What we have learned about mastitis therapy in lactation over the last few years

History of overtreatment – In a large German study from 2019 – conducted before resistance testing became mandatory before the use of critical antibiotic agents in veterinary medicine in Germany – mastitis therapy in Germany was described based on the responses of 499 surveyed farmers/milkers/herd managers. It became clear that despite an established system of herd health work for dairy farms by veterinarians and extensive cytomicrobiological diagnostics including resistance testing (more than 1.5 million cytobacteriological examinations per year), clinical mastitis was usually treated for much longer than the application instructions for the drugs (SPC) required. During this time, mastitis was also treated with critical antibiotic agents (fluoroquinolones or 3rd and 4th generation cephalosporins) in 80 % of the cases (Falkenberg et al., 2019).

While we have seen an increase in available udder health data in recent years, real written standard operating procedures for mastitis treatment were still only available in 30 % of German dairy farms. Usually, the veterinarians refer to the therapy instructions of the antibiotics used. However, this information played only a minor role in the application of the products on the farms. Thus, the usual mastitis therapy was polypharmacy – usually longer, based on different antibiotic substances and systemic and local treatment at the same time.

Tradition, experiences and expert opinions

In addition, the treatment of clinical mastitis in dairy farms was considerably influenced by traditions, experiences and expert opinions. For example, in Germany the opinion prevailed that mastitis treated with procaine penicillin should receive 3 million units per dose. This view is based exclusively on expert opinion from the early 1980s, and the evidence for this statement is accordingly weak. A scientific analysis of the available evidence was lacking. On the other hand, there were general recommendations on the rational and responsible use of antibiotics, but these remained very vague and thus had no direct influence on practice (Antibiotika-Leitlinien). 

To do’s

From our point of view, further development of mastitis therapy requires above all clear, brief, evidence-based recommendations. Wherever this was not possible due to diagnostic uncertainty, we tried to fill this gap. In particular, we have been and are still working on identification of those animals that do not benefit from antibiotic therapy in the case of clinical mastitis.

Thus, over the years, work has been done on identifying animals unworthy of antimicrobial treatment, work on alternative therapy for these animals and work on direct therapeutic decision-making using on-farm tests. Some recommendations – such as not treating subclinical mastitis in lactation (with the exception of Streptococcus (Strep.) agalactiae or Strep. canis eradications) or the use of non-steroidal anti-inflammatory drugs (NSAID’s) in every clinical mastitis case – we have derived from the available evidence. As a side effect, some field studies in recent years have shown that the systematic use of NSAID’s can reduce the time to clinical cure by one day.

Systemic treatment or not?

The first decision in the treatment of clinical mastitis can be made using the mastitis score. This score can be reliably determined by anyone involved in the treatment of mastitis. Since severe mastitis carries the risk of bacteremia resulting in sepsis with possible death, we recommend systemic antibiotic therapy in these cases.

Since parenteral antibiotic treatment of dairy cows can influence the intestinal flora of the animals and promote the development of resistance, we otherwise recommend administering antibiotics only intramammary (imm.) whenever possible in clinical mastitis.  However, the occurrence of bacteremia associated with cases of severe mastitis in dairy cows is an under-researched topic and of great practical importance for the development of evidence-based strategies in mastitis therapy. In a first study published by us on this subject, the detection of culturable pathogens in the blood of cows with severe clinical mastitis was apparently rare (1.4 %) (Brennecke et al., 2021). We are working on further studies to estimate the occurrence of bacteremia in severe bovine mastitis more precisely.

Pathogens and antibiotics

Antibiotics have the effect of killing bacteria. Their use therefore presupposes a bacterial infection of the mammary gland. Bovine mastitis is a multifactorial disease, which can be caused by a variety of pathogens. The pathogen spectrum in Northern German dairy herds has shifted from cow-associated pathogens to environment-associated pathogens in the last decades. Thus, different non-aureus staphylococci (NAS) are most frequently identified in cases of clinical mastitis, followed by Strep. uberis, Strep. dysgalactiae, and coliform microorganisms with Escherichia (E.) coli as the leading species. For about one third of all mastitis samples, no pathogen can be identified in routine microbiological investigation. Severe clinical mastitis cases are often caused by E. coli or Strep. uberis. As the eradication of environment-associated mastitis pathogens is not possible, mastitis control must also shift to reduction of the density of pathogens in the environment by prophylactic hygienic and herd management measures.

*: Prototheca spp., Bacillus spp., Enterococcus spp., yeast, Pseudomonas spp., Corynebacterium spp., other streptococci. **: More than two different pathogens were detected in one sample. NAS: Non-aureus staphylococci.

Antibiotics are not effective in all cases of mastitis

The treatment success of an antibiotic therapy is determined by the bacteriological cure rate. In the course of many mastitis cases, the bacteriological cure rate can hardly, if at all, be increased by antibiotics. However, two completely different case scenarios can occur for this: the cure risk is so poor that an antibiotic therapy can hardly increase it (a) or the self-cure rate is already so high that it can hardly be improved by an antimicrobial treatment (b). Moreover, antimicrobial treatment is not appropriate in all clinical cases without identification of a (sensitive) bacterial pathogen (c).

Treatment-unworthy animals

These are (mainly older) cows with high cell counts in the Dairy Herd Improvement (DHI) testing over a long period of time (e.g. 3x >700,000 cells/ml milk) (Østerås et al., 2006; Linder et al., 2013) or animals/quarters with several clinical cases of mastitis in the same lactation (Østerås et al., 1999; Schukken et al., 2003; Pinzón-Sánchez and Ruegg, 2011; Ziesch and Krömker, 2016). The mentioned cows will not benefit from imm. antibiotic administration, so that antibiotic treatment is not recommended, unless animal welfare issues require systemic antibiotic therapy (e.g. severe mastitis, please see: “Systemic Treatment or not”). Within the framework of various randomized field trials, we compared the antibiotic therapy of mild and moderate mastitis in the so-called treatment-unworthy cows with various alternative therapies that are approved for the therapy of mastitis in Germany. The reason for these studies was that for many farmers it is a social norm not to leave animals with clinical mastitis untreated. Therefore, we looked for therapies that were comparable to the results of antibiotic therapies. So far, we have published three comparative studies showing that by using enzyme preparations (Mastiyeyxzym ®), homeopathic nosodes (Pyrogenium ®) and NSAID’s (Ketoprofen ®), comparable results to the use of antibiotic doses can be achieved in these animals (Ziesch et al., 2017; Krömker et al., 2019; Krömker et al., 2021).

Gram-negative cases of clinical mastitis

Recent studies have shown that mastitis caused by coliform bacteria such as E. coli does not require antibiotic administration, since high self-cure rates are observed, and bacteriological cure rates do not significantly rise by antibiotic treatment, unless systemic signs of clinical illness are detected (Barlow, 2011; Suojala et al., 2013; Persson et al., 2015).

No (bacterial) growth cases of clinical mastitis

In about 30 % of all mastitis samples, no pathogen can be identified with conventional bacteriological culture (Mansion-de Vries et al., 2015; Oliveira et al., 2013). An antibiotic treatment of mastitis cases with no growth results is therefore neither necessary nor justified.

Requirements for on-farm tests

Therefore, it seemed necessary to us to develop a tool for a targeted mastitis therapy that quickly and easily detects the causative pathogen group of mastitis. The test is called mastDecide® and permitsa rapid identification of the mastitis-causing pathogen group (“Gram-positive”, “Gram-negative”, “no growth”) after a time span of 12 hours.  

On the one hand, on-farm tests are applied to enable earlier treatment decisions, while, on the other hand, they must deliver easy performance, distinct result interpretation, and a high consumer and handling safety. A close veterinary supervision in livestock and udder health management is recommended to ensure the correct handling of on-farm tests and their residues. On-farm studies applying a rapid on-farm test system (mastDecide^®, QuIdee GmbH, Homberg) for the identification of Gram-positive cocci and coliform mastitis-causing pathogens revealed, that this test system is particularly easy and safe to handle on-farm and also simple to interpret. However, especially in small dairy herds, the personnel might be missing a regular handling and interpretation of the tests because of low numbers of clinical mastitis cases. Thus, on smaller farms, the willingness to implement the test system is to some extent lower compared to larger dairy herds with an already developed daily testing routine. The reason for this might be a training effect in employees which enhances the secure handling and interpretation of the test system.

On-farm tests as a necessary tool in mastitis treatment

A discoloration of both test tubes indicates the growth of Gram-positive cocci, a discoloration of only the first tube indicates the growth of coliform bacteria, whereas no change in color indicates no microbiological growth. Since some microorganisms (such as lactic acid bacteria, yeasts, Prototheca spp., Pseudomonas spp., Bacillus spp., Corynebacterium spp., or Trueperella pyogenes) are not able to grow in the tube system, the test will result in “no growth” for these microorganisms.

Which antibiotic substances can be recommended?

Although microorganisms with antimicrobial resistance currently do not represent a burning issue in dairy farming, however, the number of studies reporting of enhanced emergence of antimicrobial resistance increases (Spohr et al., 2011; Saini et al., 2013; Jagielsky et al., 2014; da Costa-Krewer et al., 2015; Fairbrother et al., 2015; Petrovski et al., 2015; Ruegg et al., 2015; Ding et al., 2016). In general, the resistance situation varies from farm to farm as well as from region to region and country to country. To date, the issue of resistant or multi-resistant mastitis-causing pathogens such as methicillin-resistant Staphylococcus (S.) aureus (MRSA) seems to play a subordinate role in dairy industry (Erskine et al., 2002; Schröder et al., 2005; Tenhagen et al., 2006; Pol and Ruegg, 2007; Oliver et al., 2011; Kreausukon et al., 2012).

Recent data suggest, that the resistance rates of typical mastitis pathogens might be higher than expected, so that optimization of antimicrobial usage is desirable (Bolte et al., 2020). At the same time, the data show that the use of simple ß-lactam antibiotics such as procaine penicillin is highly effective for the microorganisms whose infections can basically be influenced by antibiosis (mainly Gram-positive cocci). Besides the requested general reduction of antimicrobial usage, the use of antimicrobials has to be limited to substances with less critical importance for human health (e.g. of category 1, European Medicines Agency or EMA) whenever possible. Thus, the choice and application of antimicrobial substances underlies the actual governmental restrictions.

According to the commission notice (2015/C 299/04) antimicrobial usage should comprise previous microbiological investigation and sensitivity testing if applicable (European Commission, 2015). Differences between spontaneous bacteriological cure and antibiotic treatment cure rates are biggest for streptococci and medium for staphylococci, particularly S. aureus. For most other pathogens, the spontaneous cure rates cannot be (significantly) raised by antimicrobial treatment (McDougall, 2007). This is why narrow spectrum ß-lactam antibiotics are regarded as suitable for local mastitis treatment. Especially for streptococci and most staphylococci the MIC for penicillin are still regarded as low, but must be closely monitored. However, without specific clinical breakpoints for mastitis, defining the respective concentrations of the antimicrobial at the site of infection,  MIC analysis only represents relative data.                                                                                                                                                                                                                                           

Administration of antibiotics with (highest priority) critical importance for human medicine is reserved for infections with pathogens resistant  against “uncritical” (e.g. category 1) antibiotics such as ß-lactamase-producing staphylococci (EMA, 2014). Penicillin should be the first choice antimicrobial substance for treatment of Gram-positive cocci in clinical mastitis cases, since it possesses a small spectrum of activity, is classified as a substance without critical importance for human medicine, and is proven effective against the pathogens mentioned. In affected herds, the S. aureus resistance situation should however be closely monitored.

In practice, the treatment decision usually precedes the outcome of the microbiological investigation as well as the resistance test result (Gomes and Henriques, 2016; Persson Waller et al., 2016). To address the concern that resistance to simple penicillins is present, we have added a 1-point MIC determination to our rapid test (mastDecide plus®). This means that a selection of the appropriate active substances can be made after only 12 hours.

Unfortunately, the changed test systems for inhibitors in raw milk have led to simple penicillins in particular triggering positive inhibitor findings with all the downstream consequences, even when the statutory withdrawal periods are observed. As a consequence, farmers are less willing to use these active substances.

Targeted mastitis therapy concept

We have used the aforementioned aspects as the basis for a targeted therapy concept that has been both scientifically tested and practically applied in recent years. The therapy concept helps the user to safely identify the animals that benefit from an antibiotic and those mastitis cases where antibiotics can be saved. The study by Schmenger et al. showed that with this system farmers more than halved the amount of antibiotics without having a negative impact on animal welfare and cure rates (Schmenger et al., 2020b). For a rapid identification of the mastitis-causing pathogen group (“Gram-positive”, “Gram-negative”, “no growth”) after a time span of 12 hours, farmers performed an on-farm culture (QuIdee, mastDecide®).

The treatment concept is based on three decision criteria:

1. Mastitis score: The clinical appearance alone determines whether a systemic treatment should be performed. Only cows with severe mastitis (MS 3) immediately receive systemic antimicrobials and supportive fluids. Antimicrobial treatment of mild to moderate cases (MS 1, MS 2) is delayed while the result of the on-farm test is pending. A decision concerning the imm. antibiotic therapy of all cases is made after receiving the result of the on-farm culture (point 3).
2. Treatment worthiness: Cows, which are covered by the definition of treatment-unworthy animals receive no imm. antibiotics as they would not accrue any benefit.
3. For the remaining treatment-worthy cows, the result of the on-farm rapid test, and thus the mastitis-causing pathogen, determines whether the cow receives imm. antibiotic treatment. Only those with Gram-positive test result receive imm. antimicrobials, while udder quarters with Gram-negative test result or no verified bacterial growth stay antimicrobially untreated.

Figure 3: Decision tree

The concept and application of on-farm tests are only aiding to therapeutic decision making. They are in no way a substitute for cyto-microbiological diagnostics of mastitis samples. Accordingly, we recommend the systematic examination of the collected mastitis samples in an appropriate specialized laboratory. However, this can be done without time pressure and serves to clarify the epidemiological situation on the farm.

Farmers´ compliance with treatment protocols

In past decades, the focus was on maximizing cure rates. Accordingly, a culture of overtreatment has become established.  It is therefore understandable that farmers (and also vets) have doubts when we now claim targeted mastitis treatment and suggest to treat mastitis cases without antibiotics. In the study of Schmenger et al. (2020b), farmers implemented a targeted therapy concept for clinical mastitis. Compliance was assessed and recorded over the two-year test phase. From the point when the farmers started testing the new concept, they deviated from the treatment recommendation in more cases than they strictly followed the guidelines. As expected, they treated more animals with antibiotics than indicated by the concept. Surprisingly, the opposite was just as often the case, and some cows did not receive antibiotics although the therapy concept provided for it. Reasons were the personal assessment of the mastitis case as well as an overestimation of the effectiveness of an antibiotic agent. Naturally, it depends on the person treating the cows, how strictly the treatment recommendations are implemented, but probably also on the structure of the farm. On larger, well-organized farms, where several people are responsible for the treatment of the animals, compliance with treatment protocols seems to work better (see “Requirements for On-Farm Tests”).

If a farmer is motivated to save antibiotic doses, we should support it in the best possible way with professional care and advice. The changeover will take time, but if farmers have positive experiences with the new treatment concepts, they will become more confident in implementing them.

How much antibiotic reduction is possible?

After several treatment studies indicated that antibiotics are not effective in mild to moderate mastitis cases caused by Gram-negative pathogens and cases with no bacterial growth at all (Roberson et al., 2004; Pyörälä and Pyörälä; 1998, Suojala et al., 2010), first treatment trials were conducted, providing antimicrobial treatment solely for cases with Gram-positive cocci (Wagner et al., 2007; Lago et al., 2011; Vasquez et al., 2017), where as a control group received immediately imm. antibiotics after mastitis was detected. No negative effects on cure rates were reported in the experimental group due to a postponed treatment up to 24 hours to wait for on-farm culture results or conventional bacteriological examination (Gram staining after 24 hours). Moreover, the imm. antibiotic consumption was halved (Lago et al., 2011) and reduced by 70% by Vasquez et al. (2017), reaching the same cure rates as animals of the control group. These trials included exclusively mild and moderate cases.

Our working group established a treatment concept that recommended treatment for all degrees of mastitis. At the same time, we expanded the treatment criteria, and in addition to the causative pathogen, the animal’s treatment-worthiness was also checked (Mansion de Vries et al., 2016; Kock et al., 2018). After positive results of these two controlled clinical trials, in the study of Schmenger et al. (2020b), five farms implemented an evidence-based therapy concept, performing an on-farm culture directly after mastitis detection (mastDecide®). Cure rates and antibiotic consumption during the two-year test phase were compared afterwards to the pre-study conventional treatment outcomes. With the modern treatment concept, about 60-70% less of imm. and 65 % less of parental antimicrobial doses were used, while cure rates remained consistent. These results show us that it is possible for farms to implement a therapy concept in everyday life and thus permanently avoid unnecessary antibiotics.

Possible effects of a targeted treatment concept on antimicrobial resistance rates

A treatment concept, which focuses on the sole antibiotic treatment of Gram-positive cocci in curable animals and suggests the preferential administration of penicillin can reduce the resistance rates of mastitis pathogens in a dairy herd. I) First of all, the total amount of applied antibiotics will be significantly reduced, II) Gram-negative or no growth cases will not be treated with imm. antibiotics, III) Gram-positive cases will be treated only locally with penicillin when possible, IV) Systemic treatment is applied in cases of severe mastitis only.

Effects can be I) overall reduced resistance rates II) reduced resistance rates in Gram-negative mastitis pathogens III) reduced resistance rates against third or fourth generation cephalosporins in Gram-positive cocci and IV) reduction of resistance rates of the further microbiota such as the gut microbiota.

Effects might be even more significant, if the systemic antimicrobial treatment of severe clinical mastitis could also be reduced or suspended. However, the knowledge about the development of bacteremia and septicemia in severe cases is insufficient and treatment options must be further investigated to make sure that animal welfare is secured. Surely, the same applies to other bacterial diseases apart from mastitis. 

Our data show that after the introduction of a targeted therapy concept, resistance rates decrease, at least among Gram-negative microorganisms.

Do we have to fear setbacks?

Even though many studies show that antibiotic therapy often has only a minor influence on the bacteriological and even more so on the cytological cure rate, many veterinarians are still concerned that the extensive avoidance of antibiotic doses, as applied in our targeted mastitis therapy concept, could harm the udder health of dairy herds in the long term.

For example, we usually assume that the success of the therapy is insufficient if, after a case of mastitis in one udder quarter, there are repeat cases in the same lactation in the same quarter. Although this is of course possible, recent studies show that the proportion of persistent infections in repeat mastitis cases is hardly more than 14 % and thus more than 85 % of all repeat cases are due to new infections (Wente et al., 2020).

For more than 7 years now, more and more dairy farms have been implementing the targeted mastitis therapy concept. During this time, the udder health situation has not deteriorated on any of these farms. Most farms have an improved udder health situation, but we attribute this only indirectly to our therapy system. In our view, the systematic documentation and sampling of all clinical mastitis, the further evaluation of this data and the application of the knowledge gained from it in the daily routine of the farm, but above all the motivation that comes from visible successes in the implementation of clear concepts, is responsible for the improvement of the farms.

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