In Dairy Cows with Clinical Mastitis Do Systemic Antimicrobials in Addition to Intramammary Antimicrobials Improve Clinical Cure Rates Compared to Intramammary Antimicrobials Only ?

Clinical bottom line In spite of limitations to the available studies, in cattle with clinical mastitis and an absence of systemic signs there is no evidence that combined systemic and intramammary antimicrobial therapy improves clinical cure rates compared to intramammary antimicrobial therapy only. In two studies, cattle with severe coliform mastitis showed improved clinical parameters following combined systemic and intramammary antimicrobial therapy compared to intramammary antimicrobial therapy only.


Study design: Randomised positive controlled trial
Outcome studied: Clinical cure rate, 30 day survival (culling or death)

Main findings: (relevant to PICO question):
No significant difference between cure rates in either group.
In cases of clinical mastitis caused by coliform organisms there was statistically higher survival in the group treated with combined treatment (intramammary pirlimycin and intramuscular ceftiofur) compared to the group treated with intramammary pirlimycin only.

Limitations:
 No blinding  Adjunctive therapy not standardised across sites, in some

Clinical bottom line
In spite of limitations to the available studies, in cattle with clinical mastitis and an absence of systemic signs there is no evidence that combined systemic and intramammary antimicrobial therapy improves clinical cure rates compared to intramammary antimicrobial therapy only.
In two studies, cattle with severe coliform mastitis showed improved clinical parameters following combined systemic and intramammary antimicrobial therapy compared to intramammary antimicrobial therapy only.
situations adjunctive therapy included systemic corticosteroids which are controversial  Duration of intramammary treatment varied between herds  Clinical cure assessed subjectively -no data regarding bacteriological cure or somatic cell count  Follow up limited to 30 days post-detection.Significant outcomes such as milk yield and long-term culling risk not included.

Wenz (2005)
Population: Dairy cows on a single site with mild clinical mastitis in one quarter with a positive milk culture

Sample size: n = 144
Intervention details: Outcome studied: Clinical cure rates, rate of recurrence 15 -90 days post-detection, bacteriological cure at 7 days post-treatment, loss of quarter, culling and death.

Main findings: (relevant to PICO question):
No significant difference in recurrence across groups No significant difference for any outcome across treatment groups.The was a numerical improvement in bacteriological cure at 7 days post-treatment for both groups treated with intramuscular ceftiofur in addition to the intramammary antimicrobial (27% vs 45% and 33% vs 52% for 1 and 2 and groups 3 and 4 respectively).

Limitations:
 Small group sizes  Pre-intervention differences between treatment groups not discussed  Randomisation technique not stated  Culling decisions are usually multifactorial and although culling for mastitis is used as a negative outcome for this study, previous mastitis or cell count history and factors not related to udder health will influence the decision to cull  Only cases with a positive milk culture included which may reduce the applicability of the results to clinical practice (i.e.not applicable for empirical treatment)  Outcomes such as individual cow somatic cell count data

Main findings: (relevant to PICO question):
No statistical difference in cure rate or bacteriological cure between groups receiving intramammary antimicrobials compared to group receiving intramammary and intramuscular antimicrobials.leukocytes, and peak in urea and creatinine.

Limitations
There was a statistically significant reduction in milk production post-infection in the group treated with intramammary cefquinome compared to the group treated intramammary and intramuscular cefquinome.

Limitations:
 Trial designed to test different hypothesis to PICO question (cefquinome vs amoxicillin/cloxacillin) -therefore relevant results and statistical analysis not always easy to extract. Clinical assessment with clinical mastitis score -individual parameters not given. Randomisation technique not stated  California mastitis test used in place of quantified somatic cell count data. Follow up limited to 14 days post-challenge  Strain of Escherichia coli used with known antimicrobial sensitivity which limits clinical relevance

Swinkels (2013)
Population: Dairy cows across three herds with high rates of recurrent, environmental clinical mastitis.Cows included with clinical mastitis of all grades (mild to severe).

Sample size: n = 994
Of these, 689 treated in a way relevant to PICO question

Intervention details:
1. n = 305 treated with intramammary cefquinome (75mg, two consecutive milkings on day one followed by the morning milking on day two) 2. n = 318 treated with intramammary cefquinome (75mg, two consecutive milkings on day one followed by the morning milking for four consecutive days) 3. n = 371 treated with intramammary cefquinome (75mg, two consecutive milkings on day one followed by the morning milking for four consecutive days) intramuscular cefquinome (1mg/kg, every 24 hours, five day duration)

Study design: Randomised positive controlled trial
Outcome studied: Cure rate assessed subjectively by trained personnel.Recurrence monitored until 105 days post-treatment.Cows followed for 105 days following initial treatment.Recurrence assessed at both cow and quarter level.

Main findings: (relevant to PICO question):
No statistical difference between cure rate or rate of recurrence between the group treated with intramammary cefquinome for 5 days and the group treated with intramammary cefquinome and intramuscular cefquinome for 5 days.No statistical difference at cow or quarter level.

Limitations:
 Trial not designed to compare outcomes between groups relevant to PICO question (groups 2 and 3) but lack of difference in outcome apparent and discussed. Missing data acknowledged but not clear from which treatment groups data are missing. 124 cows received NSAIDs in addition to antimicrobials; 106 cows received systemic antimicrobials off study protocolthese cows were not excluded from the trial and the group allocation is not stated. Although randomisation used, herd personnel had discretion to assign cows to treatment groups -number of 'nonrandomised' cows not clear.

Appraisal, application and reflection
The most pertinent question is whether in cases of clinical mastitis without systemic clinical signs there is a benefit to systemic antimicrobials in addition to intramammary antimicrobials.It may have been more helpful to look at treatment approaches for mild and moderate mastitis separately to severe mastitis, however, this approach would have resulted in the exclusion of at least one study (Swinkels et al 2013) where the study population included mixed severities of clinical mastitis.
The lack of demonstrable benefits of systemic antimicrobials in addition to intramammary antimicrobials for mild and moderate mastitis is relevant as this is relatively common practice; but the limitations of these studies should be considered.The benefits of combined systemic and intramammary antimicrobials for severe coliform mastitis are interesting although expected as the merits of systemic antimicrobials are more established in these cases.
The stated aims from these five studies were not directly focused on answering the PICO question, however, all provided the data for necessary comparisons to be made.The studies were of mixed but typically good quality and generally, with the exception of Swinkels et al ( 2013), included a small number of cows.
Clinical cure rate is a vague parameter with all studies using subjective assessment as the primary indicator of both clinical disease and cure.More objective and reliable outcomes such as bacteriological cure were used in some but not all studies.

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3. Hillerton and Kliem (2002) Population: Dairy
cows on a single site, experimentally infected with Streptococcus uberis in two quarters

:
 Randomisation replaced with allocation during the trial Different quarters on the same cow included in different treatment groups -systemic treatments avoided but crossover of intramammary treatments between adjacent quarters may affect results.Not all cows/quarters accounted for in results -missing data briefly mentioned but no detail relating which treatment groups.

9 Exclusion / Inclusion Criteria Exclusion
: Reviews, economic models, in-vivo studies, conference proceedings, book chapters, foreign language articles.Inclusion: Studies where comparison was possible between two groups treated with systemic antimicrobials in addition to the same intramammary antimicrobial.Mainly randomised control trials.