The present invention relates to mastitis, an extremely important veterinary disease, and to the preparation and administration of egg antibody products which may be used to neutralize a wide variety of systemic pathogens which cause or exacerbate this disease.
The term mastitis refers to inflammation of the mammary gland, regardless of cause. It is characterized by physical, chemical, and usually bacteriological changes in the milk and by pathological changes in the glandular tissue. The most important changes in the milk include discoloration, the presence of clots and the presence of large numbers of leukocytes. Although there is swelling, heat, pain, and induration in the mammary gland in many cases, a large proportion of mastitic glands are not readily detectable by manual palpation or by visual examination of the milk using a strip cup. Because of the very large numbers of such "subclinical" cases, the diagnosis of mastitis has come to depend largely on indirect tests which depend, in turn, on the leukocyte content of the milk. Thus, it is practicable to define mastitis as a disease characterized by the presence of a significantly increased leukocyte content in milk from affected glands. This leukocyte content is commonly referred to as the "somatic cell count," or SCC.
Many infective agents, primarily bacterial but occasionally fungal or protozoal, have been implicated as causes of mastitis. The most common are Streptococus agalactiae and Staphylococcus aureus, with Escherichia coli becoming a significant cause in housed or confined cattle, principally in the northern hemisphere. Other agents include Streptococcus uberis, Streptococcus dysgalactiae, Corynebacterium (Actinomyces) pyogenes, Klebsiella spp., Mycobacterium bovis, Pseudomonas pyocyaneus, Serratia marcescens, Mycoplasma bovis, Nocardia asteroides, Proteus spp., and Chlamydia psittaci.
Infection of each mammary gland occurs via the teat canal, with the infection originating from two main sources, the infected udder and the environment. In dairy cattle and milking goats, the important infections are those which persist readily in the udder, especially Str. agalactiae and Staph. aureus. The contamination of milkers' hands, washcloths, and milking machine cups by milk from infected quarters may quickly lead to the spread of infection to the teats of other animals. These are commonly referred to as infectious or contagious mastitides.
Bacteria which are normal inhabitants of the environment, such as E. coli and Ps. pyocyaneus, cause mastitis less frequently but, when they do, the disease is much more resistant to hygienic control measures. Large, zero-grazed herds in feedlots are likely to encounter more hygiene problems than conventionally housed herds. The problems relate mainly to fouling of the udder caused by inadequate or improper bedding in the larger units. Thus, these are known as environmental mastitides.
The frequency of occurrence of mastitis is dependent upon the ability of bacterial agent to set up infection in the mammary tissue. The diferences between bacteria in their ability to set up a mastitic state is dependent on at least two important groups of factors: bacterial characteristics and transmission mechanisms. Bacterial characteristics include the ability of the organism to survive in the cow's immediate environment (i.e., its resistance to environmental influences, including cleaning and disinfection procedures), its ability to colonize the teat duct, its ability to adhere to mammary epithelium and set up a mastitis reaction, and its resistance to antibiotic therapy. Transmission mechanisms are a function of the extent of the infection in the environment (including infected quarters), the efficiency of milking personnel and machinery, milking parlor hygiene, and the susceptibility of the cow. An individual cow's susceptibility, in turn, is a function of the stage of lactation (early lactation, especially the first two months, representing highest susceptibility), the age of the cow (older cows, having had more than four lactations, being more susceptible), the level of inherited resistance (possibly related to teat shape and anatomy of the teat canal), lesions on the teat skin (especially the orifice), and the immunological status of each mammary gland (including prior infections, especially with Staph. aureus).
In most countries, surveys of the incidence of mastitis, irrespective of cause, show comparable figures of about 40% morbidity amongst dairy cows and a quarter infection rate of about 25%. The incidence is similar in goats. Surveys of the prevalence of the various infections in cattle show remarkable similarity in different countries. The predominant position of Str. agatactiae as a cause of bovine mastitis has been usurped by Staph. aureus, especially in areas where the treatment of mastitis with penicillin has been practiced intensively and where machine milking has replaced hand milking. In such areas a relative incidence of Str. agalactiae, other streptococci, and Staph. aureus of 1:1:2 is a common finding.
Although the prevalence of Staph. aureus has been significantly curbed by modem control programs based on teat dipping and dry period treatment, it remains the preeminent cause of subclinical mastitis. Mastitis is said to be subclinical when there is evidence of inflammation, e.g., a high somatic cell count in the milk, without any visible abnormality of the milk or udder. Chronic cases of mastitis, particularly those caused by Staph. aureus, are often refractory to treatment while the cow is lactating. For staphylococcal infections in general, a cure rate of 30% is about the best that can be expected. An old adage holds that "once a Staph. cow, always a Staph. cow." Thus, many dairymen choose to cut their losses and simply cull Staph.-positive cows rather than to attempt treatment.
Although mastitis occurs sporadically in all species, it assumes major economic importance only in dairy cattle. In terms of economic loss it is undoubtedly the most important disease with which the dairy industry must contend. In 1992, mastitis infections cost members of the American Dairy Association over $200,000,000. High somatic cell counts in cows result in the loss of approximately 200,000 pounds of milk per cow per year at a financial cost of approximately $288 per cow. Only 10% of the approximately 9,750,000 dairy cows in the United States attain the highest ranking on somatic cell count (below 100,000). A dairyman receives an additional 50 cents per 100-wt. of milk for the highest ranking, i.e., the lowest SCC range. Thus, the insidious presence of subclinical mastitis in a herd can have a devastating effect on milk profits, even in the absence of any external manifestations of disease.
Most estimates show that on the average an affected quarter suffers a 30% reduction in productivity and an affected cow is estimated to lose 15% of its production. Total economic losses caused by mastitis comprise the value of milk production lost, the value of cows lost by premature culling, the value of milk discarded or downgraded, and the cost of treatment and veterinary expenses.
Ordinarily, mastitis is treated either systemically by parenteral injection or locally by intramammary infusion. Parenteral treatment is usually reserved for cases of mastitis in which there is a marked systemic reaction, to control or prevent the development of a septicemia or bacteremia and to assist in the treatment of the infection in the gland. The systemic reaction can usually be brought under control by standard doses of antibiotics or sulfonamides but complete sterilization of the affected quarters is seldom achieved because of the relatively poor diffusion of the antibiotic from the bloodstream into the milk. Parenteral treatment is also used when the gland is badly swollen and intramammary antibiotic is unlikely to diffuse properly. To produce therapeutic levels of antibiotic in the mammary gland by parenteral treatment, it is necessary to use higher-than-normal dose rates, which can alter milk-withholding times, sometimes with disastrous consequences, as discussed infra.
Because of convenience and efficiency, udder infusions have been the preferred method of treatment. Disposable tubes containing suitable drugs in either an aqueous or ointment base are inserted into the teat canal, providing diffusion of drug into the glandular tissue. Strict hygiene is necessary during treatment to avoid the introduction of bacteria, yeasts and fungi into the treated quarters. Diffusion of infused drugs is often impeded by the blockage of lactiferous ducts and alveoli with inflammatory debris. Drug-withholding times are just as applicable to udder infusions as parenterally administered drugs, since these infusions rapidly undergo systemic absorption from the highly vascular udder.
Choice of a suitable drug for the treatment of mastitis is often extremely difficult. In vitro laboratory testing of bacterial sensitivity is not necessarily a justifiable basis for selecting the antibacterial agent to be used in individual cows, and the response to treatment in clinical cases is often unrelated to the results of in vitro sensitivity tests.
In the opinion of the authors of one of the leading texts on large animal veterinary medicine, very little good research and development work has been performed in the field of mastitis prophylaxis and treatment, and most of the products available have been developed with very little scientific support. Attractiveness to the consumer has been placed above efficiency, in the opinion of these authors, resulting in "intramammary preparations containing a battery of antibacterial agents, one or more of a long list of generally unhelpful adjuvants, and inappropriate recommendations about their use, especially with regard to frequency of administration and length of time after treatment for which milk must be withheld from sale." Further, "[t]he indiscriminate and improper use of antibiotics for the treatment of clinical mastitis in lactating cows which has resulted from inaccurate promotion and uninformed use by farmers has meant that the control of mastitis has really received little assistance. Drug-resistant organisms, especially Staph. aureus, have been encouraged, and the chances of human consumers of dairy products being exposed to antibiotic residues has been increased." (Blood and Radostits, Veterinary Medicine: A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats and Horses, 7th ed., 1989, p. 512).
The effect of antibiotics in milk on the manufacture of dairy products and the development of sensitivity syndromes in human beings is of the utmost consequence. In most countries, the maximum intramammary dose of antibiotics is limited by legislation and the presence of detectable quantities of antibiotics in milk constitutes adulteration. Strict legislation and mandatory milk-testing in the United States have greatly decreased such risk to consumers, but the penalties for milk contamination as a result of inadequate milk-withholding times are enormous and can result in financial disaster for the dairyman and/or veterinarian found to be responsible for such a violation. Since the rate of drug excretion varies among different animals and in the same animal at different points in the lactation period, withholding times specified on drug labels are not always accurate and can lead to inadvertent violation of residue limits. As a result, some dairymen will elect to cull any but the most valuable cows rather than to run the risk of contaminated milk. Even aside from such risk, substantial loss is involved in the discarding of milk during specified withholding times, which can range anywhere from 72 hours for an udder infusion in a lactating cow to 10 days for parenteral antibiotics in long-acting bases.
For the foregoing reasons, there exists a felt need for a mastitis treatment which is not only efficacious, easily administered, and cost-effective, but which is not hampered by the uncertainty and risk of a milk-withholding period. Such a treatment would undoubtedly be enthusiastically received by the dairy industry worldwide.