PHARMACOLOGICAL CONSIDERATIONS IN ANTIMICROBIAL THERAPY OF

MASTITIS

INTRODUCTION

The Aim Best antimicrobial treatment regimen for

mastitis Administering the drug at proper dose

and route Low MIC for mastitis pathogens. Preferably bactericidal actionThe activity should not be reduced by the

presence of milk Good pharmacokinetic characterestics

Pharmacokinetic (PK) properties: Lipid solubility, Degree of ionization Extent of binding to serum and udder proteins.

Weak organic bases: macrolides, aminoglycosides, sulfonamides, polymixin tend to accumulate in milk in the ionized form after parenteral administration, and attain concentrations higher than those in blood.

Weak acids :penicillins and cephalosporins in milk are much less than those in blood.

Concentration-dependent group of antimicrobials (e.g. aminoglycosides and fluoroquinolones) Time dependent group (e.g. penicillins, cephalosporins and macrolides)

CHOICE OF ROUTE OF ADMINISTRATION

Type of infection streptococci : stay in the milk

compartment, -IMM Staphylococcus aureus penetrate into

udder tissue and cause a deep infection –Systemic and IMM

Coliforms eliminated spontaneously from the udder, risk for bacteriaemia =-the use of systemic administration of antibiotic;Efficacy of questionable

Intramammary route

Advantages

High concentrations of antibiotics Low consumption of the antimicrobial substances

as the drug is administered straight to the infection site.

Disadvantages Uneven distribution of many substances Risk for contaminationSome may disturb phagocytosisCombinations of two or three antibiotics were

introduced to mastitis therapy due to suggested synergistic action and to cover all pathogens, Gram-negative bacteria included. The idea of fixed combination tubes have shown no superiority over single components in controlled clinical trials.

Broad-spectrum intramammaries may enhance emergence of wide-spectrum beta-lactamase production among bacteria as they are less efficient than narrow spectrum preparations against Gram-positive mastitis pathogens, as they are more targeted towards Gram-negative bacteria .

Parenteral route Ruminants eliminate xenobiotics very fast and half-lives

of many antibiotics are short Intravenous administration would in general produce

higher concentrations in milk 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.

Dosage recommendations of many antibiotic preparations for adult cattle are too low with regard to the MIC of the target bacteria.

Repeated intramuscular injections of large volumes of antibiotics are not ideal from the animal welfare point of view

Interpretation IMM : preferred in subclinical,

chronic and mild clinical mastitis Parenteral together with IMM

route: in acute clinical mastitis with swollen parenchyma and inflamed, blocked milk duct system,

Approved antimicrobials for bovine mastitis treatment Pirlimycin Hetacillin Cloxacillin Nafcillin Amoxicillin Novobiocin Penicillin G Dihydrostreptomycin Cephapirin Erythromycin Sulfamethazine (nonlactating dairy cows only)

Extralabel use: fluoroquinolones, aminopenicillins, cephalosporins, chloramphenicol tetracyclines, aminoglycosides and other macrolides.

Macrolides, florfenicol, oxytetracycline, some fluoroquinolones and rifampin

Good distribution to the udder following systemic administration.

Sulfa drugs, penicillin G, ampicillin, ticarcillin and cephalosporins

Intermediate or limited distribution following systemic administration

Ceftiofur, aminoglycosides, spectinomycin, colistin and polymixin B

Poor distribution to the udder on systemic

Cephapirin , Ceftiofur Cefquinome : BSTilmicosin Macrolide closely related to tylosin, is a narrow

spectrum (gram positive) antibiotic Pirlimycin Lincosamide antibiotic, active only against gram

positive bacteria, is effective in eliminating prepartum infections

Erythromycin primarily against gram positive bacteria, such as

Staphylococcus and Streptococcus species, including penicillin resistant ones. indicated only in the treatment of subacute or subclinical mastitis manifested by mild changes in the milk or udder.

Therapy strategiesThe mastitic cows : • Concentrations of antioxidants : vitamin E,

selenium, vitamin A, vitamin C and the minerals: zinc and copper, which are essential for maintaining and protecting udder health.

• Anti-oxidant supplementation of dietary rations improves anti-bacterial function of neutrophils and decreases incidence and severity of clinical mastitis.

Combination of multiple intramuscular injections with intramammary infusions over a three-day period result in highest tissue antibiotic concentrations.

Subacute clinical mastitis • Intramammary infusion for a minimum of three

days, accompanied by frequent hand stripping to remove secretion and debris

• Treatments should be continued until at least 24 hours after the disappearance of clinical symptoms.

• A true cure, whereby all infecting microorganisms are eliminated from the affected quarter, occurs in only 10 to 50% of cases.

• The cure rate is dependent on how long the infection has been present, age of the cow, type of organism involved, and other factors

Acute mastitis• Acute, or systemic, mastitis is most often

caused by coliform and other Gram-negative organisms

• Numerous other pathogens including Gram-positive cocci and mycotic organisms can all result in severe mastitis.

• IMM therapy to inhibit Gram-positive growth in addition to parenteral (systemic) antimicrobials that have broad spectrums of activity are administered.

Macrolides: Not effective against coliform bacteria. Penicillin, oxytetracycline(IV), ceftiofur, cephapirin and

florfenicol offer some choices, although penicillin and ceftiofur do not penetrate udder tissue well.

The efficacy of systemic ceftiofur as a treatment of clinical mastitis remains unproven and caution should be exercised in continuing antimicrobial therapy

Milking out the affected quarter every 2 -3 hours. Oxytocin may be used to facilitate milk evacuation and remove toxic materials and debris. However the oxytocin treated cows had more relapses and additional infections due to environmental streptococci.

Corticosteroids only in peracute toxic cases, but should never be used in other mastitis cases. Aqueous dexamethasone sodium sulfate, a single dose one time treatment : aid in reducing swelling and pain and enhance the removal of toxic secretions as well as promote better diffusion of intramammary infusions

NSAIDS: flunixin meglumine, aspirin, phenylbutazone, and ketoprofen

Fluid replacement: Large volumes of BES; 20 litres in the first one to two hours, and up to 60 liters over a 12-hour period.

Commercial distilled water can be bought in large economical quantities and mixed with pre-weighed amounts of salt to provide the fluids needed.

Hypertonic(7.5%) saline solution (4ml/kg,IV): immediate expansion of ECF and temporarily counter some of the effects associated with endotoxemia.

Followed by 5 to 10 gallons of water orally

Administering 150 to 250 grams of sodium bicarbonate with the first three to 5 liters of electrolyte solution and adding 500 mL of 50% glucose to the first few liters of electrolyte restores vital body fluids, dilutes toxins, and counteracts acidosis .

Calcium BG and Potassium chloride

Dietary vitamin E and selenium reduce the

severity and frequency of coliform mastitis .

Chronic mastitis Long duration, frequently recur with mild clinical mastitis

despite previous therapy, and can add substantial costs and risks associated with treatment.

Identification of the pathogen should be performed before any extensive therapy is instituted.

Drug distribution, although theoretically available in the mammary gland, may not be efficacious because of extensive fibrosis and micro-abscess formation in the gland.

In herds with a high prevalence of S. aureus infections, the emphasis on teat dipping, culling, milking machine maintenance, milking hygiene, and segregation of infected cows to gradually reduce prevalence of infection.

Antibiotics : reduce shedding of bacteria by clinical cows, and thus help reduce the spread, but may not reduce overall prevalence in the herd.

Heifers calving with mastitis: Dry treated 50 to 60 days with approved dry cow therapy. and treated 7 to 14 days prior to calving

Reasons for treatment failureLack of contact between bacteria and

antibiotics due to scar tissue formation Protection within leukocytes Poor drug diffusion Inactivation by milk and tissue proteins Microbial resistance to antibiotics;

development of bacterial L-forms; metabolically inactive organisms

Improper treatment procedures like stopping the therapy too soon.

Nonantibiotic approaches for alleviating clinical signs Hypertonic saline (7.5%; 2 mL/ 45 kg BW,IV or 500 to

1000 mL, intramammarily) has been used in some cases(50-60% success rate), once after each milking for two to three days to alleviate clinical symptoms

Lactobacillus (probiotic) intramammary infusions have been tried with poor success rates (21%).

Clay mixed with water or oil (pine or thyme oil), made in to a paste adhering to the udder, has proved efficient as poultice to treat inflammation caused by mastitis

Many herbal medicines have been also considered to be quite effective in treatment of mastitis.. The formulated herbal products with antibacterial, anti inflammatory , analgesic and immunostimulatory properties and plants which boost the mammary gland health have been tried as mastitis therapeutic agents

Homeopathy Cytokines Bacteriocins

PLANTS BOOSTING MAMMARY HEALTH

Tinospora cordifolia (Amruta Balli, Madhu parni)

Cuminum cyminum (Jeerige)

Cyamopsis tetragonoloba( gori kai)

Cymbopogon martinii( kashi hullu)

Limnophila aromatica

Nigella sativa

Ocimum basilicum

Anethum graveolens(Sabbakki soppu)

Amaranthus spinosus( mullu harive soppu )

Syzygium aromaticum ( clove, lavanga)