ASPECTS OF SUCCESS IN ANTIMASTITE THERAPEUTICS

What to use? How to approach ? How to manage?

Although it is not the only measure to take into account, the therapeutic approach is key when it comes to combating this important disease of dairy cattle and of great impact on the production company.

Successful treatment depends on the causative agent, the nature and location of the infection, the antibiotic used and its concentration at the site of infection. In principle, it should be considered that the antibiotic that we administer will not determine a chemical sterilization of the mammary gland, but will help the host to get rid of the infection.

The disappearance of clinical signs, known as clinical cure, is not synonymous with bacteriological cure, which implies the elimination of the causative agent from the mammary gland. Uncured Intra-Mammary Infections can become chronic, becoming a constant source of infection for healthy quarters of the same animal and the rest of the herd. Bacteriological cure is generally evaluated 7, 14, 21 and 28 days after treatment. Bacteriological cure rates are high against the different species of the genus Streptococcus, while against Staphylococcus aureus and coliform organisms they are much lower. In the case of acute mastitis due to coliform organisms, the inflammatory response generated by bacterial endotoxin determines that most of the organisms have been destroyed when the clinical signs are noticed. Therefore, antibiotic therapy applied when clinical signs are noted may be of little use. The response to antimicrobial therapy is also poor against S. aureus, which has led to the search for answers that explain the mechanisms of therapeutic failures.

The failures are due, among other things, to the poor arrival of the active principle at the site of action due to limitations due to the ongoing inflammatory process or its pharmacokinetic characteristics, resistance, bacterial L forms, sub-doses, reinfections.

Studies carried out in Europe consider that there is an "82% barrier" of clinical cure efficacy observed at 7 days post-treatment that cannot be overcome. With any of the currently available intramammary products, this index is significantly reduced by 10-20% if measured at 14 or 21 days post-treatment. In some cases, the cure efficiency against S. aureus may be less than 35%. Generally this is due to a re-emergence of the organism that originated the infection following apparent clinical success.

Taking into account the objective of antibiotic therapy, it appears that recording the changes in the clinical condition will not be an adequate measure of the efficacy of the drug, since it only reflects the ability of the host to respond to bacterial aggression. Complete cure, which includes eradication of the causative agent and return of function of the affected organ to normal, appears to be difficult to obtain. After treatment of mastitis with antibiotics, the excretion of the bacteria in the milk ceases completely in the case of cure or for a variable period in the case of failure. For the reasons mentioned above, the evaluation of a therapeutic regimen for clinical mastitis is not a simple process. Efficacy can be evaluated at first on experimental infections, but then tests under natural conditions will be necessary. It should be noted that most efficacy studies do not contemplate the use of an untreated control group. This must be taken into account since spontaneous cures can be around 25% for mastitis caused by S. aureus.

Another limit to efficacy valid for most causative organisms is incorrect administration technique. In this regard, there is sufficient scientific evidence to prove that the total insertion of a cannula into the nipple canal can increase the rate of new MI in that room. In other words, this technique could actually cause infection rather than cure it. The partial introduction of the cannula (only at the entrance of the nipple canal) not only reduces the risk of carrying bacteria from the nipple canal to the cistern but will also allow the antibiotic to be located near the probable initial site of infection (colonization of the nipple canal).

KNOWING THE CAUSAL AGENT

?The great variations in the efficacy of cure determine that the knowledge of the causative agent is a fundamental contribution to delineate an antibiotic therapy protocol on a rational basis. Normally, when a veterinarian has to deal with a clinical case, he does not know its etiology. Although there are classifications based on the pathological characteristics of inflammation that would have a certain correlation with certain etiologies, they are manifested?

Clinical signs caused by the different infecting organisms (whether it is the presence of lumps, discoloration of the milk, inflammation of the quarter) are not easily differentiated in practice, and the causative agent can only be reliably identified by means of bacteriological analysis.

?The need to treat the clinical case quickly does not allow the identification of the etiological agent or its in vitro sensitivity to antimicrobials before initiating therapy. However, at that time a sample of mastic secretion must be taken, which will later be sent to the laboratory for identification of the causative agent.

SELECTING AN ANTIMICROBIAL TREATMENT

?The goals of antibiotic therapy imply that the expected levels of antibiotic at the site of infection after administration and the susceptibility of bacterial populations to antimicrobials must be known. The pharmacokinetic properties are: liposolubility, degree of ionization, protein binding affinity, and molecular size. These determine the ability of the drug to penetrate tissues, its partition between blood and milk and the proportion of active drug not bound to proteins in vivo. In our country, as well as in most of the countries of the world, intramammary treatment is the most common method to treat bovine mastitis, with parenteral therapy generally reserved for the most severe cases. However, there is no single criterion to determine which route to use.

Intramammary therapy is considered effective in cases of streptococcal mastitis and in some cases of staphylococcal mastitis; but cures can be clinical while bacteriological cure is low. Likewise, in the case of acute mastitis, some failures in intramammary therapy are due to a poor or irregular distribution of the drug in the intensely inflamed parenchyma and to compression or blockage of the ducts by products of inflammation. This would justify the use of parenteral treatment as an adjunct to intramammary therapy, or as the only treatment.

?As a requirement for a drug to be used parenterally, it must have an effective passage from blood to milk, which depends on the aforementioned pharmacokinetic characteristics. Most antibiotics exist in their ionized and non-ionized forms in blood and milk, but in varying proportions due to differences in pH in blood and milk. A small change in pH can affect the degree of ionization and therefore have a profound effect on the distribution of the drug in both compartments. The pH of plasma is relatively constant (7.4), but that of milk is more variable (6.5 in normal milk, but is close to that of plasma in mastic milk). Most of the drugs used for the treatment of mastitis in mastitic milk). Most of the drugs used for the treatment of clinical mastitis are salts of weak organic acids or bases or amphoteric compounds. Weak lipophilic organic bases tend to accumulate in milk in their ionized form after parenteral administration, frequently reaching higher concentrations than those obtained in blood. Weak organic bases access milk with difficulty and their concentrations in milk are lower than those obtained in blood. In cases of acute mastitis, the blood / milk barrier is partially damaged and therefore the pH of the milk approaches that of the blood; the concentration of the drug in the udder will then approximate the concentration of the fraction not bound to serum proteins. There is no drug that meets all the requirements considered ideal for an antibiotic administered by the systemic route, but the examination of all the characteristics: antibacterial properties, spectrum and pharmacokinetic properties, will allow the adequate selection of them. Table 2 shows the distribution of some antibiotics after their parenteral or intramammary administration.

?Penicillin G, ampicillin, cloxacillin, and cephalosporins have limited access to normal milk and slightly higher concentrations can be obtained in mastitic milk, but always lower than the concentrations considered effective. Penetamate, on the other hand, produces high concentrations of penicillin G in normal milk and lower concentrations in alkaline milk. Kanamycin and gentamicin are two aminoglycosides that have a low MIC against Staphylococcus aureus, and despite being poorly fat-soluble ionized bases, this low MIC means that they can maintain effective therapeutic concentrations for 8 to 12 hours. The sulfonamides and sulfonamide plus trimethoprim must be administered intravenously to achieve therapeutic concentrations, but because they lose some of their antibacterial activity in milk, the concentrations achieved are only active against the most sensitive pathogens. The macrolides such as spiramycin, can be concentrated in normal milk and, although lower concentrations are obtained in mastitic milk, they can maintain effective concentrations against S. aureus for at least 12 hours. In summary, and taking into account the spectrum of these antibiotics, against Gram positive mastitis the drugs of choice would be macrolides, while against coliforms the drugs of choice would be gentamicin, chloramphenicol and as a second choice combinations with trimethoprim.

Classification of antibacterial drugs according to their potential distribution in the mammary gland of their parenteral and intramammary administration.

GOOD DISTRIBUTION

?Erythromycin, ?Tylosin, Clindamycin, Spiramycin, ?Penetamate, Amoxicillin, Spiramycin, Cephalexin, ?Florfenicol, Rifampicin, ?Lincomycin, ?Enrofloxacin

?MEDIUM DISTRIBUTION

?Penicillin G, ?Ampicillin, Cloxacillin, Cephalothin, ?Sulfadimidine, Tetracyclines

?POOR DISTRIBUTION

?Dihydrostreptomycin, ?Neomycin, ?Neomycin, Kanamycin, Gentamicin, Polymyxins, ?Ceftiofur

?Source: adapted from Ziv, 1992 and Sandholm, 1995.

In many cases drug combinations (antibacterial and auxiliary) were used. For example, neomycin has been used as the main ingredient in combination preparations due to its broad spectrum. Erythromycin, polymyxin B, bacitracin, and penicillin G have been used because of the anti-S. aureus action of erythromycin, the synergistic and antifungal activity of polymyxin B, and because penicillin G and bacitracin possibly enhance neomycin activity. These theoretical foundations are sometimes difficult to support and for example, in practice penicillin G alone has not proven inferior to these preparations. Currently, broad-spectrum cephalosporins tend to replace these types of combinations since they have good activity against many Gram-negative and penicillinase-producing S. aureus. With data from antibiograms, even if they are qualitative, they are producers of penicillinase. With data from antibiograms, even if they are qualitative, those drugs that show a good distribution in the gland will be preferred, leaving as second choice those that show a more limited distribution. Unfortunately, some of the most active drugs in vitro do not have the best distribution characteristics. This may be one of the reasons for the discrepancy observed between clinical and bacteriological cures and in vitro susceptibility tests. As a rule, it is advisable to administer at least 3 days those products that are well absorbed. At present, to limit the losses due to milk discarding due to the presence of post-treatment antibiotic residues, pharmaceutical companies have focused their interest on the development of intramammary drugs with a short elimination period, some consisting of a single application. This may determine that bacteriological cures are not always obtained and subclinical IIMs are maintained within the herd. In most cases, when a clinically affected room is treated with antibiotics, it responds within a day or two and most infections are cleared. The exception to this pattern is the treatment of S. aureus infection, where many times the clinical response is good but the percentage of elimination of MI is variable.

?Knowing, through the pharmacokinetic characteristics of the antimicrobial, the doses that will be necessary to administer to reach a certain concentration in milk, it remains to establish what is the concentration that inhibits most of the organisms that cause mastitis in order to develop the regimen of treatment. The parameter that determines the susceptibility of a bacterium to an antimicrobial agent is the minimum inhibitory concentration (MIC). There are several ways to determine MIC. The agar diffusion or antibiogram method, which is used routinely, expresses susceptibility patterns in qualitative terms; that is: as sensitive, intermediate or resistant. This method is correlated with quantitative methods, since the potencies of the discs used are adjusted according to the expected concentrations of antibiotics in plasma after parenteral administration of the drug, but it does not have a great relationship with other body fluids. For mastitis work, the right type of quantitative evaluation is obtained by dilution methods in broth or agar. In any case, the agar diffusion method provides some usefulness, since although an antibiotic to which bacteria are sensitive in vitro may fail when applied to the animal, when resistance is observed in vitro the probability of failures when applied in vivo may be greater.

?The results of in vitro susceptibility tests to antibiotics show a sometimes variable and other times poor correlation with those of therapeutics. In general, the correlation is higher against mastitis caused by Streptococcus agalactiae and Streptococcus dysgalactiae, since these organisms are associated with ducts and milk within the gland. In contrast, S. aureus may be confined within neutrophils or protected by scar tissue, and the correlation between in vitro susceptibility testing and in vivo efficacy is lower. Finally, it is critical that cows with acute mastitis are detected early and treated quickly, as a delay of a few hours can be the difference between success and failure. Likewise, home-made preparations should be avoided, applying only formulations of recognized efficacy. The intramammary application of products not formulated for this route and in inadequate hygienic conditions can lead to the proliferation of severe infections by environmental pathogens.

TREATMENT OF SUBCLINICAL MASTITIS DURING LACTATION.

?The treatment of subclinical MI during lactation, known as "blitz therapy" ("blitz" means lightning bolt) has been occasionally used to overcome problems derived from a high prevalence of infections, at the beginning of a control program or in herds where wanted to quickly eradicate Streptococcus agalactiae. Its main advantage is that all infections are treated at the same time with an immediate reduction in the levels of infection and contagion. This decrease in the prevalence of MI is reflected in a sharp drop in somatic cell counts (SCC).

?However, this strategy has the disadvantages that the reduction in the number of MII may be temporary, the loss of milk for sale due to antibiotic contamination, the high cost of the laboratory due to the need to carry out precise diagnoses of MII prior to treatment. and the cost of the treatment itself. Also, it is not effective in infections caused by S. aureus, Streptococcus uberis, and Gram-negative germs. Therefore, special caution is recommended when carrying out these types of practices, which must always be under the supervision of a veterinary professional and with knowledge of the industrial plant receiving the milk. This practice has proven to be useful in the case of herds with a high prevalence of MI caused by S. agalactiae and as a way to sharply lower the number of affected animals and SCRs. This effect can be achieved in a longer period with a comprehensive control program, even without treating subclinical infections during lactation.

PROTOCOLS FOR THE TREATMENT OF CLINICAL CASES

?A basic requirement to design and recommend a treatment protocol is to keep records of clinical cases. This practice must be implemented in such a way that it is simple for those who have to take the data and, in turn, the recorded data must be reviewed with the necessary periodicity to be able to make the corresponding decisions. Another requirement is that there must be the results of bacteriological analyzes carried out on clinical cases in order to determine which or which are the predominant pathogens in the establishment. The simple knowledge of the causative agent makes it possible to predict the efficacy of healing in broad strokes. For example, if we are dealing with clinical cases caused by Streptococcus agalactiae, the recommendation will be to treat all cases that occur with intramammary antibiotics. If, on the other hand, these are clinical cases from which coliform organisms are sporadically isolated, it must be decided which cows to treat and with what type of drugs.

?Within a protocol, it must be clearly indicated which cases will be treated, as well as the product to be used. For this, it will be necessary to classify clinical cases in the simplest way possible. One of the ways is to consider it as a mild case when the inflammation of the tissue is not important and the milk shows lumps of different sizes, but still maintains its characteristic color and appearance. The case can be considered severe when there is marked inflammation of the mammary tissue and the milk is totally abnormal (with or without compromising the general state of the animal).

?In designing a protocol, the establishment's short- and medium-term objectives should also be taken into account. It should be considered: pathogens present in the herd, age of the cow, reproductive status, production, relative value, history of mastitis, etc. As a general rule, it should be taken into account that the most aggressive treatments will be reserved for the younger cows, in the first third of lactation, with high production and with non-recurrent mastitis.

?In case of herds with high rates of S. aureus mammary infection in which segregation programs are carried out, normally cows in which MI has been detected by bacteriological analysis are not treated if clinical episodes appear, since they will be discarded when end of breastfeeding. In these cases, frequent milking can be used (twice as many times as usual for the establishment) associated or not with the application of oxytocin (20 IU in each milking).

?In cases in which clinical cases due to contagious pathogens are not detected, it is suggested that those cases that show only some lumps at the beginning of milking are not treated, to later give rise to normal-looking milk. However, these cases must be recorded. If, on the other hand, the milk maintains an abnormal appearance after the first jets, a milk sample should be taken for bacteriological analysis and frequent milking should be established, associated or not with the application of oxytocin.

If the clinical signs do not remit and the isolated organism is susceptible to antibiotic therapy, it will be administered. This type of protocol can only be applied if the predominant flora is known. It should be noted that taking samples periodically allows to quickly detect the changes that occur in the acting flora and therefore vary the treatment protocol according to the needs.?

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