Treatment of clinical mastitis - CiteSeerX

19 downloads 0 Views 130KB Size Report
Mastitis is the most common reason for antimicrobial treatment of dairy cows ... 1998). Antimicrobials have been used to treat mastitis for more than fifty years, but.
This manuscript has been published in the IVIS website with the permission of the congress organizers. To return to the Table of Content click here or go to http://www.ivis.org

TREATMENT OF CLINICAL MASTITIS: LOCAL AND/OR SYSTEMIC? SHORT OR LONG? Satu Pyörälä University of Helsinki, Faculty of Veterinary Medicine, Dept of Clinical Veterinary Sciences, Saari, Finland [email protected]

1.

INTRODUCTION

Mastitis is the most common reason for antimicrobial treatment of dairy cows (Grave et al. 1999; Mitchell et al. 1998). Antimicrobials have been used to treat mastitis for more than fifty years, but consensus about the most efficient, safe, and economical treatment is still lacking. The concept of evidence based medicine has recently been introduced to veterinary medicine (Cockcroft & Holmes, 2003) and those principles should apply also to treatment of mastitis. The impact on public health should also be taken into account. The aim of this paper is to review current treatments of clinical mastitis during lactation and seek for evidence-based, best practice treatment recommendations for that common disease of dairy cattle. 2.

PHARMACOKINETIC AND PHARMACODYNAMIC CONSIDERATIONS

Pharmacokinetics of an antimicrobial substance greatly affects its suitability for mastitis treatment. Penetration of a substance into milk when administered parenterally or absorption and distribution throughout the udder when infused intramammarily depends on its main pharmacokinetic characteristics. These are lipid solubility, degree of ionization, extent of binding to serum and udder proteins, and the type of the vehicle (Prescott et al. 2000). Weak organic bases tend to accumulate in milk in the ionized form after parenteral administration and reach in milk concentrations higher than those in blood. On the contrary, concentrations of weak acids in milk are much lower than in blood. Pharmacokinetic studies have mostly been carried out in healthy cows, which complicates the situation. Pharmacodynamics of the substance is another aspect which should be considered. Susceptibility in vitro for the antimicrobial substance used is a prerequisite for treatment of infections, but efficacy in vitro does not guarantee efficacy in vivo. Antimicrobial resistance among mastitis pathogens has not yet emerged to a very high level, but geographical regions may differ in this respect (Lehtolainen et al. 2003; Erskine et al. 2004). The biggest problem is the widespread resistance of staphylococci, particularly S. aureus, to penicillin G (Güler et al. 2005; Olsen et al. 2006; Pitkälä et al. 2004). Coagulase-negative staphylococci tend to be more resistant than S. aureus and can WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

develop multiresistance (Pitkälä et al. 2004). Mastitis streptococci have remained susceptible for penicillin G, but emerging resistance to macrolides and lincosamides is possible (Erskine et al. 2004; Loch et al. 2005; Pitkälä et al. 2004). Antimicrobial susceptibility of coliform bacteria varies (Bengtsson et al. 2005; Lehtolainen et al. 2003; Morin et al. 1998), but antimicrobials are seldom beneficial in the treatment of coliform mastitis. Other environmental bacteria such as Enterococci are commonly resistant to several substances and respond poorly to all treatment (Pitkälä et al. 2004). Some studies have reported low correlation between cure rates of mastitis and results from susceptibility tests (Hoe & Ruegg, 2005). Poor relationship between treatment result of mastitis and in vitro susceptibility of the causing pathogen appears to be mostly typical for coliform mastitis (Pyörälä & Pyörälä, 1998; Pyörälä & Syväjärvi, 1987). The problem is that most breakpoint concentrations for in vitro susceptibility testing of animal pathogens have mainly been derived from human data (NCCLS, 2002). They do not take into account the pharmacokinetic aspects of ruminants and mammary gland. Using a β-lactamase test for determining resistance to penicillin G of staphylococci is one way to evade the problem (NCCLS 2002; Olsen et al. 2005). A novel approach to improve the accuracy of routine susceptibility tests of mastitis pathogens was recently suggested (Klement et al. 2005). Selecting a substance with a low MIC (minimum inhibitory concentration) value for the target pathogens is preferable, in particular if antimicrobials are used systemically (Prescott et al. 2000; Ziv, 1980). Antimicrobials can be divided in concentration-dependent and time-dependent drugs; in the first group (e.g. aminoglycosides and fluoroquinolones) concentrations of several magnitudes of the MIC of the target organisms at the infection site increase the efficacy, in the latter group (e.g. penicillins and macrolides) the efficacy depends on the time, during which the concentration exeeds MIC but high concentrations do not increase efficacy (Prescott et al. 2000). The antimicrobial should preferably have bactericidal action, as phagocytosis is impaired in the mammary gland (Kehrli & Harp, 2001). Milk should not interfere with the activity. Activity of macrolides, tetracyclines and trimethoprim-sulphonamides has been shown to be reduced in milk (Fang & Pyörälä, 1996; Louhi et al. 1992). 3.

INTRAMAMMARY TREATMENT

The most common route of the administration of antimicrobials in mastitis is the intramammary (IMM) route (Gruet et al. 2001). The advantages of this route are high concentrations of the substance achieved in the milk (Franklin et al. 1984, 1986; Moretain et al. 1989) and low consumption of the antimicrobial as the drug is directly infused into the diseased quarter. Disadvantages could be the uneven distribution of many substances throughout the udder (Ehinger et al. 2000; Ullberg et al. 1958), risk for contamination when infusing the product via the teat canal (Erskine, 2003), and possible irritation of the mammary tissue caused by the preparation. In addition, some earlier in vitro studies showed that antimicrobials may disturb phagocytosis when given IMM (Nickerson et al. 1986; Ziv et al. 1983), but clinical relevance of this finding is unknown. Many IMM products seem to have appeared to the market without supportive scientific data on the efficacy. Intramammary products with combinations of two or even three antimicrobials were introduced due to suggested synergistic action and broad spectrum. The evidence of their efficacy against clinical mastitis is many times lacking and synergistic action has never been proven in vivo (Taponen et al. 2003a; Whittem & Hanlon, 1997; Ødegaard & Sviland, 2001). The idea of intramammaries containing a combination of antimicrobials can be regarded outdated. The requirements for authorization of veterinary drugs have changed and efficacy claims must now be supported by scientific data. Very few new IMM products have however been authorized recently and only one product (for subclinical mastitis) via the centralized procedure in the European Union (Anon., 2006). WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

The efficacy of IMM treatment varies according to the causing pathogen. Best therapy response has been shown for mastitis caused by streptococci and coagulase-negative staphylococci (Davis et al. 1975; Deluyker et al. 1999; Taponen et al. 2003). Efficacy in clinical mastitis caused by S. aureus or some environmental pathogens has been unsatisfactory. Clinical cure rates have been lower than 60% and bacteriological cure rates as low as 10-40% (Deluyker et al. 1999; Guterbock et al. 1993; Knight et al. 2000). It is evident that bovine mammary gland is in general a difficult target for antimicrobial treatment, which is reflected in the low response of IMM treatments (Craven, 1987). 4.

SYSTEMIC TREATMENT

Systemic (parenteral) route of administration was introduced into mastitis therapy by Swedish and later Israeli authors (Ullberg et al. 1985; Ziv, 1980). It was suggested that systemic treatment would penetrate throughout the udder better and be more efficient than IMM treatment in therapy of mastitis. Systemic treatment of mastitis was widely adopted in the Nordic countries and this practice still continues (Ekman et al. 1994). However, the superiority of systemic treatment of mastitis over IMM treatment was never proven in comparative clinical trials. Pharmacokinetics of antimicrobials with systemic administration into adult ruminants is problematic (Prescott et al. 2000). It is difficult to achieve and maintain therapeutic concentrations in milk or udder tissue. Intravenous administration would in general produce higher concentrations in milk, but it is often unpractical in field conditions. The slowly absorbed antibiotic preparations for intramuscular use are the worst choice in mastitis, because they do not generally produce therapeutic concentrations in milk or tissues (Blanchflower, 1983; Prescott et al. 2000). One additional problem for the practitioner is that dosage recommendations of many antibiotic preparations for adult cattle may be too low regarding pharmacological aspects, but residue studies have been carried out using the approved dosages. Repeated intramuscular injections of large volumes of antibiotics can be irritating and cannot be recommended from the animal welfare point of view (Kaartinen et al. 1999; Pyörälä et al. 1994a). Very few substances have optimal pharmacokinetic and pharmacodynamic characteristics for systemic mastitis treatment. Even if the drug has ideal properties (Kaartinen et al. 1995; Sanders et al. 1992), the treatment results from clinical trials may still be disappointing, as in case of fluoroquinolones or macrolides. Commonly used broad-spectrum antibiotics, such as oxytetracycline and ceftiofur, have been tested for systemic mastitis treatment or prevention with no effect (Duenas et al. 2001; Erskine et al. 1996; Lents et al. 2002; Owens et al. 1999). Intramuscular ceftiofur does not attain therapeutic concentrations in the milk (Erskine et al. 1995). Published information on oxytetracycline is scant, but according to manufacturers’ data sheets, therapeutic concentrations can be achieved in milk using a dose of 10 mg/kg only against very susceptible bacteria (MIC ≤ 1 µg/ml). The same problem applies to trimethoprim-sulphonamide combinations, and very high dosing is necessary to reach therapeutic concentrations in milk (Kaartinen et al. 1999). Furthermore, the activity of oxytetracycline and trimethoprim-sulphonamides is decreased in milk (Fang & Pyörälä; Greko et al. 1999). Macrolides, which are narrow spectrum drugs with activity against Gram-positive bacteria only, would have ideal pharmacokinetics (Franklin et al. 1986). However they may have less favourable pharmacodynamics: they are bacteriostatic in action and milk interferes with their activity (Louhi et al. 1992). Good penetration into cells does not warrant intracellular killing of bacteria (Madgwick et al. 1989). These may be the reasons for the reported poor efficacy of macrolides in systemic treatment of clinical mastitis (Owens et al. 1999; Pyörälä & Pyörälä, 1998). One substance used for systemic treatment is penicillin G, which as weak acid penetrates poorly into mammary gland. Due to the very low MIC values of susceptible organisms, therapeutic WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

concentrations can be maintained in milk using the dose 20 mg/kg of penicillin G procaine (Franklin et al. 1984, 1986; Ziv & Storper, 1985). The claim dose however differs between countries (Hillerton & Cliem, 2002). Milk does not interfere with the activity of penicillin G (Louhi et al. 1992). Different systemic or combined regimens using penicillin G procaine have been tested in several trials (Funke, 1982; Jarp et al. 1989; Pyörälä & Pyörälä, 1998, Waage, 1997). Finally, the antimicrobial used for systemic treatment of mastitis must be approved for dairy cattle. The availability of substances on the market differs between countries. Currently many substances are used for that indication off-label and without proven efficacy (Zwald et al. 2004). For example, penicillin G procaine or fluoroquinolones are not approved for dairy cattle in USA. 5.

WHICH ROUTE OF ADMINISTRATION SHOULD BE SELECTED?

The ultimate question is if the antibiotic should accumulate in the milk or in the udder tissue (Table I) (Erskine, 2003). This may depend on the infection: mastitis streptococci are known to stay in the milk compartment, but S. aureus bacteria can penetrate into udder tissue and cause deep infection. Table I. Where to target antibiotic therapy in mastitis due to different pathogens (Erskine 2003) Str. Agalactiae Other streptococci S. aureus CNS Coliforms

Milk/ducts +++ +++ + +++ +

Udder tissue --+ +++ ----

Cow --------+++

Randomized comparative field trials using IMM vs parenteral treatment of mastitis with the same antimicrobial do not exist. In one study, IMM treatment was compared with combined treatment in experimental S. aureus mastitis. Different β-lactam substances were used, and no information about the penicillin susceptibility of the bacterial strain was available, so no conclusions can be drawn (Owens et al. 1988). In another study, treatment with parenteral penethamate hydroiodide was compared with IMM penicillin-dihydrostreptomycin treatment, and no difference was seen (McDougall, 1998). Penethamate is a more liphophilic penicillin G formulation and diffuses better than penicillin G procaine into milk (Ziv & Storper, 1985). As conclusion, it seems that the only type of mastitis where systemic treatment would be clearly advantageous is mastitis caused by S. aureus. This is also logical from a theoretical point of view as S. aureus causes a deep infection and penicillin G may distribute more evenly into infection focuses by the systemic administration (Erskine, 2003; Knight et al. 2000). S. aureus bacteria have many characteristics which make them difficult targets for antibiotic therapy (Sol et al. 2000). They can survive in the phagocyting cells. In mastitis caused by penicillin-susceptible S. aureus best results were achieved using combination of systemic and IMM treatment with penicillin G for 5 days (Taponen et al. 2003b). On the other hand, completing 5-day IMM penicillin G treatment of mastitis due to penicillin-susceptible S. aureus for 3 days with systemic penicillin did not increase cure rates as compared with only one additional systemic administration (Waage, 1997). Cure rates for mastitis caused by penicillin-resistant isolates seems to be inferior to those of mastitis due to penicillin-susceptible isolates (Pyörälä & Pyörälä, 1998; Sol et al 2000; Taponen et al. 2003b; Ziv & Storper 1985). It is not known if this is due to pharmacologic problems of the drugs used, or virulence factors possibly linked to β-lactamase gene of the resistant isolates (Haveri et al. 2005). In infections of the milk compartment such as streptococcal mastitis, there is probably no advantage of the systemic administration. For example concentration of penicillin G in milk remains after WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

systemic administration 100-1000 fold lower than when given IMM (Franklin et al. 1984; Moretain et al. 1989). Based on the results from separate studies, cure rates in streptococcal mastitis using IMM treatment are equal or even better than using systemic administration (Davis et al. 1975; Deluyker et al. 2005; Hillerton & Kliem, 2002; Pyörälä & Pyörälä, 1998; Taponen et al. 2003a; Waage 1997). In severe mastitis due to coliform bacteria, parenteral administration of antimicrobials has been suggested, due to the risk for bacteriaemia (Wenz et al. 2001). Generally, the efficacy of the antimicrobial treatment in coliform mastitis has been questioned as cure rates have been as high with or without antimicrobials or with drugs inefficient in vitro (Jones et al. 1990; Pyörälä et al. 1994b; Pyörälä & Syväjärvi, 1987). In serious E. coli mastitis with heavy growth of bacteria in the udder, use of systemic antimicrobial treatment can be beneficial, especially during the puerperal period when the defence mechanisms of the cow are compromised. Enrofloxacin, ceftiofur and cefquinome have shown efficacy in experimental or clinical trials (Dosogne et al. 2002; Erskine et al. 2002; Rantala et al. 2002; Shpigel et al. 1997). These substances belong to groups particularly important in human medicine, and animal use should be as restricted as possible (OIE 2006). So far there is no evidence about releasing massive amounts of endotoxin by using bactericidal antimicrobial treatment in E. coli mastitis (Dosogne et al. 2002). For a true comparison of local, systemic and combined antimicrobial treatment of mastitis, scientific studies should conducted where: • • • 6.

the bacterial isolates would be tested to be in vitro susceptible for the used antimicrobials, doses which would maintain therapeutic concentrations in the udder would be used systemically, and, the group size would be high enough for statistical comparison by bacterial species. DURATION OF TREATMENT

One reason for poor cure rates in mastitis therapy is probably the short duration of standard treatments. Unfortunately, many IMM preparations have very short treatment lengths in the approved claims. Scientific studies comparing different durations of treatment of clinical mastitis are very few. Some authors have recently built up models to study economical aspects of treatment of subclinical mastitis which possibly could also be used for clinical mastitis (Swinkels et al. 2005a, b). Mastitis caused by S. aureus is the biggest challenge in mastitis therapy (Knight et al. 2000). Some earlier studies have reported on better efficacy of a long treatment in S. aureus mastitis (Funke, 1982; Pyörälä & Syväjärvi, 1988; Ziv & Storper, 1985), and more recent studies have confirmed this (Deluyker et al. 2005; Pyörälä & Pyörälä, 1998). Also mastitis due to Streptococcus uberis has been shown to benefit from long duration of treatment (Milne et al. 2002; Oliver et al. 2005). Regarding other Gram-positive pathogens than S. aureus such as coagulase-negative staphylococci and other streptococci, treatment can probably be shorter both from efficacy and economical points of view (Deluyker et al. 2005, Pyörälä & Pyörälä 1998). This has been shown for subclinical mastitis by Swinkels et al. (2005a,b). All mastitis treatment should be evidence based i.e. the efficacy of each product and treatment length should be demonstrated in scientific studies. 7.

CONCLUSION

Treatment of clinical mastitis should be evidence based and take national (Table II) and international prudent use guidelines into account (Anon., 2003; OIE, 2005; FVE 1999). Antimicrobials should not be available for the farm personal but treatment decision and drug selection should be made by veterinarians. Treatment should be targeted towards the causing WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

bacteria whenever possible. In acute situations it is not possible, but treatment must be initiated based on herd data and personal experience. In clinical mastitis, rapid bacteriological diagnosis would facilitate the proper selection of the antimicrobial. Selective diagnostic media are available in many countries, which allow rapid (over-night) diagnosis (e.g. Selma selective agar, SVA, Uppsala, Sweden; ColiMast, ICP, Auckland, New Zealand). Recently, also a commercial, rapid PCR-based test for mastitis diagnostics has been launched to the market (PathoProof, Mastitis PCR Assay, Finnzymes Diagnostics, Espoo, Finland). When the bacteriological diagnosis is available, the treatment can be re-evaluated and targeted towards the specific pathogen (Leslie & Keefe, 1998). Table II. Recommendations for antimicrobial treatment of mastitis in Finland (Anon., 2003) Microorganism

Streptococci

Staphylococci

Coliforms

Species

Drug of choice

Alternative

Comments

Str. agalactiae dysgalactiae uberis

Penicillin G

IMM treatment preferable

Enterococci

According to susceptibility testing

Prognosis for bacteriological cure poor

Penicillin G

Combination treatment in S. aureus mastitis

S. aureus CNS ß-lactamase S. aureus CNS ß-lactamase + E. coli

Cloxacillin

Macrolides Lincosamides

Local and/or systemic treatment depending on the drug used

No antimicrobials

Enrofloxacin

Antimicrobials necessary in serious cases and during puerperal period

In principle, use of narrow-spectrum antimicrobials is preferable. First choice for mastitis due to streptococci and penicillin G susceptible staphylococci are β-lactam antibiotics, preferably penicillin G. Broad-spectrum antimicrobials such as 3rd or 4th generation cephalosporins should not be used as first alternatives for mastitis, as they may increase emergence of broad-spectrum βlactam resistance (Batchelor et al. 2005; Mayer et al. 1994). Systemic treatment is recommended in clinical mastitis due to S. aureus (in combination with IMM treatment) and severe coliform mastitis. Duration of treatment should be extended in mastitis caused by S. aureus and possibly S. uberis. Treatment results should be monitored using CMT and with bacteriological culturing when necessary (contagious mastitis). 8.

SUMMARY

This paper focuses on antimicrobial treatment of clinical mastitis during lactation. The recommendations how to treat clinical mastitis are based on published clinical studies and knowledge on pharmacokinetics and pharmacodynamics of the antimicrobial substances. Treatment of mastitis should be evidence-based and take prudent use guidelines for antimicrobial treatment of animals into account. Before treatment, an aseptic milk sample should always be taken for bacteriological examination. Diagnostic tests are available in many countries, which allow a rapid bacteriological diagnosis. In principle, use of narrow-spectrum antimicrobials is preferable and recommended in the prudent use guidelines. If the causing agent is susceptible for penicillin G, it should be used in the treatment. In mastitis due to S. aureus, resistance to penicillin G may be a problem. Mastitis caused by streptococci and coagulase-negative staphylococci is recommended to be treated intramammarily and the cure rates are generally high. S. aureus mastitis due to penicillinsusceptible strain can be treated with concomitant intramammary and parenteral treatment to increase therapy response. In coliform mastitis, parenteral antimicrobial treatment is recommended for cows with severe clinical signs and high number of bacteria in the milk. The duration of antimicrobial treatment is normally from 3 to 5 days and the longest in mastitis caused by S. aureus WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

or S. uberis. Treatment response should be followed-up using CMT and bacteriological culturing when necessary. 9.

KEY WORDS

Mastitis, clinical, treatment, antimicrobials, intramammary, systemic, prudent use. 10.

REFERENCES

Anonymous. Use of antimicrobial agents in animals. Report of the working group on antimicrobial agents. Ministry of Agriculture and Forestry in Finland. MAFF Publications 9, 2003. http://www.mmm.fi/julkaisut/tyoryhmamuistiot/2003/tr2003_9a.pdf. Last accessed February 20, 2006. Anonymous. http://www.emea.eu.int/index/indexv1.htm. Last accessed February 20, 2006. Blanchflower SE. Antibiotic concentrations in milk from normal endotoxin challenged and mastitic quarters of cows after parenteral dosing with amoxycillin. Abstract. Vet Res Commun, 1983; 7:259-260. Batchelor M, Clifton-Hadley FA et al. Detection of multiple cephalosporin-resistant Escherichia coli from a cattle fecal sample in Great Britain. Microb Drug Resist, 2005, 11:58-61. Bengtsson B, Unnerstad H et al. Prevalence and antimicrobial susceptibility of bacteria causing acute clinical mastitis in dairy cows in Sweden 2002-2003. In: Mastitis in dairy production. Current knowledge and future solutions (Ed. Hogeveen H). 4th IDF International Mastitis Conference, 2005. Cockcroft P, Holmes M. Evidence-based veterinary medicine. Blackwell Publishing, Oxford, UK, 2003. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical mastitis during lactation. A review. Br Vet J, 1987; 143:410-422. Davis WT, Maplesden DC et al. Sodium cloxacillin for treatment of mastitis in lactating cows. J Dairy Sci, 1975; 58:1922-1927. Deluyker HA, Chester ST et al. A multilocation clinical trial in lactating dairy cows affected with clinical mastitis to compare the efficacy of treatment with intramammary infusions of a lincomycin/neomycin combination with an ampicillin/cloxacillin combination. J Vet Pharmacol Therap, 1999; 22:274-282. Deluyker HA, Van Oye SN et al. Factors affecting cure and somatic cell count after pirlimycin treatment of subclinical mastitis in lactating cows. J Dairy Sci, 2005; 88:604-614. Dosogne H, Meyer E et al. Effect of enrofloxacin treatment on plasma endotoxin during bovine Escherichia coli mastitis. Inflammation Res, 2002; 51:201-205. Duenas MI, Paape MJ et al. Incidence of mastitis in beef cows after intramuscular administration of oxytetracycline. J Anim Sci, 2001; 79:1996-2005. Ehinger AM, Kietzmann M. Tissue distribution of oxacillin and ampicillin in the isolated perfused bovine udder. J Vet Med, 2000; A. 47:157-168. Ekman T, Åström G et al. Measures taken by veterinarians in Sweden in cases of bovine mastitis. Acta Vet Scand, 1994; 35:329-335 Erskine RJ. Antibacterial therapy of clinical mastitis - part I. Drug selection. Part II Administration. North Am Vet Conf, 2003:13-16. Erskine RJ, Barlett PC et al. Intramuscular administration of ceftiofur sodium vs intramammary infusion of penicillin/novobiocin for treatment of Streptococcus agalactiae mastitis in dairy cows. JAVMA, 1996; 208:258-260. Erskine RJ, Barlett PC et al. Efficacy of systemic ceftiofur for severe clinical mastitis in dairy cattle. J Dairy Sci, 2002; 85:2571-2575.

WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

Erskine RJ, Cullor J et al. Bovine mastitis pathogens and trends in resistance to antibacterial drugs. NMC Annual Meeting, 2004; 400-414. Erskine RJ, Wilson RC et al. Ceftiofur distribution in serum and milk from clinically normal cows and cows with experimental Escherichia coli -induced mastitis. Am J Vet Res, 1995; 56:481-486. Fang W, Pyörälä S. Mastitis causing Escherichia coli: serum sensitivity and susceptibility to selected antibacterials in milk. J Dairy Sci, 1996; 79:76-82. Franklin A, Holmberg O et al. Effect of procaine benzylpenicillin alone or in combination with dihydrostreptomycin on udder pathogens in vitro and in experimentally infected bovine udders. J Am Vet Res, 1984; 45:1398-1402. Franklin A, Horn af Ranzien M et al. Concentrations of penicillin, streptomycin, and spiramycin in bovine udder tissue liquids. J Am Vet Res, 1986; 47:804-807. Funke H. Practical experiences in the treatment of clinical mastitis, Proc Symp Mast, 1982; Proc. 1-2. Grave T, Greko C et al. The usage of veterinary antibacterial drugs for mastitis in cattle in Norway and Sweden during 1990-1997. Prev Vet Med, 1999; 42:45-55. Greko C, Bengtsson B et al. Efficacy of trimethoprim-sulfadoxine against Escherichia coli in a tissue cage model in calves. J Vet Pharmacol Therap, 2002; 25:413-423. Gruet P, Maincent P, et al. Bovine mastitis and intramammary drug delivery: review and perspectives. Adv Drug Deliv Rev, 2001; 50: 245-259. Güler L, Ok Ü et al. Antimicrobial susceptibility and coagulase gene typing of Staphylococcus aureus isolated from bovine clinical mastitis cases in Turkey. J Dairy Sci, 2005; 88:3149-3154 Guterbock WM, van Eenennaam AL et al. Efficacy of intramammary antibiotic therapy for treatment of clinical mastitis caused by environmental pathogens. J Dairy Sci, 1993; 76:3437-3444. Haveri M, Roslöf A et al. Toxin genes of Staphylococcus aureus isolated from bovine intramammary infection of different clinical characteristics and outcome. In: Mastitis in dairy production. Current knowledge and future solutions (Ed. Hogeveen H). 4th IDF Int Mastitis Conf, 2005:149-154. Hillerton JE, Kliem KE. Effective treatments of Streptococcus uberis clinical mastitis to minimize the use of antibiotics. J Dairy Sci, 2002; 85:1009-1014. Jarp J Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for bovine mastitis. Vet Rec, 1989; 124: 630634. Jones GF, Ward GE. Evaluation of systemic administration of gentamicin for treatment of coliform mastitis in cows. JAVMA, 1990; 197:731-735. Kaartinen L, Löhönen K et al. Pharmacokinetics of sulphadiazine-trimethoprim in lactating dairy cows. Acta Vet Scand, 1999; 40:271-278. Kaartinen L, Salonen M et al. Pharmacokinetics of enrofloxacin after single intravenous, intramuscular and subcutaneous injections in lactating cows. J Vet Pharm Ther, 1995; 18:357-362. Kehrli M, Harp J. Immunity in the mammary gland. Vet Clin North Am Food Anim Pract, 2001; 17:495-516. Klement E, Chaffer M et al. Assessment of accuracy of disk diffusion tests for the determination of antimicrobial susceptibility of common bovine mastitis pathogens: a novel approach. Microbiol Drug Resist, 2005; 11:342-350. Knight CH, Fitzpatrick JL et al. Efficacy of two non-antibiotic therapies and topical liniment, against bovine staphylococcal mastitis. Vet Rec, 2000; 146:311-316. Lehtolainen T, Shwimmer A et al. In vitro antimicrobial susceptibility of Escherichia coli isolates originating from clinical mastitis in Finland and Israel. J Dairy Sci, 2003; 86:3927-3932. Lents CA, Wettemann RP et al. Efficacy of intramuscular treatment of beef cows with oxytetracycline to reduce mastitis and to increase calf growth. J Anim Sci, 2002; 80:1405-1412.

WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

Leslie K, Keefe G. Decision-making in clinical mastitis therapy programmes. IDF Bull, 1998; 330:21-22. Louhi M, Inkinen K et al. Relevance of sensitivity testings (MIC) of S. aureus to predict the antibacterial action in milk. J Vet Med B, 1992; 39:253-262. Madgwick L, Mayer S, Keen P. Penetration of antibiotics into bovine neutrophils and their activity against Staphylococcus aureus. J Antimic Chemother, 1989; 24:709-718. Mayer KH, Opal SM et al. Mechanisms of antibiotic resistance. In: Mandell et al. (Eds.), Principles and practice of infectious diseases. 4th ed. Churchill Livingstone, New York, 1994:212-225. McDougall SM. Efficacy of two antibiotic treatments in curing clinical and subclinical mastitis in lactating dairy cows. NZ Vet J, 1998; 46:226-232. Milne MH, Barrett DC et al. Prevalence and treatment of persistent Streptococcus uberis intramammary infections. XXII th WBC, 2002:Abstracts, 135. Mitchell JM, Griffiths MW et al. Antimicrobial drug residues in milk and meat: causes, concerns, prevalence, regulations, tests and test performance. J Food Prot, 1998; 61:742-756. Moretain JP, Boisseau J. Excretion of penicillins and cephalexin in bovine milk following intramammary administration. Food Add Contamin, 1989; 6:79-90. Morin DE, Shanks RD, McCoy GC. Comparison of antibiotic administration in conjunction with supportive measures vs supportive measures alone for treatment of dairy cows with clinical mastitis. JAVMA, 1998; 213:676-684. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; approved standard. 2 nd ed. NCCLS document M31-A2, 2002. Nickerson SC, Paape MJ et al. Mammary leukocyte response to drug therapy. J Dairy Sci, 1986; 69:1733-1742. OIE. Guidelines on the responsible and prudent use of antimicrobial agents in veterinary medicine. http://www.oie.int/eng/normes/mcode/en_chapitre_3.9.3.htm. Last accessed February 20, 2006. Oliver SP, Almeida RA et al. Extended ceftiofur therapy for treatment of experimentally-induced Streptococcus uberis mastitis in lactating dairy cattle. J Dairy Sci, 2004; 87:3322-3329. Olsen JE, Christensen H et al. Diversity and evolution of blaZ from Staphylococcus aureus and coagulase-negative staphylococci. J Antimicr Chemother, 2006; 57:450-460. Owens WE, Nickerson SC, Ray CH. Efficacy of parenterally or intramammarily administered tilmicosin or ceftiofur against Staphylococcus aureus mastitis during lactation. J Dairy Sci, 1999; 82:645-647. Owens WE, Watts JL et al. Antibiotic treatment of mastitis: Comparison of intramammary and intramammary plus intramuscular therapies. J Dairy Sci, 1988; 71:3143-3147. Pitkälä A, Haveri M et al. Bovine mastitis in Finland 2001. Prevalence, distribution of bacteria and antimicrobial resistance. J Dairy Sci, 2004; 87:2433-2441. Prescott JF, Baggot JD, Walker RD. Antimicrobial therapy in veterinary medicine. 3 rd ed. Iowa State University Press, Ames, Iowa. 2000. Pyörälä S, Manner E et al. Local tissue damage in cows after intramuscular injections of eight different antimicrobial agents. Brief communication. Acta Vet Scand, 1994a; 35:107-110. Pyörälä S, Kaartinen L et al. Efficacy of Two Therapy Regimes for Treatment of Experimentally Induced Escherichia coli Mastitis in the Bovine. J Dairy Sci, 1994b; 77:453-461. Pyörälä S, Pyörälä E. Efficacy of parenteral administration of three antimicrobial agents in treatment of clinical mastitis in lactating cows: 487 cases (1989-1995). JAVMA, 1998; 212:407-412. Pyörälä S, Syväjärvi J. Bovine acute mastitis. Part II. Effect of mastitis pathogen, initial inflammatory reaction and therapy on the outcome of the disease. J Vet Med B, 1988; 34:629-639

WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE

Rantala M, Kaartinen L et al. Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally induced Escherichia coli mastitis. J Vet Pharm Therap, 2002; 25:251-258. Sanders P, Moulin G et al. Pharmacokinetics of spiramycin after intravenous, intramuscular and subcutaneous administration in lactating cows. J Vet Pharm Therap, 1992; 15:53-61. Shpigel NY, Levin D et al. Efficacy of cefquinome for treatment of cows with mastitis experimentally induced using Escherichia coli. J Dairy Sci, 1997; 80:318-323. Sol J, Sampimon OC et al. Factors associated with cure after therapy of clinical mastitis caused by Staphylococcus aureus. J Dairy Sci, 2000; 83:278-284. Swinkels JM, Hogeveen H et al. A partial budget model to estimate economic benefits of lactational treatment of subclinical Staphylococcus aureus mastitis. J Dairy Sci, 2005a; 88:4273-4287. Swinkels JM, Rooijendijk JGA et al. Use of partial budgeting to determine the estimate economic benefits of antibiotic treatment of chronic subclinical mastitis caused by Streptococcus uberis or Streptococcus dysgalactiae. J Dairy Res, 2005b; 72:75-85. Taponen S, Dredge K et al. Efficacy of intramammary treatment with procaine penicillin G vs. procaine penicillin plus neomycin in bovine clinical mastitis caused by penicillin-susceptible, gram-positive bacteria - a double blind field study. J Vet Pharm Therap, 2002; 26:193-198. Taponen S, Jantunen A et al. Efficacy of targeted 5-day parenteral and intramammary treatment of clinical Staphylococcus aureus mastitis caused by penicillin-susceptible or penicillin-resistant bacterial isolate. Acta Vet Scand, 2003; 44:53-62. Timms L. Evaluation of recommended and extended pirlimycin mastitis therapy for recent and chronic high SCC cows in two herds. Proc 37thAnnual NMC Meeting, 1998:271-272. Ullberg S, Hansson E, Funke H. Distribution of penicillin in mastitic udders following intramammary injection. an autoradiographic study. Am J Vet Res, 1958; 19:84-92 Waage S. Comparison of two regimens for the treatment of clinical bovine mastitis caused by bacteria sensitive to penicillin. Vet Rec, 1997; 141:616-620. Wagner SA, Apley MD. Pharmacodynamics of isoflupredone acetate in an endotoxin-induced mastitis model. J Dairy Sci, 2003; 86:792-798. Wenz JR, Barrington GM et al. Bacteremia associated with naturally occurring acute coliform mastitis in dairy cows. JAVMA, 2001; 219:976-981. Whittem T, Hanlon D. Dihydrostreptomycin or streptomycin in combination with penicillin in dairy cattle therapeutics: A review and re-analysis of published data, Part 1: Clinical pharmacology. NZ Vet J, 1997; 45:178-184. Ziv G. Drug selection and use in mastitis: systemic vs. local therapy. JAVMA, 1980; 176:1109-1115. Ziv G, Storper M. Intramuscular treatment of subclinical staphylococcal mastitis in lactating cows with penicillin G, methicillin and their esters. J Vet Pharm Therap, 1985; 8:276-283. Ziv G, Paape MJ, Dulin MT. Influence of antibiotics and intramammary antibiotic products on phagocytosis of Staphylococcus aureus by bovine leukocytes. Am J Vet Res, 1983; 44:385-388 Zwald, AG. Ruegg PL et al. Management practices and reported antimicrobial usage on conventional and organic dairy farms. J Dairy Sci, 2004; 87:191-201. Ødegaard S, Sviland S. Comparison of intramammary antibiotic preparations for the treatment of clinical bovine mastitis caused by bacteria sensitive to penicillin. Proc 2nd Int Symp Mast Milk Quality, 2001:502-503.

WORLD BUIATRICS CONGRESS 2006 - NICE, FRANCE