Coliform Mastitis Therapy

R. J. Erskine
Michigan State University
East Lansing, Michigan

Clinical mastitis caused by pathogens of environmental origin such as gram-negative rods and streptococci other than agalactiae, can cause substantial losses to producers. An Ohio study reported losses of $107 per clinical mastitis episode, with total losses averaging $40/cow in herd/year(17). In a Michigan study, cows affected with clinical mastitis lost an average of 750 lbs of saleable milk due to lost production, and withholding abnormal or drug contaminated milk from market(4).

Field studies in herds with low somatic cell counts from Pennsylvania, Ohio, and California have reported average herd incidence of clinical mastitis to be 45 to 50 cases/100 cows annually (10,15,18). Coliform organisms (gram-negative, lactose fermenting rods) were the single most common group of pathogens isolated from culture in these studies, accounting for 30 to 40% of the clinical cases, and as much as 61% of the cases in which a causative agent was isolated (10,15,18). Although only 10 to 30% of clinical coliform cases are acute (5,18), coliform organisms are the single most important cause of severe clinical mastitis, accounting for 35% of the cases in an Illinois study, and nearly 60% in an Ohio study (1,18). Additionally, as many as 10 to 15% of cows with severe cases die (1).

Consequently, due to economic losses resulting from infection, the relatively high incidence of infection as compared to other clinical mastitis pathogens, and the occasional severe nature of infection, coliform mastitis continues to be a major problem confronting dairy producers. It is the purpose of this paper to present methods that may assist producers in implementing treatment strategies to reduce the losses from this disease.

Increasing the Chances of Therapeutic Success

The best treatment strategy for coliform mastitis is prevention. The concept of prevention is simple; reduce exposure of the teat to pathogens in the environment. The execution can be very difficult. Increases in the size of dairy herds, the frequency of confinement housing use, milk production (with subsequent increases in dry matter intake and manure production!), and genetic pressure towards production and away from disease resistance are all modern dairy management realities that work against us in the control of environmental mastitis. Thus, the labor and expense demands on producers for maintaining clean environments increasing. To most effectively use labor resources special emphasis should be placed on dry cow housing, and particularly maternity pens.

At best, treatment of any infectious disease, including mastitis does nothing more than assist the host defenses in eliminating the infection. Thus, treatment of acute mastitis in cows with impaired immune function is likely to result in a poorer outcome compared to cows with a viable immune system. The teat sphincter is the primary barrier to infection. Once this defense is breached, secondary and less effective defenses to prevent and/or reduce the severity of infection are mobilized. Quarters with elevated somatic cell counts are more resistant to challenge with coliform organisms than quarters with low somatic cell counts (6). This may explain, in part why cow from herds with low somatic cell counts have greater incidence of coliform infections than cows in herds with high somatic cell counts.

Dietary vitamin E and selenium reduce the severity and frequency of coliform mastitis (12,24). Thus, herd dietary selenium and vitamin E supplementation, particularly that for dry cows and heifers, should be reviewed periodically.

Mammary resistance to coliform (and all gram-negative) intramammary infections can also be enhanced by use of J5 (R mutant) E. coli antigen vaccines. They have proven safe and efficacious in reducing the incidence of clinical coliform mastitis in dairy herds (8). Practical applications of research to enhance mammary gland resistance to coliform infections are advancing. However, these methods can only augment sound management to reduce exposure of pathogens to the gland, not replace them.

Therapy

Therapeutic regimens for clinical mastitis are warranted on an ethical basis. However, the treatment of each clinical case may cost as much as $ 52/case in withheld milk, drug, veterinary, and labor costs (17). In a Michigan study, cows affected with clinical mastitis lost a mean of 750 lbs from lost production and withheld milk, with 73% of the loss attributed to withheld milk (4).

Despite the costs of treatment, there have been few controlled studies on the efficacy of therapeutic regimens commonly used for the treatment of clinical mastitis. Furthermore, drug residues in milk and meat resulting from therapeutic intervention of clinical mastitis are an additional economic risk to the farmer, particularly as the pharmacokinetics of many drugs in the acutely inflamed gland are unknown. Thus, successful therapeutic management of clinical mastitis should address three points: 1) efficacy, 2) economics, and 3) residues.

Following infection, coliform bacteria rapidly increase in numbers, and often reach peak concentrations in milk within 5 to 16 hrs (12,23). Typically, a subsequent rapid decline in bacterial concentration follows neutrophil migration into the gland. Though often severe, experimental coliform infections usually clear spontaneously, and rarely are more than 4 to 9 days in duration (12). Much of the inflammatory and systemic changes observed during the course of acute coliform mastitis result from the release of lipopolysaccharide endotoxin (LPS) from the bacteria following phagocytosis and killing by neutrophils (7). This results in subsequent activation of a complex cascade of inflammatory and immune modulators released by host immune and epithelial cells. Major players in this host-derived cascade include arachidonic acid metabolites (prostaglandins, leukotrienes, and thromboxanes), immune modulators (cytokines) and reactive oxygen species (2,27). Consequently, in order to reduce the severity of acute coliform mastitis, either bacterial growth must be inhibited to reduce exposure of the quarter and the cow to LPS, or the effects of the LPS release must be neutralized. From a practical standpoint, therapy of acute coliform infections cannot begin until clinical signs appear. Clinical recognition of coliform mastitis usually occurs after peak bacterial numbers have been attained (2,7,12,16). This raises concerns regarding the advantages of antimicrobial therapy in alleviating the effects of acute coliform mastitis.

Suggested therapeutic regimens for coliform mastitis include antimicrobials, supportive fluids, stripping out of infected quarters, anti-inflammatory agents, glucose, bicarbonate, and calcium (3,9,13). However, the efficacy of therapy, particularly for antimicrobials, is unproven. Antimicrobials such as aminoglycosides and cephalosporins , that have a high proportion of bacterial isolates susceptible in vitro (3), are often selected for use.

Jones and Ward determined that 2 gm of intramuscular gentamicin q 12 was not more efficacious in preventing agalactia or death resulting from acute clinical mastitis as compared to cows receiving intramuscular erythromycin or no systemic antimicrobials (20). Cows experimentally challenged with E. coli and dosed with 500 mg of intramammary gentamicin q 12 hrs did not have lower peak bacterial concentrations in milk, duration of infection, convalescent somatic cell or serum albumin concentrations in milk, or rectal temperatures as compared to untreated challenged cows (11). Concentrations of 0.34 and 0.69 ug gentamicin/ml of milk were present in the infected quarters of two cows at least 7 days following the last infusion of gentamicin (11). Additionally, gentamicin was found to readily diffuse into serum during treatment. This resulted in gentamicin in urine concentrations as high as 74.4 m g/ml in one cow, with concentrations of 0.37 and 0.24 m g/ml in two cows 14 days after the last infusion. With increased interest of drug residues, practitioners should carefully consider the 30 to 45 day half-life of aminoglycosides in the bovine kidney, before recommending a client cow is available for culling.

Ceftiofur sodium, a third generation cephalosporin, has been reported to have excellent activity against gram-negative pathogens (25), with a suggested MIC for E. coli of 0.25 ug/ml. Ceftiofur is approved for use in lactating dairy cattle, and if the labeled dose of 1 to 2.2 mg/kg q 24 hrs is administered intramuscularly, no milk withholding time is required. Lactating cattle administered 2.29 mg/kg im per day for 5 days did not exceed 0.184 ppm of ceftiofur-related residues in milk (19). This is well below the safe concentration for milk of 1.0 ppm. However, ceftiofur is not approved, nor should it be used, for intramammary infusions due to potential problems with extended withdrawal periods of milk. Thus, the efficacy of systemic ceftiofur as a treatment of clinical mastitis remains unproven, and relies on the benefits gained from systemic use. Experimental E. coli infected cows dosed intravenously with 3 mg of ceftiofur/kg q 12 hr had total antimicrobial activity in milk of < 0.20 m g/ml of milk throughout the trial (14). Thus, despite extra-label dosing, and acute mammary inflammation, systemic ceftiofur is not likely to attain concentrations in milk that are effective (0.25 to 1.0 m g/ml) in reducing bacterial numbers. If systemic ceftiofur has a benefit in the treatment of acute coliform mastitis, it would likely be for septic infections. Although, a Cornell study suggested that coliform mastitis results in sepsis in a minority of cases (22).

Thus, it may be time that we shift the emphasis of our treatment strategy from "What antimicrobial will result in a cure?", to one of "What treatment alternatives exist?". Unlike most clinical mastitis episodes caused by other pathogens, the pathogenesis of acute coliform mastitis often confronts us with endotoxin-induced shock as the primary problem, rather than the presence of the pathogen in the gland. A severely affected cow may require 40 to 60 liters of fluid intravenously in the first 24 hr (3). Although this is admittedly difficult and time consuming in a practical situation, convenient methods of fluid therapy administration should be developed. Commercial distilled water can be bought in large economical quantities and mixed with pre-weighed amounts of salt to provide the fluids needed. Alternatively, hypertonic saline (7.5% NaCl) is gaining acceptance from practitioners as a convenient method to ameliorate circulatory collapse associated with endotoxin-induced shock. It is believed hypertonic fluids promote an immediate reapportioning of extracellular fluid to the cardiovascular system. Cows should either voluntarily drink or be administered per os 5 to 10 gallons of water following hypersaline use. Additionally, caution should be exercised in administering hypersaline to cows with marked dehydration (diarrhea, heat stress) or shock precipitated by causes other than endotoxin (26).

Anti-inflammatory agents, particularly cyclo-oxygenase inhibitors (Non-steroidal anti-inflammatory drugs), and corticosteroids have been advocated as beneficial for the treatment of acute coliform mastitis. These drugs are expected to reduce local inflammation and the severity of systemic signs. Much of this benefit may result from the suppression of arachidonic acid metabolite formation. However, there is no direct evidence that anti-inflammatory drug use positively effects cow survival or production. Experimental mastitis models often have required pretreatment of anti-inflammatory drugs to reduce severity of clinical signs (21).

Although antimicrobials may be secondary to treatment of endotoxic shock, they are probably indicated, at least initially, for acute mastitis. Occasionally coliform infections due result in a chronic outcome, and septicemia may occur. In addition, although coliform organisms may cause 85% of the severe clinical mastitis cases in herds with low SCC, numerous other pathogens cause clinical mastitis. Consequently, until culture results can confirm the causative agent, antimicrobials should be administered. Drugs with ability to readily diffuse into the gland such as oxytetracycline or erythromycin could be used. Alternatively, ceftiofur could be selected to prevent systemic infection, the advantage of this drug is that under labeled dosing, no milk withholding will result. Caution should be exercised in continuing antimicrobial therapy in cows with grossly abnormal milk, but with improved appetite, attitude, and milk production.

Summary

Ideally, a drug regimen selected for therapy of clinical mastitis should meet three criteria for success: 1) the therapeutic regimen has demonstrated efficacy in controlled studies to eliminate the infection, or reduce the pathologic effects of infection, 2) information regarding milk and meat withholding periods is available to help reduce the risk of violative residues, and 3) the regimen is cost effective in terms of benefits gained versus costs of withheld milk and treatment. Particularly for acute coliform mastitis, fluid and anti-shock therapy are indicated as the primary treatment. Ultimately, the best practical measure of treatment success will be based on decreasing the production and withheld milk losses that result from infection and treatment. All who are concerned with mastitis in the dairy industry should aspire towards these goals.

References

1. Anderson KL, Smith AR, Gustaffson BK, et al. 1982. Diagnosis and treatment of acute mastitis in a large dairy herd. J Am Vet Med Assoc 181:690-693.

2. Anderson KL, Kindahl H, Petroni A, et al. 1985. Arachidonic acid metabolites in milk of cows during acute coliform mastitis. Am J Vet Res 46:1573-1577.

3. Anderson KL. 1989. Therapy for acute coliform mastitis. Comp Cont Ed Pract Vet 11:1125-1133.

4. Bartlett PC, Van Wijk J, Wilson DJ, et al. 1991. Temporal patterns of lost milk production following clinical mastitis in a large dairy herd. J Dairy Sci 74:1561-1572.

5. Bushnell RB. 1974. Where are we on coliform mastitis? Proceedings of the 13th Annl Mtng Natl Mastitis Council 62-69.

6. Carroll EJ, Lasmanis J, Schalm OW. 1973. Experimentally induced coliform mastitis: Inoculation of udders with serum-sensitive and serum-resistant organisms. Am J Vet Res 34:1143-1147.

7. Carroll EJ, Schalm OW, Lasmanis J. 1964. Experimental coliform (Aerobacter aerogenes) mastitis: Characteristics of the endotoxin and its role in pathogenesis. Am J Vet Res 25:720-726.

8. Cullor JS. 1991. The role of vaccines in the prevention and moderation of clinical mastitis. in Proceedings of the 30th Ann Meeting National Mastitis Council 68-75.

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10. Erskine RJ, Eberhart RJ, Hutchinson LJ, et al. 1988. Incidence and types of clinical mastitis in dairy herds with high and low somatic cell counts. J Am Vet Med Assoc 192:766-768.

11. Erskine RJ, Wilson RC, Riddell MG, Jr, et al. 1992. Intramammary gentamicin as a treatment for experimental Escherichia coli mastitis in cows. Am J Vet Res 53:375-381.

12. Erskine RJ, Eberhart RJ, Grasso PJ, et al. 1989. Induction of Escherichia coli mastitis in cows fed selenium-deficient or selenium-supplemented diets. Am J Vet Res 50:2093-2100.

13. Erskine RJ, Tyler JW, Riddell MG, Jr, et al. 1991. Theory, use, and realities of efficacy and food safety of antimicrobial treatment of acute coliform mastitis. J Am Vet Med Assoc 198:980-984.

14. Erskine RJ, Wilson RC, Tyler JW, et al. 1995. Ceftiofur in milk following intravenous administration in noninfected and experimental Escherichia coli infected cows. Am J Vet Res 56:481-485.

15. Gonzalez RN, Jasper DE, Kronlund DC, et al. 1990. Clinical mastitis in two California dairy herds participating in contagious mastitis control programs. J Dairy Sci 73:648-660.

16. Hill AW, Shears AL, Hibbitt KG. 1979. The pathogenesis of experimental Escherichia coli mastitis in newly calved dairy cows. Res Vet Sci 26:97-101.

17. Hoblet KH, Schnitkey GD, Arbaugh D, et al. 1991. Costs associated with selected preventive practices and episodes of clinical mastitis in nine herds with low somatic cell counts. J Am Vet Med Assoc 199:190-196.

18. Hogan JS, Smith KL, Hoblet KH, et al. 1989. Field survey of clinical mastitis in low somatic cell count herds. J Dairy Sci 72:1547-1556.

19. Jaglan PS, Yein FS, Hornish RE, et al. 1992. Depletion of intramuscularly injected ceftiofur from the milk of dairy cattle. J Dairy Sci 75:1870-1876.

20. Jones GF, Ward GE. 1990. Evaluation of systemic administration of gentamicin for treatment of coliform mastitis in cows. J Am Vet Med Assoc 197:731-735.

21. Lohuis JACM, Van Leuwen W, Verheijden JHM, et al. 1989. Effect of steroidal anti-inflammatory drugs on Escherichia coli endotoxin-induced mastitis in the cow. J Dairy Sci 72:241-249.

22. Powers MS, White ME, Dinsmore P, et al. 1986. Aerobic blood culturing in cows with coliform mastitis. J Am Vet Med Assoc 189:440-441.

23. Schalm OW, Lasmanis J, Carroll EJ. 1964. Pathogenesis of experimental coliform (Aerobacter aerogenes) mastitis in dairy cattle. Am J Vet Res 25:75-82.

24. Smith KL, Harrison JH, Harrison DD, et al. 1984. Effect of vitamin E and selenium supplementation on incidence of clinical mastitis and duration of clinical symptoms. J Dairy Sci 67:1293-1300.

25. Soback S, Ziv G, Winkler M, et al. 1989. Pharmacokinetics of ceftiofur administered intravenously and intramuscularly to lactating cows. Isrl J Vet Med 45:118-123.

26. Tyler JW, DeGraves F, Erskine RJ, et al. 1994. Milk production in cows with experimental endotoxin-induced mastitis treated intravenously with isotonic or hypertonic saline. J Am Vet Med Assoc 204:1949-1952.

27. Zia S, Giri SN, Cullor JS, et al. 1987. Role of eicosanoids, histamine, and serotonin in the pathogenesis of Klebsiella pneumoniae-induced bovine mastitis. Am J Vet Res 48:1617-1625.


Presented at the 1995 National Mastitis Council Regional Meeting, Harrisburg, Pennsylvania; Published in the National Mastitis Council 1995 Regional Meeting Proceedings, p. 72

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