Treatment of Mild and Moderate Cases of Clinical Mastitis

TREATMENT OF CLINICAL MASTITIS CAUSED BY STREPTO­COCCI AND STAPHYLOCOCCI. The effectiveness and selection of antibiotic therapy depend on the pathogen causing clinical mastitis. Cows with cases of mild (severity score 1) or moderate (severity score 2) clinical mastitis and no bacterial growth in the milk are unlikely to benefit from antibiotic therapy, as are cows with a low concentration of E.

On the other hand, antimicrobial drugs can enhance resolu­tion of many cases of streptococcal or staphylococcal mastitis episodes. The prototype for therapeutic success is treatment of IMI caused by S. agalactiae. This organism tends to be highly susceptible to intramammary therapy with β-lactam drugs, with cure rates of 85% to 90% often reported.^196,241 This organism is essentially an obligate udder pathogen in dairy cattle, remains superficial in mammary tissue, and has a high level of susceptibility to therapy. Thus S. agalactiae can essentially be eradicated from a herd by simultaneously treating all infected cows, including those with subclinical infections.^241,413 This can be economical for a dairy, but only if proper prevention programs (e.g., postmilking teat dipping, dry cow treatment) are in place to prevent new infections after herd treatment.¹⁹³ For this and other gram-positive pathogens, systemic administra­tion of antimicrobial drugs is not likely to attain any better cure rates than intramammary infusions.

Therapeutic efficacy of other gram-positive cocci, with the exception of S.

Several studies have described the potential benefits of extended intramammary therapy (beyond the traditional two doses) for the treatment of mastitis caused by streptococci and S. aureus.^416-418 This may be appropriate from a pharmacodynamic standpoint as all antimicrobial drugs that are labeled for intra­mammary use in dairy cattle (U.S.) rely on time-dependent inhibition of bacterial growth. Thus inhibitory action of the drug is more likely to be efficacious if the concentration of the drug is maintained above the MIC for extended periods at the site of infection as opposed to at peak concentrations. Experimental S. uberis infections treated for 2, 5, or 8 days (q24h) with intramammary ceftiofur attained bacterial cures in 43%, 88%, and 100% of the infections, respectively.⁴¹⁹ Similar results were obtained for chronic streptococcal and S.

The decision to use extended therapy as part of a herd mastitis therapy protocol should be made carefully and when possible should be based on microbiological diagnosis (see the On-Farm Culture section earlier). The success of therapy with conventional dosing should first be considered. If deemed to be unsatisfactory, especially as indicated by high rates of relapses after therapy, extended therapy may be a viable choice. To date, the benefits of extended therapy have best been determined for infections caused by streptococci and S. aureus. One study has determined that extended treatment of mild cases of clinical mastitis caused by a variety of coliform bacteria increased bacteriologic cures and reduced culling but did not influence posttreatment milk yield or SCC, although the outcomes were highly herd dependent.⁴²¹ Furthermore, the ability of the herd personnel to perform aseptic infusions into the teat canal is critical. Extended therapy is associated with an increased risk of infection from opportunistic pathogens, and herds with poor infusion techniques are not good candidates for multiple doses of intramammary tubes.

S. aureus intramammary infections often result in deep-seated abscesses. Therapy is difficult, especially as resistance to antibacterials (particularly β-lactams) is more common as compared to streptococci, and S. aureus may survive intracel­lularly following phagocytosis where antibacterial concentrations are reduced.⁴⁰⁰ In addition, S.

Experimentally induced S. aureus IMI has a reported cure rate of 25% to 55% of infected quarters when evaluated 21 to 60 days after infection. However, natural infections are usually of longer duration before detection and subsequent therapy and thus more refractive to therapy. The importance of duration of infection was evident in a study that determined that intramammary penicillin and novobiocin cured 70% in quarters that had been infected for 14 days or less as compared to only 35% in chronically infected quarters.⁴²² Similarly, Barkema and colleagues⁴²³ reported a wide variation in the success of therapy, near 60% in younger, newly infected animals as opposed to less than 5% in older animals with chronic infections. Even modest results of efficacy reported in the literature may be optimistic, as relapses occurring more than 30 days after treatment are common.⁴²⁰ This not only reaffirms the difficulty in attaining successful therapy but also suggests a poor correlation between in vitro culture and susceptibility and therapeutic outcome in chronic IMI caused by this organism.⁴²⁴

Consequently, combinations of parenteral and intramammary treatment regimens have been advocated to eliminate a higher proportion of S. aureus infections. In experimental infections in lactating cows, the combined use of intramuscular procaine penicillin G and intramammary amoxicillin achieved a better cure rate (18 of 35 infected quarters) than intramammary amoxicillin did alone (10 of 40 infected quarters).⁴²⁵ Dry cows with S. aureus IMI had improved cure rates when administered 11 mg/kg IM every 24 hours of oxytetracycline in addition to intramammary antibacterials as compared to cows administered intramammary infusions only.⁴²⁶ Other studies have not found any benefit from systemic antimicrobial use to eliminate chronic infections caused by S.

USING BACTERIOLOGY AS A CRITERION FOR THERAPY. Microbial culture of milk is a practical tool to identify caus­ative agents and the foundation to better target therapeutic regimens for mastitis. A multistate study demonstrated that culture-based therapy of gram-positive and mixed isolates only, as compared to empirical therapy of all mild mastitis cases, reduced antimicrobial use by 50%.^155,163,166 Furthermore, no differences were found between mastitis cases that were assigned to the empirical therapy or culture-based treatment program in terms of recurrence of clinical mastitis (35% versus 43%), linear SCC (4.2 versus 4.4), daily milk production (30.0 kg versus 30.7 kg), and culling or death (28% versus 32%) for the rest of the lactation after the clinical mastitis case. This concept was further supported by a more recent study that found no significant differences existed between cows administered empirical therapy and culture-based therapy in days to clinical cure, milk production, survival in herd, or SCC.⁴²⁹

Thus selective treatment of mild clinical mastitis based on culture results does not affect long-term outcomes but does decrease antibiotic use.

TREATMENT OF SEVERE CLINICAL MASTITIS. Clinical mas­titis cases that include systemic involvement are considered severe (severity score 3).²⁰⁵ Coliform organisms are the most common cause of severe mastitis in most dairy herds and are the common cause of cases that result in the loss of a cow from death or agalactia (see Tables 36.1 and 36.2).^6,430 Thus primary therapy for severe clinical mastitis should be directed against coliform organisms, although secondary consideration must be given to other pathogens. From a cow-side appraisal, treatment of severe clinical mastitis is a forced decision (i.e., empirical treatment is indicated). Although the basis for antimicrobial therapy is knowledge of the causative pathogen, this is not attainable for some hours after initial case recognition, and thus the practical problem is to design a therapeutic regimen on clinical impression. In addition, systemic antimicrobial therapeutic regimens currently are not labeled by the U.S. Food and Drug Administration (FDA). As a result, veterinarians often formulate therapeutic management of severe mastitis using extralabel drugs.

Experimental challenge models have clarified much of the pathophysiology of mastitis resulting from infection with 99263387

gram-negative organisms.⁹⁹,²⁶³,³⁸' Following infection, bacterial numbers in milk rapidly increase, and depending on the size of the challenge, peak bacterial concentrations in milk often occur within a few hours. Typically, a subsequent rapid decline in bacterial concentration follows neutrophil migration into the gland. Though often severe, experimental IMI caused by E. coli usually clears spontaneously and rarely is more than 10 days in duration. The resulting inflammation and leukocytosis in the affected quarter may persist for several weeks, or the quarter may become agalactic, despite the inability to isolate bacteria on culture. Although useful for determining the pathogenesis of coliform IMI, experimental challenge models should not be universally applied for therapeutic decisions. Most challenge infections do not include recently calved cows, use strains of bacteria that may not be as virulent as some of the wild types of pathogens, and are generally not administered if other possible immune stressors (metabolic or heat) are present. All of these variables could reduce the severity of clinical outcome for experimental as compared to natural infections. In addition, herd factors such as nutrition and housing can affect the outcome of naturally occurring infections, and host-adapted strains that may persist in affected cows have

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been identified.²⁸²

Many of the inflammatory and systemic changes that occur during severe coliform mastitis result from the release of LPS from the bacteria, which is released from the bacterial cell wall following phagocytosis and killing by neutrophils. As mentioned in the Mammary Inflammation section, LPS is a potent stimulator of the inflammatory cytokine response through the action of TLRs.^431-434 This results in subsequent activation of the cyclooxygenase and lipoxygenase pathways, releasing prostaglandins, leukotrienes, and thromboxanes, compounds that are potent mediators of local inflammatory and systemic circulatory events.⁶⁷ Also, endotoxin-induced cytokines, such as IL-1 and TNF-α, initiate a wide range of systemic responses, including fever, leukocytosis, protein synthesis and release by hepatocytes, and serum iron sequestration, collectively termed the acute phase response.^433,435,436 Although LPS concentration in the milk may be high, LPS is usually nearly undetectable in plasma.⁴³⁷ This suggests that the fever, tachycardia, reduced rumen motility, and signs of shock that accompany severe coliform mastitis are not a consequence of endotoxemia but production and absorption of inflammatory mediators, such as TNF-α. The concentration of TNF-α in milk is positively correlated with coliform mastitis severity, and a high concentra­tion of TNF-α in blood is seen only in severe responders.^87,266,438 Hematologic and plasma biochemical changes that often accompany clinical coliform mastitis include leukopenia (neutropenia, lymphopenia, monocytopenia), hypocalcemia, and reductions in plasma concentrations of zinc, copper, and iron.²⁶⁸

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 severe coliform infections cannot begin until clinical signs appear. Clinical recognition of coliform mastitis usually occurs after peak bacterial numbers have been attained. Thus by the time therapy is initiated, maximal release of LPS has likely occurred. This raises concerns regarding the advantages of antibacterial therapy in alleviating the effects of acute coliform mastitis. Thus the primary therapeutic concern is the treatment of endotoxin-induced shock with fluids, and other supportive care.

Antibacterial therapy may be of secondary importance relative to immediate supportive treatment of endotoxic shock, but it remains an integral part of a therapeutic regimen for severe mastitis. Because of low MIC for gram-negative rods relative to other antimicrobials, aminoglycosides were consid­ered for many years to be a drug of choice for coliform mastitis. However, cows experimentally challenged with E. coli and dosed with 500 mg of intramammary gentamicin q12h 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.⁴³⁹ In addition, gentamicin readily diffused through the milk-blood barrier as indicated by detectable concentrations in serum throughout the treatment period and the first 12 hours after the last dose. Consequently, urine gentamicin concentrations were detectable 14 days after the last infusion, and gentamicin concentrations of 1 μgλg in renal tissue were detected in cows 6 months after the trial.⁴³⁹ As well, intramuscular gentamicin was not more efficacious in preventing agalactia or death resulting from severe coliform mastitis or in improving other clinical outcomes, as compared to cows receiving intramuscular erythromycin or no systemic antimicrobial therapy.⁴⁴⁰

Considering the lack of efficacy in controlled studies, increased sophistication of drug residue testing among regula­tory agencies, zero tolerance for residues in renal tissue of culled cows, the 30- to 45-day half-life for clearance in the bovine kidney, and extended milk withdrawal periods after use of aminoglycosides, the use of this class of drugs in adult dairy cattle has little merit.

Seminal research from Colorado found that bacteremia occurs in nearly half of severe coliforms cases and increases with the severity of the clinical signs.^313,441 Numerous pathogens, in addition to mammary-derived coliforms, that are likely opportunistic invaders from the respiratory and gastrointestinal tract were also isolated from blood.³¹³ This is likely a conse­quence of the profound neutropenia that occurs in many severe coliform cases.²⁶⁸ Cows that remain neutropenic for 4 or more days, or that have high metamyelocyte and myelocyte concentra­tions in their blood, are more likely to be bacteremic than cows with a normalizing leukon.⁴⁴¹ Bacteremia suggests a poor prognosis, and these cows are at greater risk of death or culling.³¹³ Thus a primary target of antimicrobial therapy for severe coliform mastitis should be highly perfused tissue and the selection of drugs that remain in the plasma compartment and have low MIC for gram-negative rods.

Three doses of parenteral sulfadiazine-trimethoprim failed to achieve clinical improvement in experimental E. coli infec­tions.⁴⁴² However, three intramuscular doses of cefquinome, a fourth-generation cephalosporin that has better distribution into mammary tissue than sulfonamides, was found to improve clinical outcome of experimentally infected cows as compared to use of cloxacillin or ampicillin.⁴⁴³ Further research confirmed the possible benefits of systemic antimicrobial administration; intravenous oxytetracycline improved the clinical outcome of cows with coliform mastitis (not necessarily severe) as compared to cows that did not receive systemic antibacterials.⁴⁴⁴ Ceftiofur sodium, a third-generation cephalosporin, has been reported to have excellent activity against gram-negative pathogens, with a suggested MIC for E. coli of 0.25 to 1.0 μg^L. Mammary tissue and milk concentrations of ceftiofur following systemic treatment remain below these concentrations, and treatment of mild clinical mastitis caused by coliform organisms with systemic ceftiofur did not affect clinical or bacteriologic outcome, probably due to the poor distribution of β-lactams into the mammary gland following systemic administration.^445,446

However, in a study of naturally occurring cases in Michigan, cows with severe coliform mastitis that were administered intramuscular ceftiofur at a dose of 2.2 mg/kg once per day for 5 days were three times less likely to be lost from the herd and had significantly higher marketed milk than cows not receiving systemic antimicrobial therapy.⁴³⁰ This strongly emphasizes the inclusion of bacteremia in therapeutic consid­erations for severe coliform mastitis.

Intramammary antimicrobial therapy should be administered for most severe mastitis cases, at least until bacterial culture results are determined. Numerous severe mastitis cases are caused by gram-positive cocci and can be difficult to distinguish from cases caused by coliforms at initial presentation. Chronic IMI caused by pathogens such as S. aureus can become acutely gangrenous at times of neutropenic dysfunction such as parturi- tion.⁸⁶ Bacterial culture of cases can also help to identify other causative agents that are not likely to respond to antimicrobial therapy, including M. bovis, mycotic organisms, and Prototheca spp. Severe, overwhelming IMI that leads to bacteremia can occur from S. marcescens, P. aeruginosa, and Bacillus cereus.

Thus therapeutic regimens for severe clinical mastitis should (1) administer supportive care, especially for those cows display­ing shock; (2) target antibacterial therapy to maintain effective concentrations in plasma with a drug that has a broad spectrum of activity; and (3) administer intramammary antibacterial drugs to reduce the effects of a gram-positive IMI, unless bacteriologic results suggest otherwise.