The Five Point Plan for mastitis control developed in the UK during the 1960s was directed towards the control of those pathogens predominantly spread between cows during milking (so-called ‘contagious’ mastitis) and pathogens such as Staphylococcus aureus and Streptococcus agalactiae, but also relevant for other mastitis-causing pathogens, particularly other Gram-positive pathogens. Two of these five control measures were the importance of antibiotic dry cow therapy for all cows at drying-off and the prompt detection and treatment of all clinical cases of mastitis in lactation using an antibiotic (Neave et al, 1969). Therefore, the treatment of existing infections in cows at drying-off using an antibiotic and the treatment of clinical mastitis during lactation (visual changes to the milk and/or swelling of the affected quarter) using an antibiotic remain an important part of mastitis management in conventionally managed dairy herds in the UK as well as in other countries. In response to the publication of final recommendations from a UK government-commissioned report in 2016 (O'Neill, 2016), sector-specific targets for reducing or even replacing the use of antibiotics in UK food-producing animals were published (RUMA, 2017). For the dairy sector, these included four recommendations that related directly to mastitis control, including the use of lactating cow intramammary antibiotics.
The contribution to overall antibiotic use from mastitis treatment means that the potential to reduce antibiotic use through greater control of mastitis infections using farm-specific control plans as well as farm-specific treatment protocols represents a continued opportunity for veterinary surgeons working in dairy herd health. The British Veterinary Association (BVA) seven-point plan for responsible use of antimicrobials in veterinary practice (BVA, 2019) provides a useful reminder of how reducing antibiotic use through improved mastitis control may be considered:
- Prevent new mastitis infections to avoid the need to consider using antibiotic
- Modify existing approaches to mastitis treatment to reduce unnecessary use of antibiotic
- Using on farm culture (OFC) to minimise the use of antibiotic in treatment protocols based on the likely causal pathogen(s), particularly distinguishing between Gram-positive and Gramnegative pathogens.
The aim of this article is to focus on the third of these approaches and to present some of the research evidence that surrounds the concept of OFC to inform the veterinary surgeon in practice about the likely impact of taking this approach with their clients. Irrespective of the treatment approach, veterinary surgeons must remember to assist their clients with four items:
- Detection and reporting of all clinical mastitis events (i.e. any visible changes to the milk such as clots or flakes, with or without localised swelling of the udder and/or signs of systemic illness in the cow) to an electronic database regardless of whether antibiotic has been used (Figure 1). Recently, it appears to have become ‘normal’ for herds to fail to report mild clinical cases of mastitis (grade 1, clots only) if intramammary antibiotic was not used as the client considers this to mean ‘no mastitis’.
- Ensuring that an aseptic sample is collected from all first cases of clinical mastitis (Figure 2); this sample is frozen to allow periodic submission of a batch of samples (10–20 samples twice annually for example) to an independent laboratory for quality control if an OFC approach is being used and to allow for periodic consideration of the pathogen profile in the herd.
- Monitoring of the outcome of first cases of clinical mastitis in a cow's lactation using cell count data and recurrence of clinical signs to ‘track’ the outcome of first cases and measure a cure rate.
- Monitoring the rate of first cases of clinical mastitis and continuing to focus on preventing the index case such that treatment decisions are not required. This is fundamental to any discussion around reducing antibiotic use and happens before any discussion around treatment.
Background to on farm culture
Making decisions ‘cow-side’ to select those clinical mastitis cases that are unlikely to benefit from treatment with antibiotic has become an area of considerable interest in the research literature in the last 10 years. This approach minimises the use of antibiotic in mastitis therapeutics (Ruegg, 2018) and will tend to reduce the average defined daily dose metric for antibiotic use, particularly when combined with a preventative herd health approach to reduce the rate of new cases in the herd. The approach uses OFC and is based on reports that state mild and moderate mastitis infections in lactation caused by Escherichia coli do not require treatment with antibiotic (Pyorala, 2009; Suojala et al 2010). However, there remains a body of evidence to support the treatment of mastitis using intramammary antibiotic for other infections, for example those caused by environmental streptococci (Hillerton and Kliem, 2002; McDougall et al, 2014) and Klebsiella spp. (Pinzon-Sanchez and Ruegg, 2011).
Several OFC plates and kits have been developed in recent years, including a bi-plate and tri-plate (Minnesota Easy Culture System II, University of Minnesota, Saint Paul), tri-plates (VetoRapid, Vétoquinol; AccuMast, Calibre Control International Ltd, Warrington UK) and more recently a tube test (Mast-Decide, Quidee GmbH, Homberg, Germany). All these offer results in less than 24 hours to guide farm staff in the treatment of clinical cases of mastitis. A study comparing the performance of four OFC plates using 299 milk samples from two US dairy herds reported the highest agreement for the AccuMast culture plate, with fewer false-positive and false-negative results when compared with two reference laboratories (Ferreira et al, 2018). However, there were some limitations with this study, for example the prevalence of S. aureus in the sample population was very low at just 0.7% meaning no opportunity to explore the ability of these OFC plates to differentiate between S. aureus and coagulase-negative Staphylococcus spp. In addition, there was no differentiation between Streptococcus spp. isolates in this study, which is important if we consider the likely implications of a culture positive result for S. agalactiae or are working with a herd that has a high prevalence of Enterococcus spp.
Research summary: on farm culture
Randomised clinical trials (RCT) using OFC have been published from several countries and while they report an overall benefit in terms of a reduction in antibiotic use, studies also show that a delay in the commencement of treatment results in a reduction in the likelihood of a successful outcome for the treatment of mastitis caused by Gram-positive pathogens. It is important that the clinician is aware of the advantages of RCTs in veterinary medicine, namely that a RCT is directly comparative (one treatment is directly compared with another), that an RCT minimises bias (randomisation minimises allocation bias and selection bias), and that an RCT minimises confounding factors. Examples of RCTs in the subject of OFC guided clinical mastitis treatment are explored below.
An RCT of 422 cows with clinical mastitis in eight herds in the northern US and Canada using the Minnesota Easy Culture System reported no significant difference in bacteriological cure risk for those cases where antibiotic treatment was delayed while awaiting a culture result and then withheld if the culture result was ‘no growth’ or a Gram-negative pathogen, compared with those cases treated immediately using on-label intramammary antibiotic (Lago et al, 2011a). The reported bacteriological cure risk was lower for those cases treated on the basis of OFC compared with the positive control group (60% versus 71%), with the power of the study able to detect a difference of 17% between the two treatment groups. It is important that we look at the Odds Ratio (OR) from the statistical model presented, in other words the odds that an outcome will occur given a particular treatment approach, compared with the odds of the outcome occurring in the absence of that treatment approach. The study authors produce this figure comparing the bacteriological cure of the two treatment groups: the OR from the model has a 95% confidence interval of between 0.3 and 1.4. To put that in figures, if cure rate in the positive control group was 71%, this study shows that cure rates of between 45% and 78% in the OFC group are compatible with the data. The only conclusion that can be drawn is that we need more data as based on this study alone, the impact of OFC could be anywhere from a large reduction in cure rate to a small increase.
This is important as while the results were reported as not significantly different, this does not mean that there was no difference, and in the context of cow welfare, the difference in cure risk may be important for dairy farmers and clinicians in the field to understand. A follow-up study describing longer-term outcomes such as clinical mastitis recurrence and survival in the herd also reported no significant difference between treatment groups, but suffered from similar issues regarding low power (Lago et al, 2011b).
A single herd RCT using 121 culture-negative clinical cases of mastitis using the Minnesota Easy Culture System reported no significant differences in various outcome measures including milk yield and somatic cell count between an intramammary antibiotic treatment intervention group for these culture-negative cases or a negative control group (Fuenzalida and Ruegg, 2019). This study is interesting as differences were reported between intramammary antibiotic treatment and the negative control group in other outcomes such as treatment failure (5% versus 10%) and intramammary infection at 14 or 28 days post-enrolment (13% versus 26%). While not a comparison of prompt treatment with intramammary antibiotic versus OFC guided treatment decisions like the Lago papers above, this study injects a note of caution into the interpretation of apparent culture-negative results using OFC.
A recent randomised clinical trial of 648 quarters affected with clinical mastitis in New Zealand that used a novel OFC system that reports antimicrobial sensitivity as well as pathogen (Mastatest®, Mastaplex Ltd, Centre for Innovation, Dunedin, New Zealand) reported no impact on cure rate or clinical recurrence between a positive control group treated with intramammary penicillin and an intervention group where treatment was selected based on OFC after a 24-hour delay (Bates et al, 2020). This paper reported 24% less antibiotic used compared with the positive control group but relatively small reductions in daily doses of antibiotic compared with the positive control group (1.3 versus 1.7 daily doses) making the economics of such an approach an interesting argument to develop.
The most recent publication around the implementation of OFC at the time of writing used the mastDecide tube test system under field conditions in five herds in northern Germany (Schmenger et al, 2020). While this work reported reduced antibiotic use for those clinical mastitis cases treated using the ‘targeted’ therapy concept based on OFC results and those cases belonging to a ‘modified’ targeted therapy concept (essentially where farmers deviated from study protocol) when compared with a conventional treatment group, the study authors were careful to point out that this was not a RCT.
Is on farm culture likely to be cost effective for all herds?
When veterinary advisors are asking their dairy clients to implement a number of interventions relating to health and welfare on a daily basis (e.g. monitoring live weight gain in pre-weaned heifer replacements, foot bathing adult cows, frequent bouts of heat detection, implementing a pre-milking teat disinfection routine and so on), they need to have some consideration for the likely cost benefit of the intervention. For OFC, it is necessary to consider the cost of the culture kits and the labour, as well as the likely outcome if chance of cure is reduced or recurrence rate is increased depending on prevalence of Gram-positive pathogens in the herd.
A simulation model of 5000 cow cases of clinical mastitis to investigate factors that affect the cost effectiveness of OFC used probabilistic sensitivity analysis (PSA) and reported that for herds where Gram-positive pathogens account for more than 20% of clinical mastitis cases on farm an OFC approach to clinical mastitis treatment was unlikely to be cost beneficial when factors such as bacteriological cure rate because of a delay in the instigation of treatment were explored (Down et al, 2017). The median cost related to a case treated with the conventional protocol in this study was $529 when compared with $554 for a case treated with the OFC protocol, using estimated input costs associated with OFC of between $1.45 and $2.00 for each culture plate and between 30 minutes and 60 minutes to both set up and read the culture plates. In addition to these inputs, the underlying bacteriological cure risk was of great importance when determining relative cost-effectiveness of the two approaches, particularly for Gram-positive pathogen infections.
Consideration of OFC is therefore most appropriate for those herds that maintain a low herd cell count and wish to refine antibiotic use on farm, and where Gram-negative pathogens predominate, particularly E. coli, but at present the scientific evidence remains unclear as to whether in a specific herd, OFC and deferred treatment of clinical mastitis is likely to be beneficial, neutral or harmful in terms of outcomes such as bacteriological cure risk, clinical mastitis recurrence and culling. If implemented, the attending veterinary surgeon should closely monitor clinical mastitis outcomes, using recurrence data and somatic cell count data as well as monitoring herd antibiotic use metrics.
This final point about monitoring the outcome of first cases is very important — and challenges veterinary surgeons to review the information they have on cell count and recurrence. A very useful method is to look at the next three individual cow somatic cell counts using a threshold of 200 000 cells/ml and assess likely cure using a cumulative sum (CuSum) chart where a ‘cure’ using cell count moves the CuSum one space to the right and an apparent failure to cure using cell count data moves the CuSum one space to the left. A cure rate of 50% (a good target for first cases of clinical mastitis) is therefore a straight line (Figure 3).
Conclusion
The use of antimicrobials to treat and control mastitis in dairy herds continues to provoke interest and debate, particularly as differences in husbandry, management and pathogen profiles between herds make for periods of increased challenge. While the emergence and development of rapid culture systems allow scope to make case by case treatment decisions based on likely pathogen, for those herds where the prevalence of Gram-positive pathogens is relatively high, the difference in cure rate, and therefore the likely impact on clinical mastitis recurrence, may result in poorer udder health outcomes, as well as poorer cow welfare.
If implementing treatment strategies using OFC, the attending veterinary surgeon must be sure to reinforce and demonstrate aseptic sampling technique, ensure strict hygiene around the kits on farm, submit samples for quality control to assess on farm diagnosis, and monitor apparent cure rates for first cases using individual cow somatic cell count.
KEY POINTS
- On farm culture (OFC) aims to minimise antibiotic use when treating mild and moderate clinical cases of mastitis in dairy herds.
- Reports suggest that mild and moderate clinical cases of mastitis caused by Escherichia coli infection do not require treatment using antibiotics.
- However, randomised clinical trials published to date suggest that the impact of deferring treatment and using an OFC approach may result in a poorer chance of cure, particularly for Gram-positive pathogens.
- OFC is likely to be an appropriate consideration in low cell count herds with a low prevalence of Gram-positive pathogens such as Streptococcus uberis.
- OFC is unlikely to be cost effective in herds where the prevalence of Gram-positive pathogens is greater than 20%.
- Clinicians who are working with clients to introduce OFC are urged to ensure ALL cases of clinical mastitis are reported so as to ensure the outcome of first cases that are treated/not treated can be measured using cell count and recurrence data and tracked over time.
- OFC does not prevent new cases of clinical mastitis, and therefore does not replace the need to continue monitoring and reviewing mastitis control measures depending on the current infection ‘pattern’.