REPORT FROM THE. 3 rd GLOBAL MILK QUALITY EXPERT FORUM

Transcription

1 REPORT FROM THE 3 rd GLOBAL MILK QUALITY EXPERT FORUM

2 THE ROLE OF EXTENDED THERAPY DISCUSSED BY MASTITIS EXPERTS The Global Milk Quality Expert Forum is organised and supported by Boehringer Ingelheim. It gathers world experts on milk hygiene and udder health for in-depth discussions on current issues and controversial topics. The aim is to meet on a yearly basis to share learnings and thinkings and consider how these should be disseminated to the wider veterinary profession. The benefit of extended therapy for mastitis, myth or fact? was the topic at the third global milk quality expert forum, held on January in Barcelona and organised by Boehringer Ingelheim. The forum was attended by fifteen independent milk quality experts from thirteen different countries, which allowed for an excellent interaction between participants and speakers. Chaired by Oriol Franquesa, an independent veterinary consultant from Spain, the programme included presentations by various members and invited guest speakers. CONTACT Elke Abbeloos: elke.abbeloos@boehringer-ingelheim.com Camilo de Mendonça: Camilo.de_mendonca@boehringer-ingelheim.com Chatham House rules report Usual Days Longer than usual How to define extended treatment? There was no clear consensus on the exact definition of extended therapy. For some members, extended treatment is any treatment that goes beyond the label claim. However, some products have a flexible label that allows extended treatment in certain cases. An alternative definition is a longer-than-usual course of treatment, which would be 5 to 8 days. It was noted that in human medicine, this would still fall under short-term treatments, since recommended treatment durations for human mastitis are often up to 14 days. 3

3 WHEN TO CONSIDER EXTENDED TREATMENT Both Streptococcus uberis and Staphylococcus aureus are not only highly prevalent globally in dairy cows with mastitis, they are also notoriously difficult to treat. Extended antibiotic treatment of these mastitis pathogens (here defined as 5 to 8 days of treatment) was found to significantly increase clinical and bacteriological cure rates of both clinical and subclinical mastitis, according to scientific data. However, extended therapy of mastitis also has its limitations. While risk factors (e.g. age of cow, number of colonies, somatic cell count) need to be taken into account, the additional costs of labour, antibiotics and an increased milk withdrawal time do not balance out the gain obtained with cure. Only in high transmission risk herds, there may be an economic benefit to treat longer. However, the consensus of the experts was that in such cases, all efforts should be put in reducing the transmission risk rather than in extending treatment. All participants agreed that economics should not drive decisions in responsible use of antibiotics, so it was discussed whether it should be done at all. Although in many countries, extended therapy seems to have become the norm, cases should preferably be selected on a cow-by-cow basis, taking all risk factors for cure into account, such as a recent infection in a young cow. Treatment protocols should be based on clinical cure in combination with the results of bacterial culture of milk samples, potentially with The consensus was sensitivity tests, performed either on farm or in the laboratory, participants agreed. This that extended treatment will result in the use of fewer and more appropriate antibiotics, a lower risk of residues, cannot be considered less wasted milk and all without concession to cure rates. judicious use of antibiotics, especially if used as blanket treatment of all clinical and subclinical mastitis cases. Percentage bacteriological cure 100% 50% Bacteriological cure rates for S. aureus Duration of antimicrobial treatment (Days) 0% Pirlimycin, Skoulikas et al., in preparation Pirlimycin, Gillespie et al., 2002 Pirlimycin, Deluyker et al., 2005 Ceftiofur, Truchetti et al.,2014 Ceftiofur, Oliver et al., 2004 Cefquinome, Swinkels et al., 2014 Cefquinome, Swinkels et al., 2013 Penethamate, Steele and McDougall., 2013 Cephapirin, Roy et al., 2009 Figure 1. Overview of the bacteriological cure rates for Staphylococcus aureus reported in the studies that were presented at the meeting. Duration of antimicrobial treatment (in days; horizontal axis) is plotted against percentage of bacteriological cure (vertical axis). The size of the bullets represent the number of animals involved in the respective treatment groups. Similarly coloured bullets are from the same study. RECURRENT MASTITIS: GET IT RIGHT THE FIRST TIME When treating mastitis, farmers are particularly interested in a clinical cure and a low risk of recurrence. Bacteriological cure, usually the primary outcome in research, is merely an academic concept to them. Few studies look at recurrence of mastitis as the main indicator for success of therapy. Yet, studies do so show that first-time mastitis cases should be taken seriously as they should be considered the beginning of the end. The first recurrent case is the next step, while the second and next recurrence should lead to the decision to dry off the quarter or to cull the cow prematurely. According to unpublished scientific data from Germany, nearly half (43%) of all clinical mastitis cases are recurrent cases. And of all recurrent cases, only 10% are true persistent infections with the same strain, suggesting that tissue damage, genetic predisposition and/or environmental factors play an important role. However, in practice, first-lactation mastitis cases are often treated too little too late in many farms. 4 5

4 First mastitis cases are a key moment in a cow s life and a longer treatment duration might be justified in order to prevent recurrent cases. Mastitis treatment should therefore focus on prevention and thorough treatment of firstoccurrence cases. Results of a study in 525 cows showed that intensive treatment (5-day intramammary antibiotic, 3 day systemic antibiotic treatment combined with 1 meloxicam injection) of first-time mastitis cases allowed halving the number of recurrent mastitis cases (12.6% vs. 23.9%) compared to the control group (standard intramammary treatment) even though both groups had a similar bacteriological cure rate (80.5% vs. 74.8%). Mastitis cases The first case is the worst case. First cases Recurrent cases New infections Real persistent cases microbiome imbalance, contributing to new Gram-negative infections, thus indirectly contributing to mastitis. Indeed most studies on extended therapy were performed with narrow spectrum products. This led to a discussion on the role of broad-spectrum antibiotics in mastitis therapy. EXTENDED TREATMENT IN HUMAN MEDICINE In terms of aetiology and appearance, mastitis in women is comparable to that in cows. Management usually consists of milk removal, analgesia and supportive measures. Antibiotics are only prescribed if symptoms are not improving within hours or if the woman is acutely ill. The standard antibiotic treatment of mastitis in women is usually prescribed for 10 to 14 days with on-going review of both clinical and inflammatory marker response much longer than the so-called extended veterinary treatment. All participants agreed that the milk microbiome is an exciting new field of research and that more work is needed on the impact of treatment duration and type of antibiotic on the microbial diversity in the udder. In human medicine, there is a lack of empirical evidence to support many recommendations regarding the length of treatment. For decades, the message to the general public has been to finish the course of antibiotics to avoid resistance. However it is now thought that the longer the expo- IMPACT ON THE MILK MICROBIOME The healthy mammary gland is not sterile: milk is full of bacterial aerobe and anaerobe organisms that do not appear on conventional bacterial culture. DNA sequencing of milk shows that healthy quarters have a higher microbial diversity compared to quarters with clinical mastitis. In case of clinical mastitis, it is hypothesized that the balance between the organisms is lost and some organisms outgrow the others. It is therefore proposed to rather speak of dominant organism than of intramammary infection (IMI). Some studies investigating the effect of extended therapy suggest that a longer duration of treatment increases the risk of recurrence. Participants wondered whether this was due to a more profound disruption of the microbiome. However, a study investigating microbial diversity in milk after 5-day broad-spectrum intramammary antibiotic treatment showed no real impact compared to untreated quarters. The hypothesis was raised that narrow-spectrum treatment might lead to a larger The current thinking in the medical profession is that stopping antibiotic treatment when symptoms disappear may be associated with a low clinical risk but many advantages. 6 7

5 The development of resistance is normally slower than clinical cure. Shorter courses are less selective for resistance. sure to antibiotics, the higher the potential risk of development of resistant organisms. While the duration of treatment depends on the type of infection and severity, symptom resolution has been found to be a good clinical indicator. Once the infection clears (clinical cure), it may be better to discontinue treatment than to finish the course. This topic led to a discussion among participants. In veterinary practice, it is often recommended to continue treatment until one day after clinical signs disappear even though there is no evidence to support this. In human medicine, apps are now being developed, helping patients with compliance and educating them in the principles of responsible use. Furthermore, these apps provide valuable feedback to the prescribing physician on the normal duration of clinical signs. MANAGING THE FARMER S FEARS Since human behaviour and perception is an important parameter to take into account when advising on length of treatment, the group also discussed the communication of scientific evidence to farmers. It was suggested that, as farmers are often unsure about the effect of treatment, they may consider extended antibiotic treatment as good stockmanship. And if the evidence e.g. the veterinarian s scientific advice is at odds with their own experience, they will disregard the advice. Farmers prefer to treat as long as symptoms are visible: Better safe than sorry. Communication on effective treatment is essential, and veterinarians should learn to manage the farmer s fears rather than facts if they want to guide them toward a more responsible use of antibiotics. WHY LABELS ARE WHAT THEY ARE Drug companies are often asked why label claims are limited. Many veterinarians would prefer a flexible label, allowing extended treatment in case of e.g. S. uberis or S. aureus mastitis. However, extending a label claim is nearly as complex as a full development of a completely new product. All studies in the dossier would need to be repeated: not just those concerning safety (for the target animal, the farmer, the environment and for consumer of meat or milk), but also those on the efficacy against the bacteria for which you want to prove the benefit of extended therapy. Since antimicrobials are under particular scrutiny, authorities will pay special attention and challenge the data. Such an undertaking would require an investment of 2 to 3 million euros and take at least 5 years to complete. However, the largest cost for the company would be one of lost opportunity because the R&D budget spent on label extension cannot be used on other projects that lead to a real innovation. What treatment duration do you advise? 3-4 days On label Nevertheless, this does not mean that researchers cannot influence labels. For example, by declaring lack of perceived efficacy as an adverse event, authorities may take a critical look at the dossier. Furthermore, the publication of scientific trials, e.g. informing the veterinary community about the need for extended treatment of S.uberis and S. aureus, may facilitate a label change. WHAT IS THE RIGHT TREATMENT DURATION? It is not easy to define the right treatment duration for mastitis. First, the aim of treatment can vary: to reduce recurrence, to increase bacteriological cure or to limit resistance. It is a complex question that not only involves science, but also politics, animal welfare, economics, human psychology and human health. During the final discussion, participants disagreed on their final recommendations regarding treatment duration: Most answers Decide case by case Every 12 h, 3 times Based on clinical signs _ TREATMENT DURATION Most 1 answers 1 2 Least answers 3 What treatment duration would you advise if all labels had a flexible treatment duration? 3-4 days 2 5 days Based on clinical signs Least answers 3 Decide case by case 8 9

6 CONCLUSIONS Although the group did not reach consensus on the definition of extended treatment of mastitis, nor on the right treatment duration for mastitis, most agreed that the manufacturer s recommendations would probably suffice in most cases. Although extended treatment can be considered for S. aureus and S. uberis, individual case management is important, there is no one size fits all for mastitis treatment. Also first-time mastitis cases need special consideration. The group agreed that antibiotic use should be reduced whenever possible. Communication with the farmer about prevention of disease and treatment duration was considered key. List of participants Sarne De Vliegher, Belgium Michael Farre, Denmark Oriol Franquesa, Spain Ian Hodge, New Zealand Volker Krömker, Germany Bill May, UK Martin Pol, Argentina Jean-Philippe Roy, Canada Olivier Salat, France Giacomo Tolasi, Italy Tine van Werven, The Netherlands Marcos Veiga, Brasil Elke Abbeloos (Boehringer Ingelheim) Camilo de Mendonça (Boehringer Ingelheim) Guest speakers Christian Scherpenzeel (Animal Health Service GD, Netherlands) Nabeela Mughal (Imperial College London, UK) Jolanda Jansen (St Anna Advies, the Netherlands) 10

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