Clinical mastitis treatment efficacy: Are we making progress? (Proceedings)

Mastitis is considered one of the most costly diseases of dairy cattle and one of the most common reasons for antibiotic treatment on dairy farms. There are numerous treatments (both antibiotic and non-antibiotic) for clinical mastitis. The majority of cows with clinical mastitis are treated with antibiotics but a study regarding on-farm culture indicated that withholding treatment pending culture helps reduce antibiotic usage (Neeser et al., 2006). Prior to the year 1994, there were very few studies of mastitis treatment efficacy that utilized non-treated control cases. Although it is well-known that the efficacy of a given treatment depends largely upon the agent of mastitis (Ødegaard and Sviland, 2001), few studies evaluated the effect of treatment on specific mastitis agents. Pirlimycin is highly effective against Streptococcus agalactiae but has no effect against Escherichia coli. Approximately 80% of clinical mastitis due to E. coli are mild to moderate cases and > 90% of these cases undergo spontaneous cure within a few days. Thus, an efficacy study of pirlimycin for "clinical mastitis" might suggest that pirlimycin is an effective antibiotic for E. coli. The severity level is also associated with the efficacy of a given product (Ødegaard and Sviland, 2001). There are various other factors that might alter the interpretation of the results of a clinical trial. A 2004 study identified severity of mastitis, lactation number, previous mastitis this lactation and bacteriological findings as factors that influence outcome of treatment and these factors appear relevant as stratification factors in mastitis trials (Hektoen et al., 2004a). To answer the question in the title, progress is being made as more studies utilize non-treated control cows and employ various measures to appropriately gather and analyze treatment data.

Qualities of a Sound Treatment Efficacy Study of Clinical Mastitis

     1. Should be naturally occurring cases of clinical mastitis.

     2. Must have a non-treated control group or a good reason for their absence.

     3. Must define treatment outcome parameters and have the parameters as objective as possible.

     4. Investigator must have full control of the cows

     5. Culturing should occur prior to treatment, once during treatment, once immediately after milk withdrawal time, and once 3-4 weeks after the first treatment. For studies with chronic pathogens (e.g. Staphylococcus aureus), cultures should be continued for several months.

     6. Treatments must be assigned randomly and the method of randomization should be declared.

     7. Treatment outcomes should be assessed by severity level (mild, moderate, and severe).

     8. Treatment outcomes should be assessed by etiologic agent.

Clinical Efficacy Studies for Streptococci

Clinical efficacy studies utilizing experimentally-induced mastitis can be suggestive of treatment efficacy but true efficacy requires well-designed studies of naturally occurring clinical mastitis cases. A 2001 study of experimentally-induced Streptococcus uberis clinical mastitis compared the treatment efficacy of no treatment to an intramammary (IMM) product dosed by label, the same IMM product dosed extralabel, a parenteral antibiotic, and a combination of the extralabel IMM product and parenteral antibiotic. In this study, the no treatment group (11 quarters) did not achieve clinical or bacterial cures by 6 days whereas all other treatment groups had > 90% clinical cures by 6 days and > 70% bacterial cures by 6 days. The combined treatment group had 100% clinical and bacterial cures by 3 days but this group only had 5 quarters whereas the other groups had at least 10 quarters. The authors concluded that 100% clinical and bacteriological cure is achievable with 3 days of combined treatment (Hillerton and Kliem, 2001). The authors of the previous study followed up with a similar study of experimentally-induced S. uberis clinical mastitis and concluded that aggressive IMM treatment with Leo Yellow (administered twice a day for 3 days) was the most effective treatment for fastest cure clinically and bacteriologically using the least antibiotic (Hillerton and Kliem, 2002). A 2004 treatment study of IMM ceftiofur conducted on experimentally-induced S. uberis clinical mastitis showed a significantly higher percentage of bacterial cures by extended therapy (5 or 8 infusions @ 24 hour intervals) when compared to label therapy (2 infusions @ 24 hour intervals) (Oliver et al., 2004). In a treatment efficacy study of naturally occurring clinical streptococcal mastitis, 2 of 7 quarters that received no treatment achieved bacterial cure by 2 days and 2 of 5 cases treated by label with amoxicillin were cured bacteriologically by day 2 (Roberson, 2010). Although the results of studies of experimentally-induced streptococcal clinical mastitis might differ from naturally occurring cases, all results indicate that antibiotics are necessary to achieve bacterial cures and subsequent complete resolution of the mastitis. Natural resolution of nontreated streptococcal mastitis is typically < 20%. These findings are echoed by a study in which IMM pirlimycin was found to result in gram-positive mastitis resolution 1.8 times more frequently than non-treated quarters (Cattell et al., 2001). Thus, studies of streptococcal mastitis do not necessarily require non-treated control cases (one of the few exceptions). Several studies have evaluated the effect of extended antibiotic therapy for cases of streptococcal mastitis and the majority has found extended therapy to increase bacterial cure rates over conventional therapy (Krömker et al., 2010a; Milne et al., 2005). Milne and others reported that 55% of S. uberis clinical mastitis that did not respond with a bacterial cure when treated with conventional therapy, obtained a bacterial cure with extended IMM antibiotic therapy. Milne also found that some cases of S. uberis mastitis would have falsely been identified as bacterial cures if not sampled at 21 days after the end of treatment.

Treatment Efficacy Studies for Staphylococcus aureus

Staphylococcus aureus is notoriously difficult to cure. The determination of a bacterial cure for most mastitis pathogens can reasonably be done with a couple of culture periods after the antibiotic withdrawal period (e.g. @ 14 and 28 days). This same sampling schedule will not suffice for S. aureus. Thus studies that report high bacterial cures rates for S. aureus should be viewed skeptically if long-term sampling has not been performed (long-term = at least 2-3 months post-treatment). In a study of extended IMM pirlimycin with or without vaccination for S. aureus, Timms (2001) reported 30 day bacterial cure rates of 18%, 38%, and 56% but at 60 days bacterial cures were 14, 17 and 14%. However, some factors regarding which cows have the best chance of truly obtaining a bacterial cure are becoming evident. In a 2003 study of S. aureus clinical mastitis treatment efficacy utilizing parenteral penicillin alone or in combination with an intramammary product, nearly 92% of first lactation cows affected by β-lactamase negative strains obtained bacterial cures compared to 67% of older cows (Taponen et la., 2003a). This study also emphasized the importance of determining the β-lactamase status on treatment success as nearly 72% of susceptible strains obtained a bacterial cure whereas only 33% of the β-lactamase resistant strains cured. However, the bacterial cure was based on only 1 or 2 follow-up cultures at 2 and 4 weeks or only at 4 weeks. Another study of experimentally-induced S. aureus mastitis found that neither a proprietary liniment, IMM antibiotic nor oxytocin provided significantly better efficacy than massage treatments (Knight et al., 2000). A field study of treatment of clinical S. aureus mastitis, reported 70% quarter bacterial cure when cows were treated with an IMM product containing amoxicillin as all strains of S. aureus were resistant to penicillin (Izak, 2001). This study had no controls and the last milk culture was performed on day 28.

Treatment Efficacy Studies for Coliforms

In a study of experimentally-induced E. coli mastitis resulting in at least moderate severity, enrofloxacin administered IV and then IM resulted in a faster recovery of milk production and clearance of bacteria than non-treated control cows (Hoeben et al., 2000). In a separate study, a single IV dose of danofloxacin given to cows experimentally-infected with E. coli, showed statistically significant lower local clinical scores and a more rapid return to pre-inoculation values over saline treated controls (Poutrel et al., 2008). Although enrofloxacin and danofloxacin are illegal to use in an extra-label manner in the United States, the study does suggests that cows with moderate to severe E. coli mastitis may benefit with systemic antibiotics.

Homeopathy

In this age of anti-antimicrobials, the push to use non-antibiotic methods to treat clinical mastitis will likely increase. Although more clinical trials of homeopathic mastitis treatment have been published in recent years, to date, there are no published well-designed studies that clearly indicate efficacy. A study published in 2004 (Varshney and Naresh) investigated the use of a homeopathic complex to treat cases of clinical mastitis in buffaloes. The authors reported cures of 80 to 97% for fibrosed and non-fibrosed quarters, respectively. Yet, there were no controls, cure was not specifically defined and bacteriology was not performed. These same authors performed a similar study and reported that homeopathic combination medicine resulted in cures (defined as normal milk and udder and normal CMT) of 86.6% for acute non-fibrosed mastitis compared to 59.2% cures for a historical antibiotic group (Varshney and Naresh, 2005). Some of the concerns with this study are the lack of non-treated controls, the lack of milk cultures, the use of a historical antibiotic group, and the fact that cows receiving the homeopathic combination that did not respond within the first few days were excluded from the study.

In a small study comparing homeopathy, placebo and antibiotic treatment of clinical mastitis in dairy cows, evidence of efficacy of homeopathic treatment beyond placebo was not found (Hektoen et al., 2004b).

A study comparing IMM infusion of a live culture of Lactococcus lactis with a conventional IMM product found that live culture treatment may be as efficacious as common antibiotic treatments in some instances. True negative controls were not used in the study because "it is unethical to withhold treatment from animals that are known to be infected" (Klostermann et al., 2008).

Miscellaneous

Aminoglycosides

Because mastitis treatment success is not as high as desired, there are instances in which extra-label drug use may increase cure rates. Better justification for extra-label drug use can be obtained if studies have shown increased efficacy against specific mastitis pathogens. Likewise, there is little justification for extra-label drug when studies have not demonstrated increased success. Although aminoglycosides are not available in intramammary products marketed in the United States, aminoglycosides have been used IMM to treat cases of clinical mastitis. A study of clinical mastitis of penicillin-susceptible gram-positive bacteria published in 2003 demonstrated that the inclusion of neomycin along with penicillin in an IMM preparation did not increase cure rates when compared to IMM penicillin alone (Taponen et al., 2003b).

Oxytocin

Although the use of oxytocin to treat cases of clinical mastitis is a common adjunct therapy, there is little evidence to suggest its effectiveness. When used as the sole treatment for experimentally-induced S. uberis clinical mastitis, clinical cures were minimal and mastitis severity increased (Hillerton and Kliem, 2002).

Laser therapy

In a field study of cows with chronic or mild acute clinical mastitis, laser therapy was compared to conventional antibiotic treatment (IMM or systemic, not mentioned). Laser therapy resulted in lower bacterial cures and a delayed clinical cure as compared with antibiotic therapy (Hoedemaker and Hackenforth, 2001)

Systemic antibiotics

Wenz and others (2005) found no benefit of intramuscular (IM) ceftiofur in the treatment outcomes of systemically mild clinical mastitis. Likewise, Erskine and others (2002) reported that IM ceftiofur did not affect the outcome of severe clinical mastitis when all isolates were analyzed together. However, when coliforms were evaluated separately, cows receiving IM ceftiofur had a significantly lower rate of death and culling (13.8%) versus cows with coliform mastitis that were not treated with systemic ceftiofur (37%).

Intramammary antibiotics

Although not significantly different, IMM pirlimycin (27%) treated quarters were the least likely to be culture negative 7 days after leaving the hospital pen than treatments with IMM cephapirin (33%), or IM ceftiofur with pirlimycin (45%) or cephapirin (52%) in a herd with a high percentage of Gram-negative clinical mastitis (Wenz et al., 2005).

In a multilocation clinical trial of mild clinical mastitis, an IMM lincomycin-neomycin preparation was found superior to an ampicillin-cloxacillin IMM preparation (Deluyker et al., 1999). Bacterial cures for staphylococcal species were typically < 50% for both treatments. Bacterial cures were nearly 100% for all streptococcal species except esculin-positive species (classically S. uberis) which had bacterial cures of 57-58% for both treatments.

In a dose titration trial of IMM ceftiofur, the 125 mg dose resulted in a bacterial cure of 70.4% compared to 41.3% in non-treated controls (Hallberg et al., 2001). Although cure rates by organism are not listed, ceftiofur at 125 mg was reported to be effective in treating clinical mastitis due to S. aureus, coagulase-negative Staphylococci, the Streptococci, and E. coli.

In a clinical trial of 3 IMM treatment regimens for clinical mastitis due to organisms susceptible to penicillin, the authors concluded that the addition of dihydrostreptomycin with penicillin was of little benefit over penicillin alone (Ødegaard and Sviland, 2001). Bacterial cures rates were 60% or less and utilizing a very strict definition of complete recovery, recovery rates were 45% or less for the 3 groups compared. Likewise, in a New Zealand study IMM penicillin was equally effective as an IMM product with penicillin and dihydrostreptomycin (McDougall et al., 2007a). Progress does seem somewhat limited when the aforementioned studies are compared with a 1975 study of two IMM preparation that reported 58 and 61% cures (Faull and Ward, 1975).

Frequent Milk-out

There are no peer-reviewed articles that indicate that FMO is beneficial in the treatment of clinical mastitis. A 2004 study found no benefit and even suggested that FMO may be detrimental in obtaining clinical cures for environmental streptococci (Roberson et al., 2004). A more recent study reported that milking 4x as a supportive therapy for mild, moderate and severe antimicrobially treated mastitis cases cannot be recommended (Krömker et al., 2010b).

Anti-inflammatory therapy

Several studies have been conducted on the efficacy of anti-inflammatory therapy for cases of clinical mastitis without an overall consensus as to a consistent positive effect. Dascanio and others (1995) could find no significant benefit of either phenylbutazone or flunixin melamine when compared to a negative control for cows with acute toxic mastitis. A relatively recent study was conducted with meloxicam for mild clinical mastitis (McDougall et al., 2009b). While the authors reported no difference in treatment failures or milk yield, SCC was significantly lower in the meloxicam-tread group. Whether this lowered SCC is actually worthwhile is a matter for debate. A similar study conducted on moderate and or severe clinical mastitis cases is needed.

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