Prudent antimicrobial use for mastitis therapy (Proceedings)

Despite all of the efforts that dairyman and dairy veterinarians have put into mastitis control and milk quality, mastitis continues to be one of the most common diseases on dairy farms.  Data from the United States Department of Agriculture (USDA) National Animal Health Monitoring Survey (NAHMS) completed on the US dairy industry in 2007 showed that 18.2% of all cows were treated for mastitis during the previous 12 months. 

In addition, 23% of all of the animals that were sold from the surveyed farms left due to mastitis or udder problems. This estimate does not include cows that died from mastitis, thus underestimating the percentage of cows that leave dairies from mastitis as compared to the other leading reason why cows leave dairies, reproductive failure, which would likely result in few dead cows.  Common estimates indicate US dairy producers lose approximately $185 per cow per year for every cow on their farm due to mastitis. 

Several reports have summarized culture results from clinical mastitis cases over time.  In general, the majority of these reports indicate that approximately 30-40% of all clinical mastitis samples yield no significant growth.  The possible reasons for this high level of failure to isolate an organism are many, but most researchers speculate that these may be the result of IMM infections with coliform organisms.  Coliform infections can result in a case of clinical mastitis with a single bacterial cell and tend to be short-lived within the mammary gland. 

Additionally, clinical signs of mastitis related to coliform bacteria are mediated by endotoxin release from either rapidly growing bacteria or bacterial death and lyses.  As a result, the onset of clinical disease often does not coincide with peak bacterial concentrations in the milk.  Alternatively, poor recovery rates could be associated with low diagnostic sensitivity of standard plate cultures for the isolation of certain mastitis causing organisms or possibly that these cases are being caused by microbial or viral agents that have not yet been discovered or require testing that was not specifically requested. 

For this reason, it is important to provide the diagnostic laboratory with a list of possible organisms that are suspected or are known to be present in the herd to maximize the likelihood of receiving useful results.  The second most common result from IMM infections are typically coliform bacteria making up approximately 25-30% of most surveys.  Environmental streps and coagulase negative staphs make up the majority of the remaining isolations. 

Successful treatment with intra-mammary mastitis tubes

If a poll was done evaluating dairymen's perceptions on the outcomes of clinical mastitis treatments, the results would most likely suggest that mastitis treatments are successful from zero to nearly 100% of the time.  NAHMS data suggests that dairymen select antibiotics for treatment of mastitis and route of administration based mostly on their past experiences, suggesting they perceive all mastitis to be similar, regardless of the cause of the mastitis infection.  This may help explain the frustration that many perceive concerning the lack of effective therapies for mastitis.

Effective mastitis therapy should be chosen based on culture result and severity.  Knowing the causative agent and directing treatment decisions based on the three compartment model proposed by Erskine et al3 appears to have the most validity for successful outcomes.  In their proposal, mastitis therapy and route of administration would be selected based on the probability that the treatment will reach the proper area and in sufficient concentrations to be effective.  The three areas are:

·         the lower udder including the cisterns and ducts

·         the parenchymal tissue of the mammary gland

·         the cow herself. 

For infections that are not too invasive such as Strep ag, Strep dysgalactiae, or coagulase negative staphs, Erskine et al3 propose IMM mastitis tubes as the proper approach.  For infections such as Staph aureus and Strep uberis, which tend to be deeper seated in the parenchymal tissues, they recommend IMM treatments that have the ability to penetrate deep into the parenchymal tissues (including extended therapy with IMM tubes) or a combination of IMM and systemic therapy. 

The final compartment, the cow herself, would be the appropriate route of therapy for infections that tend to also affect other locations within the body.  Examples of these types of infections would include severe E. coli infections, which result in toxemia and shock.  Another example would be Mycoplasma bovis, which can establish infections in the respiratory system, joints, etc.  In addition, many cases of mastitis from E. coli result in bacteremia necessitating the need for systemic antibacterial therapy to prevent and/or eliminate these infections.

Physical and physiological factors affecting success

The effectiveness of all of the lactating IMM tubes currently marketed United States is dependent upon the ability to keep the antibacterial concentration in the target area for a sufficient period of time.  There are two mechanisms that determine the effectiveness of IMM tubes, either time above MIC or peak concentration. Most of the classes of antibacterials in the veterinary arsenal are a time dependent killer, which means their effectiveness is determined by the ability to keep the antibacterial concentration above the MIC for a long enough period to kill the bacteria.  Aminoglycosides and fluoroquinolones, which are peak concentration dependent, need to develop a high enough peak concentration to be effective. 

While there are many factors that affect the ability of IMM antibacterials to accumulate in a specific location at sufficient concentration and for sufficient period of time to be successful, the vertical distance from the teat to the site of infection appears to be the most important variable.  As the distance between the teat and the infection increases, the chance of success decreases.  Additional concerns about getting the chosen product to the infection via the IMM route would include the presence of garget or intense swelling blocking ducts thus preventing penetration to the deeper areas or the development of fibrous tissue, as would be the case with chronic Staph aureus infections. 

In order for a drug administered systemically to be effective in the mammary gland, it must be able to penetrate the physical barriers between the circulatory system and the epithelial layers of the udder and then be in the proper pharmacologic form.  An ideal product for systemic administration that would be effective in the udder should be sufficiently lipid soluble to penetrate the blood-milk barrier, be weakly basic as to be more available (un-ionized) in mastitic milk and not be highly protein bound in serum. 

Normal milk has a pH of 6.  Mastitis causes milk to increase in pH thus making products that are weak bases more un-ionized and readily able to passively diffuse into the udder5.  Antibacterials that have good ability to penetrate in the mammary gland from systemic circulation would include macrolides, trimethoprim, tetracycline, and fluoroquinolones3.  Unfortunately, these characteristics often also predispose these products to having longer withdrawal periods that must be considered in the use of these drugs for the treatment of IMM infections.

Elimination of the antibacterial from the udder occurs by removing the antibacterial with milk at milking time and re-absorption into systemic circulation.  The rate of elimination of antibacterials from the udder is most dependent upon time between milkings.  Therefore, antibacterials that were approved using milking frequencies of 2x may not achieve effective concentrations for the entire time period between successive treatments when cows are milked more than 2x, assuming the number of hours between treatments remains the same. 

A recent paper by Stockler, et al6 looked at cephapirin concentrations in cows infused 12 hours apart and milked 2x versus cows infused either 8 or 16 hours apart and milked 3x.  In this trial, they saw no difference in inhibitory concentrations in milk or withdrawal times.  None the less, more research is needed to determine if IMM tubes that were approved prior to the early 1990's have sufficient concentrations to be effective without re-dosing more often.

Antimicrobial sensitivity

Antimicrobial sensitivity testing is often requested for mastitis pathogens to determine which product would be most efficacious.  Care should be taken in selecting a lab that has stringent quality control when performing antibacterial sensitivity tests.  In general, veterinary clinics may want to refer such submissions to diagnostic laboratories that are performing these tests on a regular basis.  The majority of diagnostic laboratories now run antibacterial sensitivity tests based on MIC's to provide the veterinary clinician a quantitative level which is necessary to be achieved in the infected tissue in order to be effective. 

Recommended breakpoints for bovine mastitis agents should be interpreted with care as many of the breakpoints have been based on data derived from bacterial isolates that came from areas other than the mammary gland, i.e. from bovine respiratory breakpoints or even human breakpoints.  These breakpoints should be interpreted with caution as there are many factors (pH and the concentrations of fat, protein, leukocyte and electrolytes) that are different between the bovine mammary gland and the other tissues (human plasma or bovine respiratory tissue) used for establishing breakpoints.  The only antibacterials to have breakpoints established for bovine mastitis are ceftiofur, pirlimycin and the dry cow therapy with a combination of penicillin and novobiocin.

Several studies have looked at the association between predicted antimicrobial sensitivities (based on Kirby-Bauer or MIC testing) and the treatment outcome of selected antibiotics.  For many antibiotics, results of in vitro testing have not shown to be reliable indicators of treatment success in the mammary gland.  This would suggest that the veterinary practitioner should not waste the expense of having antimicrobial sensitivities performed on mastitis isolates.  Many practitioners have argued that if an antimicrobial sensitivity is performed, the negative predictive value could be determined and they would know which antibacterial not to use.  Unfortunately, the negative predictive value has shown very little correlation with treatment failure in the cited studies.

Interpretive studies from diagnostic labs in Wisconsin and Michigan have reported that resistance to IMM pathogens has not been increasing for their respective submissions, which was consistent with most submissions from other parts of the world.  More recently, Pol and Ruegg compared antibiotic usage between organic and conventional farms to determine if exposures to antibiotics on conventional farms lead to increased antibiotic resistance.  In their study, there was an increase in resistance to pirlimycin in response to increasing exposure to pirlimycin for all pathogens studied.  In addition, they found a relationship between exposure to penicillin and increasing resistance for Staph aureus and coagulase negative staph (CNS).  All other pathogen/antibacterial interactions showed no relationship.

Realistic expectations from imm therapy

Regardless of the situation, it is important to have realistic expectations for the outcome.  Both dairymen and veterinarians desire to choose a treatment protocol that is efficacious, easy to administer, and cost effective.  Unfortunately, many dairy producers have unrealistic expectations for the efficacy of products that are used.  There have been several trials that have looked at cure rates for various antibacterial products against various bacterial agents.  The expected outcomes were best summarized by Wilson et al in stating that cure was dependent upon agent and antibacterial used.  These results, while intuitive, highlight the importance of acquiring culture data for mastitis cases to maximize the efficacy of therapy. 

In their evaluation of treatment response on over 9000 cases of sub-clinical mastitis, they found the cure rate of mastitis cases treated with various antibacterials to be 75%; however, that was only 10% higher than untreated controls thus demonstrating the power of the immune system.  Overall, amoxicillin showed the best cure rates of the seven antibacterials tested, followed by erythromycin and cloxicillin. The bacterial agents for which IMM treatment improved cure rates compared to no treatment were Strep ag, environmental streps, and coagulase negative staphs. 

There have been several trials that have looked at the economics of treatment of clinical and sub-clinical mastitis during the lactation.  In general, these trials have shown that lactation treatments of clinical infections have resulted in sufficient enough economic returns to justify these treatments.  Of course, these returns will vary from herd to herd depending on the bacterial pathogens and management practices present on the dairy. 

In contrast, while lactation treatment of sub-clinical infections may have resulted in fewer IMM infections, there was not enough increase in milk production or decrease in somatic cell count to produce sufficient income to outweigh the cost of treatment to eliminate an IMM infection.  One exception is the treatment of sub-clinical infections caused by Strep ag.

Conclusion

The use of antibacterials for the treatment of bacterial infections has been available to veterinarians for over 50 years.  As time goes by, more information is being gathered about the effectiveness and economics of labeled and extra-label treatments for mastitis.  In these current economic times, dairymen are questioning whether any medical treatment can be economically justified. 

Veterinarians must continually stay abreast of the latest scientific information to help their clients effectively improve milk quality and reduce violative residues.  In addition, they must work to improve their clients' overall herd health program to minimize metabolic diseases which have a negative impact on immunity and the clearance of IMM infections.