DE69321429T2 - Animal feed, feed additives or drinking water that contain an antibiotic mixture of gentamicin with lincomycin or clindamycin - Google Patents

Description

The present invention belongs to the field of veterinary medicine and relates to an additive containing an antibiotic mixture of gentamicin and lincomycin - which can be in the form of free bases, but preferably in the form of their pharmacologically acceptable acid addition salts - to animal feed or drinking water as well as animal feed for use in the prophylaxis and therapy of infections and consequently for increasing body weight and increasing the efficiency factor in fattening animals.

There is a constant need for effective prophylaxis and treatment of infections and, consequently, for body weight gain in fattening animals such as poultry, calves, pigs and lambs. For this purpose, antibiotics and their combinations are sought as additives to animal feed or drinking water that lead to the desired goal.

Lincomycin is a well-known antibiotic described in US Patent 3,086,912 that inhibits the growth and spread of many microorganisms, especially gram-positive bacteria. US Patent 3,155,580 describes galenic forms based on lincomycin and its acid addition salts as active ingredients for the treatment of infections caused by bacteria in humans and animals. In fattening animals, the antibiotic can be used for prophylactic purposes or as a growth stimulant to increase body weight. Lincomycin hydrochloride can be added to the usual feed in dosage units.

US Patent 3,150,042 discloses the use of lincomycin for the prophylactic and therapeutic treatment of coccidiosis in animals by using the antibiotic as an additive to the usual feed or to the appropriate amount of drinking water. The use of tablets and sterile injection solutions is also described.

Clindamycin is the generic name for 7(S)-chloro-7-deoxy-lincomycin and is described in US patents 3,475,407, 3,496,163, 3,509,127 and 3,539,689 as a base or its acid addition salt used in oral or parenteral galenic forms for the treatment of humans and animals infected by bacteria, coccidia and mycoplasma.

Therapeutic forms of clindamycin are used in a similar way to lincomycin, except that clindamycin has both activity against Plasmodia and a stronger activity against infections caused by bacteria. It is also used prophylactically as a feed additive for beef cattle.

Gentamicin is an antibiotic described in US patents 3,091,572 and 3,136,704, which consists of three structurally related components, gentamicins C1, C2 and C1a. Gentamicin A, which differs from the other components of the complex, is also known. In galenic forms, gentamicin occurs in the sulfa form (gentamicin sulfate). Gentamicin is a highly effective antibiotic against gram-positive and gram-negative microorganisms such as the species Staphylococcus, Klebsiella, Pneunomonas and Proteus and thus it is used in both human and veterinary medicine.

US Patent 3,261,687 describes animal feed and methods for increasing body weight gain in healthy fattening animals with a ratio in the animal feed preparation of 1 to 10 parts by weight of spectinomycin and 1 part by weight of lincomycin. It is stated that with such a combination of antibiotics in animal feed or drinking water, unexpectedly good results were obtained in increasing body weight gain and its speed as well as in increasing the efficiency factor. At the same time, the combination of the two antibiotics in the animal feed has a synergistic effect and is also suitable for the therapeutic and prophylactic treatment of poultry, pigs, sheep and cattle.

EP-A-0 026 746 describes a pharmaceutical preparation and a method for increasing the antibiotic effect of antibiotics based on the combination of one or more antibiotics and muramyl peptide of formula I. In particular, muramyl peptides of formula II can be used. Among many potential antibiotics mentioned, gentamicin can be used as an aminoglycosidic antibiotic and lincomycin or clindamycin as a lincomycinic antibiotic. The examples show the use of only one antibiotic in combination with muramyl peptides, whereby the muramyl peptides must always be used in combination with an antibiotic.

GB-A-2 159 409 describes a synergistic antibiotic combination useful for treating respiratory, gastrointestinal and urinary infections and septicemia in domestic animals, which contains tiamulin hydrogen fumarate and an aminoglycoside antibiotic such as gentamicin or its pharmaceutically acceptable salt in a weight ratio of 1:5 to 5:1. Example 5 shows a combination of tiamulin and gentamicin in a weight ratio of 4:1. The lincomycin antibiotics used in the present application in addition to gentamicin are structurally completely different from tiamulin.

WO-A-8 500 515 describes, among other things, antimicrobial agents gentamycin and chndamycin embedded in a liposome preparation for the treatment of anaerobic infections, whereby this liposome preparation is administered intraperitoneally.

The present invention is based on the task of finding an effective antibiotic combination as an additive to animal feed or drinking water for animals such as poultry, pigs, calves and lambs, which would be effective in the prophylaxis and therapy of infections and thus would rapidly increase the body weight gain in fattening animals and increase the efficiency factor with low feed conversion. The results obtained by the new mixture of antibiotics as an additive to animal feed or drinking water should be better than those obtained by using individual antibiotics or some known mixtures. of antibiotics for the same purposes (e.g. the lincomycin-spectinomycin combination of the above-mentioned US Patent 3,261,687), thus representing a valuable improvement in animal breeding.

Surprisingly, it has been found that the above-mentioned aim can be achieved by a combination of the antibiotics gentamicin and lincomycin, preferably in the form of their acid addition salts, e.g. in a combination of gentamicin sulfate and lincomycin hydrochloride, which is added to normal animal feed or drinking water.

We have found that good prophylactic and therapeutic effects and thus the greatest final body weight of fattening animals such as poultry are obtained by drinking water or normal feed containing a combination of gentamicin with lincomycin, the combination of gentamicin sulfate with lincomycin hydrochloride being preferred.

Compared to the use of a known mixture of antibiotics spectinomycin and lincomycin (Linco-Spectin 100, The Upjohn Comp., USA) in animal feed or drinking water and to the use of individual antibiotics in animal husbandry, the new antibiotic combination according to the invention, in addition to a greater body weight gain and a lower mortality rate, also has the highest efficiency factor. The higher results shown in the tests with the new antibiotic combination were actually surprising in comparison with those for the known combination of lincomycin and spectinomycin, all the more so because even a small amount of gentamicin in combination with spectinomycin is sufficient to achieve higher results. The results obtained are also significant from an economic point of view, since the use of the new antibiotic combination in fattening animals achieves a greater body weight gain, a lower mortality rate and a higher efficiency factor with a simultaneous lower consumption of the two antibiotics.

The improved results are achieved by using the new antibiotic combination in fattening animals such as calves, pigs, lambs and poultry (chickens, ducks, geese, turkeys). The antibiotics are added to ordinary animal feed or drinking water in a ratio of 1 part by weight of gentamicin and 5 to 60 parts by weight of lincomycin, preferably in the form of acid addition salts.

The dose of the new antibiotic combination in the feed or drinking water is determined with regard to the animal species, age, weight and average daily amount of feed and/or drinking water used.

The antibiotic combination can be used in the form of pure components, but it is preferred to use a liquid or solid premix, i.e. prepared in a concentrated form before being added to the feed or drinking water. The solid premix can be prepared by mixing antibiotics with solid diluents such as lactose, starch, flour or soybean meal, calcium carbonate, etc., which are added to the feed or dispersed in the drinking water.

Regular animal feed may also contain additives such as iodized salt, vitamins A, B, C and D, minerals and other appropriate salts, preservatives...

The new antibiotic combination has a synergistic effect in the prophylaxis and treatment of animal infections caused by microparasites including bacteria, coccidia and mycoplasma, especially against individual bacteria.

The invention is illustrated by the following examples.

example 1 Comparative testing of antibiotics gentamicin, a combination of lincomycin and gentamicin, a combination of lincomycin and spectinomycin and amoxicillin in broilers

In order to determine the body weight gain, growth rate and efficiency factor, a comparative test of the above-mentioned antibiotics was carried out on broilers. The antibiotics were administered in the form of commercial preparations of gentamicin powder (LEK, Ljubljana, Slovenia) with 10% gentamicin content, lincomycin-spectinomycin (Linco-Spectin 100, Upjohn Comp., USA) and amoxicil (Simivet, Pliva, Croatia). The antibiotic combination lincomycin-gentamicin according to the invention was administered in the form of a premix with lactose and powdered polyethylene glycol 400.

The concentrations of the antibiotics used in Table 1 are calculated in relation to the proportion of each antibiotic in the preparation/premix. The test included 69,600 chicks of the ARBOR ACRES genus hatched from eggs of one parent group during the same time period. They were placed in four chicken houses (C1, C2, C3 and C4) with 17,400 chicks per building.

On the first three days and on the 13th, 14th and 15th days of their life, the animals received a specific antibiotic in drinking water, as shown in Table 1. TABLE 1

Chicks received the same concentrations of antibiotics on days 13, 14 and 15 of their life, except in building C4, where the concentration of amoxicillin hydrate was increased to 5 g per 1001 drinking water.

The buildings in which the test animals were housed were disinfected by the following activities: mechanical cleaning, cold water washing, hot water washing (80ºC), dousing with 0.5% isozan solution (LEK, Ljubljana) and fumigation with 10% formaldehyde solution. Buildings disinfected in this way were closed for 14 days. The effectiveness of disinfection was checked by microbiological analysis of the swabs taken - 103 (Koch decimal dilution method, i.e. dilution 1000).

Sunflower flakes were used as bedding in a thickness of 8 to 10 cm. Before the chicks were placed, the bedding was disinfected with a 2% water solution of bluestone. The buildings were heated with gas stoves and ventilated with fans, and the temperature was controlled by thermostats. The temperature recommended for broilers according to AA (Arbor Acres) standards was as follows:

Age week Temperature (ºC)

1 32-35

2 29-32

3 26-29

4 23-26

5 21-23

6 21

7 21

According to AA standards, the daily amounts of water used (litres per 100 broilers) in relation to different temperatures and ages were as follows:

The composition of the feed was based on AA standards:

The weekly weight according to AA* standard for broilers was:

Week g

1 149

2 371

3 674

4 1040

5 1458

6 1900

*Standard AA (Arbor Acres) is named after AAF Inc., Glastonbury, Connecticut - the largest American poultry farmer.

Chicks’ weights were monitored by weighing at days 1, 2, 14, 21, 28, 35 and at slaughter (day 42).

The number of animals and the weights of day-old chicks by group are shown in Table 2. TABLE 2

From Table 2 it can be seen that at the beginning of the testing the heaviest chicks were in building C1, followed by chicks from buildings C4 and C3, while the lightest chicks were in building C2. The difference between the highest and the lowest weight was 6 g.

The health status of chicks by group was monitored by clinical, pathoanatomical and bacteriological examinations. A sample of the internal organs of five animals was taken once a week for bacteriological examination.

The animals were vaccinated against atypical fowl influenza on the 14th day of their life (administration in water).

Test results

The weighing results for chicks on the first day of their life and in the following breeding weeks are given in Table 3. TABLE 3

N = AA standard for body weight in a defined time period

DSP = day-old chicks

The weekly body weight gain of chicks by group is shown in Table 3A. TABLE 3A

From both Tables 3 and 3A it can be seen that none of the chick test groups reached the standard body weight in the first week. The chicks in building C3 reached the highest body weight and those in building C4 reached the lowest body weight.

In the second week, the chicks from building C2 had the greatest body weight and exceeded the standard for 2 grams. In the other buildings, the chicks did not reach the body weight gain standard. The chicks from buildings C 1 and C3 reached about the same weight and were about 10 g below the standard. The chicks from building C4 had the lowest weight and were 19 g below the standard.

In the third week, the chicks from building C2 had the highest weight and were the only ones that reached the standard and exceeded it by 8 g. The chicks from groups C1 and C3 reached exactly the same weight in the same time period, namely 8 g below the standard. The chicks in building C4 still had the lowest weight (19 g below the standard).

In the fourth week, the chicks in building C1 reached the body weight according to the AA standard and the chicks from building C2 exceeded it by 74 g. The chicks from building C3 were 44 g below the standard and those from building C4 were 54 g below the AA standard.

In the fifth week, the weighing results in building C2 again exceeded the AA standard by 32 g and in building C1 by only 8 g, the body weight in buildings C3 and C4 did not reach the AA standard. The highest final body weight, which was also the most economically interesting result, was achieved by the chicks from building C2, although they had the lowest body weight at settlement. In terms of body weight at slaughter, buildings C3 and C1 followed, while building C4 differed from C2 by 100 g.

The results of feed conversion are given in Table 4 (the conversion means the amount of feed required for 1 kg of body weight gain). TABLE 4

In chicken farming, conversion is a very important factor. From the table above, it can be seen that the chicks from building C3 had the least consumption of feed (1.94 kg) for 1 kg of body weight gain, while those from C1 and C2 consumed 0.02 kg more and those from C4 consumed 0.11 kg more feed.

The data on the weekly mortality rate of chicks by group are given in Table 5. TABLE 5

From Table 5 it can be seen that in the second and third weeks the mortality rate was fairly similar in all buildings. So were the clinical and pathological findings. The chicks died mostly because of apoplexy and dropsy, but also because of cachexia. Towards the end of the third week, some chicks with swollen head disease were observed in building C3, which resulted in a slightly higher mortality rate (the chick does not see, cannot reach food and water and dies).

In the fourth week, building C3 had a significantly higher mortality rate. As previously mentioned, towards the end of the third week, chicks with swollen heads were observed and their number and mortality rate increased significantly. Another problem in this building was cachexia. In the other buildings, the main problems were dropsy and cachexia.

In the sixth week there was a general increase in the mortality rate, especially in building C4, where the classic form of CRD (Cronic Respiratory Disease) appeared, along with dropsy and cachexia. In building C3 the number of swollen heads stabilized, while the main problem was dropsy and cachexia, and some CRD cases also appeared. In buildings C1 and C2 some CRD cases appeared.

Breeding efficiency factor (I)

A comparison of data on overall mortality, final body weight and conversion in individual groups is given in Table 6. TABLE 6

Table 6 shows three efficiency indicators for each breeding (mortality rate, body weight, conversion). However, it is possible that simply checking these can give a false picture of breeding efficiency. Therefore, the efficiency factor was calculated to be able to say exactly which breeding was the most effective. Table 6 shows that building C2 had the highest efficiency factor, followed by buildings C3, C1 and C4.

The amounts of meat obtained, the consumption of feed and the amounts of meat lost due to mortality are given in Table 7 (calculated per 1000 animals).

Feed = Weight · Conversion

Meat = 71% of broilers TABLE 7

From the table above it is clear that an increase in body weight also leads to an increase in feed consumption. An exception is building C4 with a high feed consumption despite a low weight.

Ending

The overall mortality rate was lowest in the group receiving the antibiotic combination of the invention, i.e. lincomycin-gentamicin (building C2), and was 4.63%, followed by amoxicillin trihydrate (building C4) with 5.43%, the combination of lincomycin-spectinomycin (building C3) with 5.99% and gentamicin (building C1) with 6.21%.

The greatest final body weight was in the group receiving the lincomycin-gentamicin combination (building C2) and was 1.87 kg, followed by the lincomycin-spectinomycin combination (building C3) with 1.85 kg, gentamicin (building C1) with 1.84 kg and amoxicillin trihydrate (building C4) with 1.77 kg, making the latter significantly different from the other three groups.

The efficiency factor was highest in the group that received the antibiotic combination lincomycin-gentamicin (building C2), followed by building C3 and then by C 1 and C4.

Conversion was lowest in the group treated with the antibiotic combination lincomycin-spectinomycin (building C3) and was 1.94 kg of feed for 1 kg of body weight gain, in the group treated with the antibiotic combination lincomycin-gentamicin the conversion value was 1.96 and thus the same as in the group treated with gentamicin. The group treated with the antibiotic amoxicillin consumed the highest amount of feed (2.05 kg) for 1 kg of body weight gain.

Example 2

Preparation for the treatment and breeding of animals

Lincomycin hydrochloride 360g

Gentamicin sulfate 10g

Polyethylene glycol 4000 in powder 40g

Lactose 590g

1000g

The preparation was prepared by mixing microgranulated solid components in a mixer and was then intended to be added to drinking water or animal feed.

Claims (5)

1. Additive to animal feed or drinking water, characterized in that it contains an antibiotic combination of gentamicin and lincomycin or of pharmacologically acceptable acid addition salts thereof. 2. Additive according to claim 1, characterized in that it contains 1 part by weight of gentamicin sulfate and 5 to 60 parts by weight of lincomycin hydrochloride as the antibiotic combination. 3. Additive according to claim 1 or 2 for use in poultry farming. 4. Animal feed, characterized in that it contains the additive according to one of claims 1 to 3. 5. Additive according to one of claims 1 to 3 or animal feed according to claim 4 for use in the prophylaxis and therapy of infections and consequently for increasing body weight and increasing the efficiency factor in fattening animals.