Pharmacokinetics MICs Good clinical practice & Outcomes Mamyzin Treatment & Interactions

Strep. uberis is one of the most common pathogens isolated from clinical and subclinical cases of mastitis in cows in VI centres in the UK¹ and penicillin is still widely regarded as the first choice treatment of these infections². Strep. uberis gives rise to clinical and subclinical infections in lactating cows where it accounts for high cell counts and poor milk quality. It may also cause subclinical mastitis in dry cows and heifers prior to calving³. Although less common, Strep. agalactiae and Strep. dysgalactiae are still occasional causes of herd outbreaks of clinical and subclinical mastitis¹.

Staph. aureus is a cause of severe and often life threatening mastitis in dairy cows. Mamyzin Injection contains penethamate hydriodide, a prodrug of penicillin G which accumulates in high levels in both mastitic and normal milk due to its unique pharmacokinetic profile. It is licensed for the treatment of mastitis caused by penicillin sensitive pathogens.

Good clinical practice in the treatment of bovine mastitis

The species of organism isolated from a case of mastitis is central to the choice of antibiotic for treatment and to determining the likely prognosis. The severity of the disease, however, although also an indicator of prognosis, is more likely to dictate whether the systemic or intramammary, or indeed both, are selected as a route of antibacterial administration or indeed whether supplementary therapy e.g. non-steroidal anti-inflammatory drugs such as meloxicam (Metacam®), are required. It will also determine the likelihood of the animal being seen by a veterinary surgeon or whether it is treated on farm using prescribed treatment protocols. A recent survey carried out amongst specialist cattle vets from the UK¹⁵ revealed that almost 80% of cows treated for mastitis are treated on farm without veterinary surgeon intervention. Of these cases, 30% are likely to receive parenteral therapy, either alone or concurrently with intramammary therapy. Of those seen by a vet, 85% receive parenteral therapy.

As is quoted in the literature² and dictated by good clinical practice, this survey also revealed that in cases where the species of pathogen is known, a narrow spectrum antibiotic would be the treatment of choice of almost 90% of veterinary surgeon responding. Despite intensive veterinary use of penicillin in recent years, most gram+ve organisms responsible for mastitis in cattle have shown little increase in resistance to it and the whole group of related antibacterial substances. This is explained by the fact that penicillins do not induce the formation of R plasmids in streptococci necessary for the transmission of the bacterial resistance1⁶. In the case of mastitis causing streptococci (Strep. uberis, Strep. dysgalactiae, Strep. agalactiae), in vitro resistance towards penicillin G appears extremely rare.

Today, in the UK, most streptococci isolated from cases of mastitis are considered to be fully³ susceptible to penicillin G yet current therapeutic options result in only a 60% perceived response rate¹⁵. In other countries, the MIC levels are generally low for these organisms confirming high levels of susceptibility^17,18. Although beta-lactamase (penicillinase) does not inactivate penethamate, it does of course inactivate penicillin G, the active product of penethamate. Beta-lactamase producing staphylococci are therefore unlikely to respond to treatment with Mamyzin. According to the literature, there is no evidence that coagulase negative staphylococci isolated from cases of clinical mastitis are resistant to penicillin G. The efficacy of the antibacterial therapy in the treatment of mastitis due to gram-ve bacteria is uncertain²⁰. Bacterial self-cure is common with clinical effects being the result of the bacterial endotoxins produced. Non-steroidal anti-inflammatory drugs such as Metacam® are usually indicated. Mamyzin is not indicated for the treatment of Escherichia coli induced mastitis.

Whilst clinical mastitis is important both in terms of animal welfare and farm economics, sub-clinical mastitis is a major source of economic loss on many dairy farms. Losses are due to elevated somatic cell counts (SCC) of infected cows and the associated loss in milk yield^{20, 21}. In addition, when the number of infected cows in a herd is high, bulk milk SCC (BMSCC) may be elevated. This may result in further economic loss because milk quality is monitored by regulatory agencies to determine its suitability for human consumption and penalties on bulk milk with high SCC have been imposed by commercial bottling and processing plants²¹. Treatment of cows with sub-clinical mastitis is a way to reduce the duration and number of infections, but treatment itself is also a cause of financial loss and is generally considered to be unsatisfactory in 30%¹⁵ of cases treated. The majority of these losses are due to lost production as a result of withholding periods and discarded milk following antibiotic therapy²¹.To be economically viable, the gains of treatment, i.e. the gains resulting from the cure of sub-clinical mastitis, must offset the losses. Conclusion In order to eliminate an infectious agent from a case of mastitis in cattle, it is important that:

- The pathogen concerned is susceptible to the antibiotic chosen
- The distribution of the active ingredient has to be excellent in the targeted tissue i.e. udder and milk
- The concentration of the active ingredient in the udder and/or the milk must be above the MIC 90 value (NB: it is unimportant how much above the MIC the concentration reaches)
- The duration of treatment must be long enough to achieve both a clinical and bacteriological cure²⁴

The treatment of mastitis in cattle - a desirable outcome

Whilst a positive response of clinical mastitis to treatment can be defined as the disappearance of clinical symptoms such as abnormalities of milk, swelling of the udder, anorexia, reduced milk production, fever etc. it is well recognised that assessment of other non-clinical indicators of disease are also important in determining recovery. Bacterial cure is defined as the disappearance of the causal organism - identified by culture -which was present at the start of treatment. Usually, two milk samples are collected after the full duration of effect of the antibiotic, taken at 7-10 day intervals. These should be free of the pathogen which was isolated prior to treatment. Since the recurrence of clinical mastitis in individual cows is high, it is likely that this occurs as a result of failure to achieve bacteriological cure despite the disappearance of clinical signs. This poor response in terms of bacterial cure can be attributed to a poor or irregular distribution of the active ingredient throughout the mammary tissue as a result of compression or obstruction of the lactiferous canals by inflammatory swelling. This may also explain why many organisms susceptible to antibiotics in vitro do not respond in the field and why prolonged therapy, often given as pulses of treatment so as to remain within the licensed recommendations, is increasingly becoming a treatment option.

Given that mastitis is an inflammatory response to infection or injury, it is valuable to measure other parameters in the laboratory so as to assess the presence of or recovery from disease. The concentration of somatic cells (SSC) measured in milk correlates with the cellular response to infection in the udder and can be used to define the severity of the inflammatory response and to measure 'cytological' recovery. By definition, since it is a non-clinical parameter, it is valuable in the assessment of both clinical and sub-clinical disease. A high SSC can be present for a long time even after elimination of the causal infectious agent and whether causing clinical or sub-clinical disease. Full recovery of the udder cannot be assumed in the presence of a persisting high SCC despite the elimination of clinical symptoms.

In acute inflammation of the udder, the cellular junctions of the tissue are destroyed so allowing chloride ions to leak out and accumulate in the milk. This augments the conductivity of the milk and this can be used as a simple, and often automated, indicator of inflammation and as an indicator of recovery.