39

vii

2.4.9 Rankings and distribution probability of IMI at calving ...................................... 40

2.4.10 Risk of bias across studies .................................................................................... 40

2.4.11 Results of additional analyses ............................................................................... 41

2.5 DISCUSSION ............................................................................................................... 42

2.5.1 Summary of evidence ........................................................................................... 42

2.5.2 Limitations of the body of literature ..................................................................... 44

2.5.3 Limitations of the review ...................................................................................... 46

2.6 CONCLUSION ............................................................................................................. 47

2.6.1 Protocol deviations................................................................................................ 47

2.6.2 Author contributions ............................................................................................. 48

2.6.3 Acknowledgements and funding........................................................................... 48

2.6.4 Conflicts of interest ............................................................................................... 48

2.7 REFERENCES ............................................................................................................. 49

2.8 TABLES ....................................................................................................................... 55

2.9 FIGURES ...................................................................................................................... 65

3 CHAPTER 3: MODIFIABLE MANAGEMENT PRACTICES TO IMPROVE

UDDER HEALTH DURING THE DRY PERIOD AND SUBSEQUENT LACTATION: A

SCOPING REVIEW ................................................................................................................... 78

3.1 ABSTRACT .................................................................................................................. 78

3.2 INTRODUCTION ........................................................................................................ 79

3.2.1 Rationale ............................................................................................................... 79

3.2.2 Objectives ............................................................................................................. 81

3.3 METHODS ................................................................................................................... 81

3.3.1 Protocol and registration ....................................................................................... 81

3.3.2 Eligibility criteria .................................................................................................. 81

viii

3.3.3 Information sources .............................................................................................. 82

3.3.4 Search .................................................................................................................... 83

3.3.5 Selecting sources of evidence ............................................................................... 83

3.3.6 Data charting process ............................................................................................ 84

3.3.7 Data items ............................................................................................................. 84

3.3.8 Synthesis of results ............................................................................................... 85

3.4 RESULTS ..................................................................................................................... 85

3.4.1 Selection of sources of evidence ........................................................................... 85

3.4.2 Characteristics of sources of evidence .................................................................. 86

3.4.3 Synthesis of results ............................................................................................... 86

3.5 DISCUSSION ............................................................................................................... 92

3.5.1 Summary of evidence ........................................................................................... 92

3.5.2 Limitations of the body of evidence ..................................................................... 95

3.5.3 Limitations of this review ..................................................................................... 97

3.6 CONCLUSION ............................................................................................................. 98

3.6.1 Protocol deviations................................................................................................ 99

3.6.2 Author contributions ............................................................................................. 99

3.6.3 Acknowledgements and funding........................................................................... 99

3.6.4 Conflicts of interest ............................................................................................... 99

3.7 REFERENCES ............................................................................................................. 99

3.8 TABLES ..................................................................................................................... 107

3.9 FIGURES .................................................................................................................... 161

4 CHAPTER 4: CONCLUSION......................................................................................... 165

4.1 GENERAL CONCLUSIONS AND FUTURE DIRECTIONS .................................. 165

ix

4.2 REFERENCES ........................................................................................................... 170

Appendices ................................................................................................................................. 173

x

LIST OF TABLES

Table 2.1 Search strategy to identify relevant articles for the network meta-analysis assessing the

relative efficacy of antimicrobial protocols for cure of existing intramammary infections during

the dry period in dairy cattle, conducted on June 14, 2019 in Science Citation Index (Web of

Science) ......................................................................................................................................... 55

Table 2.2 Currently labelled antimicrobial products for intramammary use in dairy cattle at dry-

off to cure existing intramammary infections in Canada and the United States of America (August,

2020) ............................................................................................................................................. 57

Table 2.3 Description of treatment arms included in the network meta-analysis assessing the

relative efficacy of antimicrobial dry cow products for cure of existing intramammary infections,

and the corresponding tables and figures ...................................................................................... 58

Table 2.4 (Full network) The probability of currently labelled antimicrobial treatment protocols

for ranking the best and worst treatment for cure of existing intramammary infections within the

full network meta-analysis ............................................................................................................ 59

Table 2.5 (Full network) Mean rank for currently labelled treatment arms in the full network meta-

analysis of antimicrobial protocols to cure existing intramammary infections during the dry period.

A lower mean rank score indicates a high estimated cure risk, for a possible score between 1 and

40................................................................................................................................................... 60

Table 2.6 (Full network) Summary of the overall quality of evidence of the network meta-analysis

assessing the relative efficacy of currently labelled dry-off antimicrobial protocols for cure of

existing intramammary infections during the dry period in dairy cattle, using the Confidence In

Network Meta-Analysis (CINeMA) platform, with some modifications, to determine the risk of

bias due to approach to randomization, blinding, imprecision, and heterogeneity ....................... 61

Table 2.7 (Post-1990 analysis) Mean rank for currently labelled treatment arms in the network

meta-analysis of antimicrobial protocols to cure existing intramammary infections during the dry

period, for trials published 1990 – 2019. A lower mean rank score indicates a high estimated cure

risk, for a possible score between 1 and 31 .................................................................................. 64

Table 3.1 Search strategy to identify relevant articles for the scoping review pertaining to

modifiable management practices implemented at drying off to improve udder health in dairy

cattle, published between 1990 to present, conducted in CAB Abstracts (via CABI) on January 7,

2020............................................................................................................................................. 107

Table 3.2 Article title and author information for 15 relevant journal articles to check for inclusion

in the search in order to validate the search strategy. All articles were identified by the search.

..................................................................................................................................................... 109

xi

Table 3.3 Author and descriptive information for vaccination as a management practice

implemented at drying off to improve udder health outcomes in dairy cattle, with corresponding

risk periods of outcome measurement during the dry period and post-calving. ......................... 111

Table 3.4 Author and descriptive information for non-antimicrobial intramammary (IMM) and

intramuscular (IM) products as a management practice implemented at drying off to improve udder

health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during

the dry period and post-calving................................................................................................... 118

Table 3.5 Author and descriptive information for vitamin and mineral injections as a management

practice implemented at drying off to improve udder health outcomes in dairy cattle, with

corresponding risk periods of outcome measurement during the dry period and post-calving. . 121

Table 3.6 Author and descriptive information for vitamins and minerals in feed as a management



Table 3.7 Author and descriptive information for ration formulation and delivery as a management



Table 3.8 Author and descriptive information for dry period (DP) length as a management practice

implemented at drying off to improve udder health outcomes in dairy cattle, with corresponding

risk periods of outcome measurement during the dry period and post-calving. ......................... 137

Table 3.9 Author and descriptive information for dry period length as a management practice

included as a covariate in regression modeling, with corresponding risk periods of outcome

measurement during the dry period and post-calving. Dry period length was included in trial

models to adjust for residual confounding not controlled for by allocation to treatment groups.

..................................................................................................................................................... 142

Table 3.10 Author and descriptive information for housing, pasture, bedding, and bedding

management as a management practice implemented at drying off to improve udder health

outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry

period and post-calving. .............................................................................................................. 144

Table 3.11 Author and descriptive information for milking frequency prior to drying off (DO) as

a management practice implemented to improve udder health outcomes in dairy cattle, with


Table 3.12 Author and descriptive information for reduced milk yield at drying off (DO) as a

management practice implemented to improve udder health outcomes in dairy cattle, with


Table 3.13 Author and descriptive information for reduced milk yield at drying off (DO) as a

management practice included as a covariate in regression modeling, with corresponding risk

xii

periods of outcome measurement during the dry period and post-calving. Milk yield at drying off

was included in trial models to adjust for residual confounding not controlled for by allocation to

treatment groups.......................................................................................................................... 155

Table 3.14 Author and descriptive information for bovine somatotropin (bST) administered over

the dry period as a management practice implemented to improve udder health outcomes in dairy

cattle, with corresponding risk periods of outcome measurement during the dry period and post-

calving. ........................................................................................................................................ 156

Table 3.15 Author and descriptive information for management practices not included in other

categories as a practice implemented at drying off to improve udder health outcomes in dairy cattle,

with corresponding risk periods of outcome measurement during the dry period and post-calving.

..................................................................................................................................................... 157

xiii

LIST OF FIGURES

Figure 2.1 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow

diagram of included studies and trials for the systematic review of dry-off antimicrobials to cure

existing intramammary infections in dairy cattle (Moher et al., 2009). The search, conducted by

researchers at the University of York, provided an update to a search used to identify articles for a

previous systematic review and network meta-analysis (Winder et al., 2019a) ........................... 65

Figure 2.2 (Full network) Network plot assessing the efficacy of dry-cow antimicrobials, non-

antimicrobial products, or placebos for all-cause cure of intramammary infections in dairy cattle.

This plot contains 58 trials, with the number of treatment comparisons provided in parentheses.

Non-active control had the most treatment comparisons (30 arms). Node size represents the

number of times each treatment was used. Edge size represents the number of direct comparisons

made between two treatment protocols. NAC = non-active control, Cx = cloxacillin, Cxext =

cloxacillin-extended therapy, CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA =

non-antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-

extended therapy, B = ceftiofur, C = cefapyrin, P = penicillin, PNv = penicillin-novobiocin, TS =

teat sealant ..................................................................................................................................... 66

Figure 2.3 (Post-1990 analysis) Network plot assessing the relative efficacy of dry-cow

antimicrobials, non-antimicrobial products, or placebos for all-cause cure of intramammary

infections in dairy cattle from trials published between 1990 - 2019. This plot contains 30 trials,

with the number of treatment comparisons provided in parentheses. Non-active control had the

most treatment comparisons (14 arms). Node size represents the number of times each treatment

was used. Edge size represents the number of direct comparisons made between two treatment

protocols. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxH

= cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-aminoglycosides,

PSext = penicillin-streptomycin-extended therapy, B = ceftiofur, C = cefapyrin, PNv = penicillin-

novobiocin, TS = teat sealant ........................................................................................................ 67

Figure 2.4 (Full network) Relative risk ratios of currently labelled antimicrobial protocols assessed

in the network for all-cause cure of existing intramammary infections during the dry period. The

upper right-hand side of the matrix indicates the RR of row treatment compared to column

treatment (i.e. the risk of experiencing a cure with non-active control is 0.46 times the risk of

experiencing a cure with cloxacillin). The lower left-hand side of the matrix indicates the 95%

credibility intervals for each RR. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-

extended therapy, CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-

antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-


teat sealant ..................................................................................................................................... 68

Figure 2.5 a-c (Full network) Probability distribution of experiencing an all-cause cure of existing

intramammary infections during the dry period using currently labelled antimicrobial treatment

protocols. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxL

= cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam =

xiv

penicillin-aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B = ceftiofur, C =

cefapyrin, P = penicillin, PNv = penicillin-novobiocin, TS = teat sealant ................................... 69

Figure 2.6 (Full network) Forest plot of mean treatment rank for currently labelled treatment

protocols to cure existing intramammary infections during the dry period. The black squares

indicate the mean rank of each treatment and its size reflects the precision (1/variance) of the

estimate. Values are reported as mean treatment rank with corresponding 95% credibility interval.

The number of treatment comparisons are provided in parentheses beside the treatment names.

NAC = non-active control, TS = teat sealant, NonA = non-antimicrobial therapy, P = penicillin,

Pam = penicillin-aminoglycosides, C = cefapyrin, B = ceftiofur, PNv = penicillin-novobiocin, Cx

= cloxacillin, CxH = cloxacillin-high dose, CxL = cloxacillin-low dose, PSext = penicillin-

streptomycin-extended therapy, Cxext = cloxacillin-extended therapy ....................................... 70

Figure 2.7 (Full network) The contribution of trials to the point estimate of currently labelled

antimicrobial products based on the description of randomization for trials contributing to the

network meta-analysis assessing the relative efficacy of dry-off antimicrobial protocols to cure

existing intramammary infections during the dry period in dairy cattle (n=58). Grey indicates

allocation concealment was employed, random allocation to treatment groups and a method of

sequence generation were reported, and there were no baseline imbalances between treatment

groups. White indicates allocation concealment was employed, but participants were allocated

using a non-random sequence; or allocation concealment was employed, and random allocation

was reported but no details were provided on the method of sequence generation, regardless of

baseline imbalances; or allocation concealment was employed, and random allocation with a

method for sequence generation were reported, but baseline imbalances between treatment groups

were reported; or no information on allocation concealment was reported and either no or no

information on baseline imbalances between treatment groups were reported, regardless of random

allocation. Black indicates no information was reported for allocation concealment, and there were

baseline imbalances between treatment groups, or allocation concealment was not employed,

regardless of random allocation. White vertical lines indicate the percentage of contribution of

separate trials. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy,

CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam

= penicillin-aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B = ceftiofur, C

= cefapyrin, P = penicillin, PNv = penicillin-novobiocin, TS = teat sealant ................................ 71


antimicrobial products based on the description of blinding of caregivers for trials contributing to

the network meta-analysis assessing the relative efficacy of dry-off antimicrobial protocols for

cure of existing intramammary infections during the dry period in dairy cattle (n=58). Grey

indicates blinding of caregivers was used, white indicates no information for blinding of

caregivers, and black indicates blinding of caregivers was not used. White vertical lines indicate

the percentage of contribution of separate trials. NAC = non-active control, Cx = cloxacillin, Cxext

= cloxacillin-extended therapy, CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA

= non-antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-


teat sealant ..................................................................................................................................... 73

xv

Figure 2.9 (Post-1990 analysis) Relative risk ratios of currently labelled antimicrobial protocols

included in the network for cure of intramammary infections during the dry-period from trials

published between 1990 – 2019. The upper right-hand side of the matrix indicates the RR of row

treatment compared to column treatment (i.e. the risk of experiencing a cure with non-active

control is 0.44 times the risk of experiencing a cure using cloxacillin). The lower left-hand side of

the matrix indicates the 95% credibility intervals for each RR. NAC = non-active control, Cx =

cloxacillin, Cxext = cloxacillin-extended therapy, NonA = non-antimicrobial therapy, CxH =

cloxacillin-high dose, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-

extended therapy, B = ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin ............................. 75

Figure 2.10 a-c (Post-1990 analysis) Probability distribution of experiencing a cure of


protocols for trials published between 1990 – 2019. NAC = non-active control, Cx = cloxacillin,

Cxext = cloxacillin-extended therapy, CxH = cloxacillin-high dose, NonA = non-antimicrobial

therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B

= ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin, TS = teat sealant ................................. 76

Figure 2.11 (Post-1990 analysis) Forest plot of mean treatment rank 1990 – 2019 for currently

labelled antimicrobial treatments to cure existing intramammary infections during the dry-period.

The black squares indicate the mean rank of each treatment and its size reflects the precision

(1/variance) of the estimate. Values are reported as mean treatment rank with corresponding 95%

credibility interval. The number of treatment comparisons are provided in parentheses beside the

treatment names. NAC = non-active control, TS = teat sealant, NonA = non-antimicrobial therapy,

C = cefapyrin, Pam = penicillin-aminoglycosides, B = ceftiofur, PNv = penicillin-novobiocin, CxH

= cloxacillin-high dose, PSext = penicillin-streptomycin-extended therapy, Cx = cloxacillin, Cxext

= cloxacillin-extended therapy ...................................................................................................... 77


diagram of included studies for the scoping review of modifiable management practices

implemented at dry off to improve udder health outcomes (Moher et al., 2009) ....................... 161

Figure 3.2 Number of articles by year of publication included in the scoping review for modifiable

management practices implemented at drying off to improve udder health (n=229) ................. 162

Figure 3.3 Map of the number of articles by country included in the scoping review characterizing

modifiable management practices that have been assessed for their effect on udder health (1990 to

2020). Eligible articles (n=229) were conducted in 39 countries, the majority in the USA (n=84),

Canada (n=19), and the United Kingdom (n=13). Darker shades of blue indicate a larger number

of studies ..................................................................................................................................... 163

Figure 3.4 Number of publications that reported clinical mastitis outcomes, ordered by number of

publications per risk period evaluated in the study (n=151) ....................................................... 164

xvi

LIST OF ABBREVIATIONS

ADCT Antimicrobial dry cow therapy

ADD Animal daily dosages

AMU Antimicrobial use

BDCT Blanket dry cow therapy (treatment of all quarters

of a cow regardless of infection status)

BMSCC Bulk tank milk somatic cell count

bST Bovine somatotropin

CAD Canadian dollars

CFU Colony forming units

CI Credibility interval

CM Clinical mastitis

CMT California Mastitis Test

DIM Days in milk

DP Dry period

IMI Intramammary infection(s)

OIE World Organisation for Animal Health

RCT Randomized controlled trial(s)

REFLECT Reporting guidelines for randomized controlled

trials in livestock and food safety

RR Relative risk

SCC Somatic cell count

SDCT Selective dry cow therapy (treatment is based on

the presence of an infection at the quarter- or

cow-level)

STROBE-Vet Strengthening the reporting of observational

studies in epidemiology - veterinary

TS Teat sealant

WHO World Health Organization

xvii

LIST OF APPENDICES

Appendix 1 Descriptive statistics for articles included in the network meta-analysis assessing the

relative efficacy of antimicrobial dry cow therapy products to cure existing intramammary

infections during the dry period, listed in alphabetical order of author name ............................ 173

Appendix 2 Description of treatment arms from trials included in the systematic review and

network meta-analysis assessing the relative efficacy of antimicrobial dry cow therapy products to

cure existing intramammary infections in dairy cattle during the dry period. Treatment

combinations were made in consultation with experts and based on biological and clinical

relevancy of antimicrobial products to veterinarians and dairy producers, and on the World

Organisation for Animal Health List of Antimicrobials of Veterinary Importance (World

Organization for Animal Health, 2007) ...................................................................................... 180

Appendix 3 (Full network) History plot of basic parameters included in the network meta-analysis

assessing the relative efficacy of antimicrobial dry cow products for cure of existing intramammary

infections in dairy cattle during the dry period. This plot shows convergence of all basic parameters

(n=40) over 10,000 iterations; d[1] is the log odds ratio of non-active control to non-active control,

therefore is always 0 ................................................................................................................... 187

Appendix 4 (Full network) Direct (dir) and indirect (rest) comparisons for the consistency

assumption of pairwise comparisons within the network meta-analysis assessing the efficacy of

currently labelled antimicrobial protocols for cure of existing intramammary infections in dairy

cattle during the dry period. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-




teat sealant ................................................................................................................................... 188

Appendix 5 (Post-1990 analysis) Direct (dir) and indirect (rest) comparisons for the consistency

assumption of pairwise comparisons within the network meta-analysis assessing the efficacy of

currently labelled antimicrobial protocols for cure of existing intramammary infections in dairy

cattle during the dry period from trials published between 1990 – 2019. NAC = non-active control,

Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxH = cloxacillin-high dose, NonA = non-


extended therapy, B = ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin, TS = teat sealant

..................................................................................................................................................... 191

Appendix 6 Bibliography of included studies in the systematic literature review and network meta-

analysis assessing the relative efficacy of dry off antimicrobial products for cure of existing

intramammary infections in dairy cattle during the dry period .................................................. 194

Appendix 7 Bibliography of included studies in the scoping review characterizing modifiable

management strategies that have been assessed to have an effect on udder health .................... 199

1

1 CHAPTER 1: INTRODUCTION, LITERATURE REVIEW,

STUDY RATIONALE

1.0 INTRODUCTION

Mastitis remains one of the most economically costly diseases for dairy producers (Geary et

al., 2012), and is characterized by inflammation of one or more quarters of the mammary gland,

typically caused by infectious microorganisms (NMC, 2012). Clinical mastitis is diagnosed on the

basis of visual observation of abnormal milk or physical examination of the udder for heat, pain,

swelling and redness, whereas subclinical mastitis lacks visible changes to the milk and quarter,

and inflammation is detected via milk samples (i.e. high somatic cell count (SCC) or California

Mastitis Test (CMT)) (NMC, 2012). Intramammary infections (IMI) are subclinical infections

occurring in the secretory tissue or the ducts and tubules of the mammary gland that require a

bacterial culture of milk samples for diagnosis (NMC, 2012). The presence of IMI in a dairy herd

significantly increase the risk of clinical mastitis cases, especially during the peripartum period

(Beaudeau et al., 2002; Compton et al., 2007).

In order to appropriately control and prevent new IMI, mastitis-causing bacteria are often

divided into two groups: contagious and environmental pathogens (NMC, 1997). Contagious

pathogens live on the udder skin and multiply inside infected quarters, enabling spread through

contaminated milking equipment and via milking attendants (NMC, n.d.a). Major contagious

pathogens are Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus

agalactiae and Mycoplasma bovis, which typically cause subclinical mastitis as indicated by an

increased SCC (NMC, n.d.a). Environmental bacteria grow within bedding, manure, grass and

water and multiply on udder tissue which may make these types of infections difficult to eliminate

(NMC, 1997). Major environmental pathogens are coliforms, Escherichia coli, Klebsiella spp.,

Streptococcus uberis and Streptococcus dysgalactiae, which typically lead to clinical mastitis if

left untreated (NMC, 1997). Green et al. (2002) found the presence of an IMI caused by S.

dysgalactiae, S. uberis, Corynebacterium spp., E. coli, S. faecalis and Enterobacter spp. at drying

off significantly increased the probability of clinical mastitis in the subsequent lactation.

2

Prevention and treatment of intramammary infections is essential to minimize the impact of both

clinical mastitis and IMI on productivity and animal welfare.

Treatment decisions for cure of intramammary infections and clinical mastitis benefit from

culture of milk samples to confirm the presence of pathogens and determine appropriate pathogen

antimicrobial therapy (if any). The National Mastitis Council recommends considering a quarter

infected when two out of three milk samples yield the same culture results, or when a single sample

has ≥10 colony forming units per microliter of milk (NMC, 2012). Although triplicate samples are

the gold standard for evaluating the presence of pathogens (Dohoo et al., 2011), within the

scientific literature there is variation in the definition of what constitutes a positive sample. Dohoo

et al. (2011) assessed the effectiveness of diagnosing an IMI using culture results of a single milk

sample based on the number of colony forming units (CFU) in a sample, if the sample was pure or

mixed culture, and the sample SCC. An infection was best defined by ≥100 cfu/mL in a milk

sample with mixed growth and no minimum SCC (Dohoo et al., 2011). Maximum sensitivity (the

ability of a test to correctly classify an infected sample as positive) and specificity (the ability of a

test to correctly classify an uninfected sample as negative) was achieved by using three consecutive

samples taken one week apart for determination of CFU, and culture results from the middle

samples (Dohoo et al., 2011).

Composite milk samples, which are pooled milk samples from all four quarters within a

cow, are another common method for determining the presence of pathogens, and are a less costly

sampling method as only one sample is taken per cow. Reyher and Dohoo (2011) reported an

increased sensitivity of a composite milk sample to correctly classify a cow as infected when the

number of infected quarters within the sample increased. Although potentially more practical, lack

of optimal sensitivity of a composite milk sample test leaves a cow susceptible to an undetected

quarter infection that could increase the risk of clinical mastitis.

The use of bacteriologic culture of milk samples to determine IMI is the most common

type of diagnostic used in the scientific literature, however, some studies also report the use of an

SCC cut point to diagnose IMI. Somatic cell count cut points such as ≥200,000 cells/mL (Jiménez

3

& Romero, 2011; Madouasse et al., 2012; van Hoeij et al., 2016), or ≥250,000 cells/mL (Shoshani

et al., 2014) are commonly used to define an IMI at dry off and post-calving. High SCC in heifers

is commonly defined using a lower cut-point (i.e. >150,000 cells/mL) (Santman-Berends et al.,

2012; Hawkins, 2019), as an increase in parity is associated with an increased SCC (Green et al.,

2008). Use of regular determination of SCC can be useful to identify problem cows in a herd or to

select these cows for further bacterial culture to determine causative agents (NMC, n.d.b).

Consensus for the correct sampling and analysis of milk samples in order to diagnose

intramammary infections has been a topic of discussion for years. Researchers, veterinarians and

dairy producers continue to report variation in the methodologies selected for trials, studies, and

treatment decisions.

1.1 PRODUCTION, ECONOMIC, AND WELFARE CONCERNS

A decrease in the health of a dairy cow indicates a decrease in animal welfare (Duncan &

Dawkins, 1983). Clinical mastitis may include visible signs of discomfort, such as lethargy,

depression, weight loss, abnormal posture, and swelling and sensitivity of the udder (Erskine,

2020), as well as reduced laying times (Siivonen et al., 2011). Feed intake is reduced over the days

prior to diagnosis of clinical mastitis in early lactation (González et al., 2008; Sepúlveda-Varas et

al., 2016), but this improves following treatment (Sepúlveda-Varas et al., 2016). While

behavioural changes in dairy cattle with clinical mastitis can indicate poor health and welfare,

early recognition and treatment improves well-being (Broom, 1987).

Mastitis control objectives aim to limit exposure to antimicrobial therapies while

decreasing the duration of infection in order to improve health and production (Hillerton & Berry,

2005). Bauman et al. (2016) conducted a survey of Canadian dairy industry stakeholders and found

animal welfare was the top priority area for both producers and veterinarians. Udder health was

ranked as a fifth and third management priority by farmers and veterinarians, respectively

(Bauman et al., 2016), indicating the treatment of mastitis to improve welfare and limit the

implications on milk production is an important objective for dairy producers.

4

Both clinical and subclinical mastitis have a detrimental effect on milk yield and production

parameters. Firat (1993) reported 231 kg per lactation less milk for a cow diagnosed with clinical

mastitis compared to a cow without mastitis. One case of clinical mastitis for a cow producing

7500L of milk has been reported to cause a 10% decrease in lactational milk yield (Berry et al.,

2004). Several studies have reported a substantially higher milk loss when clinical mastitis was

diagnosed during early lactation (Bartlett et al., 1991; Deluyker et al., 1991; Lescourret & Coulon,

1994). Houben et al. (1993) reported recurrent clinical cases increased milk yield losses by three

times that of non-recurring infections; recurrent infections are often deemed chronic non-

responsive infections which should not be a target of antimicrobial treatment (NMC, n.d.c).

Culling non-responsive cows is recommended but also has associated costs estimated at

approximately $505 CAD per cow (Yalcin & Scott, 2000; Berry et al., 2004).

Decreased milk yield due to clinical mastitis also leads to a decrease in the profitability at

the herd level. The cost of treating a mastitis case for a cow producing 7500L of milk is estimated

at 11.3 pounds ($20 CAD), whereas the cost of production losses from one mastitis case is

estimated at 135 pounds ($230 CAD) (Berry et al., 2004). Aghamohammadi et al. (2018)

conducted a survey of Canadian dairy producers and found mean production losses due to

decreased milk yield as a result of clinical mastitis cases were $8483 CAD per 100 cow-years and

as a result of subclinical mastitis cases, production losses were $24,461 CAD per 100 cow-years.

Similarly, a study of the economic impact of mastitis in Irish dairy herds found a close to 10,000-

pound ($17,000 CAD) difference in profitability between a farm with bulk milk tank somatic cell

count (BMSCC) <100,000 cells/mL compared to a farm with BMSCC >400,000 cells/mL (Geary

et al., 2012). Decreased milk yield and profitability can also occur due to an increase in waste milk

from high SCC or treated cows (Saville et al., 2000; Dairy Farmers of Ontario, 2017). Loss of

revenue because of milk discard during treatment of clinical mastitis is estimated at $39.17 USD

($52 CAD) per cow per year (Sadeghi-Sefidmazgi et al., 2011). In Ontario, producers with a bulk

tank milk SCC exceeding 400,000 cells/mL may be subject to consequences such as covering the

cost of lost milk truck load, suspension of milk transport, and fines (Dairy Farmers of Ontario,

2017). Although uncommon in Canada, producers have reported paying fines up to $5,000 CAD

for high BMSCC (Aghamohammadi et al., 2018).

5

Intramammary antimicrobial treatment is commonly used to both treat and prevent

intramammary infections, and teat sealants (internal or external) used to prevent infection. The

average cost of four tubes of dry cow antimicrobial is 9.5 pounds ($16 CAD), with a similar

average cost for teat sealants (Halasa et al., 2010). Antimicrobial dry cow therapy (ADCT) reduces

the risk of new intramammary infections, especially with the addition of internal teat sealant (TS)

products (Winder et al., 2019a). Both blanket dry cow therapy (BDCT – treatment of all quarters

of a cow regardless of presence of an infection) and selective dry cow therapy (SDCT – treatment

is based on the presence of an infection at the quarter- or cow-level) have been shown to decrease

prevalence of IMI during the beginning of the subsequent lactation (Winder et al., 2019b). The

small cost associated with ADCT and TS to treat one cow certainly outweighs the costs associated

with clinical mastitis that may result from an untreated IMI during the dry period.

1.2 ANTIMICROBIAL DRY COW THERAPY

Dry cow therapy, which is intramammary antimicrobial treatment at the time of dry-off, is

recommended to maintain an effective mastitis control program (NMC, 2006). The dry period, in

which the mammary gland transitions from lactating to non-lactating, is the time at which cows

are most susceptible to intramammary infections (Halasa et al., 2009b), specifically prior to

formation of a keratin plug or administration of a teat sealant to artificially close the teat canal

(Huxley et al., 2002). This period represents a crucial time to both cure existing IMI and prevent

the occurrence of new IMI (Halasa et al., 2009b), and tissue damage caused by mastitis in the

previous lactation may be regenerated prior to calving (NMC, 2006). Dry-cow therapy typically

consists of a higher dose of antimicrobial compared to treatment during lactation, as there is a

decreased risk of antimicrobial residues contaminating milk. Dry-cow antimicrobial products vary

from single-use intramammary infusions of antimicrobials to intramuscular injections given at

several times during the dry period. Most dry cow antimicrobials have maximal activity during the

first two weeks of the dry period (NMC, 2006).

The National Mastitis Council provides a ten-point recommendation plan for udder health,

which includes development of a mastitis treatment plan during lactation while considering the

6

impact of therapy decisions on herd profitability (NMC, n.d.c). Intramammary antimicrobial

treatment for clinical mastitis accounts for a substantial portion of the overall antimicrobial use

(AMU) in North America, with studies showing 38% of AMU for dairy herds from the USA (Pol

& Ruegg, 2007), and about 35% of all AMU on Canadian dairy farms (Saini et al., 2012). Use of

antimicrobials during the dry period also contributes substantially to overall AMU, accounting for

44% of the total AMU on Dutch dairy farms from 2005 to 2012 (Kuipers et al., 2016).

Also included in the ten-point mastitis control plan is blanket dry cow therapy, which is to

treat all quarters of all cows with a long-acting antimicrobial at cessation of lactation, with or

without an internal teat sealant (NMC, n.d.c). Blanket dry cow therapy has shown to be beneficial

in preventing new infections during the dry period (Browning et al., 1994), but newer work has

shown that SDCT is associated with similar incidence rates of clinical mastitis in the following

lactation compared to BDCT (Halasa et al., 2010; Scherpenzeel et al., 2016). This indicates that

SDCT can potentially be sufficient to decrease the effect of dry period infections on udder health

in the subsequent lactation while also aiding in prudent use of antimicrobials in the dairy industry

(WHO, 2017). Dutch dairy producers substantially reduced their antimicrobial use from 2010 to

2015 due to regulations banning the prophylactic use of antimicrobials, resulting in no effect on

the prevalence of subclinical mastitis (Santman-Berends et al., 2016; Vanhoudt et al., 2018).

Antimicrobial products that are used in human health with little to no availability of an

alternative antimicrobial are of high importance and should be limited in their use in agricultural

species (Health Canada, 2009). Cephalosporin products are of high importance to human health

(Health Canada, 2009), and should be limited for use in the treatment of intramammary infections

and completely avoided for use in the prevention of disease (World Organisation for Animal

Health, 2019). In a recent (2007/2008) survey, 98% of Canadian dairy farmers reported the use of

cephalosporins in their herds, and 87% reported use of first-generation cephalosporins (Saini et

al., 2012). Penicillin products were the next most common product reported for use by Canadian

dairy farmers, followed by penicillin combination products and trimethoprim-sulfa products (Saini

et al., 2012). Winder et al. (2019a) conducted a network meta-analysis on product efficacies to

prevent the occurrence of new IMI during the dry period, which found cloxacillin was the most

7

commonly reported antimicrobial product in published controlled trials, followed by penicillin-

aminoglycoside products. Pairwise meta-analyses indicated cloxacillin performed similarly for

prevention of new IMI and cure of existing IMI over the dry period when compared to other

antimicrobial dry cow therapy products (Halasa et al., 2009a; Halasa et al., 2009b). The

combination of antimicrobial dry cow therapy products with an internal teat sealant have been

shown to increase the efficacy of these products to cure and prevent IMI (Godden et al., 2003;

Berry & Hillerton, 2007; McParland et al., 2019). The application of teat sealants at dry off can

help reduce the use of antimicrobials and are important components of a selective dry cow therapy

program (Halasa et al., 2010; Rowe et al., 2020).

In 2017, the World Health Organization (WHO) recommended the complete restriction of

medically important antimicrobials for use in food-producing animals for the prevention of

disease, and also recommended the use of antimicrobials of high importance for human health be

avoided entirely (WHO, 2017). In addition, the World Organisation for Animal Health developed

guidelines to restrict the use of medically important antimicrobials for use as preventative

treatment in the absence of clinical diagnosis and limit extra-label drug use (using antimicrobials

beyond intended use or veterinary directive) (World Organisation for Animal Health, 2019). A

recent rise in consumer demand for organic dairy products, the second highest organic product in

demand in the USA in 2015 (Greene & McBride, 2015), further contributes to the call for limited

antimicrobial use on dairy farms. The demand for dairy cattle producers to move away from the

use of antimicrobials in prevention of udder disease leads to a need to assess other management

practices than can be implemented during the dry period.

1.3 DRY COW MANAGEMENT

Dairy cattle are subject to several management changes following cessation of lactation.

The majority of the literature that reports on dry cow management focuses on the efficacy of

antimicrobials (Dingwell et al., 2003; Halasa et al., 2009b; Winder et al., 2019a) and teat sealants

(Berry & Hillerton, 2002; Halasa et al., 2009a; Winder et al., 2019c) for cure and prevention of

IMI. However, environmental and other modifiable management strategies also affect the

8

susceptibility of dairy cows to intramammary infections during the transition period (Pyörälä,

2008), including dry period length, reducing milk yield prior to drying off, abrupt versus

intermittent cessation of lactation, bedding management, vaccination, pasture grazing

management, and fly control measures (Green et al., 2007). Sixty-five percent of German dairy

producers reported they dried off cows 40 to 55 days prior to expected date of calving, 73%

implemented abrupt cessation of lactation, a small number of producers adjusted the ration at

drying off, and more dry cows were housed in free-stalls with deep bedding compared to cows in

late lactation (Bertulat et al., 2015). Fujiwara et al. (2018) conducted a survey in UK dairy

producers to assess the prevalence of dry cow management practices, but they did not assess the

impact of these strategies on udder health outcomes. Intramammary infections in postpartum cows

were seen to increase following full insertion (vs. partial insertion) of dry cow antimicrobial

intramammary tubes, increase with free stalls compared to tie stalls, and decrease with a decreased

body condition score postpartum (Leelahapongsathon et al., 2016). Clinical mastitis in the post-

partum period was positively associated with a longer lactation period (i.e. more days in milk at

drying off), and negatively associated with daily barn cleaning, disinfection of teats prior to ADCT

administration, and decreased milk yield at drying off (Leelahapongsathon et al., 2016).

Other forms of dry cow management, in addition to antimicrobials and teat sealants, impact

udder health and contribute to the prevention of clinical mastitis during lactation. Characterization

of all available literature regarding modifiable management practices in relation to udder health

would be beneficial for dairy producers attempting to limit the amount of antimicrobial products

used on farm. Further knowledge synthesis work objectives can be formed following literature

characterization, and primary research gaps can be identified as an area for future trial work.

1.4 KNOWLEDGE SYNTHESIS

Policy advisors and veterinarians in the dairy industry rely on published literature in order

to make evidence-informed treatment decisions. Controlled trials in animal health, more

specifically randomized controlled trials, yield the highest degree of evidence under field

conditions for comparing the efficacy of interventions (Sargeant et al., 2010). Such trials are often

9

conducted in commercial dairy herds, which maintains relevance to real-world dairy producers.

However, quality reporting of clinical trials is needed to provide decision-makers with the best

available evidence for treatment decisions. Quality reporting of clinical trials is needed in order to

assess the level of bias in a trial, for example to indicate if post hoc decisions were formed by the

availability of data, and to ensure research is transparently reported such that trials can be

replicated (Sargeant et al., 2009). Quality reporting of trials in veterinary science is also crucial for

assessing the confidence in the estimates provided, for example, reporting random allocation of

subjects to intervention groups or blinding of caregivers are needed to inform the risk for bias in a

trial. Reporting guidelines of controlled trials have existed in human medicine since 1996, but

guidelines for trials in veterinary science were not published until more recently (O’Connor et al.,

2010; Sargeant et al., 2010). O’Connor et al. (2010) first published the Reporting Guidelines for

Randomized Controlled Trials in Livestock and Food Safety (REFLECT) Statement in 2010 to

provide trialists in livestock production with guidelines for a minimum list of items that need to

be reported in a trial for complete and accurate reporting.

Systematic literature reviews synthesize the body of literature using methodology

intending to minimize systematic and random errors (Sargeant et al., 2006). Systematic reviews

aim to answer specific clinical questions using a comprehensive literature search to identify all

relevant articles (Cook et al., 1997), which minimizes selection bias (Sargeant et al., 2006). The

Preferred Reporting Items for Systematic Reviews (PRISMA) Statement provides a minimum set

of items for reporting in systematic reviews and meta-analyses (Moher et al., 2009). An a priori

systematic literature review protocol pre-specifies the objectives and methods of the systematic

review, which decreases the chance of bias arising from post hoc decisions, such as selective

outcome reporting (Liberati et al., 2009). The use of independent in duplicate screening for title

and abstract, full-text, and data extraction processes ensures the data are doubly analyzed to

minimize errors in inclusion or exclusion of relevant literature. Systematic literature reviews and

meta-analyses provide the highest level of evidence for treatment decisions (Sargeant and

O’Connor, 2014); however, there may be a lack of available primary evidence in agri-food public

health areas (Sargeant et al., 2009). Replicated primary research is key to understanding a

treatment event, and by using the results of several studies, evidence-informed treatment decisions

10

can be made. Systematic reviews outline the results of all primary studies available on a topic to

inform end-users, which limits the risk of selection bias (O’Connor and Sargeant, 2015). Toews

(2017) assessed the use of PRISMA guidelines in systematic reviews published in veterinary

journals and found 95% of reviews did not have a reproducible search strategy. Replicated primary

research is essential to forming a solid evidence base from which clinical decision-making is

informed, but improved reporting of primary articles and systematic reviews are required for

assessing the level of bias within a study or review that may have an effect on treatment decisions.

Meta-analyses are often an extension of systematic reviews that assess the results from

previous primary research to create a conclusion about that body of research (Lean et al., 2009).

Meta-analyses typically provide a more precise estimate of the effect of a treatment or risk factor

on disease as they are a pooled analysis of multiple primary articles (Lean et al., 2009). The aim

of meta-analyses can be to determine if an effect is present, the direction of the effect, and, more

importantly, to obtain a single summary estimate of a treatment effect (Lean et al., 2009). An

advantage of meta-analyses is that they provide greater external validity compared to single

studies, since they include a range of study populations (i.e. commercial and research herds,

multiple breeds). Inclusion of grey literature, such as conference proceedings, in systematic

reviews and meta-analyses is important to avoid publication bias, meaning systematic differences

in studies that are published versus those that are not (i.e. positive treatment effects) (Lean et al.,

2009). Weighting of studies based on their value of evidence, which is a result of the number of

animals enrolled in a study and the number of animals with the outcome of interest, and also

reflects the variance of the study, is an additional feature of meta-analyses (Lean et al., 2009).

Lastly, examining sources of heterogeneity among studies included in a meta-analysis is important

for interpretation of the results, such that when large heterogeneity is present the results should be

interpreted with caution. Heterogeneity can arise from differing study methodology, such as

blinding of caregivers or in the definition and measurement of outcomes, or in the use of certain

populations and interventions (i.e. variation in the levels of risk in the control versus experimental

groups) (Lean et al., 2009). Identifying sources of heterogeneity are important to identify

determinants that may be overlooked in most primary research and as a means to direct future

study design.

11

Pair-wise meta-analyses provide valuable information for the comparison of two products,

but where multiple antimicrobial options exist, it is difficult to conclude which treatment is best

for clinical decision-making (Caldwell et al., 2005). Network meta-analyses, which are mixed-

treatment statistical analyses that compare evidence of multiple treatment options, allow

researchers to provide an overall summary estimate for the best available treatment using both

direct and indirect evidence from comparisons made in controlled trials (Caldwell et al., 2005).

Providing clinicians and veterinarians with a point estimate, and an estimate of precision for that

point estimate, for indirect comparisons of the efficacy of antimicrobial products are important so

readers are not left to make their own judgements about the efficacy of products that have not

directly been compared in a controlled trial (Hu et al., 2019).

There exists a large body of evidence that has assessed the efficacy of antimicrobial

products during the dry period following lactation in dairy cattle through controlled trials.

Summarizing the overall effects of these interventions requires knowledge synthesis methodology,

such as systematic literature reviews and meta-analyses, in order to provide an accurate

representation of treatment efficacies (Lavis et al., 2005; Sargeant & O’Connor, 2014). The

addition of a network meta-analysis allows the synthesis of estimates from all available trials to

inform an overall decision on the efficacy of products (Sargeant & O’Connor, 2014). Systematic

literature reviews in veterinary science can also allude to areas where further research is needed or

indicate the need for improvement in trial reporting (Sargeant et al., 2019; Vriezen et al., 2019;

Winder et al., 2019a).

Scoping reviews are employed to address broad research questions that have been

investigated through several types of study designs (Arksey & O’Malley, 2005). The motivations

for conducting a scoping review include to rapidly characterize the range of literature available,

determine the value of undertaking a systematic review, summarize research findings, and to

identify gaps in existing literature (Arksey & O’Malley, 2005). Constructing a broad research

question is essential for a scoping review, and requires that the search for relevant literature be as

comprehensive as possible to identify both published and unpublished research (Arksey &

O’Malley, 2005). Depending on the field of study addressed with the scoping review, the number

12

of references retrieved is typically much larger than the number identified using systematic review

methods, thus the use of reference management tools, such as EndNote (EndNote X7, Clarivate

Analytics, Philadelphia), are a necessity (Arksey & O’Malley, 2005). Alike systematic literature

reviews, the review process (i.e. screening studies for eligibility, data extraction) should be

conducted independently in duplicate (Arksey & O’Malley, 2005). Another feature of a scoping

review is that the quality of evidence within eligible articles is not assessed, as it is in systematic

literature reviews, and thus recommendations for the feasibility of a systematic literature review

may be misleading because the quality of available literature remains unknown (Levac et al.,

2010). Scoping reviews still require the synthesis of an a priori protocol to ensure the review team

is comprised of appropriate content experts, study inclusion and exclusion criteria are well

developed, and plans for data charting are identified (Levac et al., 2010). However, because the

body of literature has not been previously characterized using systematic methods, the data

charting process should be iterative in order to best present the scoping review information (Levac

et al., 2010).

In areas where few researchers have targeted efforts, such as the effectiveness of different

management practices for improving udder health during the dry period, it can be of use to

summarize the body of literature using a scoping review (Arksey & O’Malley, 2005). In veterinary

research it is common to use observational studies to highlight associations between management

factors (Sargeant et al., 2016), especially when management factors such as stall design and access

to pasture depend on the facilities available. Several controlled trials have been used for other

management strategies such as vaccines (Schukken et al., 2014; Bradley et al., 2015; Freick et al.,

2016) and nutrition (Mayasari et al., 2016; Higginson et al., 2018; Wu et al., 2019) to evaluate

their effect on udder health. Variability in the types of management factors and study designs used

to investigate the effect of management on udder health (Green et al., 2007; Bertulat et al., 2015;

Fujiwara et al., 2018) inform the need for a scoping review (Arksey & O’Malley, 2005).

13

1.5 THESIS OVERVIEW, PURPOSE, AND OBJECTIVES

Udder health is an important component of proper dairy cattle production. The detrimental

effects mastitis and IMI can have on production, economics, and animal welfare distinguish the

level of importance of this disease to dairy producers worldwide. The current movement away

from BDCT and towards SDCT, and increased scrutiny on antimicrobial use in production

animals, highlights the importance of understanding the efficacy of all available antimicrobial

products from controlled trials to cure IMI over the dry period. Although pairwise meta-analyses

exist on this topic (Halasa et al., 2009a; Halasa et al., 2009b; Winder et al., 2019b), veterinarians

and producers often want to know which treatment is best out of a number of options. A network

meta-analysis can incorporate both direct and indirect evidence to inform treatment efficacies of

multiple antimicrobial products to answer this question. In addition, consumer demand and

regulations in place throughout the world to limit the use of antimicrobials in dairy cattle warrants

the need to describe management practices evaluated in published literature that can be

implemented at drying off to improve udder health. From an initial mapping of the literature, these

management practices could further be assessed for their effectiveness to cure or prevent

intramammary infections and clinical mastitis and possibly be indicated for use in addition to or

in replacement of antimicrobial dry cow therapy if enough similar literature is found, and gaps in

research to target with future studies can be highlighted.

The specific objectives of this thesis were to:

1) Investigate the relative efficacy of antimicrobial dry cow products for cure of existing

intramammary infections in dairy cattle using a systematic literature review and network

meta-analysis; and

2) Characterize the use of modifiable management strategies that are implemented during the

dry period and have been evaluated for their impact on udder health in dairy cattle using a

scoping review framework.

14

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mastitis control decision in milk production systems. J Dairy Res, 67(4), 515-528.

https://doi.org/10.1017/s0022029900004453

24

2 CHAPTER 2: RELATIVE EFFICACY OF ANTIMICROBIAL

DRY COW THERAPY TO CURE EXISTING

INTRAMAMMARY INFECTIONS DURING THE DRY

PERIOD: A SYSTEMATIC REVIEW AND NETWORK

META-ANALYSIS

2.1 ABSTRACT

The objective of this systematic review and network meta-analysis was to estimate the

relative efficacy of dry-cow antimicrobial therapies to cure existing intramammary infections

(IMI) in dairy cattle. Eligible studies were controlled trials where authors assessed the use of an

antimicrobial product compared to no treatment or an alternative treatment in cows with an

existing IMI at cessation of lactation, and one or more of the following outcomes was reported:

all-cause cure of existing IMI from dry-off to calving, incidence of clinical mastitis over the first

30 days in milk (DIM) in cows with an existing IMI at cessation of lactation, and metrics for total

antimicrobial use over the first 30 DIM in cows with an existing IMI at cessation of lactation. Five

databases and four conference proceeding platforms were searched for relevant trials. Risk of bias

at the outcome level were assessed using the Cochrane 2.0 risk of bias tool, and the overall

confidence in the findings from the network meta-analysis was assessed using the Confidence In

Network Meta-Analyses (CINeMA) platform. Of 3743 articles screened for eligibility by two

reviewers independently, 58 trials were included in the network meta-analysis for all-cause cure

of existing IMI from dry-off to calving. No antimicrobial treatment (non-active control) was

associated with a decreased risk of a cure compared to cloxacillin (RR: 0.46, 95% CI: 0.22-0.80),

penicillin-aminoglycosides (RR: 0.51, 95% CI: 0.26-0.82), and ceftiofur (RR: 0.52, 95% CI: 0.24-

0.84). Lack of replication trials for some antimicrobial protocols created large credibility intervals

and challenged our ability to compare products on the basis of efficacy, as did poor reporting in

trial methodologies, heterogeneity in outcome measurements, and high risk of bias in some

domains. Continued improvement in the reporting of animal trials is required in order to make

recommendations for antimicrobial products on the basis of efficacy.

25

2.2 INTRODUCTION

2.2.1 Rationale

Dry-cow therapy is commonly used to both cure existing intramammary infections (IMI)

at drying off and to prevent new IMI from occurring during the dry period (Halasa et al., 2009).

The early and late dry period represents the time at which dairy cows are most at-risk for acquiring

new IMI (Halasa et al., 2009). Intramammary infections increase the risk of clinical mastitis in the

subsequent lactation, most commonly during the first 30 to 60 days in milk (Pantoja et al., 2009).

The use of antimicrobial dry-cow therapy, environmental pathogen load, and a cow’s immune

system all contribute to risk of developing a new IMI during the dry period (Green et al., 2007).

Therefore, dry-off antimicrobial use is common during this period to decrease the risk of poor

udder health outcomes.

The National Dairy Study conducted in 2015 in Canada found 84% of farmers reported use

of blanket dry cow therapy (BDCT) and 11% reported use of selective dry cow therapy (SDCT)

(D.F. Kelton, unpublished data). The Pan-European agreement on dry-cow therapy, established in

2017, indicated animals likely to be infected should receive dry-cow therapy and high-risk herds

need to be targeted (Bradley et al., 2018). In the Netherlands, approximately 61% of dairy cattle

received antimicrobial therapy at dry-off in 2013 (Santman-Berends et al., 2016), although 88%

percent of veterinarians surveyed in the Netherlands reported they actively encouraged their

farmers to reduce antimicrobial use when possible (Scherpenzeel et al., 2018). Recently selective

dry-cow therapy has gained popularity for its role in antimicrobial stewardship and as a means to

reduce antimicrobial use in the dairy sector by targeting existing IMI (Lam et al., 2017).

Use of SDCT for cure of existing intramammary infections in dairy cattle is an imperative

in agriculture to aid in the prudent use of antimicrobials. The World Health Organization

recommends against the use of medically important antimicrobials for prevention of disease

(WHO, 2017). Also, the Canadian Veterinary Medical Association (CVMA) recommends

veterinarians choose drugs of least importance to human health (CVMA, 2017). Dry-cow

26

management practices should be used for preventing intramammary infections such as clean

bedding, routine vaccinations, limited pasture grazing, and change in dry period length (Green et

al., 2007), and antimicrobial products should be reserved for use in cure of existing IMI.

Guidelines for the responsible use of antimicrobials for treating animals with an existing

IMI at drying off necessitate the evaluation of comparative efficacies of all antimicrobials used to

cure existing IMI during the dry period. A systematic review of controlled trials generates the

highest level of evidence for the efficacy of a treatment under field conditions (Sargeant and

O’Connor, 2014). The addition of a network meta-analysis creates the opportunity to assess

antimicrobial products beyond a pair-wise analysis by using direct and indirect evidence to

estimate the relative efficacy of multiple antimicrobial options. This systematic review and

network meta-analysis provides up-to-date comparisons of dry-cow antimicrobials, currently

licensed in Canada or the United States of America, to treat IMI in dairy cattle. Producers and

veterinarians can use this information of efficacy in decision-making, and where products are

equivalent in efficacy, they can use other factors such as level of importance for human health to

improve the judicious use of antimicrobials.

2.2.2 Objectives

The objective of this systematic review and network meta-analysis was to investigate the

relative efficacy of dry-cow antimicrobial therapy to cure existing intramammary infections in

dairy cattle.

2.3 METHODS

2.3.1 Protocol and registration

A review protocol was created a priori by CKM, with input from JMS, DFK, AOC, and

CBW. It is published in the online University of Guelph repository and can be accessed at:

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/16236/Protocol_NMA_efficacy_dry

off_antibiotics_cure_IMI.pdf?sequence=3&isAllowed=y. Manuscript preparation followed the

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/16236/Protocol_NMA_efficacy_dryoff_antibiotics_cure_IMI.pdf?sequence=3&isAllowed=y

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/16236/Protocol_NMA_efficacy_dryoff_antibiotics_cure_IMI.pdf?sequence=3&isAllowed=y

27

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Network

Meta-Analyses (PRISMA-NMA) reporting guidelines (Hutton et al., 2015).

2.3.2 Eligibility criteria

Controlled trials with naturally occurring disease that were published in English were

eligible for inclusion. Authors of eligible trials must have reported a population of dairy cattle with

an IMI at cessation of lactation, as defined by laboratory confirmation of one or more pathogens

or a somatic cell count (SCC) above a cut-point, and an antimicrobial dry-cow treatment

intervention, with comparison to a different antimicrobial treatment, a placebo, a non-

antimicrobial treatment method, or no treatment. The following outcomes had to be reported: all-

cause cure of existing IMI from dry-off to calving; incidence of clinical mastitis over the first 30

days in milk in cows with an IMI at cessation of lactation; or, a metric of total antimicrobial use

over the first 30 days in milk in cows with an IMI at cessation of lactation. There was no date

(other than those set by each database) or study location restrictions.

There was no restriction on eligible antimicrobial products included in the treatment

network; however, comparative efficacy reporting and risk of bias in the overall network was

limited to treatment protocols labelled for use in Canada and the USA as outlined by the

Compendium for Veterinary Products, Canada and US versions (Animalytix, 2020a; Animalytix,

2020b). These compendiums were used to identify antimicrobial compounds labelled for use;

however, products containing the same compounds, but administered via a different route or dose,

were also eligible for inclusion in comparative efficacy reporting and risk of bias analysis.

2.3.3 Information Sources

The review search was completed on June 14, 2019 by searching five databases: Medline

(via Ovid SP), CAB Abstracts (via CAB Interface), Science Citation Index (via Web of Science),

Conference Proceedings Citation Index – Science (via Web of Science), and Agricola (via

Proquest). The following conference proceedings were hand-searched from 1997 – 2019, provided

the proceedings papers were ≥500 words: Proceedings of the American Association of Bovine

28

Practitioners, World Association for Buiatrics, National Mastitis Council Proceedings, and IDF

Mastitis Conference Proceedings. The Freedom of Information New Animal Drug Approvals

(NADA) summaries from the FDA website

(https://animaldrugsatfda.fda.gov/adafda/views/#/foiDrugSummaries#foiApplicationInfo) were

searched by drug use (dry-cow therapy). Contact with study authors was not conducted for this

review.

2.3.4 Search

The full-electronic search string was initially developed for Science Citation Index (via

Web of Science) (Table 2.1). The conceptual structure of the search was created to maximize

sensitivity: (dairy cows AND dry off AND antibiotics) OR (dry cow AND antibiotics) OR (((dairy

cows AND dry off) OR dry cow) AND generic treatment terms AND intra-mammary

infections/mastitis). The search was not limited by date, language, or publication type. Search

results were downloaded into EndNote (EndNote X7, Clarivate Analytics, Philadelphia) and de-

duplicated using several algorithms. The references were then uploaded into DistillerSR (Evidence

Partners Inc, Ottawa, ON, Canada), and additionally deduplicated prior to screening.

2.3.5 Study selection

Study selection, data extraction, and risk of bias were performed using DistillerSR. Two

screening levels were conducted by CKM, CBW, and trained research assistants. The title and

abstract screening pre-test involved all reviewers screening 100 articles for eligibility, followed by

a consensus meeting to ensure reviewer consistency. Two reviewers independently screened each

title and abstract of articles identified by the search using three primary screening questions: (1) Is

the title and/or abstract available in English?; (2) Is a primary research study described in the title

and/or abstract?; and (3) Are dry-off antimicrobial treatments in dairy cattle with an existing IMI

described within the title and/or abstract?. Response selection was ‘yes’, ‘no’, or ‘unclear’, and a

response of ‘no’ from two reviewers to any of the above questions resulted in exclusion of that

reference. Conflicts were resolved by consensus or mediation by a third party if needed. The full-

text screening pre-test involved screening 10 full-text articles, followed by a consensus meeting.

https://animaldrugsatfda.fda.gov/adafda/views/#/foiDrugSummaries

29

Six secondary screening questions were applied: (1) Is the study available in English?; (2) Is this

a primary research study?; (3) Are dry-off antimicrobial treatments in dairy cattle with an existing

IMI reported within the article?; (4) Is an eligible comparison group reported within the article?;

(5) Is one or more of the following outcomes reported in the article: cure of existing IMI from dry-

off to calving, incidence of CM in the first 30 DIM in cows with an existing IMI at cessation of

lactation, or metrics for total antimicrobial use in the first 30 DIM in cows with an existing IMI at

cessation of lactation?; and (6) Is the study a controlled trial with natural disease exposure?.

Possible responses were ‘yes’ or ‘no’, where an answer of ‘no’ selected by two reviewers resulted

in exclusion of the record. Agreement was at the question level, with conflicts resolved by

consensus or mediation by a third party if needed.

2.3.6 Data collection process

Data extraction was completed using DistillerSR. The forms were pre-tested using four

references by all reviewers to ensure consistency. Data extraction from relevant studies was

conducted by CKM and CNR in duplicate, followed by consensus and consult with CBW or JMS

if consensus could not be reached.

2.3.7 Data items

Study Characteristics. Study-level data included year of publication, year of study

conduct, country, number of herds enrolled in the study, herd setting (commercial,

research/university), breed, lactation number, and inclusion criteria at herd- and cow-level.

Population. Cows must have been diagnosed with an existing IMI at cessation of lactation.

Bacteriologic culture of one or more pathogens or a somatic cell count (SCC) cut point (e.g. cows

with SCC > 200 000 cells/mL were considered infected) were acceptable definitions. The eligible

causes of an IMI at cessation of lactation was any pathogen.

Intervention and Comparators. Intervention and comparator data included allocation level

for the intervention (quarter or cow), number of study units enrolled, antimicrobial or

30

non-antimicrobial products administered, route and frequency of administration, dose, and any

concurrent treatments.

Outcomes. Eligible outcomes for inclusion in the review were:

• All-cause cure of existing IMI during the dry period,

• Incidence of clinical mastitis over the first 30 DIM in cows with an existing IMI at

dry-off, and

• Metrics for total antimicrobial use over the first 30 DIM in cows with an existing

IMI at cessation of lactation.

Authors had to provide case definitions for all-cause cure of IMI (i.e. bacteriologic culture, SCC

cut point) and for clinical mastitis (i.e. visual assessment, udder palpation, California Mastitis

Test). All-cause cure data was trial-specific and included any of the following reported outcomes:

major pathogen cure, minor pathogen cure, all pathogen cure, or Streptococci and Staphylococci

cure, or a combination of these definitions. Data for all-cause cure of IMI was extracted and

analyzed, but note was made if the authors reported bacteria-specific, gram-negative or gram-

positive cure. If only bacteria-specific, gram-negative or gram-positive cures were reported

without all-cause cure also reported, these trials were excluded. If results were presented in

multiple formats, we prioritized which results were extracted as follows: adjusted summary effect

size (adjusted ORs or RRs) for dichotomous outcomes or adjusted mean differences for continuous

outcomes (proportion differences), unadjusted summary effect estimates, and arm-level risk data.

Methods of controlling for non-independence of observations were extracted when reported.

2.3.8 Geometry of the network

An a priori plan to amalgamate treatment groups was not reported in the protocol; however,

a great deal of heterogeneity exists in the antimicrobial compounds and dosing used to treat

production animals. A previous network meta-analysis indicated creating a unique treatment

regimen for each product and dose would have led to a sparse network (Winder et al., 2019a) and

problems with interpretability of treatment efficacies. Therefore, a decision was made to merge

several treatment arms on the basis of biological and clinical relevancy. Antimicrobial products

31

were considered separately, except for penicillin-aminoglycosides which were combined based on

the World Organisation for Animal Health List of Antimicrobials of Veterinary Importance (World

Organisation for Animal Health, 2007). Secondly, different dosages of an antimicrobial product

were combined unless reported in more than three trials, but extended therapy treatment protocols

remained separate from single-therapy treatments of the same active ingredient. Also, different

routes of administration were considered separately (i.e. intramammary, intramuscular, oral).

Next, all non-antimicrobial products, such as vitamins and minerals, were merged due to their

relative unimportance in cure of IMI during the dry period (Mullen et al., 2014). Lastly, active

antimicrobial products were combined with their antimicrobial and teat sealant combinations (e.g.

cloxacillin was combined with cloxacillin-teat-seal of the same dose) as teat sealants are only

approved for use in prevention of IMI (Table 2.2) (Animalytix, 2020a; Animalytix, 2020b), and

were not considered influential on cure.

The geometry of the network was visually evaluated to analyze if all treatment protocols

were connected within the network (i.e. shared a common comparator with at least one other trial).

The probability of interspecific encounter (PIE) index was used to assess network diversity (i.e.

number of treatment protocols and relative number of times each treatment protocol was

compared), and co-occurrence (C-score) of particular comparisons was assessed (i.e. tendency for

specific treatments to be compared more often than others), as outlined by Salanti et al. (2008). A

PIE index of 0.75 or greater indicated adequate diversity in the network, and a significant C-score

(P<0.05) indicated significant co-occurrence of treatments. Co-occurrence may be attributed to

availability of antimicrobial combinations, treatment effect and safety, and an author’s or funding

body’s preference for certain comparators (e.g. non-active control for larger treatment effects)

(Salanti et al., 2008).

2.3.9 Risk of bias within individual studies

Risk of bias was assessed at the outcome level for cure of existing IMI in dairy cattle at

dry-off using the Cochrane Risk of Bias 2.0 instrument (Higgins et al., 2016), with the signaling

questions modified as necessary for the specific review question (Winder et al., 2019a). This tool

assesses the risk of bias from five domains: bias arising from the randomization process, bias due

32

to deviations from intended interventions, bias due to missing outcome data, bias in measurement

of the outcome, and bias in selection of reported results. The highest risk of bias in any of the five

domains was used to rank trials overall. Risk of bias was assessed independently in duplicate by

CKM, CBW, and a research assistant, with disagreement resolved by consensus and mediation by

a third party where needed.

2.3.10 Summary measures

Outcome data were analyzed on the log OR scale. For ease of interpretation, log ORs were

back-transformed to RRs using the baseline risk from the model data assuming the baseline prior

distribution was approximately normal. The posterior mean and standard deviation of the baseline

risk mean were -0.57393 and 0.17353. The posterior mean and standard deviation of the baseline

risk standard deviation were 0.92931 and 0.13260.

2.3.11 Network meta-analysis

Planned methods of analysis. A network meta-analysis was conducted for the outcome of

all-cause cure of existing IMI. The method has been described in detail elsewhere (Dias et al.,

2011; O’Connor et al., 2013; Hu et al., 2020). Frequency counts or ORs were converted to log

ORs (LOR). The final network meta-analysis included trials with at least two unique treatment

arms after antimicrobial treatments were merged (as described above). For trials with more than

two treatment arms, the variance of the log odds of arm one (V) was calculated from frequency

counts. For trials that included the baseline treatment (non-active control), the baseline log odds

(PLA.lo) was calculated from frequency counts. If sufficient data were not available to calculate

either V or PLA.lo, the trial was removed from further analyses.

Selection of prior distributions in Bayesian analysis. The prior distributions were

originally based on the approach reported previously (Dias et al., 2011). Vague priors (i.e. N(0,

10,000)) were used for all basic parameters (Hu et al., 2020). For this model, weakly informative

priors for variance such as U (0,2) and U (0,5) were assessed (Dias et al., 2011; Hu et al.,

33

2020). The analysis suggested similar results using both priors, thus U (0,2) was retained in

the model.

Implementation and output. All posterior summaries were generated using Markov Chain

Monte Carlo (MCMC) simulation implemented in Just Another Gibbs Sampler (JAGS) software

(version 4.3.0) (Plummer et al., 2019). All statistical analyses were performed using R software

(version 3.6.0; Planting of a Tree) in a Catalina OS system (R Core Team, 2019). The model was

fit by calling JAGS from R through the RJAGS package (Plummer et al., 2019). Three chains of

10,000 iterations were simulated and convergence was assessed using the Gelman-Rubin

diagnostic tool (Brooks & Gelman, 1998) and through visualization of basic parameters in history

plots. Five thousand ‘burn-in’ iterations were run then discarded, and inference was based on a

further 10,000 iterations. Model output included all possible pairwise comparisons of the log odds

ratios for all-cause cure of existing IMI for assessment of consistency, and relative risks, mean

treatment ranks, and the probability of being the worst treatment for efficacy reporting. The

probability of being the worst treatment was created by several simulations of indicators 1 (cure)

or 0 (no cure) for each treatment protocol, after which the 1’s for each treatment were summed

and the relative proportion of best or worst treatment were calculated (Hu et al., 2019).

Assessment of model fit. Model fit was assessed by considering an absolute measure of fit,

Dres, the posterior mean of the residual deviance (deviance of fitted model minus deviance of

saturated model). Each data point I contributes Di to the residual deviance, such that

We assumed each LOR contributed about 1 to the posterior mean deviance, therefore Dres should

have approximately equaled the number of summary-level comparisons within our data (Dias et

al., 2010).

Dres

= Di

i

å .

carriemcmullen

equation

34

2.3.12 Assessment of consistency

Assessing consistency involved comparing direct and indirect evidence for each treatment

comparison that contained direct evidence within the network, as previously described (Dias et al.,

2010; Hu et al. 2020).

2.3.13 Risk of bias in overall network

The confidence in cumulative evidence from the overall network was evaluated using the

Confidence In Network Meta-Analysis (CINeMA) platform (Nikolakopoulou et al., 2020;

Papakonstatinou et al., 2020). An evaluation of the overall network through six domains was

provided by CINeMA: within-study bias, reporting bias, indirectness, imprecision, heterogeneity

and incoherence. A contribution matrix represented the amount of information each trial

contributed to the results of our network meta-analysis. Instead of presenting within-study bias

and indirectness, we presented the risk of bias attributed to randomization and the risk of bias

attributed to blinding of caregivers because trials that fail to report these domains often have

exaggerated treatment effects (Moher et al., 1998; Sargeant et al., 2009). Risk of bias due to

randomization was reported as ‘low’ if authors employed allocation concealment, random

allocation and details on the method used to generate the allocation sequence were reported, and

no baseline imbalances were indicated between treatment groups within the trial; ‘some concerns’

if allocation concealment was employed, and random allocation was reported but no details were

provided on the method of sequence generation, regardless of baseline imbalances; ‘some

concerns’ if allocation concealment was employed, and a non-random approach to allocation was

reported, regardless of baseline imbalances; ‘some concerns’ if no information for allocation

concealment was provided, regardless of random allocation to treatment groups, and there were

no baseline imbalances indicated in the trial; ‘some concerns’ if allocation concealment was

employed, and random allocation and details on the method used to generate the allocation

sequence were reported, but there were baseline imbalances in the trial; and ‘high’ if no

information was provided for allocation concealment, regardless of random allocation to treatment

groups, and there were baseline imbalances indicated in the trial, or if allocation was not concealed.

Risk of bias due to blinding of caregivers was assessed as ‘low’ if the caregivers were blind to

35

treatment allocation, ‘some concerns’ if blinding of caregivers was not reported, and ‘high’ if

caregivers were not blind to treatment allocation. Results for blinding of caregivers were presented

rather than outcome assessors, as bias due to blinding of outcome assessors was determined to be

‘low’ in all but three trials, as the assessment was typically objective (laboratory diagnosis). In

three trials, part of the IMI diagnosis involved the use of California Mastitis Test (CMT), which

was considered subjective and therefore bias risk was determined to be ‘high’ as outcome assessors

were not blinded in these studies.

Indirectness, which refers to the generalizability of included studies, was not considered

an issue for this review due to the eligibility criteria for trials reflecting commercial farms (i.e. not

a laboratory model). Bias due to imprecision was assessed using below 0.8 or above 1.25 as

clinically important effect sizes. Credibility intervals that spanned these values in either or both

directions (protective, no effect, or hazardous) could potentially lead to different clinical decisions

and imprecise effect estimates. A 0.8 OR was also used to assess heterogeneity. Incoherence

(assessment of consistency) was evaluated using Bayesian analysis.

Across study bias was not conducted for this review because none of the pair-wise

comparisons were evaluated in more than 10 trials (Sterne et al., 2000).

2.3.14 Additional analyses

An additional analysis was conducted to evaluate the network of evidence using only trials

published between 1990 and 2019 (further referred to as the post-1990 analysis). Eradication

programs for Streptococcus agalactiae, a bacterium very susceptible to penicillin products, were

generally implemented in the 1980’s and achieved low levels of this pathogen in dairy herds

(Makovec & Ruegg, 2003; Keefe, 2012), such that penicillin products could have an inflated

measure of cure of existing IMI within the network. This analysis was not pre-specified in the

protocol, but it was provided as a comparison to the overall treatment network.

36

2.4 RESULTS

2.4.1 Study selection

Results of the search and flow of the studies are presented in Figure 2.1. Following both

levels of relevance screening, all-cause cure of existing IMI from dry-off to calving was reported

in 72 trials, incidence of clinical mastitis in the first 30 DIM in cows with an existing IMI was

reported in six trials, and a metric for total antimicrobial use in the first 30 DIM in cows with an

existing IMI was reported in one trial. Because incidence of clinical mastitis and total antimicrobial

use in the first 30 DIM were reported in a limited number of trials, these outcomes were not further

analyzed. The process for collapsing antimicrobial treatment protocols was applied to the 72 trials

within which authors reported all-cause cure of existing IMI, which resulted in removal of some

trials because the intervention and comparator treatment arms became the same (n=13). Also, one

trial was removed due to insufficient data available to calculate the variance of the log odds in one

of the treatment arms. Cure of Staphylococcus aureus was reported in 27 trials, and cure of gram-

positive bacteria was reported in two trials; these trials were excluded from the analyses because

all-cause data were not reported. Therefore, 58 trials from 53 articles were included in the network

meta-analysis.

2.4.2 Study characteristics

Study characteristics for the 58 trials within which all-cause cure of existing IMI was

evaluated are included as Appendix 1. Trials were conducted in 19 countries, the majority in the

USA (n=19), United Kingdom (n=7), or Ireland (n=7). Most trials were conducted in commercial

dairy herds (47/58; 81.0%), followed by research/university herds (4/58; 6.9%) and in both

commercial and research/university herds (2/58; 3.5%). The type of study herd was not reported

in three trials (5.2%). Twenty-eight trials were published prior to 1990, 28 trials were published in

or following 1990, and year of publication was not reported for two trials. The breed of dairy cattle

studied was not reported in over half of the trials (33/58; 56.9%), but of remaining trials, the breed

was Holstein cattle (14/58; 24.1%), multiple breeds (7/58; 12.1%), Sahiwal cattle (1/58; 1.7%),

Norwegian Red cattle (1/58; 1.7%), Lowland Black and White cattle (1/58; 1.7%), and Brown

37

Swiss cattle (1/58; 1.7%). The number of herds investigated in each trial was reported for 51 trials,

the majority of which only included one herd (17/51; 33.3%). The number of herds within a trial

ranged from 1 to 288.

2.4.3 Risk of bias within individual studies – cure of IMI from dry-off to calving

The assessment of within-study risk of bias resulted in all trials deemed to be of ‘high’ risk

(26/58; 44.8%) or ‘some concerns’ (32/58; 55.2%).

We assessed 13 trials as ‘high’ risk of bias for the randomization process, 42 trials with

‘some concerns’, and assessed three trials as ‘low’ risk (reported both random allocation with a

method of sequence generation, allocation concealment until cows were assigned to interventions,

and no baseline imbalances). The word ‘random’ was used to describe allocation in almost half of

trials without details on sequence generation (22/58; 37.9%).

Risk of bias assessment due to deviations from intended interventions resulted in 39 trials

with ‘some concerns’, 19 trials with ‘low’ risk, and no trials with ‘high’ risk in this domain. Animal

trials need to account for the potential subjectivity of farm owners, herdspersons, and researchers

by blinding. Authors from five trials reported blinding of caregivers (8.6%), and the majority of

authors failed to report information for management of study animals (31/58; 53.5%). However,

most treatments were applied once at dry-off, which reduced the risk for deviations from intended

interventions. As a result, none of the trials were assessed as ‘high’ risk bias in this domain.

We assessed five trials as ‘high’ risk of bias due to missing outcome data, 15 as ‘some

concerns’, and 38 as ‘low’ risk of bias. Losses to follow-up were <5% in over half of the trials

(30/58; 51.7%). When losses to follow-up were >5%, reasons for missing observations that likely

affected the outcome (i.e. cows were removed due to clinical mastitis) were reported in six trials

(6/14; 42.9%). Of these six trials, reasons for missing observations that likely affected the outcome

were balanced among intervention groups in two trials, which resulted in low risk of bias for these

trials. The fifth high risk trial was assessed as having missing outcome data that did not appear to

38

be missing at random, but no information was provided for loss to follow-up or reasons for missing

outcome data.

Risk of bias assessment for measurement of the outcome resulted in a large number of

‘low’ risk trials (55/58; 94.8%), as cure of IMI was most often objectively assessed in trials (i.e.

bacteriologic culture, somatic cell count). Use of CMT as part of infection diagnosis was reported

in three trials, which resulted in a ‘high’ risk of bias for these trials (3/58; 5.2%).

The fifth domain, bias in selection of the reported result, requires an a priori trial protocol

to be published and available. A protocol created prior to trial commencement was not reported in

any trial, therefore, all trials had ‘some concerns’ in this domain.

2.4.4 Results of individual studies

Of the 58 included trials, frequency counts were reported in 51 trials, and adjusted data in

seven. Quarter-level outcomes were reported in 47 trials, both cow- and quarter-level outcomes in

three trials, and cow-level outcomes in eight trials. A split udder design was used in four trials. For

trials where adjusted data were reported, the clustering effect of quarter-level treatment allocation

within a cow was controlled for in four trials, and the clustering effect of cow-level treatment

allocation within a herd was controlled for in one trial.

Following the collapse of treatment arms, comparison of a non-active control to an active

treatment was made in about half of the included trials (30/58; 51.7%), of which 19 were two-arm

trials and 11 were multi-arm (three or more) trials. Comparison of an active to an active treatment

was made in the rest of included trials, of which 21 were two-arm trials and seven were multi-arm

trials.

2.4.5 Quantitative summary

A network meta-analysis was conducted for the outcome of all-cause cure of existing IMI

from dry-off to calving. Incidence of clinical mastitis over the first 30 DIM in cows with an existing

39

IMI at drying off and total antimicrobial use over the first 30 DIM with an existing IMI at drying

off were reported in an insufficient number of trials to inform useful networks.

2.4.6 Network meta-analysis: all-cause cure of existing IMI from dry-off to calving

The full network plot for all-cause cure of existing IMI is shown in Figure 2.2. Forty

unique treatment protocols from 58 trials were included in the network, of which 40 were two-arm

trials, 12 were three-arm trials, four were four-arm trials, and two were five-arm trials. Thirty-two

treatment protocols were administered via intramammary route, six treatment protocols were

administered via intramuscular route, and one protocol was a combination intramammary and

intramuscular treatment (Table 2.3). The post-1990 network meta-analysis is shown in Figure 2.3,

which included 31 unique treatment protocols from 30 trials, of which 19 were two-arm trials,

seven were three-arm trials, two were four-arm trials, and two were five-arm trials. A list of

antimicrobial treatment acronyms used in both network plots is provided in Table 2.3.

2.4.7 Summary of network geometry

The list of treatment protocols before and after the grouping process is included as

Appendix 2. All treatments were connected within both networks. The geometry of the full

network was visually dominated by non-active control, cloxacillin, and penicillin-

aminoglycosides, and the observed network C-score was 7.9 (95% CI: 7.4-7.8), which indicated a

selective pattern of treatments used within network comparisons. The network PIE score for the

full network was 0.9 indicating a diverse network. Convergence of all basic parameters within the

network meta-analysis was reached following 10,000 iterations (Appendix 3).

2.4.8 Assessment of consistency

None of the estimates resulting from direct comparisons of treatment protocols were

inconsistent with the estimates from indirect comparisons (Appendix 4); therefore, no trials were

removed from further analyses.

40

The residual deviance of the full network model was 82.9, and our data was comprised of

84 LORs suggesting no issues with model fit.

2.4.9 Rankings and distribution probability of IMI at calving

Relative risks from the full network meta-analysis for intramammary dry-cow treatments

currently labelled for use in Canada or the USA to cure existing IMI are provided in Figure 2.4.

The relative risk is the number of cure events out of total number treated in the trial-specific

comparator treatment divided by the number of cure events out of the total number treated in trial-

specific baseline treatment, provided in the upper right-hand side of the matrix. The lower left-

hand side of the matrix represents the corresponding 95% credibility intervals for each RR. No

antimicrobial treatment (non-active control) was associated with a decreased risk of experiencing

a cure when compared to cloxacillin (RR: 0.46, 95% CI: 0.22-0.80), penicillin-aminoglycosides

(RR: 0.51, 95% CI: 0.26-0.82), and ceftiofur (RR: 0.52, 95% CI: 0.24-0.84). The distribution of

the probability of a cure event for the full network for labelled antimicrobial treatment protocols

compared to non-active control is provided in Figure 2.5 a-c. The probability of a treatment being

the ‘best’ or worst’ treatment option is provided in Table 2.4.

The mean treatment ranks of labelled protocols from the full network are provided in Table

2.5 with corresponding 95% credibility intervals. Cloxacillin-extended therapy appeared to

perform the best relative to other labelled antimicrobial protocols (mean rank: 8.5, 95% CI: 2.0-

21.0), but due to the imprecision of the credibility intervals, differences in all-cause cure of IMI

during the dry period could not be established between antimicrobial therapies (Figure 2.6).

2.4.10 Risk of bias across studies

The contribution of trials within the full model to estimates of the relative efficacy of

labelled antimicrobial treatment protocols for all-cause cure of IMI based on the domain of risk of

bias due to randomization is presented in Figure 2.7, and the contribution of trials based on

blinding of caregivers in Figure 2.8. Most pairwise comparisons (71/78) had a majority

contribution from trials where allocation concealment was employed, but a non-random sequence

41

for treatment allocation was reported; or allocation concealment was employed, and random

allocation was reported but no details were provided on the method of sequence generation,

regardless of baseline imbalances; or allocation concealment was employed and a random

sequence for treatment allocation was reported, but baseline imbalances between treatment groups

were also reported; or no information on allocation concealment was reported, regardless of

random allocation to treatment groups, and either there were no baseline imbalances or no

information on baseline imbalances between treatment groups was available. Seven pairwise

comparisons had a majority contribution from trials where authors did not describe the process

used to generate the random sequence, or reported a non-random approach, and reported that

allocation was not concealed. Although a random method of sequence generation and allocation

concealment were reported in a few trials (3/58), this was not the majority contribution for any

pairwise comparisons of labelled antimicrobial treatment protocols. Most pairwise comparisons

had a majority contribution from trials where authors provided no information for blinding of

caregivers (71/78), followed by a small number with a majority contribution from trials where

authors did not blind caregivers (4/78), and a smaller number of trials with a majority contribution

where authors reported blinding of caregivers (3/78). Table 2.6 summarizes the majority

contribution for pairwise comparisons that included labelled antimicrobial products for

randomization, blinding, imprecision, and heterogeneity.

2.4.11 Results of additional analyses

From the 58 trials included in the full network meta-analysis, 30 trials were published in

1990 or later (including two trials where a year of publication was not reported). None of the

estimates resulting from direct comparisons of treatment protocols were inconsistent with the

estimates from indirect comparisons; therefore, no trials were removed from further analyses

(Appendix 5).

The PIE score of the post-1990 network geometry indicated sufficient diversity in the

network (PIE=0.9). The observed C-score was 4.3 (95% CI: 4.0-4.2), which indicated a selective

pattern of treatments. Convergence of all basic parameters of the post-1990 network meta-analysis

42

was reached following 10,000 iterations. The deviance residual of the model was 46.2, and our

dataset was comprised of 47 data points suggesting no issue with model fit.

Relative risks for all-cause cure of existing IMI in the post-1990 analysis were similar to

the RRs reported under the full network meta-analysis (Figure 2.9). Further, the mean treatment

ranks of labelled products in the post-1990 analysis had more precise 95% credibility intervals,

which also suggested cloxacillin-extended therapy performed best for cure of IMI during the dry

period (mean rank: 3.0, 95% CI: 1.0-10.0) (Table 2.7). The distribution of the probability of a cure

event for labelled antimicrobial treatments in the post-1990 analysis is provided in Figure 2.10 a-

c. Although we found improvement in precision estimates, there was still large overlap between

95% credibility intervals of the treatment protocols; therefore, the relative efficacy of treatment

protocols should be interpreted with caution (Figure 2.11).

2.5 DISCUSSION

2.5.1 Summary of evidence

Non-active control consistently resulted in relative risks for cure of intramammary

infections (IMI) less than 1 when compared to other treatment protocols, indicating each

intramammary dry-cow treatment currently labelled for use in Canada or the USA performed better

than no treatment. The results of this research are consistent with recommendations from the

National Mastitis Council to include dry-cow therapy as a component of an effective mastitis

control program. As we recognize cure of existing IMI is only part of an effective dry-cow therapy

program, a more advantageous use for our data is to describe which antimicrobial treatment

protocols can typically be avoided in decisions for the treatment of existing IMI at drying off. For

example, on the basis of the probability of treatments for ranking the ‘best’ or ‘worst’, cloxacillin,

cloxacillin-extended, cloxacillin-high dose, penicillin-aminoglycosides, penicillin-streptomycin-

extended, ceftiofur, cefapyrin, and penicillin-novobiocin never ranked as the worst treatment

protocol (Table 2.4). Products such as penicillin, teat sealant and non-active control ranked as the

worst treatment at least some of the time, thus indicating other products could be considered as

potentially more efficacious for cure. However, the basis for forming an evidence-based decision

43

on which products are more efficacious for treatment decisions in dry cows requires considerations

beyond the cure of existing intramammary infections. For example, previous meta-analyses have

assessed the application of teat sealants (Dufour et al., 2019; Winder et al., 2019b) at drying off

and the relative efficacy of antimicrobial products to prevent the occurrence of new IMI during the

dry period (Winder et al., 2019a).

Our results allow us to compare antimicrobial protocols important for human health to

those of lesser importance within the network. Cephalosporin protocols are of very high

importance in human health for the treatment of serious bacterial infections with limited or no

availability of an alternative (Health Canada, 2009). We found cefapyrin and ceftiofur, which are

first- and third-generation cephalosporins, respectively, had equivalent efficacy to other labelled

antimicrobials such as penicillin-aminoglycosides, cloxacillin, and penicillin-novobiocin.

Moreover, we found no advantageous use of extended therapy treatments, thus these treatments

could be reserved for special cases, for example chronically infected quarters (Gillespie et al.,

2002; Roy et al., 2009), in order to limit the use of antimicrobials important for human health on

dairy farms.

One article identified by the search defined antimicrobial use as the number of animal daily

dosages (ADD) for dry-cow therapy. One ADD was assigned per quarter treated with

antimicrobials at drying off (Scherpenzeel et al., 2014). This method of measuring antimicrobial

use is an important comparative approach that could be used by researchers to monitor

antimicrobial use in animal trials. The treatment of cows that have an existing infection at drying-

off is advantageous over no treatment, which could lead to a high ADD value at dry-off, but the

reduction of IMI during the dry period may also reduce the risk of clinical mastitis in the

subsequent lactation, and in turn reduce the amount of ADD needed for the treatment of clinical

mastitis. Monitoring the sources of ADD across dairy farms could identify areas where the prudent

use of antimicrobials should be improved, or for areas that could benefit from preventative disease

measures.

44

2.5.2 Limitations of the body of literature

Incidence of clinical mastitis up to 30 DIM in cows with an existing IMI at cessation of

lactation and total antimicrobial use up to 30 DIM in cows with an existing IMI at cessation of

lactation were defined as critical outcomes to inform the antimicrobial dry-cow therapy selection

process within the present review, yet neither outcome was commonly reported within the

literature. There is a need to develop consistency among researchers in the use of outcomes of

critical importance. The Core Outcome Measures in Effectiveness Trials (COMET) Initiative was

launched to guide the development of a set of core outcomes that should, at a minimum, be reported

in all clinical trials for specific topic areas (Kirkham et al., 2019). Currently, no such initiatives

exist that are specific to livestock species, but dairy researchers should consider adopting this

approach to identify core outcome measures that should be used in mastitis-related trials. Kelton

et al. (1998) developed recommendations in the reporting of case definitions for clinical disease in

dairy cattle, as well as guidelines to calculate and report incidence rates for disease occurrence.

Prior to this report, there was a lack of consistency in the definitions for clinical disease in dairy

cattle used by trialists (Kelton et al., 1998). These recommendations are an example of an early

initiative employed to standardize reporting in trials involving dairy cattle that can be built on

further to include a minimum set of outcomes that could be used when investigating clinical

diseases in dairy cows. In addition, standardized protocols have been developed by the National

Mastitis Council and the International Dairy Federation, such as documents on procedures for

collecting milk samples and guidance on standardized methods for bacteriologic culture (NMC,

2004; IDF, 2020), that aid in consistent classification of IMI. These guidance documents have

helped to reduce the variability in diagnostic methods for outcome determination; however,

support from these agencies is needed to inform consensus on a minimum set of outcomes to be

reported. Further, triplicate samples are the gold standard approach to sampling milk for

bacteriologic culture (Andersen et al., 2010; Dohoo et al., 2011); however, in the present review

bacteriologic cultures were performed using single, duplicate, and triplicate samples. Dohoo et al.

(2011) reported the best practices for taking milk samples that will be analyzed by bacteriologic

culture, but the reporting of milk sampling methodologies continues to vary in dairy trials.

45

In addition, our present review included trial-specific all-cause cure data, which varied by

definition between trials – likely as a result of the large range in year of publication. For example,

all-cause cure was reported as Staphylococcal spp. and Streptococcal spp. in some trials, reported

as only major pathogen cures in others, and reported as all major and minor pathogens in a few

trials. A future approach to analyzing such data would be to evaluate pathogen-specific cure

between antimicrobial treatment protocols, especially with the large body of evidence

investigating Staph aureus infected cows (Nickerson et al., 1999; Østerås et al., 1999; Mendoza et

al., 2016). Also, different antimicrobial products will be more efficacious against certain

pathogens, thus pathogen-specific cure data will help reduce differing pathogen susceptibilities as

a source of possible heterogeneity. In addition, the body of literature reporting cure of existing all-

cause bacterial infections in dry cows is much larger than the body of literature reporting cure data

for pathogen-specific infections; therefore, a network meta-analysis using pathogen-specific data

likely would have led to an increasingly sparse network. Further, we did not conduct a network

meta-analysis using pathogen-specific cure data in the present review because a network meta-

analysis evaluating antimicrobials to cure all-cause infections was vital to form a foundation for

further network meta-analyses that could stem from this current review.

A further limitation of the body of literature included in this systematic literature review

was the definition for the incidence of clinical mastitis risk period. In addition to lack of consensus

for a minimum set of core outcomes in livestock trials, there has been no consensus on an

appropriate risk period to measure these outcomes. We included trials that reported the incidence

of clinical mastitis over the first 30 days of the subsequent lactation, which is a commonly used

follow-up period to determine the effect of a dry cow intervention on the risk of clinical mastitis

in early lactation, but this may have been too short. If the risk period for CM had been increased

to over 100 DIM there likely would have been several additional articles for inclusion (Huxley et

al., 2002; Zecconi et al., 2014). Trialists conducting research on the efficacy of dry-cow

antimicrobials should explore all aspects involved in veterinary and producer treatment decisions,

which include cure of existing IMI, prevention of new IMI, and incidence of clinical mastitis, and

report metrics, such as ADD, for total antimicrobial use within the herd. Inclusion of these relevant

outcomes in trials will promote uniform data collection and reporting, and ease the trial replication

46

process in order to add to disparate bodies of literature, such as the body of literature included in

this network meta-analysis.

Trial replication, meaning several evaluations of the same outcome for the same

intervention (Sargeant et al., 2019), was an additional major limitation of the body of literature

included in this systematic literature review and network meta-analysis. In addition to issues in the

reporting of outcomes and the risk period for measurement of these outcomes, poor trial replication

rendered us unable to form a solid foundation of evidence (Sargeant et al., 2019). Although all

treatment protocols were connected within our network, some treatment protocols were only used

in one (i.e. gentamicin) or two (i.e. cefquinome) comparisons meaning the evaluation of these

products on the basis for effectiveness to cure IMI were not well replicated in available literature.

Improved replication of antimicrobial interventions in dairy science, and consistency of outcome

reporting, are needed in order take advantage of the benefits of network meta-analyses.

2.5.3 Limitations of the review

A large number of trials were excluded at full-text screening because they were not

published in English, and translation was not a viable option. By using trials that reported all-cause

cure of existing IMI, pathogen profiles could have differed by country, and therefore so could have

antimicrobial efficacies. Inclusion of these trials may have resulted in differing evidence on the

basis of efficacy for these products to cure existing IMI; however, inclusion of further relevant

trials could have increased the precision of our summary estimates and led to a more meaningful

interpretation of results. Furthermore, the collapse of treatment protocols within our network meta-

analysis could have resulted in some treatment protocols appearing more or less efficacious than

in actuality (i.e. some treatment protocols included products of varying dosages and active

treatment compounds). However, the lack of available evidence necessitated combining

antimicrobial treatments to provide sufficient replication of interventions for analysis, and the

attempt was made to not compromise clinical relevancy for veterinarians and dairy producers.

In addition, limitations in precision of effect estimates of individual trials resulted in

several pairwise comparisons within our network meta-analysis with ‘major concerns’ for risk of

47

contradictory evidence that could potentially lead to different clinical decisions. Continued

improvement in methodological reporting and replication of controlled trials in dairy science is

needed to better inform cure decisions. Poor reporting is an issue that is recognized across trials in

dairy cattle science (Winder et al., 2019c), which can be mitigated by the use of reporting

guidelines such as the Reporting Guidelines for Randomized Controlled Trials for Livestock and

Food Safety (REFLECT) statement (O’Connor et al., 2010; Sargeant et al., 2010). The use of such

reporting guidelines appears to be advantageous to decreasing within-trial biases and increases the

transparency of trial methodologies (Moura et al., 2019); therefore, use of reporting guidelines

should be mandatory for journal publication.

2.6 CONCLUSION

Antimicrobials most often reported in trials evaluating the treatment of existing

intramammary infections (IMI) during the dry period were cloxacillin, penicillin-aminoglycosides,

and cefapyrin products. Non-active control was the most common comparator group. Although 58

trials were included in this analysis, the low number of trials contributing to each direct comparison

created imprecise credibility intervals which challenged our ability to provide a ranked order of

products on the basis of efficacy. Consensus statements regarding a minimum set of required

outcomes that should be reported in effectiveness trials investigating antimicrobial products to

improve udder health are needed and should be referenced in future dairy research. Further, trial

replication evaluating antimicrobial treatment protocols is required in order to avoid disparate

network meta-analyses and form a solid evidence base for clinical decision-making. These major

limitations of the body of evidence included in this network meta-analysis prevented us from

evaluating dry-cow antimicrobials products on their basis of effectiveness to cure IMI during the

dry period.

2.6.1 Protocol deviations

The additional post-1990 network meta-analysis was not planned at the time of protocol

registration. However, this analysis was used for the purpose of comparing estimates between the

48

full network before and after a temporal change in the prevalent bacterial species associated with

mastitis.

2.6.2 Author contributions

CKM developed the review protocol, coordinated the research teams, conducted data

screening, data extraction, and risk of bias assessment, conducted the analyses, interpreted the

results, and developed the manuscript drafts. JMS, DFK, AMO, and CBW provided

methodological support and content expertise, commented on manuscript drafts, and approved the

final manuscript. JG and HW developed the literature search strategies, conducted all searches,

commented on manuscript drafts, and approved the final manuscript. DH developed the user-

defined functions in R for data analysis, provided methodological support, aided in risk of bias

assessment, commented on manuscript drafts, and approved the final manuscript. CNR conducted

data extraction, commented on manuscript drafts, and approved the final manuscript.

2.6.3 Acknowledgements and funding

There was no external funding support for this network meta-analysis. Stipend funding

support for CKM was provided by the OVC Entrance Award and the Queen Elizabeth II Graduate

Scholarship in Science and Technology from the University of Guelph and the Ministry of

Training, Colleges and Universities. Additional acknowledgements to the donors of the Dr. Francis

H.S. Newbould Award, the Dr. Casey Buizert Memorial Award, the Dr. R.A. McIntosh Graduate

Award (OVC ‘45) and the Barbara Kell Gonsalves Memorial Scholarship for their funding

support. Kineta Cousins, Katheryn Churchill and Shannon Hookey provided support for all levels

of screening and the assessment of risk of bias of individual trials.

2.6.4 Conflicts of interest

None of the authors have conflicts to declare.

49

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55

2.8 TABLES

Table 2.1 Search strategy to identify relevant articles for the network meta-analysis assessing the

relative efficacy of antimicrobial protocols for cure of existing intramammary infections during

the dry period in dairy cattle, conducted on June 14, 2019 in Science Citation Index (Web of

Science)

# 19 982 #18 OR #17 OR #12

# 18 443 TS=(("dry cow" OR "dry cows") NEAR/3 (therap* OR manag* OR intervention*

OR treat* OR strateg*))

# 17 195 #16 AND #15 AND #7

# 16 17,432 TS=(mastiti* OR ((intramammar* OR "intra-mammar*") NEAR/3 (infect* OR

inflamm*)))

# 15 463,593 #14 OR #13

# 14 290,302 TS=(("mass" OR "blanket" OR "whole population*" OR "population wide"

OR selectiv* OR "targeted" OR prevent*) NEAR/5 (treat* OR therap* OR medicat* OR "dosing"

OR "administration"))

# 13 186,857 TS=(prophyla* OR chemoprophyla* OR chemoprevent* OR "chemo-

prevent*" OR metaphyla* OR "meta-phyla*" OR premedicat* OR "pre-medicat*")

# 12 760 #11 AND #7

# 11 651,187 #10 OR #9 OR #8

# 10 174,174 TS=("albamycin" OR "amoxicillin" OR "amoxycillin" OR "ampicillin" OR

"benzathine" OR "cathomycin" OR "cefalexin" OR "cefapirin" OR "cefalonium" OR

"cefquinome" OR "ceftiofur" OR "cephalexin" OR "cephapirin" OR "cephalonium" OR

"cephapirin" OR "chlortetracycline" OR "cloxacillin" OR "CTC" OR "danofloxacin" OR

"dicloxacillin" OR "dihydrostreptomycin" OR "enrofloxacin" OR "erythromycin" OR

"florfenicol" OR "framycetin" OR "gamithromycin" OR "gentamicin" OR "gentamycin" OR

"lincomycin" OR lincosamide* OR "neomycin" OR "novobiocin" OR "oxytetracycline" OR

"penethamate" OR "penicillin" OR "pirlimycin" OR "piroline" OR "spectinomycin" OR

"sulfadimethoxine" OR "sulfafurazole" OR "sulfamethoxazole" OR "sulfisoxazole" OR

"sulphadimethoxine" OR "tetracycline" OR "tildipirosin" OR "tilmicosin" OR "trimethoprim" OR

"tulathromycin" OR "tylosin")

# 9 551,381 TS=(antimicrobial* OR "anti-microbial*" OR antibiotic* OR "anti-biotic*"

OR antibacterial* OR "anti-bacterial*" OR antiinfect* OR anti-infect* OR bacteriocid* OR

bactericid* OR microbicid* OR "anti-mycobacteri*" OR antimycobacteri*)

# 8 175 TS=("SDCT" OR "BDCT")

# 7 10,132 #6 OR #5

56

# 6 1,246 TS=("dry cow" OR "dry cows")

# 5 9,426 #4 AND #3

# 4 248,441 TS=("drying off" OR "dry off" OR "dried off" OR "dry up" OR "drying up"

OR "dried up" OR "drying period*" OR "dry period*" OR "dry udder*" OR "dry teat*" OR "pre-

partum" OR "prepartum" OR (("end" OR finish* OR stop* OR ceas*) NEAR/3 lactat*) OR

nonlactat* OR "non-lactat*" OR postlactat* OR "post-lactat*" OR postmilk* OR "post-milk*" OR

"involution" OR "steady state")

# 3 510,434 #2 OR #1

# 2 56,599 TS=(ayrshire* OR "brown swiss*" OR "busa" OR "busas" OR canadienne*

OR dexter* OR "dutch belted*" OR "estonian red*" OR fleckvieh* OR friesian* OR girolando*

OR guernsey* OR holstein* OR illawarra* OR "irish moiled*" OR jersey* OR "meuse rhine

issel*" OR montbeliarde* OR normande* OR "norwegian red*" OR "red poll" OR "red polls" OR

shorthorn* OR "short horn*")

# 1 483,761 TS=("cow" OR "cows" OR "cattle" OR heifer* OR "dairy" OR "milking"

OR bovine* OR "bovinae" OR buiatric*)

57

Table 2.2 Currently labelled antimicrobial products for intramammary use in dairy cattle at dry-

off to cure existing intramammary infections in Canada and the United States of America (August,

2020)

Treatment Country Ingredients

ALBADRY PLUS

(intramammary)

USA1 Penicillin G procaine and

novobiocin sodium

suspension

Dry-Clox (intramammary) USA, Canada2 Cloxacillin benzathine

GO-DRY USA Penicillin G procaine in

sesame oil

Orbenin-DC (intramammary) USA Cloxacillin benzathine

QUARTERMASTER

SUSPENSION

(intramammary)

USA Penicillin-

dihydrostreptomycin in oil

SPECTRAMAST DC

(intramammary)

USA, Canada Ceftiofur hydrochloride

ToMORROW USA Cefapirin benzathine

Cefa-Dri (intramammary) Canada Cefapirin benzathine

Novodry Plus

(intramammary)

Canada Penicillin and novobiocin

1Data from the Compendium of veterinary products – US edition (Animalytix, 2020a)

2Data from the Compendium of veterinary products – Canada edition (Animalytix, 2020b)

58

Table 2.3 Description of treatment arms included in the network meta-analysis assessing the

relative efficacy of antimicrobial dry cow products for cure of existing intramammary infections,

and the corresponding tables and figures

Treatment Description

NAC Non-active control

Cx* IMM1 cloxacillin (therapeutic dosage)

Cxext* IMM cloxacillin – extended therapy (given at two or three times during dry period)

CxL* IMM cloxacillin – low dosage

CxH* IMM cloxacillin – high dosage

CNC IMM cortisone/neomycin/chlorobutanol

NonA IMM non-antimicrobial treatment (includes holistic, vitamin and mineral products)

Pam* IMM penicillin/aminoglycoside combinations (OIE list)

PSext* IMM penicillin/streptomycin – extended therapy

PCS IMM penicillin/chloramphenicol/sulfa

Ox IMM oxacillin

B* IMM ceftiofur

CP IMM cephalonium

C* IMM cefapyrin

Cdext IMM cefradine – extended therapy

CfN IMM cefalexin/neomycin

Cq IMM cefquinome

Cz IMM cefazolin

CA IMM cloxacillin/ampicillin

DiCx IMM dicloxacillin

E-IMM IMM enrofloxacin

Erm IMM erythromycin

G IMM gentamicin

OxN IMM oxytetracycline/neomycin

N IMM novobiocin

P* IMM penicillin

PNv* IMM penicillin/novobiocin

PNext IMM penicillin/neomycin – extended therapy

S IMM spiramycin

SN IMM spiramycin/neomycin

T IMM tilmicosin

OxE IMM oxacillin, intramuscular enrofloxacin

ELext IM2 enrofloxacin/levamisole – extended therapy

L IM levamisole

E-ext IM enrofloxacin – extended therapy

E-INJ IM enrofloxacin

LSext IM lincomycin/spiramycin

EVeS IM enrofloxacin/vitamin E/selenium

TS Teat sealant (various trade names)

*Treatment arms of currently labelled antimicrobials for use in Canada and the USA to cure IMI

in dairy cattle at dry-off (Animalytix, 2020a; Animalytix, 2020b)

1IMM = intramammary route of administration

2IM = intramuscular route of administration

59

Table 2.4 (Full network) The probability of currently labelled antimicrobial treatment protocols

for ranking the best and worst treatment for cure of existing intramammary infections within the

full network meta-analysis

Name1 Probability of Best Rank Probability of Worst Rank

NAC 0 0.074

Cx 0 0

Cxext 0.01 0

CxL 0.008 0

CxH 0 0

NonA 0 0

Pam 0 0

PSext 0.002 0

B 0 0

C 0 0

P 0 0.001

PNv 0 0

TS 0 0.12

1NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxL =

cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam =


cefapyrin, P = penicillin, PNv = penicillin-novobiocin, TS = teat sealant

60

Table 2.5 (Full network) Mean rank, standard deviation, and rankings at the 2.5%, 50%, and 97.5%

points of the distribution for currently labelled treatment arms in the full network meta-analysis of

antimicrobial protocols to cure existing intramammary infections during the dry period. A lower

mean rank score indicates a high estimated cure risk, for a possible score between 1 and 40

Treatment1 Mean SD 2.5% 50% 97.5%

NAC 37.36 1.75 33 38 40

TS 32.18 8.05 10 35 40

NonA 28.56 4.89 17 29 36

P 27.19 6.37 13 28 37

Pam 23.41 4.01 15 23 31

C 23.01 5.99 11 23 34

B 22.95 6.36 10 23 34

PNv 21.14 6.57 9 21 33

Cx 18.15 3.55 12 18 25

CxH 15.86 6.49 6 15 30

CxL 14.27 8.68 2 12 34

PSext 13.49 6.91 3 12 30

Cxext 8.45 4.7 2 8 21





61

Table 2.6 (Full network) Summary of the overall quality of evidence of the network meta-analysis

assessing the relative efficacy of currently labelled dry-off antimicrobial protocols for cure of

existing intramammary infections during the dry period in dairy cattle, using the Confidence In

Network Meta-Analysis (CINeMA) platform, with some modifications, to determine the risk of

bias due to approach to randomization, blinding, imprecision, and heterogeneity

Comparison1 Number of studies Randomization Blinding Imprecision Heterogeneity

B:C 2 Some concerns Some concerns Major concerns No concerns

B:Cx 1 Some concerns Some concerns Major concerns No concerns

B:NAC 1 Some concerns Some concerns No concerns Some concerns

B:Pam 2 Some concerns Some concerns Major concerns No concerns

C:NAC 4 Some concerns Some concerns No concerns Some concerns

C:Pam 2 Some concerns Some concerns Major concerns No concerns

Cx:CxH 2 Some concerns Some concerns Major concerns No concerns

Cx:Cxext 2 Some concerns Some concerns Some concerns Some concerns

Cx:NAC 8 Some concerns Some concerns No concerns No concerns

Cx:NonA 2 Some concerns Some concerns Some concerns Some concerns

Cx:PNv 1 Major concerns Major concerns Major concerns No concerns

Cx:Pam 9 Some concerns Some concerns Some concerns Some concerns

CxH:CxL 1 Some concerns Some concerns Major concerns No concerns

Cxext:CxH 1 Some concerns Some concerns Major concerns No concerns

CxH:NAC 1 Some concerns Some concerns No concerns No concerns

CxL:NAC 1 Some concerns Some concerns No concerns No concerns

Cxext:NAC 2 Some concerns Some concerns No concerns No concerns

NAC:NonA 2 Some concerns Some concerns No concerns Major concerns

NAC:P 2 Some concerns Some concerns No concerns Major concerns

NAC:PNv 3 Some concerns Some concerns No concerns No concerns

NAC:PSext 2 Some concerns No concerns No concerns No concerns

NAC:Pam 6 Some concerns Some concerns No concerns Some concerns

NonA:Pam 2 Some concerns Some concerns Major concerns No concerns

P:PNv 1 Major concerns Major concerns Major concerns No concerns

P:Pam 1 Some concerns Some concerns Major concerns No concerns

Pam:PSext 1 Some concerns No concerns Major concerns No concerns

B:CxH 0 Some concerns Some concerns Major concerns No concerns

B:CxL 0 Some concerns Some concerns Major concerns No concerns

B:Cxext 0 Some concerns Some concerns No concerns Major concerns

62

B:NonA 0 Some concerns Some concerns Major concerns No concerns

B:P 0 Some concerns Some concerns Major concerns No concerns

B:PNv 0 Some concerns Some concerns Major concerns No concerns

B:PSext 0 Some concerns Some concerns Major concerns No concerns

B:TS 0 Some concerns Some concerns Major concerns No concerns

C:Cx 0 Some concerns Some concerns Major concerns No concerns

C:CxH 0 Some concerns Some concerns Major concerns No concerns

C:CxL 0 Some concerns Some concerns Major concerns No concerns

C:Cxext 0 Some concerns Some concerns No concerns Major concerns

C:NonA 0 Some concerns Some concerns Major concerns No concerns

C:P 0 Some concerns Some concerns Major concerns No concerns

C:PNv 0 Some concerns Some concerns Major concerns No concerns

C:PSext 0 Some concerns No concerns Major concerns No concerns

C:TS 0 Some concerns Some concerns Major concerns No concerns

Cx:CxL 0 Some concerns Some concerns Major concerns No concerns

Cx:P 0 Some concerns Some concerns Major concerns No concerns

Cx:PSext 0 Some concerns Some concerns Major concerns No concerns

Cx:TS 0 Major concerns Some concerns Major concerns No concerns

CxH:NonA 0 Some concerns Some concerns Major concerns No concerns

CxH:P 0 Some concerns Some concerns Major concerns No concerns

CxH:PNv 0 Some concerns Some concerns Major concerns No concerns

CxH:PSext 0 Some concerns Some concerns Major concerns No concerns

CxH:Pam 0 Some concerns Some concerns Major concerns No concerns

CxH:TS 0 Some concerns Some concerns Major concerns No concerns

Cxext:CxL 0 Some concerns Some concerns Major concerns No concerns

CxL:NonA 0 Some concerns Some concerns Major concerns No concerns

CxL:P 0 Some concerns Some concerns Major concerns No concerns

CxL:PNv 0 Some concerns Some concerns Major concerns No concerns

CxL:PSext 0 Some concerns Some concerns Major concerns No concerns

CxL:Pam 0 Some concerns Some concerns Major concerns No concerns

CxL:TS 0 Some concerns Some concerns Major concerns No concerns

Cxext:NonA 0 Some concerns Some concerns No concerns Major concerns

Cxext:P 0 Some concerns Some concerns No concerns Major concerns

Cxext:PNv 0 Some concerns Some concerns Some concerns Some concerns

Cxext:PSext 0 Some concerns Some concerns Major concerns No concerns

63

Cxext:Pam 0 Some concerns Some concerns No concerns Major concerns

Cxext:TS 0 Some concerns Some concerns No concerns Major concerns

NAC:TS 0 Major concerns Some concerns Major concerns No concerns

NonA:P 0 Some concerns Some concerns Major concerns No concerns

NonA:PNv 0 Some concerns Some concerns Major concerns No concerns

NonA:PSext 0 Some concerns Some concerns Major concerns No concerns

NonA:TS 0 Some concerns Some concerns Major concerns No concerns

P:PSext 0 Some concerns Major concerns Major concerns No concerns

P:TS 0 Major concerns Some concerns Major concerns No concerns

PNv:PSext 0 Some concerns Major concerns Major concerns No concerns

Pam:PNv 0 Some concerns Some concerns Major concerns No concerns

PNv:TS 0 Major concerns Some concerns Major concerns No concerns

PSext:TS 0 Some concerns Some concerns Major concerns No concerns

Pam:TS 0 Major concerns Some concerns Major concerns No concerns





64

Table 2.7 (Post-1990 analysis) Mean rank for currently labelled treatment arms in the network

meta-analysis of antimicrobial protocols to cure existing intramammary infections during the dry

period, for trials published 1990 – 2019. A lower mean rank score indicates a high estimated cure

risk, for a possible score between 1 and 31

Treatment1 Mean SD 2.5% 50% 97.5%

NAC 28.67 1.78 24 29 31

TS 23.13 6.84 7 25 31

NonA 20.81 5 10 21 29

C 19.79 5.01 9 20 28

Pam 19.75 3.77 12 20 27

B 17.72 4.81 8 18 27

PNv 17.53 7.89 4 18 30

CxH 17.26 7.31 4 17 30

PSext 16.02 6.88 4 16 29

Cx 10.22 3.22 5 10 17

Cxext 2.97 2.43 1 2 10

1NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxH =

cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-aminoglycosides,


novobiocin, TS = teat sealant

65

2.9 FIGURES


diagram of included studies and trials for the systematic review of dry-off antimicrobials to cure

existing intramammary infections in dairy cattle (Moher et al., 2009). The search, conducted by

researchers at the University of York, provided an update to a search used to identify articles for a

previous systematic review and network meta-analysis (Winder et al., 2019a)

66

Figure 2.2 (Full network) Network plot assessing the efficacy of dry-cow antimicrobials, non-

antimicrobial products, or placebos for all-cause cure of intramammary infections in dairy cattle.

This plot contains 58 trials, with the number of treatment comparisons provided in parentheses.

Non-active control had the most treatment comparisons (30 arms). Node size represents the

number of times each treatment was used. Edge size represents the number of direct comparisons

made between two treatment protocols. NAC = non-active control, Cx = cloxacillin, Cxext =

cloxacillin-extended therapy, CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA =

non-antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-


teat sealant

67

Figure 2.3 (Post-1990 analysis) Network plot assessing the relative efficacy of dry-cow

antimicrobials, non-antimicrobial products, or placebos for all-cause cure of intramammary

infections in dairy cattle from trials published between 1990 - 2019. This plot contains 30 trials,

with the number of treatment comparisons provided in parentheses. Non-active control had the

most treatment comparisons (14 arms). Node size represents the number of times each treatment

was used. Edge size represents the number of direct comparisons made between two treatment

protocols. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxH

= cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-aminoglycosides,


novobiocin, TS = teat sealant

68

NAC 0.461 0.405 0.453 0.455 0.595 0.505 0.439 0.516 0.511 0.581 0.497 0.790

(0.218,

0.802) Cx 0.886 0.947 0.970 1.210 1.070 0.944 1.066 1.064 1.168 1.034 1.575

(0.138,

0.781)

(0.567,

1.027) Cxext 1.048 1.084 1.389 1.219 1.048 1.214 1.213 1.341 1.174 1.822

(0.157,

0.831)

(0.612,

1.585)

(0.814,

2.110) CxL 1.023 1.270 1.128 0.999 1.125 1.125 1.230 1.093 1.655

(0.182,

0.805)

(0.717,

1.317)

(0.911,

1.785)

(0.613,

1.582) CxH 1.248 1.102 0.975 1.101 1.099 1.205 1.068 1.625

(0.302,

0.905)

(0.976,

2.292)

(1.037,

3.450)

(0.792,

3.045)

(0.908,

2.678) NonA 0.896 0.778 0.899 0.897 0.977 0.873 1.265

(0.260,

0.820)

(0.951,

1.445)

(1.014,

2.251)

(0.697,

2.044)

(0.836,

1.759)

(0.502,

1.170) Pam 0.878 0.996 0.998 1.083 0.974 1.443

(0.164,

0.799)

(0.639,

1.310)

(0.822,

1.774)

(0.527,

1.600)

(0.604,

1.453)

(0.342,

1.068)

(0.523,

1.158) PSext 1.134 1.134 1.246 1.100 1.688

(0.238,

0.836)

(0.862,

1.717)

(0.981,

2.516)

(0.677,

2.265)

(0.790,

1.998)

(0.470,

1.335)

(0.731,

1.467)

(0.819,

2.169) B 1.001 1.082 0.976 1.441

(0.245,

0.828)

(0.866,

1.661)

(0.987,

2.397)

(0.682,

2.174)

(0.796,

1.917)

(0.470,

1.296)

(0.733,

1.426)

(0.826,

2.082)

(0.664,

1.450) C 1.083 0.977 1.441

(0.278,

0.909)

(0.907,

2.352)

(1.014,

3.377)

(0.751,

2.998)

(0.857,

2.687)

(0.526,

1.763)

(0.796,

1.976)

(0.891,

2.909)

(0.694,

2.124)

(0.722,

2.108) P 0.897 1.298

(0.224,

0.826)

(0.817,

1.613)

(0.959,

2.336)

(0.655,

2.060)

(0.755,

1.855)

(0.441,

1.280)

(0.672,

1.424)

(0.777,

2.025)

(0.587,

1.503)

(0.615,

1.494)

(0.460,

1.305) PNv 1.490

(0.290,

3.512)

(0.892,

9.425)

(1.002,

12.648)

(0.817,

11.260)

(0.881,

10.357)

(0.573,

6.977)

(0.783,

8.168)

(0.909,

11.092)

(0.726,

8.438)

(0.742,

8.449)

(0.579,

7.448)

(0.763,

8.920) TS

Figure 2.4 (Full network) Relative risk ratios of currently labelled antimicrobial protocols assessed

in the network for all-cause cure of existing intramammary infections during the dry period. The

upper right-hand side of the matrix indicates the RR of row treatment compared to column

treatment (i.e. the risk of experiencing a cure with non-active control is 0.46 times the risk of

experiencing a cure with cloxacillin). The lower left-hand side of the matrix indicates the 95%

credibility intervals for each RR. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-




teat sealant

69

Figure 2.5 a-c (Full network) Probability distribution of experiencing an all-cause cure of existing


protocols. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxL

= cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam =



70

Figure 2.6 (Full network) Forest plot of mean treatment rank for currently labelled treatment

protocols to cure existing intramammary infections during the dry period. The black squares

indicate the mean rank of each treatment and its size reflects the precision (1/variance) of the

estimate. Values are reported as mean treatment rank with corresponding 95% credibility interval.

The number of treatment comparisons are provided in parentheses beside the treatment names.

NAC = non-active control, TS = teat sealant, NonA = non-antimicrobial therapy, P = penicillin,

Pam = penicillin-aminoglycosides, C = cefapyrin, B = ceftiofur, PNv = penicillin-novobiocin, Cx

= cloxacillin, CxH = cloxacillin-high dose, CxL = cloxacillin-low dose, PSext = penicillin-

streptomycin-extended therapy, Cxext = cloxacillin-extended therapy

71

Figure 2.7 (Full network) The contribution of trials to the point estimate of currently labelled antimicrobial products

based on the description of randomization for trials contributing to the network meta-analysis assessing the relative

efficacy of dry-off antimicrobial protocols to cure existing intramammary infections during the dry period in dairy

cattle (n=58). Grey indicates allocation concealment was employed, random allocation to treatment groups and a

method of sequence generation were reported, and there were no baseline imbalances between treatment groups. White

indicates allocation concealment was employed, but participants were allocated using a non-random sequence; or

allocation concealment was employed, and random allocation was reported but no details were provided on the method

of sequence generation, regardless of baseline imbalances; or allocation concealment was employed, and random

allocation with a method for sequence generation were reported, but baseline imbalances between treatment groups

were reported; or no information on allocation concealment was reported and either no or no information on baseline

imbalances between treatment groups were reported, regardless of random allocation. Black indicates no information

was reported for allocation concealment, and there were baseline imbalances between treatment groups, or allocation

concealment was not employed, regardless of random allocation. White vertical lines indicate the percentage of

contribution of separate trials. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxL

= cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-

aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B = ceftiofur, C = cefapyrin, P = penicillin, PNv

= penicillin-novobiocin, TS = teat sealant

72

Figure 2.7 (Continued)

73


antimicrobial products based on the description of blinding of caregivers for trials contributing to

the network meta-analysis assessing the relative efficacy of dry-off antimicrobial protocols for

cure of existing intramammary infections during the dry period in dairy cattle (n=58). Grey

indicates blinding of caregivers was used, white indicates no information for blinding of

caregivers, and black indicates blinding of caregivers was not used. White vertical lines indicate

the percentage of contribution of separate trials. NAC = non-active control, Cx = cloxacillin, Cxext

= cloxacillin-extended therapy, CxL = cloxacillin-low dose, CxH = cloxacillin-high dose, NonA

= non-antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-


teat sealant

74

Figure 2.8 (Continued)

75

NAC 0.439 0.384 0.556 0.610 0.560 0.529 0.537 0.576 0.572 0.734

(0.168,

0.817) Cx 0.887 1.136 1.273 1.220 1.098 1.153 1.225 1.147 1.500

(0.100,

0.799)

(0.519,

0.994) Cxext 1.315 1.471 1.402 1.259 1.325 1.413 1.321 1.744

(0.199,

1.225)

(0.858,

3.429)

(1.016,

4.886) CxH 1.085 1.047 0.977 1.009 1.053 1.007 1.244

(0.267,

1.070)

(0.943,

3.471)

(1.04,

5.176)

(0.407,

2.878) NonA 0.962 0.894 0.922 0.969 0.933 1.138

(0.278,

0.872)

(1.007,

2.302)

(1.047,

3.728)

(0.406,

2.039)

(0.436,

1.620) Pam 0.931 0.961 1.006 0.965 1.202

(0.195,

0.970)

(0.805,

2.867)

(1.000,

4.172)

(0.328,

2.369)

(0.340,

1.919)

(0.506,

1.823) PSext 1.032 1.081 1.033 1.290

(0.237,

0.871)

(0.951,

2.205)

(1.031,

3.504)

(0.373,

1.920)

(0.387,

1.585)

(0.617,

1.413)

(0.479,

1.976) B 1.048 1.001 1.259

(0.265,

0.914)

(0.965,

2.727)

(1.040,

4.246)

(0.400,

2.314)

(0.426,

1.864)

(0.648,

1.729)

(0.512,

2.383)

(0.706,

1.836) C 0.961 1.181

(0.200,

1.362)

(0.787,

4.246)

(0.995,

6.060)

(0.342,

3.349)

(0.343,

2.835)

(0.474,

2.946)

(0.423,

3.555)

(0.505,

3.211)

(0.422,

2.930) PNv 1.224

(0.257,

2.841)

(0.931,

8.626)

(1.024,

12.655)

(0.463,

6.805)

(0.444,

5.893)

(0.61,

5.932)

(0.546,

7.403)

(0.636,

6.570)

(0.545,

6.068)

(0.387,

7.114) TS

Figure 2.9 (Post-1990 analysis) Relative risk ratios of currently labelled antimicrobial protocols

included in the network for cure of intramammary infections during the dry-period from trials

published between 1990 – 2019. The upper right-hand side of the matrix indicates the RR of row

treatment compared to column treatment (i.e. the risk of experiencing a cure with non-active

control is 0.44 times the risk of experiencing a cure using cloxacillin). The lower left-hand side of

the matrix indicates the 95% credibility intervals for each RR. NAC = non-active control, Cx =

cloxacillin, Cxext = cloxacillin-extended therapy, NonA = non-antimicrobial therapy, CxH =

cloxacillin-high dose, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-

extended therapy, B = ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin

76

Figure 2.10 a-c (Post-1990 analysis) Probability distribution of experiencing a cure of


protocols for trials published between 1990 – 2019. NAC = non-active control, Cx = cloxacillin,

Cxext = cloxacillin-extended therapy, CxH = cloxacillin-high dose, NonA = non-antimicrobial

therapy, Pam = penicillin-aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B

= ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin, TS = teat sealant

77

Figure 2.11 (Post-1990 analysis) Forest plot of mean treatment rank 1990 – 2019 for currently

labelled antimicrobial treatments to cure existing intramammary infections during the dry-period.

The black squares indicate the mean rank of each treatment and its size reflects the precision

(1/variance) of the estimate. Values are reported as mean treatment rank with corresponding 95%

credibility interval. The number of treatment comparisons are provided in parentheses beside the

treatment names. NAC = non-active control, TS = teat sealant, NonA = non-antimicrobial therapy,

C = cefapyrin, Pam = penicillin-aminoglycosides, B = ceftiofur, PNv = penicillin-novobiocin, CxH

= cloxacillin-high dose, PSext = penicillin-streptomycin-extended therapy, Cx = cloxacillin, Cxext

= cloxacillin-extended therapy

78

3 CHAPTER 3: MODIFIABLE MANAGEMENT PRACTICES

TO IMPROVE UDDER HEALTH DURING THE DRY

PERIOD AND SUBSEQUENT LACTATION: A SCOPING

REVIEW

3.1 ABSTRACT

The objective of this scoping review was to characterize all available literature on modifiable

dairy management practices used during the dry period which have been evaluated for their impact

on udder health in dairy cattle, both during the dry period and the subsequent lactation. Five

databases and two conference proceedings were searched for relevant literature. Articles published

in or after 1990 were eligible for inclusion and required a population of dairy cattle at cessation of

lactation, an intervention or exposure of any modifiable management practice which could be used

by investigators at the time of dry off for their impact on udder health, and had to provide

comparison to at least one other different intervention or exposure, a different level of the given

intervention/exposure, or a non-treated control group or placebo. Eligible interventions or

exposures were restricted to modifiable management practices; however, antimicrobial and teat

sealant products were only enumerated and not further characterized in this scoping review due to

several systematic reviews on this topic. Of the initial 4425 articles screened by two reviewers,

420 articles were included in the quantitative summary. Antimicrobials and teat sealants alone

were assessed in 74 articles, antimicrobials alone in 108 articles, and teat sealants alone in 9

articles. Other modifiable management practices were reported in 229 articles. Ration formulation

and delivery was the most commonly reported practice in included articles (n=44), followed by

vaccines (n=40), vitamin and minerals supplements in the feed (n=35), and dry period length

(n=27). Less commonly evaluated management practices were extending teat dip protocols into

the dry period (n=5) and photoperiod manipulation (n=2). Clinical mastitis was the most

commonly reported outcome (n=151); however, large between article variation was found in the

reporting of outcome risk periods. Cure of existing intramammary infections (IMI) over the dry

period (n=40) and prevention of new IMI over the dry period (n=54) were most commonly reported

with a risk period between calving and 30 days in milk (DIM). Future systematic reviews with

meta-analyses should target management practices such as nutrition and vaccine regimens.

79

However, the variation in reporting of time at risk for clinical mastitis and other outcomes

challenges the ability of future synthesis work to inform management decisions on the basis of

efficacy to cure or prevent IMI and clinical mastitis. Consensus on which core outcomes should

be evaluated in mastitis research and the selection of consistent risk periods for specific outcomes

in animal trials is imperative.

3.2 INTRODUCTION

3.2.1 Rationale

The dry period following lactation represents the time dairy cows are most at-risk for

developing intramammary infections (IMI) (Halasa et al., 2009a). The presence of IMI during the

dry period also increase the risk of clinical mastitis in the subsequent lactation, most commonly

during the first 30 to 60 days in milk (DIM) (Pantoja et al., 2009). One case of clinical mastitis has

been reported to cause a 10% decrease in lactational milk yield (Berry et al., 2004), and clinical

mastitis cases diagnosed in early lactation result in significantly higher milk loss (Bartlett et al.,

1991; Lescourret & Coulon, 1994). A traditional approach to decrease the impact of IMI and

clinical mastitis on milk quality and quantity in the subsequent lactation is the use of long lasting

intramammary antimicrobials at dry-off. Use of blanket dry cow therapy (BDCT) was reported by

88% of farmers in the Canadian National Cohort of Dairy Farms in 2007 to 2008 (Dufour et al.,

2012), and by 93% of Wisconsin dairy farmers (Rodrigues et al., 2005). Dry cow therapy

accounted for nearly half of the total antimicrobial use on dairy farms in the Netherlands between

2005 to 2012 (Kuipers et al., 2016), and in 2013, following a ban on BDCT, approximately 61%

of dairy cattle received antimicrobial dry cow therapy in the Netherlands (Santman-Berends et al.,

2016). Results from a survey of dairy farmers in Germany indicated 79% of farms performed

BDCT and 31% performed selective dry cow therapy (SDCT) (Bertulat et al., 2015). However,

concern over the prudent use of antimicrobials in agriculture (World Organisation for Animal

Health, 2019) has informed a shift towards increased use of SDCT and creates the need to assess

the efficacy of additional management practices that can be used to protect udder health during the

dry period either in addition to or in place of antimicrobial dry cow products.

80

Dairy cattle experience some form of management changes when entering the dry period

(Zobel et al., 2015). The majority of the published literature regarding management practices that

improve udder health around the time of drying off center around intramammary antimicrobials

(Dingwell et al., 2003b; Halasa et al., 2009a; Halasa et al., 2009b) and teat sealants (Berry &

Hillerton, 2002; Halasa et al., 2009a; Rabiee & Lean, 2013). However, other reviews have

discussed the importance of other management strategies and their impact on udder health,

including method of milk cessation (Dingwell et al., 2003a; Vilar & Rajala-Schultz, 2020) and

bedding/housing of dry cows (Dufour et al., 2011). Other systematic reviews and meta-analyses

have assessed the impact of adjusting dry period length on the risk of clinical mastitis (van Knegsel

et al., 2013), antimicrobials (Winder et al., 2019a) and teat sealants (Dufour et al., 2019; Winder

et al., 2019b) given at dry off to prevent IMI and mastitis post-calving, and a meta-analysis

assessing the effect of dry off antimicrobials, teat sealants, and vaccines in nulliparous heifers

(Naqvi et al., 2018). However, it is likely there are a variety of other forms of dry cow management

that have been evaluated for their impact on udder health in multiparous cows, including strategies

for cessation of lactation, bedding materials, hygiene of the environment, standing behaviour

following dry-cow therapy, vaccinations, fly control, and nutrition (Green et al., 2007). With

increased scrutiny on use of antimicrobials in food animals, there is a need to characterize all

literature regarding modifiable management practices of dairy cattle during the dry period that

have been evaluated for their impact on udder health.

Scoping reviews are a form of knowledge synthesis which aim to characterize the range of

available literature for broad research questions, determine the value of undertaking a systematic

literature review in a particular area of research, provide a high-level summary of research

findings, and identify gaps in existing literature (Arksey & O’Malley, 2005). Currently, no scoping

reviews exist that have characterized literature reporting modifiable management practices that

can be implemented at drying off to improve udder health in dairy cattle. Additionally, there is

variation in the type of study designs used to investigate these modifiable management practices

in the literature (Green et al., 2007; Fujiwara et al., 2018), and thus it is beneficial to characterize

the number and type of studies available. This variation in the types of management practices that

81

exist in the literature, and the variation in study designs used to investigate the effect of these

management practices on udder health, warrant the need for a scoping review.

Understanding the efficacy of management practices that can be modified during the dry

period of lactation is essential to help producers maintain good animal health and milk quality

while supporting the prudent use of antimicrobials in agriculture. If enough available literature

exists on this topic, this scoping review will provide an indication of the feasibility of a systematic

literature review and meta-analysis into areas of dairy cattle management at dry-off, and it will

identify gaps in existing literature.

3.2.2 Objectives

The objective of this scoping review was to characterize all available literature on modifiable

dairy management practices used during the dry period which have been evaluated for their impact

on udder health in dairy cattle, both during the dry period and the subsequent lactation.

3.3 METHODS

3.3.1 Protocol and registration

A scoping review protocol was created a priori by CKM, with input from JMS, DFK, and

CBW. It was published in the online University of Guelph repository and can be accessed at:

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/17788/McMullenProtocol_DryCow

Mgm_PROTOCOL.pdf?sequence=1&isAllowed=y. Manuscript preparation followed the

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping

Reviews (PRISMA-ScR) reporting guidelines (Tricco et al., 2018). This scoping review followed

the framework proposed by Arksey and O’Malley (2005).

3.3.2 Eligibility criteria

Eligible articles were published in English and reported results of primary research.

Articles had to be ≥500 words and published within the last 30 years (1990 to 2020). As major

changes have occurred in prevention of disease in dairy cattle within the last few decades (Leblanc

et al., 2006), restricting the publication date ensured this scoping review captured and presented

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/17788/McMullenProtocol_DryCowMgm_PROTOCOL.pdf?sequence=1&isAllowed=y

https://atrium.lib.uoguelph.ca/xmlui/bitstream/handle/10214/17788/McMullenProtocol_DryCowMgm_PROTOCOL.pdf?sequence=1&isAllowed=y

82

data which would be temporally relevant to dairy producers and veterinarians. As the review

required evaluation of management practices on udder health, only analytical study designs (i.e.

analytic observational studies, controlled trials, and challenge trials) were eligible for inclusion.

A population of dairy cattle at cessation of lactation, and an intervention or exposure to

any modifiable management practice which could be used by farmers or researchers at the time of

drying off with a goal of improving udder health were required for an article to be eligible. We

initially characterized these interventions into the following categories: antimicrobials, teat

sealants, vaccines, non-antimicrobial products, housing, pasture, bedding, nutrition, dry-cow

preparation, and other. Although there was no restriction on eligible modifiable interventions or

exposures if they fell outside of these categories, non-modifiable management practices were

excluded from this review (i.e. breed, parity, season of dry off). Analytical studies had to provide

comparison of the intervention or exposure to at least one other different intervention, a different

level of the given intervention or exposure, or a non-treated control group or placebo. Finally,

eligible articles had to provide mention of one of the following udder health outcomes in the title

or abstract: risk of clinical mastitis at any period post-calving, prevention of new IMI during the

dry period, cure of existing IMI during the dry period, or prevalence of IMI at any period post-

calving. Prevention of new IMI and cure of existing IMI were eligible outcomes only when milk

samples were taken at least at dry off and post-calving for determination of IMI status. There was

no restriction on how IMI was defined in the primary literature, which could have included (but

was not limited to) bacterial culture, SCC, electrical conductivity, or NAGase.

3.3.3 Information sources

The search was completed by CKM on February 18, 2020 by searching five databases for

relevant literature: Medline (via OvidSP), CAB Abstracts (via CAB Interface), Science Citation

Index (via Web of Science), Scopus, and Agricola (via Proquest). CKM also hand-searched the

table of contents from 1990 to 2020 of the World Association for Buiatrics conference proceedings

and the National Mastitis Council Conference Proceedings. Contact with study authors was not

conducted for this review.

83

3.3.4 Search

The full-electronic search string was initially developed in CAB Abstracts (via CAB

Interface) (Table 3.1). Key population and outcome terms and concepts were connected using

Boolean operators to maximize the sensitivity of the search. The search was restricted to

publication year from 1990 to 2020. The search was validated by checking inclusion of 15 articles

pre-selected by DFK (Table 3.2); all articles were detected by the search strategy. Search results

were downloaded into EndNote (EndNote X7, Clarivate Analytics, Philadelphia) and de-

duplicated using several algorithms. The references were then uploaded into DistillerSR (Evidence

Partners Inc, Ottawa, ON, Canada) and additionally deduplicated prior to the screening process.

3.3.5 Selecting sources of evidence

Study selection and data extraction were performed in DistillerSR. Two levels of screening

were conducted by CKM, CBW, KJC and KC. The title and abstract pre-test involved screening

100 articles for eligibility, followed by a consensus meeting to ensure reviewer consistency and

clarity of the screening questions. Reviewers independently in duplicate screened the title and

abstract of articles identified by the search using four primary screening questions: (1) Is a

modifiable dry-period management practice in dairy cattle reported in the title/abstract?; (2) Is a

relevant udder health outcome described in the title/abstract?; (3) Is the title/abstract available in

English?; and (4) Is an analytic primary research study described in the title/abstract?. Response

selection included ‘yes’, ‘no’, or ‘unclear’, and a response of ‘no’ from two reviewers to any of

the above questions resulted in exclusion of that reference. All disagreements were resolved by

consensus. The full-text pre-test involved screening 10 full-text articles for eligibility, followed by

a consensus meeting. The following secondary screening questions were used for full-text

screening: (1) Is the study available in English?; (2) Is this an analytic primary research study?;

(3) Is a population of dairy cattle after their first or subsequent lactation reported within the article?;

(4) Was the modifiable management practice implemented at drying off?; and (5) Is a relevant

udder health outcome reported in the article?. Possible response options were ‘yes’ or ‘no’, where

an answer of ‘no’ selected by two reviewers resulted in exclusion of that record. Agreement was

84

at the question level, and a third party was consulted for conflict mediation if consensus could not

be reached.

3.3.6 Data charting process

Data extraction was completed independently in duplicate by CKM, CBW, KJC and KC

using a structured pre-tested form created in DistillerSR. The form was pilot tested using five

articles by all reviewers in order to ensure consistency and clarity of the questions. Thereafter,

disagreements were resolved by consensus.

3.3.7 Data items

Study Characteristics. Study-level data included year of publication, year of study

conduct, country of study conduct, study design, study objectives, farm or herd type

(research/university dairy or commercial dairy), and breed.

Intervention, Comparators, and Exposures. Intervention, comparator and exposure data

included definition of and type of management practice, intervention unit (farm, herd, cow, or

quarter), implementation strategy of intervention or exposure, and implementation of the

comparator.

Outcomes. Eligible outcomes for inclusion in the review were:

• Risk of clinical mastitis (author defined risk period),

• Cure of existing IMI from dry off to calving,

• Prevention of new IMI from dry off to calving, and

• Prevalence of IMI (author defined risk period).

Authors had to report that milk samples were collected at drying off and at calving, or at another

point post-calving, for IMI determination in order for cure of existing IMI and prevention of new

IMI to be eligible outcomes. These samples are later referred to as cure and prevention of IMI over

the dry period in this manuscript, but authors could have included milk samplings that extended

into lactation. In addition, risk period evaluation for clinical mastitis and prevalence of IMI could

be author defined and extend throughout the next lactation, as long as the risk period was not only

85

defined as the incidence or prevalence of disease over the entire lactation. This decision was made

in order to include studies reporting a risk period that was not so long such that the influence of

factors other than the dry period management practice became more substantial reasons for a case

or non-case (i.e. contaminated milking equipment). Somatic cell count as a continuous measure of

udder health was not reported in the protocol, however, SCC is a very common sampling method

to identify potential intramammary infections and thus was included as an additional outcome in

this scoping review. Articles that only mentioned antimicrobials or teat sealant interventions were

enumerated but not further characterized, since they were included in previous systematic literature

review and meta-analyses on the efficacy of these products to improve udder health during the dry

period (Dufour et al., 2019; Winder et al., 2019a; Winder et al., 2019b). Other modifiable

management strategies reported within an article with antimicrobial and/or teat sealant products

remained eligible for inclusion.

3.3.8 Synthesis of results

Tables were used to provide descriptive analysis of study characteristics, target population,

and the study approach. Descriptions and implementation practices of the management strategies

found in relevant literature were reported, along with any risk periods for cure, prevention, or

prevalence of IMI or clinical mastitis. A histogram was used to depict the total number of eligible

studies published by year.

3.4 RESULTS

3.4.1 Selection of sources of evidence

Results of the search and the flow of study inclusions and exclusions are presented in Figure

3.1. Of the initial 4425 records identified for title and abstract screening, 955 records were

reviewed at full-text screening. Following both levels of relevance screening, 420 articles were

included in the quantitative summary: antimicrobials and teat sealants alone were assessed in 74

articles, antimicrobials alone in 108 articles, teat sealants alone in 9 articles, and other modifiable

management practices (with or without comparison to antimicrobials or teat sealants) were

assessed in 229 articles. Only the 229 articles which included the report of additional modifiable

86

management practices that were not antimicrobials or teat sealants were further described in this

scoping review.

3.4.2 Characteristics of sources of evidence

Articles published in or after 1990 were eligible for inclusion, but year of publication

ranged from 1990 to 2020 (Figure 3.2). The majority of studies were conducted in the USA

(84/229; 36.7%), Canada (19/229; 8.3%), and the United Kingdom (13/229; 5.7%). Figure 3.3

depicts the number of studies conducted in each country. Although controlled trials were the most

common study design identified (174/229; 76.0%), challenge trials (22/229; 9.6%), cohort studies

(18/229; 7.9%), and cross-sectional studies (15/229; 6.6%) were also identified by our review

team. A commercial herd type was reported in half of the articles (113/229; 49.4%), followed by

research/university herds (70/229; 30.6%), and both herd types reported in a smaller number of

articles (5/229; 2.2%). Herd type was not reported in 41 articles. Breed of cattle included in each

article was mainly Holstein (106/229; 46.3%) and multiple breeds (35/229; 15.3%), followed by

crossbreeds (7/229; 3.1%), Jersey (5/229; 2.2%) and other breeds (6/229; 2.6%). Breed was not

reported in 70 articles.

3.4.3 Synthesis of results

Vaccines. The effect of vaccination on eligible udder health outcomes was assessed in 40

articles, of which 20 were controlled trials, 17 were challenge trials, and three were observational

studies (Table 3.3). Within controlled trials, the two most common types of vaccine regimen were

E. coli J5 vaccine (9/20) and Startvac (a vaccine for E. coli and S. aureus; 7/20), followed by S.

aureus vaccination (3/20), and a vaccine for coliforms (1/20). Comparison to an untreated control

group was made in over half of controlled trials (12/20), and to a placebo product in four trials.

The E. coli J5 vaccine was administered in the majority of challenge trials (11/17), with S. uberis

immunization reported in two challenge trials. Vaccine regimens that were each reported once in

separate challenge trials were S. aureus compared to S. chromogenes, and E. coli curli-positive

compared to curli-negative producing bacteria. Most comparators in challenge trials were

untreated control (14/17), comparison to a different vaccination (10/20), or placebo vaccination

(3/20). Intramuscular Startvac and a leptospirosis vaccine for herds at pasture were assessed for

87

their effect on udder health in three observational studies. For all vaccination studies, clinical

mastitis was reported in the majority of articles (36/40), with a range in risk period from dry off to

240 DIM (mode: 90 DIM). Cure of existing IMI over the dry period was reported in six articles,

prevention of new IMI over the dry period in nine articles, and prevalence of IMI over the dry

period in 16 articles. Somatic cell count was measured in 30 articles from dry off to 240 DIM.

Non-antimicrobial intramammary products. Non-antimicrobial intramammary products

were reported in 12 articles, of which 10 were controlled trials and two were challenge trials (Table

3.4). Products reported included interleukin-2 (3/12), Phyto-Mast and/or Cinnatube (3/12), bovine

lactoferrin (2/12), and lysostaphin (2/12). Clinical mastitis was reported as an outcome in 11

articles, with a risk period range from dry off to 42 DIM (mode: at calving). Cure of existing IMI

over the dry period was reported in eight articles, prevention of new IMI over the dry period in

five articles, and prevalence of IMI over the dry period in five articles. Somatic cell count was

measured in nine articles from dry off to 90 DIM. Intramuscular injection of non-antimicrobial

products was reported in two additional controlled trials, of which recombinant bovine granulocyte

stimulating factor was administered in one trial and Propionibacterium acnes immunostimulatory

product in the other trial (Table 3.4).

Vitamin and mineral injections. Vitamin and mineral products were injected via

intramuscular or subcutaneous route in 14 articles, all of which were controlled trials (Table 3.5).

Vitamin E and selenium products were most commonly reported (9/14). Untreated control was

used as a comparator in 10 trials and a placebo product in four trials. Clinical mastitis was reported

in eight trials, with a range in risk period from 30 to 200 DIM (mode: 30 DIM). Cure of existing

IMI over the dry period and prevention of new IMI over the dry period were each reported in three

trials, prevalence of IMI over the dry period in five trials, and SCC was reported in six trials from

calving through the entire lactation.

Vitamin and mineral (feed). Vitamin and mineral feed additives were reported in 35

articles, of which 30 were controlled trials, one was a challenge trial, and four were observational

studies (Table 3.6). Vitamin E, or combinations of vitamin E and other minerals, was the most

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commonly evaluated vitamin as an additive in transition cow diets for an effect on udder health

(13/35), followed by selenium (6/35), and calcium (4/35). Untreated control was the most common

comparator in controlled trials (24/30). Clinical mastitis was reported in 22 articles, with a risk

period range of dry off to 300 DIM (mode: 30 DIM). Cure of existing IMI over the dry period was

reported in three articles, prevention of new IMI over the dry period was reported in seven articles,

and prevalence of IMI over the dry period was reported in seven articles. Somatic cell count was

reported in 25 articles from dry off to 240 DIM.

Ration formulation and delivery. Ration formulation and delivery were the most common

types of dry cow management practices reported in the articles included in this scoping review

(n=44), of which 39 were controlled trials, one was a challenge trial and four were observational

studies (Table 3.7). Variation in the length of time close-up rations and far-off rations were offered

was evaluated in seven articles. OmniGen-AF, a product that contains microbials, vitamins and

aluminosilicates, was evaluated for its effect on udder health in five articles. Change in plane of

nutrition, such as a decreased concentrate level, restricted feeding at pasture, and variation in

protein supplements were evaluated in 11 articles. Probiotic, microbial, or yeast supplements in

transition cow diets were evaluated in five articles. Clinical mastitis was reported in 26 articles,

with a range in risk period of calving to 308 DIM (mode: 30 and 150 DIM). Cure of existing IMI

over the dry period was reported in two articles, and prevention of new IMI over the dry period

and prevalence of IMI over the dry period were reported in eight articles. Somatic cell count was

measured in the majority of articles (37/44) from dry off to 308 DIM.

Dry period length. The effect of dry period (DP) length on a relevant udder health outcome

was reported in 27 articles, of which 17 were controlled trials and 10 were observational studies

(Table 3.8). Length of dry period ranged from 0 to 250 days. In controlled trials, the most common

dry period length comparator groups were 30 day DP length and 60 day DP length (10/17). Most

authors were interested in comparison of a conventional dry period length (55-60 days; 13/27) to

that of a shorter dry period length (30-40 days; 14/27), or complete omission of the dry period (0

days; 10/27). Clinical mastitis was reported in 16/27 articles, with a range in the risk period from

at dry off to 308 days in milk (DIM) (mode: 90 DIM). Cure of existing IMI over the dry period

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was reported in 4/27, prevention of new IMI over the dry period in 5/27, and prevalence of IMI

over the dry period in 5/27. Somatic cell counts were measured in 23/27 articles from dry off to

308 DIM. Additionally, the authors of seven controlled trials, which investigated the efficacy of

antimicrobial or teat sealant products, also included dry period length as a covariate in regression

modeling (Table 3.9). The authors of two observational studies also reported days in milk at drying

off or DP length as a covariate in the model.

Housing, bedding, pasture. Housing, pasture, and bedding management were reported in

12 articles, of which five were controlled trials and seven were observational studies (Table 3.10).

The evaluation of tie stall vs. free stall on udder health outcomes was reported in four articles,

indoor stall housing or loose housing was reported in three articles, and cows at pasture were

reported in four articles. Bed or barn cleaning routines were reported in five articles, and type of

bedding was reported in seven articles which included sand, straw, woodchip, compost bedded

packs, and mattresses. Other housing management strategies evaluated for their effect on udder

health included stall drainage, pasture grazing policy of rest for four weeks graze for two weeks,

stall design so at least 90% of cows can lie correctly, and access to a housed lying area for cattle

at pasture. Clinical mastitis was reported in 10 articles, with a risk period range of calving to 150

DIM (mode: 30 DIM). Cure of existing IMI over the dry period and prevention of new IMI over

the dry period were reported in the same two articles, prevalence of IMI over the dry period was

reported in four articles, and SCC was measured in seven articles from dry off to 113 DIM.

Milking frequency prior to drying off. Milking frequency prior to drying off was evaluated

in 16 articles, of which 13 were controlled trials and three were observational studies (Table 3.11).

Abrupt cessation of lactation (milking cows twice daily until the last day before drying off) was

compared to gradual/intermittent cessation of lactation (lessening the number of times a cow is

milked prior to drying off) in almost all articles (15/16). Gradual or intermittent cessation of

lactation was most often defined as a milking frequency change in the last week of lactation

(10/16), between 14 days pre-dry to 3 days pre-dry in the majority of other studies (5/16), and

report of assessing milk yield records within the last 60 DIM was used in one observational study.

Clinical mastitis was reported in four articles, with a range in risk period from DO to 90 DIM.

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Cure of existing IMI over the dry period was reported in four articles, prevention of new IMI over

the dry period was reported in three articles, and prevalence of IMI over the dry period was

reported in 10 articles. Somatic cell count was reported in eight articles from dry off to 120 DIM.

Reduced milk yield at drying off. Milk yield at drying off was reported in nine articles,

two of which were controlled trials and seven were observational studies (Table 3.12). Milk yield

was defined as low, medium, or high in one trial, while milk yield at dry off >115kg was reported

as a risk factors for IMI in the other trial. Milk yield was defined using cut points in three

observational studies: a) 0-10kg, >10-20kg, >20kg, b) ≤12kg, 12-18kg, ≥18kg, and c) >21kg at

drying off. Clinical mastitis was reported in three articles, with a risk period range from dry off to

60 DIM. Cure of existing IMI over the dry period was reported in one article, prevention of new

IMI over the dry period was reported in three articles, and prevalence of IMI over the dry period

was reported in five articles. Somatic cell count was reported in three articles from dry off to 30

DIM. Authors of four additional controlled trials included milk yield at drying off as a covariate

in regression modeling to control for its effect on udder health (Table 3.13).

Other management. Bovine somatotropin (bST) is a growth hormone approved for use in

dairy cattle to increase milk production (FDA, 2020). Bovine somatotropin was allocated to cows

during the dry period in five trials to assess its impact on udder health outcomes, either via

intramuscular or subcutaneous injections (Table 3.14). Whole herd concurrent treatment with bST

during the dry period was reported in a small number of articles included in this scoping review

(4/229). Additional management strategies of interest are reported in Table 3.15 and include

extending post-milking teat dip regimens into the dry period (n=5), monensin given as a controlled

release capsule or bolus (n=2), cabergoline, a hormone receptor inhibitor used to stimulate

mammary involution, was assessed in two articles, and casein hydrolysate, which is another

treatment used to stimulate mammary involution, was assessed in one trial. The effect of heat stress

versus cooling of cattle using fans and sprinklers was assessed in one trial, while short day versus

long day photoperiods were assessed in two trials (one controlled trial and one challenge trial).

Long cannula infusion of antimicrobial dry cow therapy (ADCT) versus short cannula infusion

was assessed in another trial. Additional management strategies reported in the observational

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studies included not drying off cows during hoof trimming procedures and segregate infected

cows, especially those with S. aureus, from uninfected cows.

Clinical mastitis was reported as an outcome in over half of the articles identified (151/229;

65.9%), including a corresponding definition in 93 articles as the presence of visible signs,

abnormal milk, or systemic illness. A risk period for observation of clinical mastitis was reported

for the majority of these articles (137/151; 90.7%), however, this ranged from dry off through the

entire subsequent lactation (Figure 3.4). The most common maximum number of days in milk for

which authors evaluated the risk of clinical mastitis was 30 DIM (19/137; 13.9%), 60 DIM

(12/137; 8.8%), 90 DIM (10/137; 7.3%), and 100 DIM (10/137; 7.3%).

Cure of existing IMI was reported in 40 articles, of which 35 provided a definition used to

classify cows with an existing infection at drying off or over the dry period that cured post-calving.

The majority of articles determined cure of IMI through bacteriologic cultures (30/35; 85.7%),

which is the method recommended by the National Mastitis Council for determining the presence

of subclinical mastitis (NMC, 2012). The remainder used SCC as a proxy for infection status (5/35;

14.3%), defined as somatic cell count of ≥200 000 cells/mL in three of these articles, SCC ≥250

000 cells/mL in one article, and with no reported cut-point in one article. The risk period for

measuring cure of existing IMI was not reported in three articles, but of those that did report a risk

period ranged from dry-off to 130 DIM, most commonly between a maximum of calving and 30

DIM (29/37; 78.4%).

Prevention of new IMI was reported in 54 articles, of which 50 provided a definition. Most

authors defined presence of a new IMI using bacteriological culture (44/50; 88.0%) for quarters

negative at drying off but presented with an infection post-calving, SCC was used as a proxy for

infection status in five articles, and a modified CMT was used to define infection status in one

article. Somatic cell count ≥200 000 cells/mL was the cut-point used to define the presence of an

infection in three articles, while SCC ≥250 000 cells/mL was the cut-point used in one. The risk

period for new IMI was reported in 52 articles, of which IMI was measured between calving and

a maximum of 7 DIM in almost half of articles (23/52; 44.2%). Further, new IMI outcome was

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measured between calving and a maximum of 30 DIM in the majority of articles (40/52; 76.9%),

with a range in risk period measurement of calving to 240 DIM.

Prevalence of IMI, which refers to IMI that authors reported were measured once over a

defined time period, was the most commonly reported metric for IMI (72/229; 31.4%). This differs

from articles that measured cure of IMI over the dry period and prevention of new IMI over the

dry period since both of these outcomes required at least two measurements to determine the

incidence of an IMI from dry off to calving. Somatic cell counts were used to define infection

status in eight articles (8/72), somatic cell count plus bacteriology in five articles, and the

remainder performed bacteriologic analysis of milk samples to define infection status (59/72). The

risk period for measurement of prevalence of IMI ranged from dry off to 270 DIM, with a

maximum risk period between calving to 30 DIM reported in most articles (40/72; 55.6%). A risk

period of ≥100 DIM was reported in 10 articles.

Although few studies reported use of SCC in determination of IMI, SCC was the most

commonly reported outcome measure (n=161), which was reported as a continuous measure in the

majority of articles (155/161) or reported as an elevated SCC (6/161) in the remainder.

Transformation of SCC to somatic cell score or linear score was reported in 24 articles (24/161;

14.9%). Maximum risk period measurements for SCC between calving and 30 DIM were reported

in a third of articles (48/161; 29.8%), and ≥100 DIM in 38/161 articles (23.6%).

3.5 DISCUSSION

3.5.1 Summary of evidence

This scoping review provides a synthesis of the types of modifiable management strategies

that have been investigated in available literature for their impact on udder health outcomes over

the dry period. We classified management practices under 10 groups, that included dry period

length, vaccines, non-antimicrobial intramammary or intramuscular (IM) products, vitamins and

minerals (IM), housing bedding and pasture management, ration formulation and delivery,

vitamins and minerals (feed), milking frequency, reduced milk yield at dry off, and other. The

number of articles reporting dry cow antimicrobials and teat sealants to cure and prevent

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intramammary infections and clinical mastitis was provided, but not further characterized in this

review. The body of literature pertaining to other dry cow management strategies that have been

implemented to improve udder health during the dry period and post-calving had not been

previously characterized using a systematic approach.

We identified substantial literature that assessed a few modifiable management strategies,

which indicates systematic reviews and meta-analyses may be feasible to assess their effect on IMI

and clinical mastitis, specifically vaccines (n=40), ration formulation and delivery (n=44), vitamin

and mineral feed additives (n=35), and dry period length (n=27). Naqvi et al. (2018) recently

published a systematic review and meta-analysis on the effectiveness of pre-calving treatment on

post-calving udder health in nulliparous dairy heifers, which included mastitis vaccination.

Extending this research to populations of multiparous dairy cows would be highly beneficial to the

mastitis research community. Additionally, a recently published meta-analysis assessed the effects

of vitamin E and vitamin E/selenium adjuvants to establish the effect of treatment on SCC in milk

(Moghimi-Kandelousi et al., 2020), but future work could be extended to included other vitamin

and mineral products such as beta-carotene and Vitamin A. Santos et al. (2019) conducted a meta-

analysis on the effect of a prepartum dietary anion-cation difference (DCAD), by means of altering

the mineral composition of diets, which found less than half of included studies reported the effect

of DCAD on mastitis, and some trials even removed animals diagnosed with mastitis from the

statistical analysis. Additionally, a paired meta-analysis to Santos et al. (2019) further noted

mastitis was not well reported in trials evaluating DCAD, and more studies that report these

outcomes could increase the power of future meta-analyses (Lean et al., 2019). A future directive

for meta-analyses could assess the effect of prepartum DCAD on SCC postpartum, as SCC is a

commonly reported measure of udder health. Lastly, van Knegsel et al. (2013) conducted a meta-

analysis to assess the effect of shortening or omitting the dry period on the incidence of clinical

mastitis, and found an inconsistent summary effect that was likely due to variation between studies

and variation in disease definitions. An updated systematic review and meta-analysis could

indicate whether the consistency between studies for measurement of mastitis in relation to dry

period length and mastitis disease definitions have improved. The assessment of the effect of these

modifiable management strategies on intramammary infections or SCC during the dry period and

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post-calving through systematic literature reviews and meta-analyses may be feasible additions to

mastitis research.

Current recommendations in the 10 point mastitis control plan pertaining to management

of dry cows are to decrease the energy density of late lactation rations to in turn reduce milk

production prior to drying off, dry cows off abruptly, use antimicrobial dry cow therapy by partial

insertion in combination with an internal teat sealant, tailor dry cow nutrition to boost the immune

system, allow for a clean and dry environment, and vaccinate against mastitis pathogens (NMC,

n.d.). Investigations regarding each of these suggested management objectives were found in the

literature and are referenced in this scoping review. Further quantification of the efficacy of such

strategies is warranted to evaluate the associations of these practices with intramammary infections

and clinical mastitis.

The majority of articles included in this scoping review were controlled trials (n=174),

which when allocation to treatment group is randomized, are the best study designs to evaluate the

efficacy of a modifiable intervention under field conditions (O’Connor et al., 2010; Sargeant et al.,

2010). The ability for random allocation to intervention groups, blinding of trialists, similar

management of intervention groups (Sibbald & Roland, 1998), and ability to evaluate interventions

in commercial dairy herds are important features of randomized controlled trials (RCT).

Observational studies are useful for exploring risk factors for disease and comparing the effect of

management strategies that may be difficult to artificially implement (i.e. housing and stall design

or pasture grazing), on udder health outcomes (Sargeant et al., 2016). However, the lack of control

of allocation of cows to exposure groups and differential management of exposure groups can lead

to biased results. Additionally, challenge trials, like randomized controlled trials, allow trialists to

randomly allocate cows to interventions, blind treatment staff or outcome assessors, and maintain

equal management of intervention groups, but lack external generalizability (Shirley & McArthur,

2011). Systematic reviews and meta-analyses that include randomized controlled trials provide the

highest level of evidence of the efficacy of interventions under field conditions (Sargeant &

O’Connor, 2014), and the randomized allocation of participants to treatment groups reduces the

potential for selection bias (O’Connor & Sargeant, 2014). However, for comparative efficacy

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meta-analyses it may be warranted to include observational studies for areas of veterinary research

where relatively few RCT exist, but meta-analysts need to be aware of the potential biases that the

inclusion of observational studies can have on the summary effect size (O’Connor & Sargeant,

2014). Therefore, the large proportion of controlled trials included in this scoping review could

warrant the exclusion of observational studies from future synthesis work, but for areas of research

that are mainly composed of observational studies, such as housing, pasture, and bedding

management and decreased milk yield at dry off, remain to provide valuable information about the

effect modifiable management strategies have on udder health outcomes.

Lastly, we aimed to quantify the number of articles that investigated each management

practice in relation to relevant udder health outcomes. Somatic cell count as a continuous metric

was the most common measure used to identify udder health issues during lactation, followed by

prevalence of intramammary infection during the subsequent lactation. The risk of clinical mastitis

was another commonly investigated outcome, more so than cure or prevention of new IMI. Most

risk periods for each outcome were defined to a maximum of 30, 60 or 90 DIM; however we

identified discrepancies in author defined risk periods.

3.5.2 Limitations of the body of evidence

Risk period measurement ranged from dry off through the entire lactation for clinical

mastitis, cure of existing IMI, prevention of new IMI and prevalence of IMI. This variation

becomes a problem in further knowledge synthesis, such as systematic reviews and meta-analyses,

that require strict definitions of eligible outcomes and length of follow-up for studies to be included

in the review (Liberati et al., 2009). If we cannot compare the results of multiple studies due to

this variation in reporting of outcomes and follow-up periods, then we cannot form a solid evidence

base for decision making (Sargeant et al., 2019). Consensus on one or more risk periods to evaluate

clinical mastitis and IMI outcomes in mastitis research, in addition to other investigator-

determined outcomes, would enable the formation of a solid evidence based for decision-making

related to udder health. Appropriate follow-up periods need to be long enough to evaluate the effect

of a dry period management strategy on clinical mastitis, but not so long that the influence of

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factors other than the dry cow management practice become more substantial reasons for a case or

non-case.

Evidence exists suggesting optimal thresholds and risk periods for determination of

subclinical and clinical mastitis. Sargeant et al. (2001) found optimal sensitivity and specificity for

the ability to detect an IMI using an SCC threshold of 100,000 cells/mL was at 5 DIM. A California

Mastitis Test using a reaction greater than zero had the highest sensitivity and specificity at 3 or 4

DIM (Sargeant et al., 2001; Dingwell et al., 2002). Bradley et al. (2010) excluded milk samples

collected after 10 DIM from analysis of the efficacy of cephalonium containing dry cow therapy

and an internal teat sealant to cure and prevent IMI during the dry period. Bradley and Green

(2000) reported 53% of enterobacterial mastitis cases occurring in the first 100 DIM arose from

quarters infected with the same pathogen during the dry period. Another study indicated that the

first case of clinical mastitis occurred between calving and 120 DIM, with a median of 40 DIM

(Pantoja et al., 2009). Sixty percent of clinical mastitis cases that were identified to be caused by

the same pathogen isolated during the dry period occurred within 14 DIM, and 90% within 150

DIM (Green et al., 2002). One article defined the incidence rate of clinical mastitis within 30 DIM

and referenced previous work that showed a correlation between IMI acquired during the dry

period and clinical mastitis within 30 DIM (Down et al., 2016). The association between dry period

management and first case of clinical mastitis beyond 90, 100 or 150 DIM is questionable, thus

trialist are urged to provide reasoning for choice of follow-up period by, for example, referencing

previous literature similar to the aforementioned articles.

Further, the majority of articles used bacteriologic culture as the definition for presence of

an intramammary infection; cultures are useful measurements when appropriate guidelines are

followed such as the National Mastitis Council guidelines for collecting milk samples (NMC,

2004). A series of studies by Dohoo et al. (2011a; 2011b) evaluated one versus two samples for

culture on the basis of sensitivity and specificity for determining infection status. Compared to the

gold standard test (a positive culture on 2 of 3 consecutive samples) these methods performed

adequately. Some articles in our scoping review only evaluated one sample to determine infection

status post-calving (Dingwell et al., 2003a; Mullen et al., 2014), while others defined cure of

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quarters based on the results of three or four cultures (Middleton & Fox, 1999; Church et al., 2008;

Leitner et al., 2011). Likewise, determination of new IMI post-calving was evaluated using at least

two samples (Berry & Hillerton, 2007; Church et al., 2008; Leitner et al., 2011). The use of somatic

cell counts to determine subclinical infection status was only reported in a few articles, and

although SCC is an important indicator of IMI (Lam et al., 2009), IMI should be confirmed by

bacteriology (NMC, 2012). It appears the reporting of IMI measurement techniques and sampling

periods is adequate within research; however, limiting the variation in such methodology would

be additionally beneficial in forming a solid evidence base for decision-making.

Reporting guidelines for controlled trials, such as reporting guidelines for Randomized

Controlled Trials in Livestock and Food Safety (O’Connor et al., 2010), are available to improve

the quality of reporting of trials. Further, the Strengthening the Reporting of Observational Studies

in Epidemiology - Veterinary (STROBE-Vet) Statement (Sargeant et al., 2016) exists for

observational studies in veterinary science, but there are still deficiencies in reporting of key trial

features. Winder et al. (2019c) evaluated the quality of reporting in journal articles published in

the Journal of Dairy Science in 2017, which indicated 93% of authors reported information on

outcomes measured and methods that were used to enhance the quality of measurements. Our

research indicates agreement with adequate reporting of the laboratory analysis methods used to

define intramammary infections. However, the lack of consistency in and reasons for choice of

outcome follow-up periods further identify the need for consensus on a minimum set of core

outcomes to be included in mastitis research.

3.5.3 Limitations of this review

The most commonly reported management practices during the dry period to improve

udder health post-calving were dry cow antimicrobials and teat sealants. Although there is interest

in the industry for additional resources investigating the efficacy of these products, this was not

the purpose of this scoping review and previous systematic reviews and meta-analyses should be

referenced. Due to the current COVID-19 global pandemic, inter-library loan of resources from

the University of Guelph and other affiliated libraries were limited during this review process,

which has impacted our ability to access full text articles. Fifty-one articles were not able to be

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accessed via full-text by librarians. These articles may have contributed further evidence within

our scoping review. However, the 229 articles included in this review provides a basis for future

synthesis work into areas of management such as vaccines, dry period length, ration formulation

and delivery, and vitamin and mineral feed additives.

Several articles were not available in English. Although these articles may have added

relevant information, the body of literature encompassed in this review informs the utility of a

systematic literature review and meta-analysis on the efficacy of management practices to improve

udder health post-calving, specifically for nutrition, dry period length, and vaccines. Further, less

than half of the articles in this scoping review were from Canada or the USA, indicating literature

outside of North America was well represented. Lastly, we did not conduct a critical appraisal of

the articles included in this scoping review, as such future researchers should be aware that the

eligible body of literature reviewed here requires assessment for risk of bias following quantitative

synthesis.

3.6 CONCLUSION

Ten groups of management practices identified as strategies implemented at drying off that

improve udder health post-calving were formed. Nutrition management, including vitamin and

mineral feed supplements, was the most common type of management strategy, followed by

vaccination, and dry period length. Further research could use systematic review and meta-analysis

methods to target these areas of dry cow management and to quantify their role in prevention and

cure of intramammary infections and clinical mastitis, and may be able to compare these

management strategies to antimicrobial or teat sealant interventions. Areas with few available

research articles include bovine somatotropin injections, and intramammary and intramuscular

injections of non-antimicrobial remedies. In addition, relevant outcomes, such as clinical mastitis,

cure prevention and prevalence of IMI, and measurement of somatic cell count were widely

considered, however, there is large variation in the risk periods considered for each outcome.

Organizations focusing on udder health in the dairy industry could form consensus statements

regarding optimal follow-up periods that should be used in mastitis research to decrease the

variability in the measurement of outcomes and risk period selection.

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3.6.1 Protocol deviations

There were no protocol deviations in this scoping review.

3.6.2 Author contributions

CKM developed the review protocol, coordinated the research teams, developed the search

strategy, conducted all searches, created data screening and data extraction tools, conducted data

screening and data extraction, conducted data characterization, interpreted the results, and

developed the manuscript drafts. JMS, DFK, and CBW provided methodological support and

content expertise, commented on manuscript drafts, and approved the final manuscript. KC and

KJC conducted data screening, data extraction, commented on manuscript drafts, and approved

the final manuscript.

3.6.3 Acknowledgements and funding

There was no external funding support for this scoping review. Stipend funding support for

CKM was provided by the OVC Entrance Award and the Queen Elizabeth II Graduate Scholarship

in Science and Technology from the University of Guelph and the Ministry of Training, Colleges

and Universities. Additional acknowledgements to the donors of the Dr. Francis H.S. Newbould

Award, the Dr. Casey Buizert Memorial Award, the Dr. R.A. McIntosh Graduate Award (OVC

‘45) and the Barbara Kell Gonsalves Memorial Scholarship for their funding support.

3.6.4 Conflicts of interest

None of the authors have conflicts to declare.

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107

3.8 TABLES

Table 3.1 Search strategy to identify relevant articles for the scoping review pertaining to modifiable management practices

implemented at drying off to improve udder health in dairy cattle, published between 1990 to present, conducted in CAB Abstracts (via

CABI) on January 7, 2020

# Search Terms Results

1 ("cow") OR ("cows") OR ("cattle") OR (heifer*) OR ("dairy") OR ("milking") OR (bovine*) OR ("bovinae")

OR (buiatric*) AND yr:[1990 TO 2020]

538 300

2 (ayrshire*) OR ("brown swiss") OR ("busa") OR ("busas") OR (canadienne*) OR (dexter*) OR ("dutch

belted") OR ("estonian red*") OR (fleckvieh*) OR (friesian*) OR (girolando*) OR (guernsey*) OR

(holstein*) OR (illawarra*) OR ("irish moiled*") OR (jersey*) OR ("meuse rhine issel*") OR

(montebeliarde*) OR (normande*) OR ("norwegian red*") OR ("red poll") OR ("red polls") OR (shorthorn*)

OR ("short horn*") AND yr:[1990 TO 2020]

61 277

3 1 OR 2 554 679

4 (("drying off") OR ("dry off") OR ("dried off") OR ("dry up") OR ("drying up") OR ("dried up") OR

("drying period") OR ("dry period") OR ("dry udder") OR ("dry teat*") OR ("pre-partum") OR ("prepartum")

OR ("end" NEAR lactat*) OR (finish* NEAR lactat*) OR (stop* NEAR lactat*) OR (cess* NEAR lactat*)

OR (ceas* NEAR lactat*) OR (nonlactat*) OR ("non-lactat*") OR (postlactat*) OR ("post-lactat*") OR

(postmilk*) OR ("post-milk*") OR ("involution") OR ("steady state") AND yr:[1990 TO 2020])

41 877

5 3 AND 4 12 175

6 ("dry cow") OR ("dry cows") AND yr:[1990 TO 2020] 1856

7 5 OR 6 13 092

8 ((mastiti*) OR ((intramammar* NEAR infect*)) OR ((intramammar* NEAR inflamm*)) OR (("intra-

mammar*" NEAR infect*)) OR (("intra-mammar*" NEAR inflamm*)) OR ("udder health*") OR ("somatic

cell*") OR ("linear score*") OR ("bulk tank*") OR ("bulk-tank*") OR ("somatic-cell*") OR ("linear-

score*")) AND yr:[1990 TO 2020]

33 547

9 7 AND 8 2697

10 (("dry cow" NEAR therap*)) OR (("dry cow" NEAR manag*)) OR (("dry cow" NEAR intervention*)) OR

(("dry cow" NEAR treat*)) OR (("dry cow" NEAR strateg*)) OR (("dry cows" NEAR therap*)) OR

704

108

11 9 OR 10 2885

109

Table 3.2 Article title and author information for 15 relevant journal articles to check for inclusion in the search in order to validate the

search strategy. All articles were identified by the search

Author

(Year)

Article Title Country Management

Practice in

Title/Abstract

Outcome in

Title/Abstract

1 Arruda et al.

(2013)

Randomized noninferiority clinical trial

evaluating 3 commercial dry cow mastitis

preparations: I. Quarter-level outcomes

USA Antimicrobials IMI1 at calving / CM2

up to 100 DIM

2 Bradley and

Green

(2001)

An investigation of the impact of intramammary

antibiotic dry cow therapy on clinical coliform

mastitis

England Antibiotics CM up to 100 DIM

3 Cameron et

al. (2015)

Evaluation of selective dry cow treatment

following on-farm culture: milk yield and

somatic cell count in the subsequent lactation

Canada Antimicrobials and

Teat sealants

SCC3 in following

lactation

4 Green et al.

(2007)

Cow, farm, and management factors during the

dry period that determine the rate of clinical

mastitis after calving

United

Kingdom

Antimicrobials,

Vaccines,

Housing, Pasture,

and Dry-cow

preparation

CM within 30 DIM

5 Godden et

al. (2003)

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

USA Antimicrobials and

Teat sealants

IMI during dry period /

linear score after

calving / CM up to 60

DIM

6 Gott et al.

(2016)

Intramammary infections and milk leakage

following gradual or abrupt cessation of milking

USA Dry-cow

preparation

IMI at calving

7 Gott et al.

(2017)

Effect of gradual or abrupt cessation of milking

at dry off on

USA Dry-cow

preparation

Somatic cell score up

to 120 DIM

110

milk yield and somatic cell score in the

subsequent lactation

8 Newman et

al. (2010)

Association of milk yield and infection status at

dry-off with intramammary infections at

subsequent calving

USA Dr-cow preparation IMI at calving

9 Odensten et

al. (2007)

Effects of two different feeding strategies

during dry-off on certain health aspects of dairy

cows

Sweden Nutrition SCC during dry period

10 Odensten et

al. (2007)

Metabolism and udder health at dry-off in cows

of different breeds and production levels

Sweden Dry-cow

preparation

IMI after calving

11 Rajala-

Schultz et al.

(2005)

Short Communication: Association between

milk yield at dry-off and probability of

intramammary infections at calving

USA Dry-cow

preparation

IMI at calving

12 Rajala-

Schultz et al.

(2011)

Milk yield and somatic cell count during the

following lactation after selective treatment of

cows at dry-off

USA Antimicrobials SCC during follow

lactation

13 Schukken et

al. (1993)

A randomized blind trial on dry cow antibiotic

infusion in a low somatic cell count herd

Netherlands Antimicrobials CM during dry period

14 Tucker et al.

(2009)

Effect of milking frequency and feeding level

before and after dry off on dairy cattle behavior

and udder characteristics

New

Zealand

Dry-cow

preparation and

Nutrition

IMI during dry period

15 Zobel et al.

(2013)

Gradual cessation of milking reduces milk

leakage and motivation to be milked in dairy

cows at dry-off

Canada Dry-cow

preparation

Somatic cell score at

calving

1IMI = intramammary infection

2CM = clinical mastitis

3SCC = somatic cell count

111

Table 3.3 Author and descriptive information for vaccination as a management practice implemented at drying off to improve udder

health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry period and post-calving

Authors Vaccine1 Comparator Concurrent

treatments2

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New IMI Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Wagter et al.

(2000)

E. coli J5, ovalbumin (IM) Not reported

(NR)

42 DIM Calving to

42 DIM

Dingwell et

al. (2003a)

Coliform

(IM)

Dry period

length

(continuous)

ADCT 3 to 9 DIM

Freick et al.

(2016)

Startvac (E.

coli and S

aureus) (IM);

Herd specific

autologous

vaccine

Untreated

control

NR 52 DIM

Hogan et al.

(1992a)

E. coli J5

(SC)

Untreated

control

ADCT 90 DIM DO3 to 7

DIM

Misra et al.

(2018)

S aureus

(intranasal);

S aureus

(intranasal,

different

dose)

Placebo

vaccine

NR 10 DIM 10 DIM

112

Selvaraj et al.

(2013)

R mutant E.

coli (SC);

E. coli

vaccine (SC,

different

adjuvant)

Untreated

control

NR 60 DIM 30 to 60

DIM

Solmaz et al.

(2009)

R mutant E.

coli J5 (IM)

Untreated

control

NR 90 DIM

Vakanjac et

al. (2010)

S aureus (SC) ADCT,

untreated

control

NR Calving to

240 DIM

Calving to

240 DIM

DO to 210

DIM

Wilson (2007)

E. coli J5

(SC)

Untreated

control

NR 77 DIM

Mallard et al.

(1997)

E. coli J5 (IM, high

response);

E. coli J5 (IM, lack of

response post-partum);

E. coli J5 (IM, lack of

response pre- and post-

partum)

NR 42 DIM DO to 42

DIM

Bradley et al.

(2015)

Startvac

(IM);

Startvac (IM,

different

vaccine

schedule)

Untreated

control

NR 120 DIM DO to 1st test

post-calving

120 DIM 30 DIM 5 to 120

DIM

Hoedemaker

et al. (2001)

S aureus (SC) Placebo

vaccine

NR Monthly;

1st test

post-

calving

Monthly;

1st test

post-

calving

30 to 210

DIM

113

Schukken et

al. (2014)

Startvac (IM) Untreated

control

ADCT NR4 NR 30 to 240

DIM

30 to 270

DIM

Wilson et al.

(2009)

E. coli J5

(SC)

Untreated

control

NR 200 DIM

McClure et al.

(1994)

Re-17 mutant

bacterin-

toxoid (IM)

Untreated

control

NR 150 DIM

Petersson et

al. (2003)

E. coli J5 (SC);

E. coli J5 (SC, different

vaccine schedule)

NR 60 DIM DO to 60

DIM

Jiménez &

Romero

(2011)


control

NR 52 DIM DO to 1st test

post-calving

DO to 1st

test post-

calving

DO to 1st

test post-

calving

Noguera et al.

(2011)

Startvac (IM) Placebo

vaccine

NR 130 DIM DO to 130

DIM

DO to 130

DIM

DO to 130

DIM

March et al.

(2010)

Startvac (IM) Placebo

vaccine

NR 130 DIM DO to 130

DIM

DO to 130

DIM

DO to 130

DIM

Pinho et al.

(2016)


control

NR 90 DIM Calving to

90 DIM

Challenge trials

Hogan et al.

(1992b)

E. coli J5

(SC)

Untreated

control

ADCT DO to 21

DIM

DO to 21

DIM

Post-

challenge;

37 DIM

114

Hill et al.

(1994)

S uberis (SC) Placebo

vaccine;

untreated

control

NR Post-

challenge;

49 DIM

Pre- and

post-

challenge;

14 to 49

DIM

Post-

challenge;

21 to 49

DIM

Gurjar et al.

(2013)

E. coli J5

(SC)

Untreated

control

ADCT, No

TS

100 DIM Pre- and

post-

challenge;

DO to

calving

Hogan et al.

(1993)

E. coli J5

(SC);

E. coli J5

(SC, vitamin

E adjuvant);

E. coli J5

(SC, vitamin

E and Freud’s

incomplete

adjuvant);

E. coli J5

(SC, PBS

adjuvant)

Untreated

control

ADCT Pre- and

post-

challenge;

calving to

39 DIM

Pre- and

post-

challenge;

calving to

39 DIM

Finch et al.

(1994)

S uberis

(IMM);

S uberis (SC)

Untreated

control

NR Calving Post-

challenge;

20 to 48

DIM

Post-

challenge;

20 to 48

DIM

Todhunter et

al. (1991)

E. coli (curli - producing

bacteria) (SC + IMM);

E. coli (curli + producing

bacteria) (SC + IMM)

ADCT Post-

challenge;

30 to 90

DIM

Post-

challenge;

30 to 90

DIM

115

Piepers et al.

(2017)


control

NR Post-

challenge;

17 DIM

Post-

challenge;

17 DIM

Pomeroy et al.

(2016)

E. coli J5 (SC

+ IMM);

E. coli (IMM)

Untreated

control

No ADCT,

No TS

7 DIM 7 DIM 7 DIM

Hogan et al.

(1995b)

E. coli J5

(SC)

Placebo

vaccine

ADCT 21 DIM DO to 21

DIM

DO to 21

DIM

Post-

challenge;

28 to 66

DIM

Merrill et al.

(2019)

S aureus

(SC);

S

chromogenes

(SC)

Placebo

vaccine


14 DIM

Takemura et

al. (2001)

Ferric acid

vaccine (SC

+ IMM);

E. coli J5 (SC

+ IMM)

Untreated

control

NR Post-

challenge;

13 to 31

DIM

Tomita et al.

(2000)

J-VAC (SC);

E. coli J5

(SC)

Untreated

control

NR 45 DIM Post-

challenge;

44 DIM

Hogan et al.

(2005)

E. coli J5

(SC);

E. coli J5

(SC, different

adjuvant)

Untreated

control

ADCT 7 DIM Pre- and

post-

challenge;

21 to 42

DIM

Pre- and

post-

challenge;

21 to 42

DIM

Smith et al.

(1999)

E. coli J5 (SC

+ IMM);

Untreated

control

ADCT Post-

challenge;

37 DIM

Pre- and

post-

challenge;

Pre- and

post-

challenge;

116

E. coli J5

(SC)

DO to 56

DIM

DO to 56

DIM

Steele et al.

(2019)

E. coli J5

(SC);

E. coli J5

(SC, different

vaccine

schedule)

Untreated

control

ADCT Post-

challenge;

162 DIM

Pre- and

post-

challenge;

calving to

197 DIM

Pre- and

post-

challenge;

calving to

197 DIM

Pre- and

post-

challenge;

calving to

197 DIM

Tomita et al.

(1998)

J-VAC (SC);

J-VAC

(SMLN*)

Untreated

control

NR 20 DIM Post-

challenge;

24 DIM

Field et al.

(1994)

E. coli J5

(SC)

Untreated

control

NR Pre- and

post-

challenge;

C @ 40 to

50 DIM

Pre- and

post-

challenge;

C @ 40 to

50 DIM

Pre- and

post-

challenge;

C @ 40 to

50 DIM

Observational studies

Green et al.

(2007)

Leptospirosis vaccine for

herd at pasture;

Dry cows not housed with

milking herd; good drainage

in stalls; graze on pasture for

4 weeks, rest for 2 weeks,

Straw yard; mattresses in

stalls; disinfect stalls in early

DP; reduce milk yield before

DO;

cows remain standing after

ADCT;

scrape feed and loaf area

2x’s per week

NR 30 DIM

117

1Vaccines were administered via intramuscular (IM) or via subcutaneous (SC) route. A few studies also report administration of a

comparator via intramammary (IMM) route

2Concurrent treatments were antibiotic dry cow therapy (ADCT) or teat sealant (TS) products reported as administered, or not

administered, in addition to the modifiable management practice of interest

3DO = at dry off

4An outcome that has Not Reported (NR) in the column indicates that outcome was measured within the study, but the authors did not

define the risk period evaluated

Ortega (2013)

Startvac (IM)

NR NR Calving to

65 DIM

Calving to

240 DIM

Meza &

Barrios

(2015)

Startvac (IM) NR 60 DIM 60 DIM

118

Table 3.4 Author and descriptive information for non-antimicrobial intramammary (IMM) and intramuscular (IM) products as a

management practice implemented at drying off to improve udder health outcomes in dairy cattle, with corresponding risk periods of

outcome measurement during the dry period and post-calving

Authors Non-antimicrobial

IMM1

Comparator2 Concurrent

treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell

count

(SCC)

Controlled trials

Hogan et al.

(1995a)

Recombinant bovine

interleukin-2 (rbIL-2)

ADCT;

PBS placebo

ADCT DO3 to 7 DIM DO to

7 DIM

Calving

to 90

DIM

Green et al.

(2003)

Cinnatube ADCT;

TS

Not

reported

(NR)

DO to

calving

DO to

35 DIM

Komine et al.

(2006)

Bovine lactoferrin

(Lf);

ADCT + Lf

ADCT NR 7 DIM 7 DIM

Mullen et al.

(2014)

Phyto-Mast;

Cinnatube;

Phyto-Mast +

Cinnatube

ADCT +

TS;

Untreated

control

NR DO to 5

DIM

DO to calving DO to

calving

DO to 3-5

DIM

DO to

1st herd

test

post-

calving

Erskine et al.

(1998)

IL-2 ADCT;

PBS placebo

ADCT Calving DO to 7 DIM DO to

7 DIM

Kai et al.

(2002)

Bovine Lf ADCT NR 7 DIM 7 DIM

119

Koseman et al.

(2019)

Sanofoam (Ozone

containing foam);

Sanofoam (different

frequencies)

ADCT;

TS

NR Calving

to 42

DIM

DO to 42

DIM

DO to

42 DIM

Britten et al.

(2018)

Casein hydrolysate;

ADCT + casein

hydrolysate;

TS + casein

hydrolysate;

ADCT + TS + casein

hydrolysate

ADCT +

TS;

NR calving Calving Calving

Mullen et al.

(2014)

Phyto-Mast;

Cinnatube;

Phyto-Mast +

Cinnatube

ADCT +

TS;

Untreated

control

NR Calving

to 5

DIM

DO to 3-5

DIM

DO to

3-5

DIM

DO to 3-5

DIM

DO to

3-5

DIM

Erskine et al.

(1998)

IL-2 ADCT;

PBS placebo

ADCT Calving DO to 7 DIM DO to

7 DIM

Challenge trials

Hoernig et al.

(2016)

Recombinant

lysostaphin

Placebo TS, No

ADCT

30 DIM Calving to 30

DIM

Calving

to 30

DIM

Hoernig et al.

(2013)

Lysostaphin Placebo TS, No

ADCT

30 DIM DO to 30

DIM

DO to 30

DIM

DO to

30 DIM

Non-antimicrobial Intramuscular

Controlled trials

Heiser et al.

(2018)

Recombinant bovine

granulocyte colony-

stimulating factor

(G-CSF) + full

ration;

Full ration +

placebo IM;

Restricted

ration +

placebo IM

NR 4 to 7

DIM

4 to 7 DIM

120

Recombinant bovine

G-CSF + restricted

ration

Hogan et al.

(1994)

ADCT +

Propionibacterium

acnes

immunostimulatory

(PAI);

PAI

ADCT;

Untreated

control

NR 7 DIM DO to 7 DIM DO to

7 DIM

1Non-antimicrobial IMM or IM treatments of interest were sometimes combined with antimicrobial dry cow therapy (ADCT) or teat

sealant (TS) products

2Comparator groups of interest included antimicrobial dry cow therapy (ADCT), teat sealants (TS), or phosphate-buffered saline (PBS)

3DO = at dry off

121

Table 3.5 Author and descriptive information for vitamin and mineral injections as a management practice implemented at drying off

to improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry period and

post-calving

Authors Vitamin/mineral

(injection)1

Comparator2 Concurrent

treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Caballos et al.

(2010)

Selenium (SC) Untreated

control

ADCT Not

reported

(NR)3

calving calving 7 DIM,

every 14

DIM

thereafter

7 DIM,

every 14

DIM

thereafter

Cengiz and

Bastan (2015)

Alpha-tocopherol

(IM)

ADCT;

ADCT + TS;

TS;

Untreated

control

NR 5 to 10

DIM

Bayrİl et al.

(2015)

Selen E-Sol (IM;

alpha-tocopherol

+ selenite);

Selen E-Sol (IM,

different

frequency)

Untreated

control

NR NR 30 DIM

Duplessis et al.

(2014)

Folic acid +

vitamin B12

Placebo (IM) NR 60 DIM

Gakhar et al.

(2010)

Copper glycinate

(SC)

Untreated

control

NR DO4 to 60

DIM

Hoque et al.

(2016)

E-Vet Plus!

Solution (alpha-

ADCT; NR 90 DIM 90

DIM

122

tocopherol +

selenium) (IM)

E-Sel!

powder

(Oral; alpha-

tocopherol +

selenium);

Untreated

control

Kurt et al.

(2019)

Ademin (vitamin

A, D, E) +

activate

(selenium,

copper, zinc,

manganese) (IM)

Placebo (IM) NR 14 DIM

Machado et al.

(2013)

Multimin (IM;

trace mineral

supplement

containing zinc,

manganese,

selenium, copper)

Untreated

control

NR 150

DIM

150 DIM 150 DIM

Bourne et al.

(2008)

Vitenium (alpha-

tocopherol) (IM)

Untreated

control

NR 200

DIM

180 DIM

Erskine et al.

(1997)

Vitamin E (IM) Untreated

control

NR 30 DIM

LeBlanc et al.

(2002)

Vitamin E (SC) Placebo (IM) NR 30 DIM Calving to

7 DIM

Pavlata et al.

(2004)

Selevit (IM,

selenite, alpha-

tocopherol);

Selevit (IM,

different

frequency)

Untreated

control

NR 30 DIM

123

Saluja et al.

(2005)

ADCT + vitamin

E and selenium

(IM);

Vitamin E and

selenium (IM)

ADCT;

Levamisole;

ADCT +

levamisole;

Untreated

control

NR DO to 7 DIM DO to 7

DIM

Filho et al.

(2018)

Adaptador (IM;

mineral

supplement)

Placebo (SC) NR 45 to 105

DIM

1Vitamin and mineral injections were given via subcutaneous (SC) or intramuscular (IM) route

2Comparator products of interest included antimicrobial dry cow therapy (ADCT) or teat sealant (TS) products

3 An outcome that has Not Reported (NR) in the column indicates that outcome was measured within the study, but the authors did not


4DO = at dry off

124

Table 3.6 Author and descriptive information for vitamins and minerals in feed as a management practice implemented at drying off to

improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry period and post-

calving

Authors Vitamin/Mineral

(feed)

Comparator Concurrent

treatments

Risk period

Clinical

mastitis

Cure of

inramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Weiss et al.

(1997)

Vitamin E;

Vitamin E (different doses)

Not reported

(NR)

7 DIM DO1

to 7

DIM

Bouwstra et

al. (2010a)

Vitamin E Untreated

control

NR 100

DIM

Politis et al.

(2004)

Vitamin E Untreated

control

NR 84 DIM

Bouwstra et

al. (2010b)

Alpha-tocopherol;

Alpha-tocopherol (different dose)


90 DIM

Whitaker et

al. (1997)

Bioplex zinc Untreated

control

NR NR2 7 to 24 DIM 7 to

24

DIM

DO to 100

DIM

Whitaker et

al. (1997)

Calcium;

Calcium with bovine somatotropin

(bST) (IM3);

High calcium;

High calcium + bST (IM)

ADCT4;

Leptospirosis

vaccine

NR 7 to 21

DIM

125

Formigoni et

al. (2011)

Organic trace

minerals (copper,

manganese, zinc)

Untreated

control

NR Calving

to 150

DIM

Calving to

28 DIM

Enjalbert et

al. (2008)

Biotin Untreated

control

NR 14 to 119

DIM

Batra et al.

(1992)

Vitamin E Untreated

control

NR Calving

to 300

DIM

NR DO to

calving

DO to

calving

Bhanderi et

al. (2016)

Trace minerals

(copper, zinc,

chromium),

vitamin E, vitamin

A, iodine

Untreated

control

NR 10 to 90

DIM

90 DIM

Hoque et al.

(2016)

Alpha-tocopherol,

sodium selenium

Alpha-

tocopherol,

sodium

selenium

(IM);

ADCT;

Untreated

control

NR 90 DIM 90

DIM

Kaewlamun

et al. (2012)

Beta-carotene Untreated

control

NR NR Calving to

70 DIM

Kinal et al.

(2005)

20% minerals

(zinc, copper,

manganese)

covered by

bioplexes;

Untreated

control

NR Calving

through

early

lactation

126

30% minerals

covered by

bioplexes

Nehru et al.

(2018)

Mammidium (milk

buffer,

antioxidants,

vitamins, minerals)

Untreated

control

NR 120

DIM

120 DIM

O'Donoghue

et al. (1995)

Bioplex (copper,

zinc, selenium)

Untreated

control

NR Calving to

84 DIM

Oliveira et al.

(2015)


control

NR 15 to 42

DIM

15 to 42

DIM

Sharma et al.

(2017)

Soya-DOC

(phosphate

dehydrate, zinc,

copper, vitamin A,

vitamin E)

Untreated

control

NR 30 DIM 30 DIM

Sahu & Maiti

(2014)

Vitamin A + beta-

carotene;

Zinc, copper;

Vitamin E +

selenium;

Vitamin A + beta-

carotene + zinc +

copper + vitamin E

+ selenium

Untreated

control

NR 10 to 30

DIM

Silvestre et

al. (2007)

Organic selenium;

Inorganic selenium

Cows also

under

reproductive

management

81 DIM Calving to

240 DIM

127

Thilsing et al.

(2007)

Phosphorous

supplemented diet;

Calcium

supplemented diet;

Calcium +

phosphorous

Untreated

control

NR 21 DIM

Baldi et al.

(2000)

Basal diet + calcium soap;

Vitamin E + corn;

Basal diet + corn;

Vitamin E + calcium soap

NR 7 to 14

DIM

Bian et al.

(2007)

Beta-carotene;

Beta-carotene,

(different dose)

Untreated

control

NR 60 DIM

Chang et al.

(1996)

Metalosate

(chelated

chromium)

Untreated

control

NR 112

DIM

Calving to

56 DIM

Calving to

56 DIM

Mandebvu et

al. (2003)

NutroCAL;

Beta-carotene

Untreated

control

NR NR 7 to 56

DIM

Oldham et al.

(1991)

Vitamin A Untreated

control

ADCT 180

DIM

DO

to

180

DIM

Calving to

42 DIM

Yuan et al.

(2012)

Rumen protected

niacin

Untreated

control

NR 21 DIM

Evans et al.

(2006)

Vitamin and

choline (VC)

supplement close-

up;

Untreated

control

NR 100

DIM

90 DIM

128

VC during

lactation;

VC close-up and

during lactation

Roshanzamir

et al. (2020)

Sulphates (zinc,

manganese,

copper);

Glycine salts (zinc,

manganese,

copper);

Methionine salts

(zinc, manganese,

copper)

Untreated

control

NR Calving to

100 DIM

Bian et al.

(2007)


control

NR 70 DIM

Chatterjee et

al. (2005)

Alpha-tocopherol;

Alpha-tocopherol (different

application times)

NR 30 DIM 15 to

30

DIM

15 to 30

DIM

Challenge trials

Weiss &

Hogan (2005)

Selenium yeast;

Sodium selenite

NR Post-

challenge;

28 to 36

DIM


Politis et al.

(2012)

Alpha-tocopherol NR DO to

calving

Weiss et al.

(1990)

Vitamin E, selenium, alpha-

tocopherol

NR 21 DIM Weekly

129

Ceballos-

Marquez et

al. (2010)

Selenium;

Free stall, no grazing allowed;

Tie-stall, allowed to graze

NR DO to 7 DIM DO

to 7

DIM

DO to 7

DIM

Down et al.

(2016)

Calcium and magnesium;

ADCT;

Stall design so 90% of cows can

lie correctly;

Clean stalls at least twice daily;

Apply clean bedding at least once

daily if organic;

Do not dry off during hoof

trimming;

Spread bedding evenly in dry cow

yard;

Abrupt cessation of lactation;

Differentiate infected from

uninfected cows

NR 30 DIM DO to 1st

milk

sample

post-

calving

1DO = at dry off



3IM = intramuscular route of administration

4ADCT = antimicrobial dry cow therapy

130

Table 3.7 Author and descriptive information for ration formulation and delivery as a management practice implemented at drying off


post-calving

Authors Ration formulation

and delivery


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Carvalho et al.

(2011)

Glycerol Untreated

control

Not

reported

(NR)

Weekly at

two

consecutive

samples

Amirabadi

Farahani et al.

(2017)

Conventional close-up period;

Short close-up period;

Low metabolizable protein;

Medium metabolizable protein;

High metabolizable protein

NR 21 DIM 1 to 21

DIM

Heiser et al.

(2018)

Full ration + Recombinant bovine

G-CSF (intramuscular, IM);

Full ration + placebo (IM);

Recombinant bovine G-CSF +

restricted ration;

Restricted ration + placebo (IM)

NR 4 to 7

DIM

4 to 7

DIM

Higginson et al.

(2018)

Yeast-derived

microbial protein

Untreated

control

NR 4 to 27

DIM

Khazanehei et

al. (2015)

Far-off and close-up diet with 60

day dry period (DP) length;

ADCT1 NR2 112 DIM

131

Close-up diet with 40 day DP

length

Stein et al.

(2006)

Low-dose

Propionibacterium

strain;

High-dose

Propionibacterium

strain

Untreated

control

bST (SC3) Calving to

175 DIM

Ort et al. (2017)

0g/day direct fed microbial

(DFM) and enzyme product;

45.4g/day DFM;

45.4g/day DFM + enzyme

product

NR 56 DIM

How you dry

off cows affects

udder infections

(1991)

Ration change at DO (average

hay only) + abrupt cessation of

lactation;

No ration change + abrupt

cessation;

Ration change + intermittent

milking;

No ration change + intermittent

milking

ADCT DO4 to 7 DIM DO to

7 DIM

Aceto et al.

(2010)

Close-up ration;

Far off + close-up diet

NR 30 DIM

Mayasari et al.

(2016)

Glucagonic ration

vs. lipogenic ration

0 day DP

length

30 day DP

length;

60 day DP

length

ADCT 7 to 98

DIM

7 to 98

DIM

132

Piepers & de

Vliegher (2013)

Aromabiotic Cattle

(Medium-chain

fatty acids)

Untreated

control

ADCT 30 DIM DO to

early

lactation

137 DIM

Ramsing et al.

(2009)

57g/day yeast

culture;

227g/day yeast

Untreated

control

NR 21 DIM

Santos et al.

(1999a)

Moderate crude protein;

High crude protein

NR Calving

Santos et al.

(1999b)

Moderate crude protein;

High crude protein w/ Prolak

(animal-marine protein blend)

NR Calving

Summers et al.

(2004)

Restricted feeding level (fed

pasture);

Unrestricted feeding level (higher

dry matter (DM) intake)

ADCT 21 DIM 7 to 21

DIM

NR

Wu et al. (2019)

60 g/day

OmniGen-AF;

90g/day OmniGen-

AF

Untreated

control

NR Calving

to 28

DIM

Calving to

28 DIM

Zachwieja et al.

(2007)

Fish and rapeseed

oil;

Protected fat

Untreated

control

NR Calving

Singh et al.

(2020)

33% less concentrate;

Normal concentrate level

NR 120

DIM

120 DIM 120 DIM

Babir et al.

(2017)

0mEq/kg DM dietary cation-

anion difference (DCAD);

-15mEq/kg DM DCAD;

-30mEq/kg DM DCAD;

-45mEq/kg DM DCAD;

NR 60 DIM

133

+134.32mEq/kg DM DCAD

Baldi et al.

(2000)

Basal diet plus corn;

Basal diet + calcium soap;

Vitamin E plus corn ration;

Vitamin E plus calcium soap

NR 7 to 14

DIM

Cappelli et al.

(2007)

Individually fed in tie-stalls;

Free stall fed TMR

NR calving Calving to

30 DIM

Dann et al.

(2000)

Yeast culture

supplement

Untreated

control

NR 140

DIM

Calving to

140 DIM

Formigoni et al.

(1996)

300g propylene

glycol

Placebo

(water

orally)

NR Calving to

91 DIM

Lee et al. (2019)

Rumen protected

lysine/methionine

pre- and post-

calving;

Rumen protected

Lys/Met only pre-

calving;

Rumen protected

Lys/Met post-

calving only

Untreated

control

NR 22 DIM 3 to 91

DIM

Liu et al. (2013)

Chestnut tannins Untreated

control

NR 21 DIM

Mallick &

Prakash (2012)

Dried guduchi stem

powder

Untreated

control

NR Calving to

70 DIM

Mammi et al.

(2018b)

OmniGen-AF Untreated

control

NR 150

DIM

DO to 150

DIM

134

Mashek &

Beede (2000)

Corn grain Untreated

control

bST (IM) 12 to

150

DIM

Calving to

150 DIM

Mashek &

Beede (2001)

Energy-dense diet >26 days;

Energy dense diet <26 days

bST (IM) 150

DIM

Calving to

150 DIM

McFadden et al.

(2008)

Sorbitol-mannitol

blend

Untreated

control

NR Calving to

98 DIM

Nickerson et al.

(2019)

OmniGen-AF Control diet NR 30 DIM 30

DIM

DO to 30

DIM

DO to 30

DIM

Odensten et al.

(2007b)

Ad lib straw;

Ad lib straw + 4kg DM silage

NR 10 DIM 4 to 8

DIM

DO to 42

DIM

Shoshani et al.

(2014)

Close-up ration + 40 day DP

length;

Far-off and close-up ration + 60

day DP length

NR DO to 1st test

post-calving

DO to

1st test

post-

calving

Monthly

Stefenoni et al.

(2020)

Celmanax

(hydrolyzed yeast)

Untreated

control

ADCT;

TS5;

No E. coli

J5 or

clostridia

vaccine

given

60 DIM DO to

calving

Calving to

21 DIM

Stone et al.

(2012)

Conventional corn silage;

Brown midrib corn silage

NR 42 DIM 7 to 105

DIM

Lyles et al.

(2017)

OmniGen-AF Control diet NR 30 DIM DO to

30

DIM

DO to 30

DIM

DO to 30

DIM

van Hoeij et al.

(2017)

Standard energy level + 30 day

DP length;

NR 21 to

308

DIM

DO to 35

DIM

21 to 308

DIM

135

Standard energy level + 0 day DP

length;

Low concentrate level + 0 day

DP length

France et al.

(2020)

Decreased feed, decreased

milking frequency;

Decreased feed, normal milking

frequency;

Non-decreased feed, decreased

milking frequency;

Non-decreased feed, non-

decreased milking frequency

No ADCT DO to 28

DIM

Hash & Pighetti

(2020)

OmniGen-AF Untreated

control

ADCT;

TS

DO to 28

DIM

DO to 28

DIM

Challenge trials

Kornalijnslijper

et al. (2003)

Twice energy

requirements

Untreated

control

NR 26 to

40 DIM

12 to 38

DIM


Rukkwamsuk et

al. (2007)

Fatty liver-inducing diet;

Control diet

NR 28 DIM

DeGaris et al.

(2010)

Transition diet 0-10 days;

Transition diet for 11-20 days;

transition diet for >20 days

NR 150

DIM

Kaneene et al.

(1997)

Feed dry cows separate from

lactating cows;

Grain fed

NR 90 DIM

136

Santschi et al.

(2011)

Pre-calving ration, 35 day DP

length;

Pre-calving ration, 60 day DP

length

ADCT Calving

to 90

DIM

NR 1st test day

post-

calving




3SC = subcutaneous route of administration

4DO = at dry off

5TS = teat sealant

137

Table 3.8 Author and descriptive information for dry period (DP) length as a management practice implemented at drying off to improve

udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry period and post-calving

Authors Dry

period

length


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New IMI Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Andree

O'Hara et al.

(2019a)

56 days;

28 day DP

No ADCT1 or

TS2

Not

reported

(NR)3

Monthly

Bates &

Saldias

(2018)

30-80 days;

81-149 day DP

TS 84 DIM 36 to 109

DIM

de Vries et al.

(2015)

30 days;

60 days DP;

0 day DP

ADCT DO4 to 84

DIM

Enevoldsen &

Sorensen

(1992)

28 days;

49 day DP;

70 day DP

No ADCT Calving

to 84

DIM

Khazanehei et

al. (2015)

60 days;

40 days DP

ADCT NR 112 DIM

El-Gaafarawy

et al. (2009)

60 days;

45 day DP

ADCT Calving to

7 DIM

van Hoeij et

al. (2018)

0 days;

30 day DP

No ADCT NR DO to 35

DIM

DO to 1st

herd test

138

post-

calving

van Hoeij et

al. (2016)

0 days;

30 day DP;

60 day DP

ADCT 14 to 308

DIM

NR DO to 23

DIM

14 to 308

DIM

Mayasari et

al. (2017)

30 days;

60 day DP;

0 day DP

ADCT 7 to 14

DIM

Weekly

Mayasari et

al. (2016)

30 days;

60 day DP;

0 day DP

ADCT 7 to 98

DIM

7 to 98

DIM

Berry &

Hillerton

(2007)

<70 days with ADCT;

<70 days with ADCT +

TS;

≥70 day DP with

ADCT;

>70 day DP with

ADCT + TS

NR 100 DIM DO to 7

DIM

Church et al.

(2008)

60 days;

45 day DP;

30 day DP

ADCT DO to 21 DIM DO to 21

DIM

DO to 21

DIM

Laven &

Lawrence

(2008)

>70 days

<70 days

ADCT + TS 90 DIM 60 to 240

DIM

Mantovani et

al. (2010)

55 days;

0 day DP

NR DO to 90

DIM

Shoshani et

al. (2014)

40 days;

60 day DP

NR DO to 1st herd

test post-calving

DO to 1st

herd test

Monthly

139

post-

calving

Watters et al.

(2008)

55 days;

34 day DP

ADCT + TS,

bovine

somatotropin

1 to 300

DIM

Calving to

100 DIM

van Hoeij et

al. (2017)

30 days;

0 day DP with standard

energy diet;

0 day DP with low

concentrate level

NR 21 to 308

DIM

DO to 35

DIM

21 to 308

DIM


Januś &

Borkowska

(2013)

0-21 days;

22-41;

42-56;

57-84;

>84 day DP

NR NR

Rémond &

Bonnefoy

(1997)

0 days NR Monthly

Robert et al.

(2008)

>65 days;

<65 days;

milk yield at DO ≤12kg

vs. 12-18kg vs. ≤18kg

ADCT DO to 5

DIM

Sawa et al.

(2015)

≤10 days;

11-30;

31-50;

51-70;

71-90;

>90 day DP

NR 30 DIM 30 DIM 30 DIM

140

Węglarzy

(2009)

≤30 days;

31-60;

61-90;

≥91 day DP

NR Monthly

Zecconi et al.

(1995)

<50 days;

ADCT products;

Intermittent cessation

of lactation;

>50 day DP with abrupt

cessation of lactation


DIM

Andree

O'Hara et al.

(2019b)

30-39 days;

40-49;

50-59;

60-69;

70-79;

80-89 day DP

NR 90 DIM 5 to 90

DIM

Bates &

Dohoo (2016)

<112 days;

≥112 day DP

ADCT Calving

to 90

DIM

Pinedo et al.

(2011)

0-30 days;

31-52;

53-76;

77-142;

143-250 day DP

NR 100 DIM 100 DIM

Santschi et al.

(2011)

35 days;

60 day DP

ADCT 30 to 90

DIM

NR 1st test day

after

calving


2TS = teat sealant



141

4DO = at dry off

142

Table 3.9 Author and descriptive information for dry period length as a management practice included as a covariate in regression

modeling, with corresponding risk periods of outcome measurement during the dry period and post-calving. Dry period length was

included in trial models to adjust for residual confounding not controlled for by allocation to treatment groups

Authors Dry period

length


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell

count

(SCC)

Controlled trials

Dingwell et al.

(2003b)

Covariate in

model

ADCT1

trial

ADCT 3 to 30 DIM

Dingwell et al.

(2002)

Covariate in

model

ADCT trial ADCT 3 to 9

DIM

Dingwell et al.

(2003a)

Covariate in

model

ADCT

trial;

Coliform

vaccine

ADCT 3 to 9 DIM

Laven et al. (2014)

Covariate in

model

ADCT trial ADCT + TS2 Calving

to 250

DIM

Godden et al. (2003)

Covariate in

model

ADCT trial ADCT + TS 60 DIM DO3 to 8 DIM DO to

8 DIM

DO to 8

DIM

DO to 8

DIM

Bates & Chambers

(2014)

Covariate in

model

ADCT trial ADCT + TS 100

DIM

1st herd test

post-calving

1st herd

test

post-

calving

McIntosh et al.

(2014)

Covariate in

model

ADCT trial ADCT + TS DO to

1st herd

1st herd

test

143

test

post-

calving

post-

calving


Leelahapongsathon

et al. (2016)

Covariate in model;

Free stall;

tie-stall;

milk yield at DO;

full or partial insertion of

ADCT;

daily barn cleaning

Not reported

(NR)

14 DIM DO to 14

DIM

Sol et al. (1994)

Covariate in model;

Hygiene score of farm

ADCT DO to 5 DIM DO to

5 DIM


2TS = teat sealant

3DO = at dry off

144

Table 3.10 Author and descriptive information for housing, pasture, bedding, and bedding management as a management practice

implemented at drying off to improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement

during the dry period and post-calving

Authors Housing,

Pasture,

Bedding


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Astiz et al. (2014)

Loose housing w/ compost

bedded barn;

Loose housing with barley

straw

Not

reported

(NR)

150

DIM

NR1

O'Driscoll et al.

(2008)

Indoor stall housing;

Uncovered woodchip pad with

concrete feed face;

Covered woodchip pad with

concrete feed face

NR 21 DIM DO2 to 21

DIM

DO to 21

DIM

Black & Krawczel

(2016)

Free stall;

Sand beds;

Raked clean 1-2 times daily;

At pasture

ADCT3 7 DIM Calving to

2 DIM

Cappelli et al.

(2007)

Tie stall w/ individual fed

cows;

Free stall w/ TMR

NR calving 30 DIM

O'Driscoll et al.

(2008)

Indoor stall housing;

Uncovered woodchip pad with

concrete feed face;

Covered woodchip pad with

concrete feed face;

NR NR DO to 113

DIM

DO to 113

DIM

145

Uncovered woodchip pen with

self-feed silage pit


Green et al. (2008)

Access to housed lying area

while grazing vs. sometimes

access to housed lying area vs.

no access to housed lying

area;

Straw in early bedding

(always chopped vs.

unchopped vs. sometimes

chopped);

Milk yield before DO (0-10kg,

>10-20kg, >20kg)

ADCT;

TS4

30 DIM

Breen et al. (2017)

Fill slatted floor;

Tractor scrape transition yard

daily;

Deep sand beds;

Apply new clean sand at 1-2

week intervals

NR 30 DIM

Ceballos-Marquez

et al. (2010)

Free stall;

No grazing at pasture;

Tie-stall;

Grazing at pasture;

Add selenium to diet

NR NR DO to 7 DIM DO

to 7

DIM

DO to 7

DIM

Down et al. (2016)

Stall design so 90% of cows

can lie correctly;

Clean stalls at least twice

daily;

Apply clean bedding at least

once daily if organic;

NR 30 DIM DO to 1st

milk

recording

post-

calving

146

Balance calcium and

magnesium in dry cow ration;


trimming;

Spread bedding evenly in dry

cow yard;

Abrupt vs. gradual cessation

of lactation;

Differentiate infected cows

from uninfected at drying off

Green et al. (2007)

Dry cows not housed with

milking herd;

Drainage in stalls;

Pasture grazing policy (rest 4

weeks, graze 2 weeks);

Straw yard;

Stalls with mattresses;

Disinfect stall bedding in early

dry period (DP);

Scrape feed and loaf areas at

least 1-2 times daily

Reduce milk yield of high-

yielding cows before DO;

Cows remain standing for 30

minutes after administration of

dry cow therapy (DCT)

NR 30 DIM

Leelahapongsathon

et al. (2016)

Free stall;

Mixed stall;

Tie stall;

Milk yield prior to drying off;

NR 14 DIM DO to 5-14

DIM

147

Full vs. partial insertion of

DCT;

Daily barn cleaning;

Dry period length

Sol et al. (1994)

Good hygiene score of farm

vs.

Average hygiene score of farm

vs.

Bad hygiene score;

Dry period length

ADCT DO to 1-5 DIM DO

to 1-

5

DIM



2DO = at dry off


4TS = teat sealant

148

Table 3.11 Author and descriptive information for milking frequency prior to drying off (DO) as a management practice implemented


post-calving

Authors Milking

frequency prior

to DO


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New

IMI

Prevalence

of IMI

Somatic cell

count (SCC)

Controlled trials

Ferris et al.

(2008)

Once daily milking;

Twice daily milking

Not

reported

(NR)

56 DIM DO to 3 DIM

How you dry

off cows

affects udder

infections

(1991)

Abrupt cessation, ration change;

Abrupt cessation, no ration

change;

Ration change, intermittent

milking;

No ration change, intermittent

milking

ADCT1 DO to 7 DIM DO

to 7

DIM

Douglas et al.

(1997)

Once daily milking;

Every other daily milking

NR 14 DIM DO to 14

DIM

Gott et al.

(2017)

Abrupt cessation;

Gradual cessation

ADCT;

TS2

DO to 7

DIM

120 DIM

Zobel et al.

(2013)

Abrupt cessation;

Gradual cessation

ADCT;

TS

DO to

10 DIM

DO to 10

DIM

Gott et al.

(2016)

Abrupt cessation;

Gradual cessation

ADCT;

TS

DO to 7 DIM DO

to 7

DIM

149

Newman et

al. (2010)

Intermittent milking;

Twice daily milking

ADCT DO to 3

DIM

Martin et al.

(2020)

Gradual cessation;

Twice daily milking

(conventional)

ADCT;

TS

90 DIM 10 to 26

DIM

10 to 26 DIM

Rajala-

Schultz et al.

(2010)

Intermittent

milking;

Twice daily

milking

Milk yield

>115kg at DO

vs. <75kg at

DO

ADCT DO to 3

DIM

Gott et al.

(2014)

Abrupt

cessation;

Gradual

cessation

Milk yield at

DO

ADCT DO to 3

DIM

Gott et al.

(2015)

Abrupt

cessation;

Gradual

cessation

Milk yield at

DO

ADCT DO to 7

DIM

France et al.

(2020)

Decreased feed,

decreased

milking

frequency;

Decreased feed,

non-decreased

milking

frequency;

Non-decreased

feed intake,

decreased

milking

frequency;

No ADCT DO to 28

DIM

150

Non-decreased

feed, non-

decreased

milking

frequency

Ferris et al.

(2008)

Once daily milking;

Twice daily milking

NR DO to 42

DIM

DO to 42

DIM


Zecconi et al.

(1995)

Intermittent cessation, ADCT,

<50 day DP length;

Abrupt cessation, ADCT, >50

day DP length


DIM

Down et al.

(2016)

Abrupt cessation vs. once daily

milking;

ADCT;

Stall design so 90% of cows can

correctly lie down;

Clean stalls at least twice daily;

apply clean bedding at least once

daily if organic;

Balance calcium and magnesium

in dry cow ration;

Do not dry off curing hoof

trimming;

Spread bedding evenly;

Differentiate infected from

uninfected cows

NR 30 DIM Last milk

recording

prior to DO to

1st milking

post-calving

de Prado-

Taranilla et

al. (2018a)

Abrupt cessation vs.

Gradual cessation

NR 30 DIM 30

DIM

Last milk

sample prior

to DO to 1st

151

sample post-

calving


2TS = teat sealant

152

Table 3.12 Author and descriptive information for reduced milk yield at drying off (DO) as a management practice implemented to

improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry period and post-

calving

Authors Milk

yield at

DO


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New IMI Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Odensten et al.

(2007a)

Low milk yield at

drying off;

Medium milk yield at

drying off;

High milk yield at

drying off

Not

reported

(NR)

60 DIM DO to 28

DIM

Calving to

28 DIM

Rajala-Schultz et

al. (2010)

Milk

yield

>115kg

before

DO vs.

<75kg

Intermittent

milking;

Twice daily

milking

prior to DO

ADCT1 DO to 3

DIM


Green et al. (2008)

Milk yield before

drying off (0-10kg,

>10-20kg, >20kg);

Straw in early bedding

(not chopped, always

chopped, sometimes

chopped);

No access, full access,

or partial access to

ADCT,

TS2

30 DIM

153

housed lying area while

grazing

Rajala-Schultz et

al. (2005)

Milk yield before

drying off

ADCT 3 DIM

Robert et al. (2008)

Milk yield at drying off

(≤12kg, 12-18kg,

≥18kg);

>65 day DP length vs.

<65 day DP length

ADCT DO to 5

DIM

Green et al. (2007)

Reduce milk yield of

high yielding cows

before DO;

ADCT;

Leptospirosis vaccine

for cows at pasture;

Dry cows not housed

with milking herd;

Good drainage in stalls;

Pasture grazing policy

rest 4 weeks, graze 2

weeks;

Straw yard;

Stalls with mattresses;

Disinfect stalls in early

dry period;

Cows remain standing

for 30 minutes after

administration of dry

cow therapy (DCT);

NR 30 DIM

154

Scrape transition stall

feed and loaf areas at

least once/twice daily

Leelahapongsathon

et al. (2016)

Milk yield before

drying off;

Free stall vs. mixed vs.

tie stall;

Full vs. partial insertion

of DCT;

Daily barn cleaning;

Dry period length

NR 14 DIM DO to 14

DIM

Madouasse et al.

(2012)

Milk yield at last milk

recording

NR Last milk

recording prior

to DO to 1st

milk recording

post-calving

Last milk

recording

prior to DO

to 1st milk

recording

post-

calving

Last milk

recording

prior to DO

to 1st milk

recording

post-calving

Last milk

recording

prior to DO

to 1st milk

recording

post-

calving

Dingwell et al.

(2003c)

Milk yield >21kg ADCT DO to

calving


2TS = teat sealant

155

Table 3.13 Author and descriptive information for reduced milk yield at drying off (DO) as a management practice included as a

covariate in regression modeling, with corresponding risk periods of outcome measurement during the dry period and post-calving. Milk

yield at drying off was included in trial models to adjust for residual confounding not controlled for by allocation to treatment groups

Authors Milk yield at

DO


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New IMI Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Østerås et

al. (2008)


(covariate in model)

Not reported

(NR)

6 DIM 6 DIM

Cook et

al. (2005)


(covariate in model)

ADCT1,

TS2

100 DIM Calving to 3 DIM Calving

to 3 DIM

Gott et al.

(2014)

Milk yield

before DO

(covariate in

model)

Abrupt

cessation;

Gradual

cessation

ADCT DO to 3

DIM

Gott et al.

(2015)

Milk yield at

DO (covariate

in model)

Abrupt

cessation;

Gradual

cessation

ADCT DO to 7

DIM


2TS = teat sealant

156

Table 3.14 Author and descriptive information for bovine somatotropin (bST) administered over the dry period as a management

practice implemented to improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during

the dry period and post-calving

Authors Bovine

somatotropin1


treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections (IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Eppard et

al. (1996)

bST (IM),

normal calcium

in feed;

High calcium in

feed, bST (IM)

Normal

calcium in

feed, no bST;

High calcium

in feed, no

bST

ADCT2;

Leptospirosis

vaccine

Not

reported

(NR)3

7 to 21

DIM

Gulay et

al. (2004)

bST (IM) Untreated

control

Whole herd

bST treatment

3 to 150

DIM

Gohary et

al. (2014)

bST (SC) Placebo (SC) NR 63 DIM

Gulay et

al. (2007)

bST (IM) Untreated

control

Leptospirosis

vaccine

60 DIM

Eppard et

al. (1996)

bST (SC),

calcium diet

Calcium diet,

placebo (SC)

ADCT 98 DIM 7 to 91

DIM

NR

1Bovine somatotropin was administered either via intramuscular (IM) or subcutaneous (SC) route




157

Table 3.15 Author and descriptive information for management practices not included in other categories as a practice implemented at

drying off to improve udder health outcomes in dairy cattle, with corresponding risk periods of outcome measurement during the dry

period and post-calving

Authors Other management Comparator Concurrent

treatments

Risk period

Clinical

mastitis

Cure of

intramammary

infections

(IMI)

New

IMI

Prevalence

of IMI

Somatic

cell count

(SCC)

Controlled trials

Whist et al.

(2007)

Teat dip continued

into dry period

TS1;

Untreated

control

ADCT2 6 DIM 6 DIM Calving to

305 DIM

Timms et al.

(1997)

Barrier teat dip

during the dry period

Untreated

control

ADCT DO to 3

DIM

Middleton &

Fox (1999)

Chlorhexidine at drying off;

Betadine

ADCT;

Banamine

(IM)

Calving to 90

DIM

Timms

(2001)

Teat dip during the

dry period

Untreated

control

ADCT DO3 to

3 DIM

Timms

(2001)

Teat dip into the dry

period + ADCT;

Teat dip into the dry

period

ADCT;

Untreated

control

Not

reported

(NR)

DO to 3

DIM

Mammi et al.

(2018a)

Monensin controlled

release capsule

Untreated

control

NR Calving to

123 DIM

Mammi et al.

(2016)

Monensin bolus Untreated

control

NR Calving to

119 DIM

158

Wagenaar et

al. (2011)

Homeopathic oral

product

TS;

Untreated

control

NR 100

DIM

Post-

calving

DO to

post-

calving

NR4

Klocke et al.

(2010)

Homeopathic dry

cow therapy (DCT)

orally (Mercurius

solubilis, Lachesis

mutus, Sulfur,

Calcium carbonicum,

Calcium

phosphoricum,

Pulsatilla pratensis,

Sepia, Silica)

TS;

Untreated

control

NR 100

DIM

DO to 14 DIM DO to

14 DIM

DO to 14

DIM

DO to 14

DIM

Hop et al.

(2019)

Cabergoline

(intramuscular, IM)

Placebo

(IM);

ADCT

NR 30 DIM Calving

to 8

DIM

Calving to

8 DIM

Calving to

30 DIM

Hop et al.

(2019)

Cabergoline

(intramammary,

IMM);

TS + Cabergoline;

ADCT + TS +

Cabergoline

ADCT;

TS;

ADCT +

TS

NR 100

DIM

DO to

post-

calving

DO to

post-

calving

Kumar et al.

(2012)

Shatavari root

powder in feed

Untreated

control

NR 150

DIM

Calving

to 150

DIM

Weekly

Tao et al.

(2011)

Heat stress;

Cooling via fans and sprinklers

ADCT 280 DIM

159

Leitner et al.

(2011)

Casein hydrolysate

(IMM) + ADCT

ADCT;

Untreated

control

NR Calving

to 100

DIM

DO to 100

DIM

DO to

100

DIM

DO to 100

DIM

DO to 100

DIM

Lien et al.

(2010)

Oral drench

propylene glycol

Placebo

drench

NR 14 to 28

DIM

Sol & ter

Balkt (1990)

Long cannula infusion of ADCT;

Short cannula infusion of ADCT

ADCT DO to 5

DIM

DO to 5 DIM DO to 5

DIM

Auchtung et

al. (2003)

Short day photoperiod;

Long day photoperiod

NR 10 DIM DO to

calving

DO to 3

DIM

Challenge trials

Pomeroy et

al. (2016)

UV-irradiated E. coli

(IMM)

E. coli J5

vaccine;

Untreated

control

No ADCT,

No TS

DO to 7

DIM

DO to 7

DIM

DO to 7

DIM

Morin et al.

(2003)

Long day photoperiod;

Short day photoperiod

NR 14 DIM 14 DIM


Reeve-

Johnson &

Nickerson

(2007)

Segregation of S aureus infected

cows

vs. no segregation


DIM

Down et al.

(2016)


trimming procedures;

Differentiate infected cows from

uninfected at drying off;

ADCT;

NR 30 DIM Last milk

recording

at DO to

1st milk

recording

160

Stall design so 90% of cows can lie

correctly;

Clean dry cow stalls at least twice

daily;

Apply clean bedding to dry cow

stalls if organic;

Balance calcium and magnesium in

dry cow ration;

Spread bedding evenly;

Abrupt cessation vs. once daily

milking

post-

calving

1TS = teat sealant


3DO = at dry off



161

3.9 FIGURES


diagram of included studies for the scoping review of modifiable management practices

implemented at dry off to improve udder health outcomes (Moher et al., 2009)

162

Figure 3.2 Number of articles by year of publication included in the scoping review for modifiable

management practices implemented at drying off to improve udder health (n=229)

0 2 4 6 8 10 12 14 16

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

NR

Number of Publications

Year

163

Figure 3.3 Map of the number of articles by country included in the scoping review characterizing

modifiable management practices that have been assessed for their effect on udder health (1990 to

2020). Eligible articles (n=229) were conducted in 39 countries, the majority in the USA (n=84),

Canada (n=19), and the United Kingdom (n=13). Darker shades of blue indicate a larger number

of studies

164

Figure 3.4 Number of publications that reported clinical mastitis outcomes, ordered by number of

publications per risk period evaluated in the study (n=151)

0 5 10 15 20

567

101420212228303137404245495052606370778081849098

100112120130140150162180200240250300308

calvingweekly

monthlyNR

Number of Publications

Days

in milk

165

4 CHAPTER 4: CONCLUSION

4.1 GENERAL CONCLUSIONS AND FUTURE DIRECTIONS

The dry period following lactation is a critical time for maintaining and improving udder

health in dairy cattle. Intramammary infections (IMI) commonly develop during this time because

milk flow has ceased and the teat canal remains open prior to formation of a keratin plug (Huxley

et al., 2002). Further, IMI can develop into clinical mastitis if left untreated (Pantoja et al., 2009).

The costs associated with mastitis, such as lost milk production and a decrease in herd profitability,

warrant the need to think preventatively about mastitis and limit the duration of infections. Nearly

half of antimicrobials used to treat IMI and clinical mastitis are administered at drying off as

antimicrobial dry cow therapy (Kuipers et al., 2016). The use of antimicrobial dry cow therapy is

an essential management tool that producers and veterinarians use to cure existing IMI and to

prevent the occurrence of new IMI over the dry period. Targeting antimicrobial dry cow therapy

for the cure of existing intramammary infections is essential during the dry period, because other

forms of management, such as teat sealants, can be used to prevent IMI but are not efficacious for

cure of existing cases. Assessing the relative efficacy of antimicrobial products is imperative to

provide dairy producers and veterinarians with the best knowledge for treatment of IMI during the

dry period. Improvement in the prudent use of antimicrobials also can be accomplished through

assessing alternative management practices that can be implemented at drying off to improve udder

health. The effectiveness of dry cow management either in conjunction with or in replacement of

antimicrobials to prevent IMI and clinical mastitis can be assessed following a scoping review

characterizing the types of management strategies in the literature. Therefore, the objectives of the

research in this thesis were to assess the relative efficacy of dry cow antimicrobial products for

cure of existing IMI during the dry period, and to characterize modifiable management strategies

that have been assessed for their impact on udder health over the dry period.

In chapter two of this thesis, a systematic review and network meta-analysis was used to

identify all relevant literature and compare the efficacy of multiple antimicrobial options to cure

existing all-cause IMI during the dry period from published controlled trials. Fifty-eight trials were

included, from which 40 unique treatment protocols were compared, including antimicrobials

166

(with or without teat sealants), non-antimicrobial options, and non-active control groups. Bayesian

statistical analyses with posterior summaries generated using Markov Chain Monte Carlo

(MCMC) simulation, implemented in Just Another Gibbs Sampler (JAGS) software were used (Hu

et al., 2020). Model outputs included measures of treatment efficacy, such as relative risks, mean

treatment rank summaries, and the probability of a treatment protocol being the best or worst. As

pathogen profiles have changed over time, an additional analysis including only articles published

in or after 1990 was conducted, but results were similar to that of the overall network.

The network was dominated by non-active controls, cloxacillin, and penicillin-

aminoglycoside products; these were the most common types of antimicrobial treatments reported

in relevant literature. However, product comparisons were not replicated enough in the literature

to create meaningful comparisons on the basis of efficacy, thus the relative risks should be

interpreted with caution. The mean rank value of each product was reported, but wide credibility

intervals prevented the establishment of one product being superior to another. A lack of reported

data and inconsistency in outcome measures precluded inclusion of many potentially relevant

studies; continued improvement in the reporting of outcomes in dairy cattle science is needed in

order to inform meaningful knowledge synthesis work in the future.

Dairy cattle undergo several management changes at drying off. The literature is dominated

by studies that assess the impact of antimicrobial and teat sealant products for their effect on the

cure and prevention of IMI during the dry period through to early lactation. Earlier systematic

literature reviews and meta-analyses have been used to compare several antimicrobial or teat

sealant options (Robert et al., 2006; Halasa et al., 2009a; Halasa et al., 2009b) for their role in cure

and prevention of IMI and clinical mastitis over the dry period. More recent systematic reviews

and meta-analyses, as well as network meta-analyses, have compared antimicrobials (Winder et

al., 2019a, Winder et al., 2019b; Chapter 2 of this work) and teat sealants (Rabiee & Lean, 2013;

Dufour et al., 2019; Winder et al., 2019c) for their role in cure and prevention of IMI and clinical

mastitis over the dry period. However, many other potentially modifiable management practices

are implemented at drying off which may impact udder health, such as planned days dry,

decreasing milk yield prior to dry off, nature of cessation of lactation (abrupt or gradual), bedding

167

type and management, and stall design (Green et al., 2007). There is a body of work evaluating

the effect of management strategies on udder health outcomes such as cure of existing IMI over

the dry period, prevention of new IMI over the dry period, prevalence of IMI, and risk of clinical

mastitis post-calving.

In chapter three of this thesis, modifiable management practices that have been evaluated

for their impact on cure or prevention of IMI over the dry period, prevalence of IMI post-calving,

and the risk of clinical mastitis post-calving were described and characterized using a scoping

review. To maintain relevance to modern dairy producers and veterinarians we restricted the search

strategy from 1990 to current (2020). All analytical study designs were eligible, as we were

interested in studies that compared one management practice to that of a different level or practice

that was implemented at drying off, and some management strategies may be difficult to evaluate

using controlled trials. The impact of antimicrobials and teat sealants on cure or prevention of IMI

over the dry period is well researched, therefore, we only quantified this body of literature and did

not characterize it further. Of 420 eligible articles, antimicrobial or teat sealant products, without

comparison to another modifiable dry cow management strategy, were assessed in 191 articles,

and other modifiable management practices were assessed in 229 articles. Therefore, these 229

articles were further characterized in this scoping review.

The most commonly reported management practices were ration formulation and delivery,

vitamin and mineral feed additives, and vaccination against mastitis pathogens. Management

practices recommended for use at dry off in the 10 point mastitis control plan by the National

Mastitis Council are to: decrease the energy density of late lactation rations, employ abrupt

cessation of lactation, use the partial insertion method of application of antimicrobial dry cow

therapy, use an internal teat sealant, feed additives to boost the immune system, manage cows in a

clean and dry environment, and vaccinate against mastitis pathogens (NMC, n.d.). All of these

recommendation areas were reported within the body of work included in this scoping review.

Clinical mastitis and somatic cell count (SCC) were the most commonly reported udder health

outcomes, followed by prevalence of IMI post-calving and prevention of IMI over the dry period.

Cure of existing IMI over the dry period was reported in the fewest number of articles, which is

168

expected provided non-antimicrobial management strategies are generally implemented to prevent

the occurrence of new IMI. Despite the reporting of relevant outcomes in a number of articles, we

found significant variation in the reporting of risk periods used to measure each outcome. Clinical

mastitis was most commonly reported over 30, 60 or 90 DIM, but the range in risk periods reported

was from calving to 308 DIM. There is a need for consensus on the most appropriate number of

days post-calving that will represent an association to the dry period management practice and not

also reflect an association with other causal factors occurring during early lactation. At a minimum,

authors are encouraged to provide a reason for the selection of the risk period used to measure

outcomes.

Implications of research chapter two indicated significant improvement in consistent

outcome selection in dairy science is required. The Core Outcomes Measures in Effectiveness

Trials (COMET) Initiative was launched to guide the development of a set of outcomes that, at a

minimum, should be evaluated in all clinical trials for specific areas of health (Kirkham et al.,

2019). Outcomes we defined as critical to determine the effectiveness of a dry off antimicrobial as

a therapeutic agent, such as incidence of clinical mastitis over the first 30 DIM and total

antimicrobial use over the first 30 DIM, were uncommonly reported in eligible trials. Further, very

few studies defined clinical mastitis over the first 30 DIM, and often extended the incidence risk

period over 90 or 100 DIM. The use of antimicrobial daily dosages is a term coined to provide a

comparative measure of antimicrobial use on farms. Monitoring antimicrobial use such as

antimicrobial dry cow therapy and treatment of clinical mastitis are imperative to proper

antimicrobial stewardship. It is evident that in addition to improved reporting of clinical trials in

dairy science using reporting guidelines such as the REFLECT statement (O’Connor et al., 2010;

Sargeant et al., 2010), consensus in a list of outcomes that should be measured when conducting

research on cure, prevention, or prevalence of IMI and clinical mastitis needs to be established.

Implications of research chapter three indicate a need for authors to include rationale for

the choice of risk periods in the outcome reporting section. Variability in the measurement of

outcomes makes further knowledge synthesis methods difficult and can lead to large credibility

intervals where meaningful differences between interventions cannot be established. As there is

169

increased interest in continued use of selective dry cow therapy, and other forms of management

that limit antimicrobial use on dairy farms, this scoping review was a necessary first step to

informing the possibility of using dry cow management to alter the susceptibility of cows to IMI

and mastitis over the dry period and post-calving, and ultimately reduce the need for

antimicrobials.

This thesis provides direction for future research in two main areas: improvement in the

consistency of outcome definitions and risk periods for trials evaluating udder health, and

identification of areas for further systematic review and meta-analyses into dry cow management

practices. To address the first area, organizations such as the National Mastitis Council, the

International Dairy Federation and the Canadian Bovine Mastitis and Milk Quality Research

Network have already reported methods for collecting milk samples, guidance documents on

bacteriologic culture, and recommendations for effective management of dry cows that are well

recognized (NMC, 2004; CBMQRN, 2019). These bodies maintain good rapport with dairy

producers and researchers throughout the world. Therefore, they could lead conversations for

consensus of a minimum set of outcomes that should be evaluated by trialists when investigating

clinical mastitis and IMI over the dry period. Ensuring researchers provide a reason for selection

of the risk period to assess clinical mastitis and cure or prevention of IMI should be at the forefront

of these conversations. To address the second area, dry cow nutrition and administration of mastitis

vaccines at dry off (such as E. coli J5 and S. aureus) were widely reported management strategies

in the literature and could be the target of future systematic review and meta-analytic methods,

and, more specifically, a network meta-analysis to examine the relative efficacy among all of these

interventions. Feed additives such as vitamins, minerals, and probiotics may have an effect on a

cow’s immune system at drying off and should be investigated for their role in prevention of IMI

or clinical mastitis over the dry period and into early lactation. Increased primary research in other

areas of dry cow management are needed to inform the effectiveness of these strategies in the

prevention of IMI and clinical mastitis.

The dry period of lactation is essential to cure existing intramammary infections and

prevent the occurrence of new IMI, which also decreases the risk of clinical mastitis in the early

170

subsequent lactation. Previous work has shown that antimicrobial products are the most effective

method for cure of existing IMI over the dry period, but until reporting of outcome measures

becomes more uniform in published trials to inform future synthesis work, product choice should

be based on previously published evidence and expert opinion of veterinarians and producers. In

addition, other modifiable management strategies surrounding dry off warrant increased primary

research in order to ultimately compare the efficacy among many different strategies.

4.2 REFERENCES

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paper]. Retrieved August 4, 2020, from https://www.dairyproducer.ca/canadian-bovine-mastitis-

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APPENDICES

Appendix 1 Descriptive statistics for articles included in the network meta-analysis assessing the relative efficacy of antimicrobial dry

cow therapy products to cure existing intramammary infections during the dry period, listed in alphabetical order of author name Author (year) Country Breed Herd

type1

# of Herds # samples to

confirm dry-

off diagnosis

# with IMI at

dry-off2

Definition of all-cause

bacterial cure

Arruda et al. (2013) USA NR C 6 2 741 Q Aerococcus spp., Bacillus spp., CNS,

Corynebacterium spp., Enterococcus

spp., other Gram-positive, other

streptococcal spp., Staph aureus, Strep

dysgalactiae, Strep uberis, E. coli,

Enterobacter spp., Klebsiella spp.,

other Gram-negative (Serratia spp.).

(Gram-negative and Gram-positive

groups) (NMC guidelines)

Barrett et al. (2006) Ireland NR C 10 1 197 C Bacteria not typed (infection defined

by SCC cut point)

Christie & Strom

(1978)

USA NR C NR 2 1394 Q Strep agalactiae, Strep uberis, Staph

aureus, Staph spp., Corynebacterium

bovis, miscellaneous (Klebsiella spp.,

and other gram-negative bacteria)

(NMC guidelines)

Clegg et al. (1975) United

Kingdom

NR C 1 1 330 Q Staph aureus, Strep uberis,

Corynebacterium bovis

Cornelis et al.

(1996)

Netherlands NR C 1 2 583 Q Staph aureus, streptococci

Cummins &

McCaskey (1987)

USA NR R/U 1 2 150 Q Coagulase-positive staphylococci

(includes Staph aureus, Staph hyicus,

Staph warneri, Staph epidermidis,

Staph xylosus, Staph hominis),

Streptococcus spp., CNS,

Corynebacterium spp., Bacillus spp.,

174

Pseudomonas spp., yeast (NMC

guidelines)

Eberhart &

Buckalew (1972)

USA Holstein, Jersey,

Brown Swiss,

Guernsey,

Arryshire

R/U 5 2 207 Q Strep agalactiae, Staph aureus, other

streptococci, coliform, staphylococci

and streptococci (mixed)

Fonseca et al.

(1998)

Brazil NR C 5 1 154 Q No species specified except for

difference in cure rate of C. bovis

Funk et al. (1982) USA NR C 141 2 1229 Q Staphylococci, Strep agalactiae, other

streptococci, coliform (NMC

guidelines)

Hallberg et al.

(2006)

USA Holstein C 21 1 535 Q CNS, S aureus, environmental

streptococci spp., Corynebacterium

spp., and gram-negative mastitis

pathogens (NMC guidelines)

Hanschke & Aberka

(1983)

Morocco Holstein C,

R/U

24 1 214Q/86C Staph aureus, Staph epidermides,

other Staphyloccoci, Strep agalactiae,

Strep dysgalactiae or Strep uberis, E.

coli

Harmon et al.

(1986)

USA Holstein, Jersey NR 1 1 167 Q Corynebacterium bovis, Coagulase-

negative staphylococci, streptococci,

Staph aureus, other (NMC guidelines)

Heald et al. (1977) USA Holstein C 18 2 302 Q Strep agalactiae, other streptococci,

Staph aureus, other cocci (gram-

positive)

Hernandez et al.

(2014)

Spain NR C 6 1 68 C Major pathogens (Staph aureus, Strep

uberis, E. coli); SCC used to define

infection, bacteria not full typed

Hill & Keefe (1974) USA NR C NR 2 783 Q Strep agalactiae, Strep dysgalactiae,

Strep uberis and Staph aureus. E. coli

considered but not reported by

treatment group.

Hogan et al. (1994) USA Holstein C 4 2 322 Q Staph aureus, Staph species,

environmental streptococci, gram-

175

negative bacilli, Corynebacterium

bovis, and other microbes

Hoque et al. (2016) Bangladesh Mixed breed C NR 1 498 Q Major pathogens (Staph aureus, Strep

agalactiae, Strep uberis, Strep

dysgalactiae, E. coli), minor pathogens

(CNS, Bacillus spp., Corynebacterium

bovis) (NMC guidelines)

Huxley et al. (2002) United

Kingdom

NR C 16 2 705 Q All major/minor pathogens

(Coagulase-positive staphylococci,

Strep uberis, E. coli, Streptococcus

spp., Enterococcus spp., Klebsiella

spp., Pantoea spp., Pseudomonas spp.,

Acinetobacter spp., nonfermenters,

Aspergillus spp., yeast, Bacillus spp.,

Micrococcus spp., CNS,

Corynebacterium spp.)

Johnson et al.

(2016)

USA Holstein C 4 1 774 Q Gram-positive (Aerococcus spp.,

Bacillus spp., CNS, Corynebacterium

spp., Enterococcus spp., Strep

dysgalactiae, Strep uberis, Strep

agalactiae, Staph aureus, other Gram-

positive), Gram-negative (E. coli,

Klebsiella spp., Enterobacter spp.,

Serratia spp., other Gram-negative)

(NMC guidelines)

Keefe (1975) USA NR NR NR 2 783 Q Staph aureus, Strep agalactiae, Strep

dysgalactiae, Strep uberis

Kingwill et al.

(1967)

United

Kingdom

NR C 27 NR 561 Q Staph aureus, streptococci (Strep

agalactiae, Strep dygalactiae, Strep

uberis) (mixed infections separate)

Kirk et al. (1997) USA Holstein C 1 1 89 C Coagulase-negative staphylococci,

streptococci, mixed (NMC guidelines)

Loosmore et al.

(1968)

United

Kingdom

NR C 10 (3 dropped

out due to

Foot and

Mouth

2 458 Q Haemolytic Staph aureus, Strep

agalactiae, Strep dysgalactiae, Strep

uberis, negative

176

Disease

restrictions)

Mahmoud (1991) Egypt Holstein C 1 1 323 Q Strep agalactiae, Strep dysgalactiae,

Staph aureus, E. coli

Malhotra et al.

(1980)

India Mixed breed C 1 1 90 Q Staph aureus, Staph epidermidis,

micrococci, Strep agalactiae, Strep

dysgalactiae, other streptococci,

Corynebacterium spp. (mixed

infections included separate)

Martins et al. (2017) Brazil NR C 7 1 398 Q Coagulase-negative staphylococci,

Corynebacterium spp., Strep uberis,

Staph aureus, other

Meaney (1986) Ireland Holstein C 2 2 78 Q Staph aureus, Strep agalactiae, Strep

uberis, Staphylococci/streptococci,

Staphylocci/E. coli, Gram-negative,

none

Meaney (1976) Ireland NR R/U 2 2 102 Q Staph aureus, Strep

dysgalactiae/uberis, mixed

staphylococci/streptococci,

Corynebacterium pyogenes, Gram-

negative, none

Meaney (1986) Ireland NR C NR 2 102 Q Staph aureus, Strep

dysgalactiae/uberis, mixed

staphylococci/streptococci, C

pyogenes, Gram-negative, none

Meaney & Nash

(1977)

Ireland Holstein R/U 2 2 78 Q Staph aureus, Strep uberis, Strep

agalactiae, mixed staph/strep, mixed

staph/E. coli, gram-negative, none

Mohammadsadegh

(2018)

Iran Holstein C 1 2 315 Q Staph aureus, CNS, Strep agalactiae

(mixed infections included separate)

(NMC guidelines)

Mullen et al. (2014) USA Holstein, Jersey,

Holstein X

Jersey

C,

R/U

5 1 205 Q Gram-positive (CNS, Corynebacterium

spp., Enterococcus spp., Staph aureus,

Streptococcus spp. (not agalactiae),

other gram-positives (Bacillus spp.,

nocardia spp., Trueperella pyogenes),

gram-negative (Enterobacter

177

aerogenes, E. coli, Klebsiella spp.),

yeast, mixed infections (NMC

guidelines)

Musal & Izgur

(2006)

Turkey Brown Swiss C 1 1 152Q/59C Staph aureus, Strep agalactiae,

streptococcus spp., CNS, A. pyogenes,

Corynebacterium spp., bacillus spp.,

coliform

Ospina et al. (2016) Italy NR C 8 1 347 Q CNS, Staph aureus, Strep

dysgalactiae, Strep uberis, Strep spp.,

Enterococcus faecalis, Bacillus spp.,

Corynebacterium spp., E. coli,

Enterobacter spp., Serratia spp. (NMC

guidelines)

Østerås et al. (1994) Norway Norwegian Red

or Swedish

C 288 2 320 C Major pathogen (Staph aureus, Strep

dysgalactiae, Strep agalactiae,

Actinomyces pyogenes)

Østerås et al. (1999) Norway NR C 288 1 686 C Major pathogen (Staph. aureus, Strep

dysgalactiae, Strep agalactiae)

(Nordic recommendations)

Pankey et al. (1982) New

Zealand

Jersey, mixed

breed

C 6 2 387 Q Staph aureus, Strep uberis, Strep

agalactiae (NMC guidelines)

Pearson & Wright

(1969)

Ireland NR C 1 2 71 Q Staphylococci, streptococci, none

Pearson & Wright

(1969)

Ireland NR C 6 1 121 Q Staphylococci, streptococci, none

Petzer et al. (2009) South

Africa

Holstein C 1 1 193 Q Major/minor pathogens and other

(Staph aureus, Strep agalactiae, Strep

dysgalactiae, CNS, Enterococcus

faecalis, E. coli, Strep uberis). (IDF

guidelines)

Pinedo et al. (2012) USA NR C 2 2 402 C Staph aureus, staphylococcus spp.,

Bacillus spp., coliform, streptococcus

spp. (NMC guidelines)

Polkowski et al.

(1981)

Poland Lowland Black

and White

C 4 2 620 Q Any pathogen (Strep agalactiae, other

streptococci, Staph aureus, other

major pathogens) (IDF guidelines)

178

Postle & Natzke

(1974)

USA Holstein C NR 2 704 Q Staph aureus, Strep agalactiae, other

streptococci, and coliform (NMC

guidelines)

Postle & Natzke

(1974)

USA Holstein C NR 2 4417 Q Staph aureus, strep agalactiae, other

streptococci (NMC guidelines)

Qaisar et al. (2017) Pakistan NR R/U 1 1 33 Q Staph aureus, Strep agalactiae, E. coli

(NMC guidelines)

Rao & Choudhuri

(1994)

India Mixed breed C 1 1 37Q/20C No bacterial diagnoses listed

Saluja et al. (2005) India NR C 1 1 76 (6 controls

not used in

analysis)

Staph epidermidis, Staph aureus,

Micrococcus spp., Corynebacterium

spp., Strep agalactiae

Schultze & Mercer

(1976)

USA NR R/U 1 3 112 Q Staph aureus, Staph epidermidis, other

streptococci, coliform, pseudomonas

spp., Strep agalactiae, yeast

Singh et al. (2018) India Sahiwal C 1 1 26 Q Bacteriology type not reported (NMC

guidelines, IDF guidelines)

Smith et al. (1966) United

Kingdom

NR C 36 2 403 Q Staph aureus, streptococcal infection

(only 21/1800 quarters infected with

Corynebacterium ulcerans at drying

off)

Smith et al. (1975) United

Kingdom

NR C 14 2 424 C Staphylococci, streptococci, other

bacteria

Sol & Sampimon

(1995)

Netherlands NR C 22 2 112 Q Staph aureus penicillin-sensitive,

Staph aureus penicillin-resistant,

Coagulase-negative staphylococci,

Strep uberis, Strep dysgalactiae, Strep

agalactiae, Corynebacterium spp., E.

coli

Swenson (1979) USA NR C 75 2 1142Q/698C Staph aureus, Strep agalactiae, other

streptococci (NMC guidelines)

Tuteja et al. (1994) India NR C 1 1 155 Q Staph aureus, Coagulase-negative

staphylococci (CNS), Strep agalactiae,

Strep dysgalactiae, Strep bovis,

enterococci, Corynebacterium spp.,

Bacillus spp. (mixed infections

counted separately)

179

Zecconi et al.

(2014)

Italy NR C 2 2 516 Q Staph aureus, Strep uberis, Strep

dysgalactiae, CNS, coliforms,

Corynebacterium bovis (NMC

guidelines)

Ziv (1976) Israel Holstein C 5 2 427 Q Strep agalactiae, Strep dysgalaciae,

Strep uberis, Staph aureus, E. coli, C.

pyogenes, Ps. aeruginosa (Coagulase-

negative micrococci and C. bovis

infections were disregarded)

Ziv et al. (1978) Israel NR C 5 2 395 Q Strep agalactiae, non-agalactiae

streptococci, Staph aureus, coliforms,

others (Corynebacterium bovis,

coagulase-negative micrococci) (NMC

guidelines)

Ziv et al. (1978) United

Kingdom

NR C 6 2 163 Q Strep agalactiae, Strep dysgalactiae,

Strep uberis, Strep faecalis, Staph

aureus, Coagulase-negative

micrococci, Corynebacterium

pyogenes, E. coli (NMC guidelines)

1C = commercial dairy, R/U = Research/University dairy

2Q = quarter, C = cow

180

Appendix 2 Description of treatment arms from trials included in the systematic review and network meta-analysis assessing the relative

efficacy of antimicrobial dry cow therapy products to cure existing intramammary infections in dairy cattle during the dry period.

Treatment combinations were made in consultation with experts and based on biological and clinical relevancy of antimicrobial products

to veterinarians and dairy producers, and on the World Organisation for Animal Health List of Antimicrobials of Veterinary Importance

(World Organization for Animal Health, 2007) Route Treatment description Dose T Treatment Map Network

Iteration

11

Network

Iteration

22

Intramammary

Cloxacillin 500mg Clox Cx Cx

Cloxacillin 600mg Clox Cx Cx

Cloxacillin 500mg (given at dry off and

a 2nd infusion was made 3

weeks later)

Clox - extended Cxext Cxext

Cloxacillin 500mg (given at 0, 7, and 14

days into the dry period)

Clox - extended Cxext Cxext

Cloxacillin 200mg Clox - low CxL CxL

Cloxacillin 1000mg Clox – high CxH CxH

Cloxacillin 1280mg Clox – high CxH CxH

Hydrocortisone acetate, hydrocortisone sodium

succinate, neomycin sulphate, chlorobutanol

anhydrous

20mg, 12.5mg, 500mg,

500mg

Cort/neo/chlor CNC CNC

Penethamate hydroiodide BAN,

dihydrostreptomycin sulphate

300mg, 300mg

Pen/strep PS Pam

Nafcillin, procaine penicillin G,

dihydrostreptomycin

NR Pen/strep PS Pam

Penicillin streptomycin NR Pen/strep PS Pam

Procaine benzylpenicillin and

dihydrostreptomycin

4.9% m/m, 6.5% m/m Pen/strep PS Pam

Benzathine penicillin G, dihydrostreptomycin 1 200 000IU, 1.0g Pen/strep PS Pam

Procaine penicillin G and dihydrostreptomycin 500 000IU, 500mg Pen/strep PS Pam

Procaine penicillin G and dihydrostreptomycin 100 000IU, 100mg Pen/strep PS Pam

Procaine penicillin G and dihydrostreptomycin 1 000 000IU, 0.5g Pen/strep PS Pam

Procaine penicillin G and dihydrostreptomycin 1 000 000 IU, 1g

Pen/strep PS Pam

Procaine penicillin G and dihydrostreptomycin 1 000 000IU, 0.5g Pen/strep PS Pam

181

Benzathine nafcillin 500mg Nafcillin Nf -



Benzathine benzylpenicillin, chloramphenicol,

sulfatolamide

2 500 000IU, 2.5g, 2.5g Penicillin/chloramphenicol/sulfa PCS PCS

Benthamine benzylpenicillin, penethamate

hydrioide, framycetin sulphate

300 000IU, 100 000IU,

100mg

Penicillin/framycetin PF Pam

Penthamate framycetin NR Penicillin/framycetin PF Pam

Penethamate hydrioidide, benethamine

penicillin, framycetin sulphate

100mg, 280mg, 100mg

Penicillin/framycetin PF Pam

Penethamate hydriodide BAN,

benethaminpenicillin, framycetin sulphate

100mg, 300mg, 100mg Penicillin/framycetin PF Pam

Leocillin, benethaminpenicillin, framycetin

sulphate

100 000IU

300 000IU

100mg

Penicillin/framycetin PF

Pam

Procaine penicillin and neomycin sulfate

50mg, 300mg

(and 500 000IU, 300mg)

Pen/neo PN Pam

Neomycin sulphate, penicillin V 500mg

325 000IU

Pen/neo PN Pam

Procaine benzylpenicillin, nafcillin,

hydrostreptomycin

300 000IU

100mg

100mg

Penicillin/nafcillin/strep PNS Pam

Ceftiofur 125mg Ceftiofur B B



Cephalonium 250mg Cefalonium CP CP

Cephapirin benzathine 300mg Cefapyrin C C

Cephapirin benzathine 500mg Cefapyrin C C

Cephapirin sodium 200mg Cefapyrin C C

Cephradine (asemisynthetic cephalosporin) 250mg (twice at one week

intervals)

Cefradine Cdext Cdext

Cephalexin

Dose unknown, product

contained cephalexin

microspheres

Cefalexin Cf -

182

Dose unknown, only the

antibiotic product - no

microspheres

Cephalexin, neomycin sulphate 250mg, 250mg Cefalexin/neomycin CfN CfN

Cefquinome 150mg Cefquinome Cq Cq

Cephazoline 250mg Cefazolin Cz Cz

Cloxacillin & Ampicillin 500mg, 250mg Cloxacillin/ampicillin CA CA

Dicloxacillin sodium 7.5g Diclox DiCx DiCx

Enrofloxacin NR Enrofloxacin IMM E-IMM E-IMM

Erythromycin 600mg Erythromycin Erm Erm

Gentamicin NR Gentamicin G G

Penicillin 100 000IU Pen P P



Procaine penicillin g 300mg Penicillin P P

Procaine penicillin g 1 000 000IU Penicillin P P

Benzathine oxacillin

Benzathine oxacillin equal

to 800 mg oxacillin,

oxacillin sodium

monohydrate equal to 200

mg oxacillin

Oxacillin Ox Ox

Neomycin sulphate and oxytetracycline 200mg, 300mg Oxytet/neo OxN OxN

Novobiocin 50mg Novobiocin N N




Penicillin, novobiocin

100 000IU, 400mg Pen/novo PNv PNv

Procaine penicillin g and novobiocin 200 000IU, 400mg Pen/novo PNv PNv

Penicillin, novobiocin

400 000IU, 400mg Pen/novo PNv PNv

Intramammary,

continued

Penicillin and sodium novobiocin 300 000IU, 250mg (and

300mg, 250mg)

Pen/novo PNv PNv

Procaine penicillin g and novobiocin 500 000IU, 600mg Pen/novo PNv PNv

Procaine penicillin and neomycin sulfate 50mg, 300mg Pen/neo/extended PNext PNext

183

(after complete milking

starting from day 30-20

prior to calving: 4

consecutive infusions and

all infused syringes were

removed 24 hours after

infusion)

Procaine penicillin G and dihydrostreptomycin 200 000IU, 100mg

(2 times: during the first

week and again during the

second week of the dry

period)

Pen/strep/extended PSext PSext

Penethamate hydriodide BAN,

dihydrosteptomycin sulfas

300mg, 300mg

(4 injections, administered

every 2nd day before drying

off)

Pen/strep/extended PSext PSext

Spiramycin 500mg Spiramycin S S

Spiramycin

& neomycin

400mg, 100mg Spiramycin/neo SN SN

Tilmicosin 1500mg Tilmicosin T T

Intramammary &

Parenteral

Benzathine oxacillin

& Enrofloxacin

benzathine oxacillin equal to

800 mg oxacillin, oxacillin

sodium monohydrate equal

to 200 mg oxacillin

&

2.5mg/kg IM

Oxacillin/Enrofloxacin OxE OxE

Parenteral Enrofloxacin & Levamisole

5 mg/kg body weight for 3

days IM + 2.5mg/kg body

weight as a single dose

subcutaneously

(3 days IM (enrofloxacin)

but single dose of

levamisole)

Enro/levamisole/extended ELext ELext

Levamisole

2.5mg/kg body weight

(single dose subcutaneously)

Levamisole L L

Enrofloxacin 5 mg/kg body weight EnrofloxacinINJ E-ext E-ext

184

(for 3 days IM)

Enrofloxacin (Baytril)

2.5mg/kg IM

EnrofloxacinINJ E-INJ E-INJ

Lincomycin & spiramycin (Lispiricin) 5mg/kg, 10mg/kg

(at end of lactation and at

14th days pre calving)

Lincomycin/spir LSext LSext

Intramammary &

Non-

antimicrobial

treatment

Cephapirin benzathine

&

1mg recombinant bovine interleukin-2 (rbIL-2)

in each quarter immediately preceding

intramammary infusion of DCT

300mg

& 1mg

CephInt

CIn CIn


& 2mg interleukin-2 per gland (10mL,

bioactivity 44 x 10^6 IU/mg in a bovine T cell

assay)

300mg

& 2mg

CephInt2mg CIn2 CIn2


& 10 mL of endotoxin-free PBS in each quarter

immediately preceding antibiotic DCT or 10 mL

phosphate-buffered saline (after antibiotic

treatment)

300mg

& 10mL

Cefapyrin PBS is a placebo) C C

Ceftiofur hydrochloride

+ Orbeseal

500mg Ceftiofur/TS BTS B

Cephalonium + TeatSeal 250mg Cephalonium/TS CPTS CP

Cephapirin benzathine + Orbeseal 300mg Cefapyrin/TS CTS C

Ciprofloxacin hydrochloride + Sellat (bismuth

subnitrate 4g) Ourofino Saude Animal, Brazil

400mg Ciprofloxacin/TS CpTS Cp

Cloxacillin benzathine + Orbeseal 500mg Clox/ts CxTS Cx

Cloxacillin + Orbeseal 600mg Clox/ts CxTS Cx

Cloxacillin + Osmondes Teat Seal 600mg Clox/ts CxTS Cx

Procaine penicillin G and dihydrostreptomycin +

Orbeseal

1 000 000IU, 1g Pen/strep/ts PSTS Pam

Parenteral &

Non-

antimicrobial

treatment

Enrofloxacin

+ vitamin E and selenium

5 mg/kg body weight for 3

days IM + Vitamin E and

Selenium @ 55 IU and

1.5mg/25kg body weight as

a single dose IM

Enrofloxacin/VitE EVeS EVeS

185

(3 days IM for enrofloxacin,

but single dose for vitamin

E and Se)

Non-

antimicrobial

treatment

Cinnatube: contains Calendula

(antiinflammatory), Cinnamomum spp

(antibacterial), Eucalyptus gobulus

(antibacterial), Melaleuca alterniflora

(antibacterial), Beeswax).

NR Cinnatube Cinn NonA

Iodinated diaminodiphenylsulphone (A

suspension of dapsone, reinforced by iodine,

with the addition of iodoform and a surfactant

(Texofor, I.S.U.) in a soft paraffin base (Super

Cryozol, IDDS 17%, equivalent to 1·0 g

dapsone, Crown Chemical Company,

Lamberhurst, Kent))

1.0g ? IDDS IDDS NonA

Phyto-Mast: contains angelica dahuricae

(antiinflammatory), Angelica sinensis

(immunomodulatory), gaultheria procumbens

(analgesic), and glycyrrhiza uralensis

(antiinflammatory), and thymus vulgaris

(antibacterial)

NR Phyt Py NonA

Phyto-Mast + Cinnatube NR PhtyCinna PyCinn NonA

TeatSeal 4g TS TS TS

0.5g alpha-tocopherol acetate + 0.25mg sodium

selenite orally (E-Sel Powder, Square

Pharmaceuticals Limited)

(oral) 0.5g, 0.25mg

(orally daily for the last 30

days before calving)

TocoSe x30 TSe30 NonA

IM injections of 1g alpha-tocopherol acetate +

5mg sodium selenite per cow (Inj. E-Veet Plus

Solution, The ACM Laboratories Limited)

1g, 5mg

(on day 30 (Dry-off) and

day 20 before calving: 2 per

day)

Toco1gSe5mg x4 TSe4 NonA

Vitamin E and Selenium @ 55IU and

1.5mg/25kg body weight as a single dose IM

55IU, 1.5mg/kg VESe VeS NonA

No treatment Negative control NAC NAC NAC

1Network iteration one refers to the first stage of product combination, whereby products were combined based on similar dosages, but products of varying active

compounds remained separate

186

2Network iteration two refers to the second stage of product combination, whereby penicillin-aminoglycoside products were combined based on the World

Organisation for Animal Health (2007) list of antimicrobials of human importance, and active antimicrobial products were combined with their antimicrobial and

teat sealant combination products (i.e. cloxacillin was combined with cloxacillin-teat sealant of the same dose)

187

Appendix 3 (Full network) History plot of basic parameters included in the network meta-analysis assessing the relative efficacy of

antimicrobial dry cow products for cure of existing intramammary infections in dairy cattle during the dry period. This plot shows

convergence of all basic parameters (n=40) over 10,000 iterations; d[1] is the log odds ratio of non-active control to non-active control,

therefore is always 0

188

Appendix 4 (Full network) Direct (dir) and indirect (rest) comparisons for the consistency assumption of pairwise comparisons within

the network meta-analysis assessing the efficacy of currently labelled antimicrobial protocols for cure of existing intramammary

infections in dairy cattle during the dry period. NAC = non-active control, Cx = cloxacillin, Cxext = cloxacillin-extended therapy, CxL

= cloxacillin-low dose, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-aminoglycosides, PSext =

penicillin-streptomycin-extended therapy, B = ceftiofur, C = cefapyrin, P = penicillin, PNv = penicillin-novobiocin, TS = teat sealant

Comparison d_dir sd_dir d_MTC sd_MTC d_rest sd_rest w sd_w z_score p_value

NAC vs Cx 1.84 0.46 1.9 0.25 1.92 0.29 -0.08 0.54 -0.14 0.89

NAC vs C 1.53 0.61 1.57 0.4 1.61 0.54 -0.08 0.81 -0.1 0.92

NAC vs PCS 2.52 1.21 2.51 0.92 2.49 1.41 0.02 1.86 0.01 0.99

NAC vs SN 3.74 1.18 3.74 0.9 3.74 1.38 0.01 1.82 0 1

NAC vs CNC 3.74 1.42 3.71 1.16 3.64 2.02 0.11 2.47 0.04 0.97

NAC vs PNv 1.48 0.51 1.7 0.47 2.89 1.18 -1.41 1.29 -1.09 0.27

NAC vs PSext 2.41 0.91 2.35 0.62 2.3 0.85 0.11 1.24 0.09 0.93

NAC vs CP 2.43 1.63 1.65 0.61 1.52 0.66 0.9 1.75 0.52 0.61

NAC vs N 1.48 0.55 1.5 0.52 1.6 1.67 -0.12 1.76 -0.07 0.95

NAC vs LSext 3.94 1.57 3.92 1.38 3.87 2.87 0.07 3.27 0.02 0.98

NAC vs P 1.28 0.78 1.24 0.51 1.21 0.68 0.07 1.04 0.07 0.95

NAC vs Cxext 1.78 1.15 2.87 0.58 3.24 0.67 -1.46 1.33 -1.1 0.27

NAC vs Pam 1.13 0.48 1.56 0.28 1.79 0.35 -0.67 0.59 -1.13 0.26

NAC vs CxH 4.15 1.23 2.12 0.53 1.64 0.59 2.51 1.36 1.84 0.07

NAC vs NonA 1.2 1.04 1.14 0.45 1.13 0.5 0.07 1.15 0.06 0.95

NAC vs B 0.58 1.16 1.57 0.46 1.76 0.51 -1.19 1.26 -0.94 0.35

NAC vs CxL 3.31 1.21 2.33 0.84 1.42 1.17 1.9 1.68 1.13 0.26

189

NAC vs Ox 1.68 1.27 1.66 1.01 1.64 1.66 0.04 2.1 0.02 0.99

NAC vs DiCx 2.98 1.2 2.4 0.83 1.86 1.16 1.13 1.67 0.68 0.5

NAC vs OxE 1.92 1.35 1.91 1.11 1.9 1.98 0.02 2.4 0.01 0.99

NAC vs PNext 2.83 1.2 2.24 0.84 1.69 1.16 1.14 1.67 0.68 0.5

NAC vs E-INJ -0.33 1.27 -0.35 0.99 -0.38 1.59 0.05 2.04 0.02 0.98

Cx vs T -1.07 1.19 -1.08 0.83 -1.09 1.16 0.02 1.66 0.01 0.99

Cx vs Pam 0.05 0.43 -0.34 0.27 -0.57 0.34 0.62 0.55 1.12 0.26

Cx vs CP -0.64 0.77 -0.24 0.53 0.11 0.73 -0.75 1.06 -0.7 0.48

Cx vs CxH -0.35 0.78 0.22 0.46 0.53 0.58 -0.89 0.97 -0.91 0.36

Cx vs Erm 0.16 1.21 0.16 0.83 0.17 1.15 -0.01 1.67 0 1

Cx vs Cxext 1.65 1.2 0.98 0.5 0.84 0.55 0.81 1.33 0.61 0.54

Cx vs E-IMM 1.15 1.24 1.17 0.9 1.18 1.32 -0.03 1.81 -0.02 0.99

Cx vs PNv 0.21 1.19 -0.19 0.41 -0.25 0.43 0.46 1.27 0.36 0.72

Cx vs G 1.11 1.22 1.1 0.88 1.09 1.27 0.03 1.76 0.01 0.99

Cx vs S -0.51 1.19 -0.71 0.73 -0.83 0.92 0.32 1.5 0.21 0.83

Cx vs CA -1.27 1.32 -1 0.8 -0.84 1 -0.43 1.66 -0.26 0.79

Cx vs CfN -0.59 1.37 -0.32 0.87 -0.14 1.12 -0.45 1.77 -0.25 0.8

Cxext vs CxH -0.25 0.3 -0.76 0.56 -0.04 NA -0.2 NA NA NA

NonA vs Cx 0.82 0.67 0.75 0.39 0.72 0.47 0.1 0.82 0.12 0.9

NonA vs Pam 0.39 1.2 0.42 0.39 0.42 0.41 -0.03 1.27 -0.02 0.98

NonA vs L -0.24 1.43 -0.24 1.14 -0.23 1.9 -0.01 2.38 0 1

NonA vs EVeS 0.34 1.47 0.32 1.18 0.29 1.98 0.05 2.47 0.02 0.98

190

NonA vs ELext 0.33 1.4 0.3 1.11 0.24 1.82 0.09 2.29 0.04 0.97

NonA vs E-ext -0.1 1.41 -0.12 1.12 -0.16 1.83 0.06 2.31 0.03 0.98

Pam vs B 0.49 1.26 0.01 0.4 -0.04 0.43 0.53 1.33 0.4 0.69

Pam vs Cdext 0.81 1.2 0.81 0.84 0.8 1.18 0.01 1.68 0 1

Pam vs OxN -0.7 1.22 -0.69 0.88 -0.67 1.27 -0.03 1.76 -0.02 0.99

Ox vs OxE -0.06 0.5 0.25 1.07 -0.15 NA 0.09 NA NA NA

Ox vs E-INJ -0.38 0.71 -2.01 1 1.25 NA -1.63 NA NA NA

B vs Cx -0.08 1.19 0.32 0.4 0.37 0.43 -0.45 1.27 -0.36 0.72

CP vs Cz -0.22 1.21 -0.22 0.96 -0.24 1.59 0.02 2 0.01 0.99

CP vs Cp 0.02 1.25 0.02 1 0.02 1.66 0 2.07 0 1

C vs B -0.23 1.2 0 0.44 0.04 0.47 -0.26 1.29 -0.2 0.84

C vs Pam -0.1 1.21 -0.01 0.36 -0.01 0.38 -0.09 1.27 -0.07 0.94

Cq vs Pam -0.33 0.67 -0.33 0.63 -0.31 1.78 -0.03 1.9 -0.01 0.99

P vs Pam 0.46 1.16 0.32 0.44 0.3 0.48 0.16 1.26 0.13 0.9

OxE vs E-INJ -0.33 0.74 -2.26 1.06 1.48 NA -1.8 NA NA NA

ELext vs E-ext -1.02 0.89 -0.42 1.27 -1.6 NA 0.58 NA NA NA

L vs EVeS 0.62 0.91 0.56 1.32 0.68 NA -0.06 NA NA NA

L vs ELext 1.09 0.91 0.54 1.28 1.64 NA -0.55 NA NA NA

L vs E-ext 0.08 0.85 0.12 1.29 0.04 NA 0.03 NA NA NA

EVeS vs ELext 0.45 0.92 -0.02 1.3 0.93 NA -0.48 NA NA NA

EVeS vs E-ext -0.56 0.9 -0.44 1.31 -0.67 NA 0.11 NA NA NA

TS vs CP 1.14 1.18 1.15 0.93 1.15 1.5 -0.01 1.91 0 1

191

Appendix 5 (Post-1990 analysis) Direct (dir) and indirect (rest) comparisons for the consistency assumption of pairwise comparisons

within the network meta-analysis assessing the efficacy of currently labelled antimicrobial protocols for cure of existing intramammary

infections in dairy cattle during the dry period from trials published between 1990 – 2019. NAC = non-active control, Cx = cloxacillin,

Cxext = cloxacillin-extended therapy, CxH = cloxacillin-high dose, NonA = non-antimicrobial therapy, Pam = penicillin-

aminoglycosides, PSext = penicillin-streptomycin-extended therapy, B = ceftiofur, C = cefapyrin, PNv = penicillin-novobiocin, TS =

teat sealant

Comparison d_dir sd_dir d_MTC sd_MTC d_rest sd_rest w sd_w z_score p_value

NAC vs Cx 2.45 0.82 2.27 0.42 2.21 0.49 0.24 0.95 0.25 0.8

NAC vs C 0.92 0.83 1.28 0.52 1.51 0.67 -0.59 1.06 -0.55 0.58

NAC vs CP 2.42 1.64 1.87 0.65 1.77 0.71 0.65 1.78 0.37 0.71

NAC vs PNv 1.49 1.27 1.49 1 1.48 1.61 0 2.05 0 1

NAC vs LSext 3.94 1.57 3.93 1.38 3.91 2.85 0.03 3.25 0.01 0.99

NAC vs Cxext 4.27 1.98 3.97 0.87 3.89 0.97 0.37 2.2 0.17 0.87

NAC vs Pam 1.22 0.31 1.31 0.4 1.08 NA 0.14 NA NA NA

NAC vs NonA 1.2 1.03 1.14 0.62 1.11 0.78 0.09 1.3 0.07 0.94

NAC vs B 0.59 1.18 1.49 0.5 1.69 0.55 -1.1 1.31 -0.84 0.4

NAC vs PSext 1.7 1.21 1.67 0.81 1.65 1.1 0.06 1.64 0.03 0.97

NAC vs Ox 1.68 1.27 1.69 1 1.7 1.6 -0.01 2.05 -0.01 0.99

NAC vs DiCx 3.01 1.19 2.41 0.86 1.76 1.24 1.25 1.72 0.73 0.47

NAC vs OxE 1.91 1.37 1.92 1.11 1.94 1.88 -0.03 2.32 -0.01 0.99

NAC vs PNext 2.83 1.2 2.24 0.87 1.6 1.25 1.23 1.74 0.71 0.48

NAC vs E-INJ -0.33 1.25 -0.33 0.99 -0.32 1.64 -0.01 2.06 -0.01 1

Cx vs T -1.08 1.18 -1.08 0.85 -1.09 1.25 0 1.71 0 1

192

Cx vs CP -0.63 0.77 -0.4 0.57 -0.12 0.85 -0.51 1.15 -0.45 0.66

Cx vs Cxext 1.64 1.19 1.69 0.75 1.73 0.97 -0.08 1.54 -0.05 0.96

Cx vs E-IMM 1.15 1.24 1.17 0.92 1.19 1.37 -0.05 1.85 -0.02 0.98

Cx vs CxH -0.75 1.17 -0.73 0.82 -0.71 1.15 -0.04 1.64 -0.02 0.98

Cx vs G 1.1 1.23 1.11 0.91 1.13 1.35 -0.04 1.83 -0.02 0.98

Cx vs CA -1.25 1.34 -1.33 0.8 -1.37 1 0.12 1.67 0.07 0.94

Cx vs CfN -0.6 1.38 -0.64 0.88 -0.67 1.13 0.07 1.79 0.04 0.97

Cx vs Pam -1.24 1.3 -0.97 0.41 -0.94 0.43 -0.3 1.37 -0.22 0.83

Cxext vs CxH -0.06 0.5 -2.42 0.91 0.99 NA -1.05 NA NA NA

NonA vs L -0.23 1.43 -0.19 1.17 -0.12 2.05 -0.11 2.5 -0.04 0.96

NonA vs EVeS 0.32 1.47 0.38 1.21 0.5 2.12 -0.18 2.58 -0.07 0.94

NonA vs ELext 0.32 1.43 0.36 1.16 0.44 1.99 -0.12 2.45 -0.05 0.96

NonA vs E-ext -0.1 1.4 -0.07 1.16 0.01 2.08 -0.12 2.5 -0.05 0.96

Pam vs B 0.5 1.26 0.18 0.46 0.14 0.49 0.36 1.36 0.27 0.79

Pam vs Cdext 0.81 1.2 0.8 0.86 0.78 1.24 0.03 1.73 0.01 0.99

Ox vs OxE 0.02 0.87 0.23 1.06 -0.41 NA 0.43 NA NA NA

Ox vs E-INJ -1.33 0.89 -2.02 0.99 1.58 NA -2.9 NA NA NA

B vs Cx -0.06 1.2 0.78 0.47 0.93 0.51 -1 1.3 -0.77 0.44

CP vs Cz -0.21 1.22 -0.22 0.99 -0.22 1.7 0.01 2.09 0 1

CP vs Cp 0.02 1.25 0.01 1.02 0 1.75 0.01 2.15 0 1

C vs B -0.2 1.19 0.21 0.51 0.31 0.57 -0.51 1.32 -0.38 0.7

C vs Pam -0.11 1.19 0.03 0.47 0.05 0.51 -0.16 1.29 -0.12 0.9

193

Cq vs Pam -0.33 0.67 -0.33 0.67 -0.51 5.14 0.18 5.18 0.04 0.97

OxE vs E-INJ -1.35 0.98 -2.25 1.05 4.07 NA -5.43 NA NA NA

ELext vs E-ext -1.02 0.91 -0.42 1.34 -1.52 NA 0.5 NA NA NA

L vs EVeS 0.65 0.91 0.57 1.37 0.71 NA -0.06 NA NA NA

L vs ELext 1.1 0.9 0.55 1.35 1.55 NA -0.44 NA NA NA

L vs E-ext 0.09 0.84 0.12 1.35 0.06 NA 0.03 NA NA NA

EVeS vs ELext 0.47 0.93 -0.02 1.37 0.88 NA -0.42 NA NA NA

EVeS vs E-ext -0.54 0.9 -0.45 1.37 -0.61 NA 0.07 NA NA NA

TS vs CP 1.14 1.17 1.13 0.95 1.11 1.61 0.03 1.99 0.01 0.99

194

Appendix 6 Bibliography of included studies in the systematic literature review and network meta-

analysis assessing the relative efficacy of dry off antimicrobial products for cure of existing

intramammary infections in dairy cattle during the dry period

Arruda, A. G., Godden, S., Rapnicki, P., Gorden, P., Timms, L., Aly, S. S., Lehenbauer, T. W., &

Champagne, J. (2013). Randomized noninferiority clinical trial evaluating 3 commercial dry cow

mastitis preparations: I. Quarter-level outcomes. J Dairy Sci, 96(7), 4419-4435.

https://doi.org/https://dx.doi.org/10.3168/jds.2012-6461

Barrett, D. J., Clegg, T., Healy, A. M., & Doherty, M. L. (2006). A study of dry cow therapy and

effects on SCC in 10 Irish dairy herds. J Vet Med A Physiol Pathol Clin Med, 53(3), 140-144.

https://doi.org/10.1111/j.1439-0442.2006.00794.x

Christie, G. J., & Strom, P. W. (1978). Intramammary infusion of cephapirin benzathine for

treatment of mastitis in dry cows. Vet Med Small Anim Clin, 73(9), 1192-1194.

Clegg, F. G., Halliday, G. J., & Hardie, H. (1975). Dry cow therapy: a comparative field trial using

benzathine cloxacillin and erythromycin. Br Vet J, 131(6), 639-642.

https://doi.org/10.1016/s0007-1935(17)35134-5

Cornelis, C., van Laar, P., & van Rij, H. (1996). Nafcillin antibiotic combinations in modern dry

cow therapy. Cattle Practice, 4(2), 213-219.

Cummins, K. A., & McCaskey, T. A. (1987). Multiple infusions of cloxacillin for treatment of

mastitis during the dry period. J Dairy Sci, 70(12), 2658-2665. https://doi.org/10.3168/jds.S0022-

0302(87)80336-3

Eberhart, R. J., & Buckalew, J. M. (1972). Evaluation of a hygiene and dry period therapy program

for mastitis control. J Dairy Sci, 55(12), 1683-1691. https://doi.org/10.3168/jds.S0022-

0302(72)85745-X

Funk, D. A., Freeman, A. E., & Berger, P. J. (1982). Environmental and physiological factors

affecting mastitis at drying off and postcalving. J Dairy Sci, 65(7), 1258-1268.


Hallberg, J. W., Wachowski, M., Moseley, W. M., Dame, K. J., Meyer, J., & Wood, S. L. (2006).

Efficacy of intramammary infusion of ceftiofur hydrochloride at drying off for treatment and

prevention of bovine mastitis during the nonlactating period. Vet Ther, 7(1), 35-42.

Hanschke, G., & Aberka, M. (1983). Experience in the use of Tardomyocel-L-Suspension at

drying off in the control of bovine mastitis under Moroccan conditions. Veterinary Medical

Review, German Federal Republic, (1), 70-80.

https://doi.org/https:/dx.doi.org/10.3168/jds.2012-6461




195

Harmon, R. J., Crist, W. L., Hemken, R. W., & Langlois, B. E. (1986). Prevalence of minor udder

pathogens after intramammary dry treatment. J Dairy Sci, 69(3), 843-849.

https://doi.org/10.3168/jds.S0022-0302(86)80474-X

Heald, C. W., Jones, G. M., Nickerson, S., & Bibb, T. L. (1977). Mastitis control by penicillin and

novobiocin at drying-off. Can Vet J, 18(7), 171-180.

Hernández, M., Nistal, L., Durel, L., & Macdonald, V. (2014). Assessment of efficacy of two dry

cow therapies in Spanish dairy herds. A practitioner perspective. Proceedings of the 28th World

Buiatrics Conference, Mastitis, Australia, 200.

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