A Comprehensive Review on Pharmacotherapeutics of Bovine mastitis  

Chirag M Modi , Hitesh B Patel , H B Patel , Shailesh K Mody
Department of Pharmacology & Toxicology, College of Veterinary Science & Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Gujarat, India
Author    Correspondence author
Molecular Microbiology Research, 2012, Vol. 2, No. 1   doi: 10.5376/mmr.2012.02.0001
Received: 29 Oct., 2012    Accepted: 05 Nov., 2012    Published: 25 Dec., 2012
© 2012 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Modi et al., 2012, A Comprehensive Review on Pharmacotherapeutics of Bovine Mastitis, Molecular Microbiology Research, Vol.2, No.1 1-9 (doi: 10.5376/mmr.2012.02.0001)

Abstract

In 1926 land has first time reported records of mastitis in India. Mastitis is defined as inflammatory reaction of parenchyma of mammary gland that can be of infectious, traumatic or toxic nature. Mastitis is one the most prevalent disease of dairy animals characterized by pathological changes in glandular tissues of udder and physical, chemical and microbiological changes in milk. More than 100 different microorganisms can cause mastitis, and these vary greatly in the route by which they reach the cow and the nature of the disease they cause. The disease is most common cause of antimicrobial agent use on dairy farms. In USA one study has indicated 82% of antibiotic residue violations were related to the treatment of mastitis. In on basis of effects on productivity, international trade animal warfare and zoonotic risk mastitis was ranked highest above all other infectious diseases such as salmonellosis, Para tuberculosis and bovine viral diarrheoa. The present paper describes the detailed account of antimicrobial use and treatment decisions for mastitis in bovine include the return of the cow to normal milk production and composition, prevention of mortality in peracute cases, elimination of infectious microorganisms, and elimination of practices that may lead to drug residues in milk or meat.

Keywords
Pharmacotherapeutics; Bovine; mastitis

1 Introduction
Mastitis is one the most prevalent disease of dairy animals characterized by pathological changes in glandular tissues of udder and physical, chemical and microbiological changes in milk (Prasad, 2000). Mastitis is defined as inflammatory reaction of parenchyma of mammary gland that can be of infectious, traumatic or toxic nature (International dairy federation, 1987). The disease is most common cause of antimicrobial agent use on dairy farms (Erskine, 2000). In USA one study has indicated 82% of antibiotic residue violations were related to the treatment of mastitis (Reneau, 1993). In 1926, land has first time reported records of mastitis in India. On basis of effects on productivity, international trade animal warfare and zoonotic risk mastitis was ranked highest above all other infectious diseases such as salmonellosis, Para tuberculosis and bovine viral diarrheoa (Wells et al., 1998).

Effective and economical mastitis control programs rely on prevention rather than treatment. Herds practicing mastitis prevention produce higher quality milk at less cost than herds that do not. Nonetheless, therapeutic intervention is an important part of a control program for bovine mastitis. This describes the strategies of therapy for bovine mastitis, with an emphasis on antibacterial and anti-inflammatory therapy. The concept of administering intramammary infusions of antiseptic solutions as a treatment for mastitis caused by infectious agents has been present for at least a century.

Widespread availability and use of antibacterials in animal agriculture in the 1950s cultivated the development of a wide variety of commercial products for intramammary infusion in the 1960s and 1970s. Initial successes suggested 75% efficacy (cures) in both lactating and dry-cow formulations; however, there has been growing skepticism that in many cases, therapeutic reality falls short of expectations. Chronic intramammary infections (IMI) with extensive fibrotic change caused by pathogens such as Staphylococcus aureus pose difficult therapeutic problems. It is unlikely that typical labeled-dose regimens, despite providing antibacterial concentrations above minimal inhibitory concentrations (MIC) in milk for 24 to 48 hours, will eliminate the pathogen from infected mammary glands. In addition, the major developmental thrust for antibacterials as a treatment for mastitis has been directed against gram-positive organisms, particularly staphylococci and streptococci. Many herds, however, have seen the emergence of pathogens with greater resistance to antibacterials such as gram-negative rods and Mycoplasma bovis as a substantial cause of mastitis losses.

2 Etiology
Mastitis causing pathogens includes bacteria, non bacterial pathogens like mycoplasma, fungi, yeasts and Chlamydia (Watts, 1988). Still 20%~35% cases remains of unknown causation (Miltenburg et al., 1996). Susceptibility to the infection attributed 25% to the environmental factors, 22% to genetic, and 52% to herd management (Klastrup, 1996). Different pathogens play role in development of mastitis are culture negative contributes -43%, second to this Staphylococcus aureus -11%, E. coli -8%, Streptococcus uberis -6%, CNS (coagulase negative staphylococci) -5%, rest by Klebsiella, Enterococcus, Yeast, A. pyogens, and other contaminants.

Bovine herpesvirus 2, vaccinia, cowpox, pseudocowpox, vesicular stomatitis, foot-and-mouth disease viruses, and bovine papillomaviruses can play an indirect role in the etiology of bovine mastitis. These viruses can induce teat lesions, for instance in the ductus papillaris, which result in a reduction of the natural defence mechanisms of the udder and indirectly in bovine mastitis due to bacterial pathogens. Bovine herpesvirus 1, bovine viral diarrhoea virus, bovine immunodeficiency virus, and bovine leukaemia virus infections may play an indirect role in bovine mastitis, due to their immunosuppressive properties. But, more research is warranted to underline their indirect role in bovine mastitis. We conclude that viral infections can play a direct or indirect role in the etiology of bovine mastitis; therefore, their importance in the etiology of bovine mastitis and their economical impact needs further attention. It is concluded that isolation and specific identification of the tiological agents were still one of the most efficient procedures for the diagnosis of the disease (mastitis), since the pathogenic organisms were isolated from CMT- negative quarters (normal). This should be taken into account in hygiene training to ensure that dairy practitioners understand the role of mastitis pathogens, which can serve as food borne disease and illness. Similarly special attention should be directed towards the broad environmental factors in order to improve and enhance proper preventive measures for the disease.

3 Incidences and Economic Importance
The weighted average of incidence of SCM and CM worked out as 50.47%, 44.92%, 30.74% and 16.9%, 7.71%, 4.89% for crossbreds, local cattle and buffaloes, respectively. Economic losses associated with disease incurred from reduced milk yield, loss of milk sale due to antibiotic residue concerns, cost of drug, and death in per acute cases (Gruet et al., 2001). Worldwide losses due to mastitis have been estimated to be approximately 35 billion US dollars and USA it self suffers from 1.5~2.0 billion US dollar loss (Wells et al., 1998). India having >50% dairy cattle and buffalo population under influence of mastitis inflicting a loss of 2809 crores rupees/annum among, sub clinical mastitis contributes 67.7% (Singh and Singh, 1994).

4 Why Comman Antibiotic Treatment Gets Failure
Bovine mastitis treatment failure is common despite an appropriate choice of antimicrobial. Current treatments of clinical mastitis during lactation often have a poorer cure rate than is predicted by in vitro sensitivity, especially in the case of Staphylococcus aureus which, as a chronic infection, is responsible for huge economic losses. Estimates of bacterial cure rate for Staph aureus mastitis during lactation mastitis fall between 25% and 50% (Sol et al., 2000). Antimicrobial resistance of mastitis-causing organisms (MCOs) is commonly not the precipitating factor in treatment failure (Constable and Morin, 2003; Pengov and Ceru, 2003; Hoe and Ruegg, 2005). The explanation should therefore be sought in terms of other factors, which also influence the outcome of therapy (Pengov and Ceru, 2003).

The bovine mammary gland is an immunologically inept organ, both because dilution effect of milk on immune defences and poor phagocytic activity. Intracellular slow growth rate of S. aureus and failure of antibiotics to penetrate and act effectively within phagocytic environment leads clinical cure but bacterial cures being curtailed (Sandholm et al., 1990). Poor contact of the antimicrobial with micro organisms at the site of infection is a major cause of mastitis treatment failure (Serieys et al., 2005).

The successful use of antimicrobial drugs for mastitis treatment depends on the same basic principles that apply to all microbial infections: (1) Selecting an effective antimicrobial agent, (2) Attaining and maintaining therapeutic concentrations of the drug at the infection site for long enough, (3) Minimising local or systemic side effects of therapy, and (4) The administration of supportive, non-antimicrobial therapy when indicated (Ziv, 1980).

There are four major groups of factors associated with bovine mastitis treatment failure:
a Management and iatrogenic factors
b Drug factors
c Mastitis-causing organism factors
d Mammary gland factors

Additionally, herd, cow and quarter level factors, can also affect results of the bovine mastitis treatment.
a Management and iatrogenic factors: in accurate diagnosis:
(1) Inadequate supportive treatment
(2) Partial or full insertion of cannula
(3) Re-infection
(4) Delayed initial treatment
(5) Duration of treatment
(6) Super infection
(7) Improper route of administration
b Drug factors:
(1) Improper antimicrobial selection
(2) Short half-life of the drug
(3) Inadequate local tissue concentration
(4) Side effects of the drug
(5) High degree of milk and serum protein binding
(6) Combined use of bactericidal and bacteriostatic antimicrobials
(7) Other factors that will lead to inactivation of the antimicrobial invivo or in vitro
(8) Low bio-availability
(9) Weak passage of drug across the blood-milk barrier
c Mastitis pathogens related factors:
(1) Tissue invaders or intracellular location
(2) Microbial dormancy and metabolic state
(3) Microbial mechanisms that overcome antimicro- bial effects in milk
(4) Mastitis causing organisms that are short lived in mammary gland, such as Coliforms
(5) Drug tolerance and resistance (Ziv, 1980; Erskine et al., 2003)
d Mammary gland factors
(1) Poorer and uneven distribution and physical obstruction
(2) Trauma
(3) Udder tissue necrosis
(4) Adverse effects of drug
(5) Teat canal infection
(6) Irritation

Despite of appropriate choice of antimicrobial, treatment of mastitis may be unsuccessful. Current treatments of mastitis in during lactation are not very successful and cure rates are poorer, especially in case of Staphylococcus aureus usually between 25%~50% (Gruet et al.,2001).

Veterinarians should have an active role in the education of the farmers in the treatment and management of bovine mastitis. Management and iatrogenic factors can be easily influenced. One of the main objectives must be early treatment initiated as soon as signs of the disease become apparent. The length of treatment should be accordingly to the speed of recovery. Extended therapy protocols are designed to maintain antimicrobial levels in milk greater than the minimum inhibitory concentration for a period that extends beyond the lifespan of neutrophils, aiming to kill organisms that seek a refuge into the white blood cells.

Veterinarians’ role in the improvement of the drug storage conditions is also important. It is imperative to treat younger cows on time, and prevent damage to the secretory tissue, resulting in increased susceptibility of repeats. Additionally, veterinarians can influence the choice of antimicrobials, based on the in vitro susceptibility testing. The choice of inappropriate drug should not be an excuse for bovine mastitis treatment failure, particularly when antimicrobial sensitivity/ resistance testing is readily available.

5 Making Mastitis Treatment Decisive
An approach to the therapeutic decisions for mastitis must address the three fundamental “E” Efficacy, Economics, and Evasion of dry residue (Morin et al., 1988). The key variables that influence the approach to formulating a treatment protocol are mainly causative agent, drug selection and cow immune status. Goal of successful therapy is to attain effective concentration of drug at site of infection (Anderson and smith, 2001).

5.1 Three potential therapeutic targets or three Pharmacological compartment models for therapy (Table 1)

 
Table 1 Three pharmacological compartment models for therapy

(1) First compartment: Milk, Epithelial lining, Alveoli of gland.
This organisms resides in milk and non invasive, non abscess forming type.
(A) S. agalactiae, S. dysagalactiae, Klebsiella, CNS (coagulase negative staphylococci)
(B) Route of choice to treat- Intramammary.
(C) Most effective antibiotic- Pirlimycin, Ceftiofur.
(2) Second compartment: Parenchyma.
These organisms are invasive and abscess forming type.
(A) S.aureus, S. uberis etc.
(B) Route of choice to treat-Systeamic.
(C) Most effective antibiotic-Macrolids (Erythromycin Lincomycin), Rifampicin,
(D) Trimethoprime, tetracycline and floroquinolones.
(3)Third compartment: Cow
These organisms cause severe clinical cases with systemic involvement.
(A) Treatment targeted towards endotoxin induced shock
(B) Coli forms are the main culprits: E. coli
(C) Systeamic antibacterial therapy. Ceftriaxone, Oxytetracycline with fluid infusion.

6 Practical Pharmacological Consideration
Antibiotic shows cultural sensitivity may not be efficacious in in-vivo, so at that time we have to consider pharmacokinetic behavior of drug in mastitic milk. Number of quarter affected per cow by clinical/ sub clinical mastitis should be considered when selecting an antibiotic treatment with local or systemic route (Seriys, 1998). After systemic administration penetration of drug mainly depend on milk: plasma concentration ratio. However many factors affect udder tissue concentration like lipid solubility, tissue protein binding of drug, pH of milk. Intra mammary route prefer for mild mastitis, in acute severe inflammed quarter distribution of drug will be impaired so parental administration may overcome these problems. Although both route concurrent administration enhanced the results. Intra mammary route increases new portal of infection and stress to the udder so if, systemic route achieves sufficient MIC for desirable period, previous administration should be discouraged.

The route of administration either intra mammary or parental of medicinal products to treat mastitis is an important issue and relative interest of each route mainly depends on location of bacteria in udder and physicochemical properties of therapeutic molecule.

Bacteriological cures reduced with: 1. Increase age of cow; 2. In early lactation; 3. Severity of infection; 4. No. of quarter affected; 5. In hind quarters; 6. With shorter duration of treatment.
However after intra-mammary infusion many factors affect udder tissue concentration like lipid solubility, tissue protein binding of drug, pH of milk, inflammatory exudate at the site (Table 2; Table 3).

 
Table 2 Milk: Plasma concentration for some antimicrobials used in the treatment of bovine mastitis (Rasmussen, 1996; Ziv, 1980)

 
Table 3 Plasma protein bindings of antimicrobials in bovines (Srivastava, 2000)

7 Selection of Therapy Regimens for Mastitis
7.1 Selection of antibiotic
Practical consideration to be taken in to account in relating the time course of antibiotic concentration in milk and udder to potentiate cilinical and bacteriological efficacy after parentral and intra mammary administration. Streptococcus uberis infection treated with Penethamate systemic route shows bacteriological cure rate of 76.4% whereas intra mammary with 1 g procaine penicillin+ 0.05 g dihydrostreptomycin achieves 84.9% bacteriological cure. This depicts significantly better efficacy of intra mammary treatment against systemic in coagulase negative staphylococci infection (Mc Dougall, 1998).

Weakly acidic antibiotic are present in milk at low concentration than serum but their distribution shifted in udder in mastitis, reverse is also true for basic drugs.Mean tissue concentration of penethamate and macrolids 8 times higher than in plasma in normal milk which reduces with mastitis.

Sulpha drug and Penicillin-G, Ampicilin, Cloxacillin, Cephalosporins concentration increases in mastitis which is poorly in normal milk. OTC having high MIC against S. aureus whereas Gentamycin, Kanamycin have lower one and hence maintains effective concentration for 8~12 hours.

7.2 Selection of route of administration
7.2.1 Duration of treatment
For effective therapy of mastitis antibiotic must be administered repeatedly for 5~7 days (Rasmussen and sulman, 1996).

7.2.2 Route of treatment
(A) Intra mammary
Majority of antibiotics instigated to cross blood-milk barrier by passive diffusion, and non ionized fraction of them is usually more lipid soluble hence easily penetrate through passive diffusion. This is a route of choice in mild cases. Sequence of events occurs after intra mammary administration (Ziv, 1985).

(1) Pharmaceutical phase
This phase is important for bio-availability depends on
type of vehicle (aquous, gelatineous, oil, or use of suspending agents, particle size, solubility).
Quick release formulations for lactating animals (Length of withdrawal period economic concern). Slow release for dry cow treatment.

(2) Pharmacokinetic phase
It includes absorption, distribution, metabolism, excretion, which effects drug concentration in milk, mammary tissue.

(3) Pharmacodynaemic phase
â‘  Concentration-dependent killing
Magnitude above MIC enhances killing
Aminoglycosides, Floroquinolones
Peak serum > 10 times MIC
â‘¡ Time-dependent killing
Time above MIC, not peak concentration
Macrolids, Sulphonamide, Tetracycline, Penicillin Cephalosporin, Lincosamides

(B) Parentral Route
Highly lipophilic molecules pass through epithelia such as Macrolids, Floroquinolones and Penethamate hydroiodide (pro drug of Benzyl penicillin) are suitable for systemic administration in mastitis. Passage in both directions depends on the drug lipid solubility and acid base properties. Normal milk is acidic 6.5~6.9 than mastitic milk 6.9~7.5. So milk: plasma concentration ratio is >1 for basic drugs and <1 for acidic drugs. Lipophilic weak bases erythromycin, lincomycin, spiramycin are easily accessible in milk than benzyl penicillin, OTC, dihydrostreptomycin.
(1) Ideal characteristics of antimicrobial agent
Low MIC.
High bioavailability.
Highly lipophilic.
High volume of distribution (Vd).
Macrolids are the best for gram positive infection.
Gentamicin, Polymyxin-B, Cephalosporins are the best for gram-negative bacteria.
(2) Drugs In lactation period
Minimum irritation to udder.
Low MIC.
Low degree of binding to milk and udder proteins.
Low degree of ionization in udder.
Quick release rate from ointment or vehicle base.
Short milk withholding time.
(3) Dry period
Completely non irritation to udder.
Bactericidal action.
Slow release rate from base.
Large molecular weight.
Low volume of requirement of drug.
No withdrawal losses.
Treating udder in dry period is simply cost effective way to manage pre-existing sub clinical infections and prevent new ones from occurring (Hilson et al., 1986).

8 Clinical Pharmacology of Antimicrobial Use in Mastitis
8.1 Striking pharmacokinetic features of different antibiotics in mastitic milk
(A) Penicillins
In cow serum, normal milk and mastitic milk peak ampicillin concentration are 5.2, 0.14, 0.28 respectively indicates two fold higher than that of normal milk. This drug shows MIC against all types of pathogens for 24 hrs at 20 mg/kg IM dose rate. However amoxycillin=clavulenic acid @8.8 mg/kg exhibits 0.6 µg/mL concentration is highly effective (Table 4; Table 5) (Kartinnen et al., 1995).

 
Table 4 The disposition parameters in healthy and affected

 
Table 5 Relationship between MIC and resistance to the drug by Organisms, More MIC more resistance and vice versa

(B) Sulphonamides (Srivastava, 1998)
Pharmacokinetic studies of various sulpha drug depicts maximum concentration (Cmax) of Sulpha- dimidine, Sulphasomidine, Sulphaphenazole, Sulpha- dimethoxyzine, and Sulphadiazine are 5.94, 1.55, 1.34, 0.96, 0.90 after 12 hrs of therapy @ 200 mg/kg through systemic route (Sharma and Gupta, 1980). Milk to plasma ratio for Sulphadimidine and Sulphamethoxypyridazine are 0.8 and 0.07 at the same dose level of 4 gm IV (Table 6) (Srivastava et al., 1998).
 
 
Table 6 Recovery free Sulphadimine in mastitic milk following single IV admn (100 mg/kg)

(C) Tetracycline (Table 7)

 
Table 7 Pharmacokinetic profile of tetracycline group in mastitis affected dairy cows

(D) Gentamicin
Recoveries of Gentamicin in infected quarters are 40-80% higher than normal one. Poor lipid solubility limits parental application. 90% of Coliforms are sensitive to Gentamicin therapy. Milk to plasma ultra filtrate ratio is 0.95 (Table 8) (Anderson, 1999).

 
Table 8 Milk and plasma levels of Gentamicin in mastitic buffaloes following single intra mammary at dose rate of 0.4 mg/kg

(E)Enrofloxacin
Enrofloxacin first time exclusively used for veterinary practice having MIC >1µg/mL for Coli forms (Neer, 1998). It is detected in milk within 1 hour post treatment and persists for 24 hours having five times higher concentration than plasma (Pugliese et al., 1991). Therapy at dose rate of 5 mg/kg body weight is most effective and imparts >80% cure rates in buffaloes (Table 9).

 
Table 9 Milk and plasma levels of Gentamicin in mastitic buffaloes

9 Usage rationality
Effective therapy is a balance among detrimental effects on the infectious agents andtoxic effects to the host tissue.

Selection of an appropriate drug based on subject factors, if possible use narrow spectrum antibiotics, which are more selective and causes less interference to normal resident bacteria.
Antibiotic activity of particular dose is inversely proportional to the number of growing bacteria present. Therefore, in earlier treatment there is more chance that infectious agents to be caught in their early logarithmic growth phase. Therapeutic index/ Safety margin consideration.

Effete on infectious agents and host phagocytes should be in balance (Not deleterious effect on host phagocytes). If, infection with susceptible bacteria at usual site then low doses with long interval are instigated, but less susceptible organisms at remote site dosage should be elevated (Pappe et al., 1991).

10 Conclusion
Knowledge of types and characteristics of pathogens, MIC of antimicrobials and drug resistance are having paramount importance and having aided values in the treatment of mastitis. Beside the consideration of pharmacokinetic alone, the relationship of pharmacokinetic / pharmacodynamics of antimicrobial drugs resolve the solution of selection and application of antimicrobial agents used for rational treatment of mastitis on basis of pharmacotherapeutic knowledge.

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