Summary of Antimicrobial Therapy

Judicious antibiotic use is necessary for successful mastitis treatment programs. Case selection is critically important to avoid unnecessary antibiotic use, which is costly to the producer and of concern to the public.

MASTITIS THERAPY: SUPPORTIVE TREATMENT. A variety of supportive measures are used in cows with severe clinical mastitis, often in conjunction with antibiotic therapy. Fluids and electrolytes are administered to correct circulatory and electrolyte disturbances (also see Chapter 44). Steroidal and nonsteroidal antiinflammatory agents are used to reduce pain, inflammation, and fever. Dairy producers and veterinarians use many other systemic and local treatments, most of which have not been scientifically evaluated or shown to be effective. This section discusses the most frequently used supportive treatments.

Fluid and Electrolyte Therapy. Cows with severe clinical mastitis can develop fluid and electrolyte disturbances as a result of decreased feed and water intake, rumen stasis, ileus, and diarrhea. Severely affected cows, particularly those with coliform mastitis, may develop septic or endotoxic shock; death or organ damage can result from decreased effective circulating volume.

The hydration status of an adult cow is assessed subjectively by observing skin tent duration on the neck or eyelid and position of the globe in the orbit. Unfortunately, findings can be influenced by the body condition of the cow. Objective criteria for estimating the extent of dehydration have been reported for dairy calves but have not been established for adult cows.⁴⁴⁷ Extrapolating from calves, a healthy cow should have cervical skin tenting of 2 seconds or less and no recession of the eyeball. Skin tent durations of 4, 6, or 8 seconds and eyeball recession of 2, 4, or 7 mm would correlate with 4%, 8%, and 12% dehydration, respectively. Indicators of reduced peripheral perfusion are cold extremities (ears, tail, fetlocks— only reliable at moderate ambient temperatures) and a dry muzzle or mouth.⁴⁴⁸ Hematocrit and plasma protein concentra­tion are not reliable indicators of hydration status in an individual cow because of the wide range of normal values and the effects of inflammation and stage of lactation on total protein concentration.

Most cows with clinical mastitis, even severe mastitis, have normal acid-base balance or metabolic alkalosis; metabolic acidosis is uncommon and associated with a poor prognosis.^441,449 Therefore there is no need for routine IV administration of alkalizing agents, such as bicarbonate or lactate. Also, oral products containing magnesium hydroxide or sodium bicarbon­ate should not be administered.

Fluids can be administered by the oral (intraruminal) or IV route. The oral route is least expensive and is often adequate for cows with mild to moderate dehydration. Oral fluids should be hypotonic or isotonic and should contain sodium, to create an osmotic gradient between rumen fluid and blood and enable sustained absorption of fluid and electrolytes; hypertonic oral fluids should be avoided.⁴⁵⁰ A 600-kg cow that is 6% dehydrated needs to absorb 36 L of fluid to replace her deficit.

Ringer's solution, which is an isotonic (isosmotic), mildly acidifying solution that contains physiologic concentrations of sodium, chloride, potassium, and calcium, is the fluid of choice for rapid IV resuscitation of adult ruminants.⁴⁵⁰ Isosmotic (0.9%) sodium chloride is an alternative that can easily be constituted using table salt and distilled water in a sterile carboy. However, administration of isosmotic crystalloid solutions is impractical in many situations because of the large volume of fluid required and the need for IV catheterization. A 600-kg cow that is 10% dehydrated requires 60 L of fluid to replace her deficit.

A more practical alternative for on-farm therapy to isosmotic IV fluid therapy is IV administration of hypertonic (7.2%, 2460 mOsm/L) saline. Hypertonic saline is administered through a large-bore needle at 4 to 5 mL/kg body weight over 4 to 5 minutes, in conjunction with oral administration of water (5 gal). Rapid administration of hypertonic saline is required to effectively create an osmotic gradient that draws fluid from the intercellular spaces and gastrointestinal tract (mainly rumen) into the vasculature. Although hypertonic saline does not have a sustained effect and will not completely correct a large fluid deficit, it rapidly increases plasma volume and improves cardiac output and tissue perfusion. Hypertonic saline has been shown 452 453

to be safe in cows with endotoxic mastitis.⁴,

Mild to moderate hypocalcemia often accompanies clinical mastitis, with the odds of hypocalcemia increasing with the severity of mastitis,¹⁴⁵ although other serum electrolytes are variable. Affected cows may show muscle tremors or weakness but are seldom recumbent.

Anti-inflammatory Drugs. Most of the physiologic and pathologic changes associated with clinical mastitis are a result of the inflammatory response to infection. Therefore it is logical to administer anti-inflammatory agents. Also, anti-inflammatory agents can reduce the pain associated with clinical mastitis.⁴⁵⁵ However, the inflammatory response is necessary for resolving intramammary infection, and anti-inflammatory agents can produce detrimental side effects. Many of the agents used in other countries are not labeled for use in lactating dairy cows in the United States. The choice of anti-inflammatory agents in the United States is limited to three approved drugs— dexamethasone, isoflupredone acetate, and flunixin meglumine— although none is approved for the treatment of severe clinical mastitis.

Dexamethasone and isoflupredone acetate are inexpensive steroidal anti-inflammatory agents that have no milk­withholding requirement. Glucocorticoid drugs inhibit the production of inflammatory molecules and the adhesion molecules that facilitate transport of inflammatory cells from the bloodstream to the site of inflammation.

Data on the efficacy of steroidal anti-inflammatory agents for treatment of clinical mastitis are limited to experimental mastitis trials. A single, 30-mg IM dose of dexamethasone given at the time of E. coli inoculation reduced local signs of inflammation, tachycardia, rumen motility impairment, and 14-day milk production loss, compared with untreated con­trols.^457,458 A large IV dose of dexamethasone (0.44 mg/kg) given to goats 12 hours after E. coli infusion reduced fever and appetite suppression but had no effect on heart rate, rumen contractions, serum biochemical parameters, SCCs, milk yield, or histopathologic changes.⁴⁵⁹ Isoflupredone acetate (20 mg IV) administered to endotoxin-challenged cows after the onset of clinical mastitis had no beneficial effect on systemic param­eters, mammary gland swelling, or milk production, compared with untreated controls.⁴⁶⁰

However, each of these agents has potential adverse effects. Dexamethasone can cause abortion in pregnant cows, espe­cially after 5 months of gestation, although this would be less of a concern for cows in early lactation.

The above studies suggest that the most likely benefit for corticosteroid treatment would be for severe coliform mastitis, and delays in therapy relative to the onset of infection may hamper efficacy. Nonetheless, dexamethasone is a potent anti-inflammatory agent, and it is difficult to extrapolate the benefit for cattle in terms of improved attitude and shock mitigation from experimental mastitis trials to naturally occur­ring clinical mastitis. Because of mineral corticoid effects on serum potassium, dexamethasone may be preferred over iso- flupredone. In addition, corticosteroid use in chronic IMI should be contraindicated.

A variety of nonsteroidal antiinflammatory drugs (NSAIDs) are used to treat clinical mastitis worldwide.⁴⁵⁵ However, only flunixin meglumine is approved for use in lactating dairy cows in the United States. Dipyrone and phenylbutazone are banned, and other NSAIDs can be used in an extralabel manner only if appropriately justified. The NSAIDs are not immunosup­pressive but carry a risk of abomasal ulceration and renal damage. These complications are not well documented in cattle and presumably are minimized if treatment is of short duration, hydration is maintained, and appetite is restored. The primary mode of action of NSAIDs is to inhibit the synthesis of prostaglandins and thromboxanes by inhibition of cyclooxy­genase. NSAIDs also inhibit the formation of prostaglandin E2 in the brain, which effectively reduces fever.⁴⁶⁵

Treatment of cows with flunixin meglumine at 0 and 3 to 5 hours after E. coli inoculation abolished fever and improved rumen motility, compared with untreated controls, but had no effect on gland or milk appearance, heart rate, or respiratory rate.⁴⁶⁶ Similarly, administration of flunixin meglumine every 8 hours beginning 2 hours after endotoxin infusion reduced fever and improved gland appearance and attitude, compared with untreated controls, but had no effect on milk appear­ance, heart rate, rumen motility, SCC, or milk production.⁴⁶⁷ When administered after the onset of fever and gland swelling, flunixin meglumine (2.2 mg/kg IV) reduced heart rate and rectal temperature and increased rumen motility in cows with endotoxic mastitis but had no effect on milk production or mammary gland inflammation.⁴⁶⁸ As with the steroids, the relevance of these trial results to cows with naturally occur­ring clinical mastitis is uncertain. Meloxicam, administered at a dose of 0.5 mg/kg subcutaneously, was found to have a beneficial effect in relieving pain, decreasing udder edema, and reducing body temperature response following an LPS-induced clinical mastitis.^468a Although not labelled for use in cattle in the United States, this drug may have potential in the future for analgesia and as an anti-inflammatory agent. It appears that NSAIDs can improve well-being and outcome in cows with clinical mastitis. However, specific criteria for instituting NSAID therapy, the timing of therapy relative to infection onset, and the optimal duration of treatment remain to be determined.

Oxytocin and Frequent Milking. Oxytocin is admin­istered to stimulate milk ejection and facilitate removal of secretions from mastitic mammary glands. Frequent milk-out (stripping) reputedly augments the removal of pathogens, toxins, and inflammatory mediators from the mammary gland. Although these are seemingly logical practices, no solid evidence exists to support their routine use, and some data suggest they can be detrimental. Oxytocin (20 IU IM twice daily for 3 days) at milking time prevented development of clinical mastitis in only two of eight cows experimentally inoculated with S. uberis; once clinical mastitis developed, oxytocin was ineffective at resolving the S. uberis infections.⁴⁶⁹ When initiated at the onset of clinical S. uberis mastitis, oxytocin (80 IU IM, followed by 20 IU IM twice daily) resulted in no clinical or bacteriologic cures by 3 or 6 days.⁴⁷⁰ In contrast, clinical and bacteriologic cure rates of 91% and 64% were achieved by intramammary antibiotic administration by 3 and 6 days, respectively. When oxytocin was used in conjunction with intramammary antibiotics, clinical and bacteriologic cure rates at 6 days dropped to 10%, implying a significant adverse effect of oxytocin and stripping. Frequent milk-out (every 4 to 6 hours) in conjunction with oxytocin administration did not shorten the time to clinical or bacteriologic cure or resolution of systemic illness in cows with experimentally induced coliform mastitis, compared with no treatment.⁴⁷¹ When oxytocin administration (100 IU IM twice daily for 1 week) was compared with no treatment (udder massage only) in cows experimentally inoculated with S. aureus, oxytocin administration reduced bacterial concentrations in the milk but did not improve the bacteriologic cure rate or reduce SCCs.⁴⁷² Oxytocin administration increases the perme­ability of mammary epithelial tight cell junctions in a dose­dependent manner, which can alter milk composition in nonmastitic glands, particularly if high doses (100 IU) are administered repeatedly.⁴⁷³

Oxytocin and frequent milk-out have not been evaluated extensively in the field. In a California study, oxytocin (100 IU IM twice daily for three treatments) at milking time resulted in similar clinical and bacteriologic cure rates, as compared to intramammary antibiotics, although an untreated control group was not evaluated.⁴⁷⁴ However, no overall benefit resulted because the oxytocin-treated cows had a higher recurrence rate of clinical mastitis, particularly environmental streptococcal mastitis.⁴⁷⁵ In a Virginia study, frequent milk-out (six times daily) in conjunction with oxytocin administration (20 IU) did not improve clinical or bacteriologic cure rates, time to cure, or return to milk production compared with no treatment.⁴⁷¹ In an Illinois herd, cows treated with supportive therapy alone (oxytocin administration [all cases], frequent milk-out [moderate and severe cases], anti-inflammatory therapy [severe cases], and fluid therapy [severe cases]) had lower clinical and bacte­riologic cure rates and a higher recurrence rate than cows given antibiotics in addition to the same supportive therapy.⁴⁴⁴ Furthermore, two studies have cited that 50 IU of oxytocin administered q12h for 19 or 22 days increased residual (non­harvested) milk by 15% at each milking.^476,477 Bruckmaier⁴⁷⁶ noted, “Cows increasingly refused to enter the milking parlor voluntarily and had to be fetched by the milker and cow entry into the parlor remained disturbed for up to one week after the end of injections.”

In summary, oxytocin administration and frequent milk-out are not likely to be effective standalone treatments for clinical mastitis, particularly mastitis caused by streptococci, and may even be detrimental. In certain circumstances, when a cow clearly will not eject milk or when garget in the milk prevents effective milk removal, these practices may be of some benefit. Otherwise, unnecessary administration of oxytocin injections and frequent milking of painful teats should be avoided for welfare reasons. Sustained use of this drug as a routine therapy is a poor substitute for good milking preparation and will likely incite cows to be reluctant to enter the milking parlor and milk out effectively, which is the opposite of therapeutic inten­tions with this drug.