CA1059910A

CA1059910A - Control of lactic acidosis in ruminants

Info

Publication number: CA1059910A
Application number: CA219,858A
Authority: CA
Inventors: Larry A. Muir; Albert Barreto
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1974-02-22
Filing date: 1975-02-11
Publication date: 1979-08-07
Also published as: FR2261778A1; FR2261778B1; GB1479496A; ZA751091B; DE2507565A1; AU7807775A; JPS6037091B2; NL7501246A; JPS50129714A

Abstract

ABSTRACT OF THE DISCLOSURE

The nutritional disease, lactic acidosis, is successfully prevented by orally administering to the animal an effective amount of a sulfur-containing peptide antibiotic.
In particular thiopeptin and thiostrepton are particularly effective sulfur-containing peptide antibiotics useful against lactic acidosis.

Description

Backg'roun'd of'the'Inventi'on Lact;c acidosis has long been recognized as a nutritional disease that often occurs in ruminants following an extra large intake of readily fermentable carbohydrate. Traditionally, lactic acidosis occurred when cattle accidently gained access to the farmer's grain fields or grain supply. Today with the advent of high concentrate rations for cattle, lactic acidosis occurs frequently in high producing dairy cows that are placed on high concentrate diets too quickly following initiation of lactation; in feedlot cattle that are rushed too-quickly onto high concentrate rations and more subtly in feedlot cattle that are adapted to high concentrate consumption but experience changes in ration or feeding pattern.
In particular, lactic acidosis is a serious problem in cattle during the first few weeks in the feed-lot because of the stress due to starvation from shipping and conversion from a roughage to a concentrate diet.

' 10599~0 1 Cattle normally consume 10-12 meals per day which allows

2 rumen microbes to thrive. When no feed is ingested for

3 a prolonged period,such as when cattle are shipped to the

4 feedlot, most protozoa and many types of rumen bacteria perish. The lactate producer Streptococcus bovis,however, 6 survives starvation better than most rumen microbes so 7 that starvation increases the relative number of Strepto-8 coccus bovis. Most bacteria in the rumen are gram nega-9 tive and are involved in the conversion of dietary carbo-hydrates to volatile fatty acids. Streptococcus bovis on 11 the other hand is a gram positive rumen microorganism 12 that converts readily fermentable carbohydrates to DL-13 lactic acid. Normally Streptococcus bovis does not play a 14 predominant role in rumén fermentation and lactic acid is a minor product of rumen fermentation, however, when 16 ruminants not adapted to high starch ration consume lar~e 17 quantities of readily fermentable carbohydrate Strepto-18 coccus bovis multiplies rapidly often outgrowing all other19 rumen microorganisms,and produces great quantities of DL-lactic acid. The lactic acid lowers rumen fluid pH which 21 prevents normal fermentation by inhibiting other rumen 22 microorganisms and eventually enablQs lactobacillus, 23 another lactic acid producer, to establish itself in the 24 rumen. The large quantities of DL-lactic acid produced in 25 the rumen are absorbed. L-lactic acid is metabolized by 26 the animal but D-lactic acid accumulates in the blood 27 causing a depletion of the alkali reserve and a shift in 28 blood pH which can cause death.

2~ Lactic acidosis is a major problem in feedlot cattle. Lactic acidosis causes a significant loss in l animal production even when the animal survives because 2 of conditions associated directly or indirectly with the 3 disease. These conditions include anorexia, rumen dis-4 function, diarrhea, weight loss, founder and rumenitis.
Rumenitis,an ulceration of the ruminal wall,allows rumen 6 microorganisms especially Spherophorus necrophorus to 7 gain access to the portal circulatory system. These 8 microbes are removed by the liver where they cause liver 9 abscesses which reduce weight gain and feed efficiency.In addition the abscessed livers are condemned at slaughter 11 resulting in further economic losses. Thus lactic acidosis 12 reduces animal productivity not only through death losses 13 but also through reduced performance caused by poor animal 14 health. The only known method of preventing lactic acido-sis is to slowly adapt cattle to a high energy ration. The 16 time required to adapt cattle is not well defined,however, 17 most cattle feeders allow at least 3 to 4 weeks. During 18 this time most feeders gradually switch from a ration l9 having a concentrate to roughage ratio of 1:3 to a ration having a ratio of 3:1 or higher. One of the problems 21 with this approach is that the low energy rations used 22 initially do not produce sufficient energy for restoration 23 of animal health and disease resistance following the 24 stre~s of shipping to the feedlot. In addition, slow adaptation does not allow for rapid adjustment to fatten-26 ing (high energy) rations which cost the cattle feeder 27 time and money. None of the antibiotics presently avail-28 able for use in ruminants control lactic acidosis.

29 It is an aspect of this invention that the antibiotics employed in the treatment of lactic acidosis be effective against the microorganism Strepto~oocu~ bovis, however, all antibiotics effective against Streptoaoa~us bovis may not be effective against lactic acidosis. Should the antibiotic destroy significant numbers of rumen microorganisms beyond Strepto~ocaus bov~s then rumen functions will effectively cease and metabolism of ingested feed will also cease resulting in serious nutritive disorders. Normal rumen bacteria consists primarily of gram negative bacteria. Thus it is also an aspect of this invention that the antibiotic have a spectrum substantially limited to gram positive bacteria and excluding the majority of the normal rumen bacteria in order that the normal rumen microorganisms not be effected so that normal rumen function continues while the antibiotic is being administered to the ruminant.
Description of the Invention Thus it is an object of the instant invention to provide for a composition for the prevention of lactic acidosis in ruminants. Another object is to provide for the oral administration of an agent to prevent the occurrence of lactic acidosis in ruminants. A further object is to provide for compositions for the prophylactic or therapeutic treatment of lactic acidosis in ruminants employing sulfur-containing peptide antibiotics administered orally. A still further object of this invention is to provide for compositions for the prevention of lactic acidosis in ruminants containing sulfur-containing peptide antibiotics. Further objects will become apparent upon reading the complete disclosure.

1 It has been discovered that certain antibiotics, 2 specifically that class of antibiotics described as sulfur-3 containing peptide antibiotics having a molecular weight 4 in excess of 900 which are active against gram positive bacteria, are effective in preventing and treating lactic 6 acidosis in ruminant.s. Such sulfur~containing peptide 7 antibiotics have been discovered to be narrow spectrum anti-8 biotics particularly effective against Streptococcus bovis, 9 however, having no substantial effect at use levels on other rumen microbes, thus allowing for the normal rumen 11 function to continue. The narrow-spectrum, sulfur-contain-12 ing peptide antibiotics of this invention are defined as 13 those antibiotics which are effective in inhibiting the 14 growth of Streptococcus bovis while at the same time having a minimal effect on the growth of the gram negative bacteria 16 normally present in the digestive system of ruminants and 17 which antibiotics are peptidal in nature and contain sulfur 18 as an integral element thereof, and exceed 900 molecular 19 weight.
Examples of such sulfur-containing peptide anti-21 biotics are: thiopeptin, thiostrepton, theiomycetin, ami-22 cetin C, siomycin, sporangiomycin, thermothiocin,sulfomycin, 23 multhiomycin, cyromycin, actinotiocin, leucopeptin, arsi-24 mycin and the like.
In addition to the utility of the above disclosed 26 antibiotics as lactic acidosis preventive agents, they also 27 find utility as growth permittants in ruminants.

., 15~41 1~59910 1 The above sulfur-containing peptide antibiotics 2 may be administered orally to a ruminant when the 3 conditions are such that the animal is predisposed to 4 lactic acidosis. That is when it is suspected that ingestion of high carbohydrate feed will cause the 6 fermentation thereof due to the microorganism Strepto-7 coccus bovis and results in the production of quantities 8 of lactic acid detrimental to the health of the animal.
9i Under such conditions the oral administration of a sulfur-containing peptide antibiotic will result in a 11 prevention of the production of toxic quantitites of 12 lactic acid. The antibiotic may be orally administe.red 13 in a solid dosage from such as a tablet, bolus, capsule 14 and the like or in a liquid unit dosage form such as a drench. In addition thé antibiotic may be administered 16 as a component of the animal's normal daily feed ration.
17 That is it may be uniformly admixed with the animal's ~8 solid feed or uniformly dispersed or dissolved in the ~9 animal's drinking water supply.

lOS9910 When the antibiotics of this invention are included in a drench formulation, it is normally as an aqueous suspension or dispersion of the antibiotic together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally the drenches also contain an antifoaming agent. Preferred drench formulations contain from about 0.1 to 50% by weight of the antibiotic. Especially preferred are drench fonmulations containing from about 2 to 25% by weight of the antibiotic. When the antibiotics of this invention are employed in a solid unit dosage form such as tablets, capsules and boluses the active ingrediene is admixed with a carrier vehicle such as starch, talc, magnesium stearate, or dicalcium phosphate. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents,fillers disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. The antibiotic may be present in the solid unit dosage formulation at a concentration of from about 0.1 to 95% by weight. Such unit dosage formulations both liquid and solid may be varied widely with respect to their total weight and content of antibiotic agent depending upon factors such as the type of host animal to be treated, and the weight of the host.
When the antibiotic is to be administered via the animal feedstuff it is intimately dispersed in the feed or else used as a top dressing or in the form of pellets which are then added to the finished feed.

10599~0 The antibiotic agents of this invention find their primary used in the treatment of ruminants such as sheep and cattle~ ~he optimum amount of antibiotic to be employed for the treatment of a particular animal, will depend on the particular antibiotic employed, the species of animal to be treated, and the weight the animal.
Generally good results are obtained with the antibiotics of this invention by the oral administration of from about 0.05 to 10 mg. per kg. of animal body weight per day, such dose being given at one time or in divided doses over a period of time. With the preferred antibiotics of this invention, excellent control of lactic acidosis is obtained in cattle and sheep by administering from about 0.20 to 10 mg. per kg. of body weight in a single dose. The antibiotic may be administered to the ruminant for a period of time which corresponds to the period of time necessary for the animal to become adjusted to the high energy feed that is up to about 30 days. In this way the antibiotic treatment may be withdrawn and the animal allowed to feed normally on the high energy feed. However, as afore-mentioned an animal already ad~usted to high energy feed may sometimes for reasons not fully understood develop lactic acidosis. Thus it may be desirable to maintain the animal on these antlbiotics for the entire duration of the animals being fed high energy feed. The techniques for administering these materials to animals are known to those skilled in the veterinary field.
When the antibiotics described herein are administered as a component of the animals feed or ` 10599~0 dissolved or suspended in the animal ! S drinking water, compositions are provided in which the antibiotic is intimately dispersed in an inert carrier or diluent.
By inert carrier, is meant one that will not react with the antibiotic and one that may be administered safely to animals. Preferably the carrier is one that is or may be an ingredient of the animal ration.
Suitable compositions include feed supplements in which the active ingredient is present in relativelg large amounts and which are suitable for addition into the feed either directly or after an intermediate dilution or blending step. Such compositions may also be added to the animals feed in the form of a top dressing. Typical carriers or diluents suitable for such compositions include for example distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, wheat shorts, molasses solubles, corncob meal, edible bean mill feed, soyagrits, crushed limestone and the like. The active antibiotics are intimately dispersed throughout the carrier by methods such as grinding, stirring, milling or tumbling.
Compositions containing from about 0.1 to 50% by weight, especially from about 0.5 to 25% by weight of the antibiotic are particularly suitable as feed additives.
Such supplements are added to the animal feed in an amount to give the finished feed the concentration of antibiotic desired for the treaement and control of lactic acidosis. Although the desired concentration of antibiotic will vary depending on the factors previously mentioned as well as upon the 1 particular antibiotic employed, the sulfur-containing 2 peptide antibiotics of this invention are usually fed at 3 concentrations of between 0.0002 and 0.02% in the feed in 4 order to achieve the desired effect against lactic acidosis.
The sulfur-containing peptide antibi~tics of 6 this invention may be added to the feed supplements and unit 7 dosage forms described above in the form of a purified anti-8 biotic or as a component of the mycelium cake obtained 9 directly from the fermentation broth.
Thiopeptin is a sulfur-containing peptide anti-11 biotic whichhas proven to be an active agent against lactic '~ acidosis. Thiopeptin has been discovered as being an active 13 agent against Streptococcus bovis while, however, being 14 narrow in spectrum and in fact having no effect upon most microorganisms present in ruminants which control the normal 16 digestive function. Furthermore, being of high molecular 17 weight, thiopeptin is retained in the rumen fluid and is 18 not lost by absorption.
1~ For comparison purposes, the activity of a ~0 broad spectrum antibiotic was compared with thiopeptin to 21 demonstrate that merely because an antibiotic is active 22 against Streptococcus bovis is no indication that said _.
23 antibiotic will be effective against lactic acidosis.
24 Thiopeptin is active against Streptococcus bovis in an in vitro test at a minimum inhibitory concentration 26 of 0.016 ~g per ml while penicillin G is active at 0.004 ~g 27 per ml in the same in vitro test. However, in order to 2& test whether or not antibiotic is effective against lactic 29 acidosis, an in vivo test has been developed in which the efficacy of antibiotics for preventing lactic acidosis can 31 be readily determined.

1 Lactic acidosis is consistently induced in 2 sheep that have been fasted for 24 hours by dosing 3 them with a slurry of finely ground wheat at 4% of 4 body weight and water (1:2, weight to volume) through a rumen fistula. The pH of rumen fluids samples taken 6 every 2 hours for 28 hours dropped quickly from about 7 7.0 to 4.0 and remained at about 4.0 until death which 8 occurred between 18 and 40 hours. Lactic acid in the 9 rumen fluid of these sheep increased extremely rapidly from normal levels of about 20 ~g. per ml. to over 11 11,000 ~g. per ml. by 8 hours and remain elevated until 12 death. Volatile fatty acids in the rumen fluid increased 13 temporarily but by 12 hours were below the ~4 hour 14 starvation levels indicating that almost all normal rumen fermentation was inhibited. Plasma lactic acid levels 16 increased as lactic acidosis developed increasing from 17 a normal range of from about 150 to 400 pg. per ml. to 18 about 1,300 ~g. per ml. at death. When penicillin G is 19 administered to the above fistulated sheep at a dose or 150 mg. per sheep at 0 and 6 hours after dosage with 21 ground wheat, there is no observed lactic acidosis, 22 however, almost all rumen fermentation was eliminated.
23 Penicillin G is active against too broad a spectrum of 24 microorganisms, so that it eliminated not only the Streptococcus bovis microorganism but also it eliminated 26 most of the other microorganisms in the rumen, thus 27 effectively stopping all digestive processes. Such a 28 situation is not desirable and results in the cessation 29 of the production of volatile fatty acids which are the primary energy source for the animal derived from the digestion of the feed. With the ceased production of volatile faety acids due to the stoppage of normal rumen function, anorexia, a loss of energy, and either a loss of weight or at least a lack of a gain of weight was observed. Thus penicillin G being too broad a spectrum antibiotic and being active against Strepto-coccus bovis is seen to be unacceptable as an agent for the prevention and cure of lactic acidosis.
Experimental in vivo studies in sheep have shown that thiopeptin at levels of 17.5 mg. per animal or higher successfully prevented lactic acidosis in ruminants. Four groups of 2 fistulated sheep each are dosed with wheat and 17.5, 35, 70 and 140 mg. of thiopeptin (rates of about 0.4, O.ô, 1.75 and 3.5 mg./kg.
respectlvely) in a same manner as previously described for the control of animals. Rumen fluid pH dropped quickly but leveled off at a higher level (4.5 to

5.0) than controls given wheat alone. Rumen fluid lactic acid levels increased moderately after dosing, peaking at about 4,000 ug. per ml. at 8 hours and returning to normal levels of about 20 ug. per ml. by 12 hours after dosing. Plasma lactic acid levels were not altered in thiopeptin protected ruminants. Total volatile fatty acid levels in the rumen fluid of thio-peptin protected ruminants increased over the 30 hours test period from a range of 25 to 50, to 150 to 200 micromoles per ml. lndicating that rumen fermentation was not inhibited. Thus thiopeptin at 17.5 mg. or higher per animal(0.4 mg./kg.) protected 8 of 8 ruminants against lactic acidosis following administration of a large 1564~

1 quantity of carbohydrate while control animals consistently 2 developed severe lactic acidosis resulting in death.
3 Studies have been conducted to determine any 4 possible effects of thiopeptin on normal rumen fermentation and/or feed intake of ruminants adapted to various levels

6 of readily fermentable carbohydrate consumption. Two dose

7 levels of thiopeptin (0, 10 and 25 grams per ton) added to

8 3 rations containing different levels of grain and were

9 fed normally to 9 groups of 2 or 3 sheep each. The animals weigh~d an average of 45 kg and ate from 1 to 2 kg of feed 11 per day. Ration A contained 32% cracked corn; ration B
l~ contained 70% cracked corn; and ration C contained 30%
13 ground corn plus 50~ ground wheat. ~fter an adaptation 14 period feed intake is measured daily for 2 weeks and rumen fluid samples taken twice daily on 4 days during a 2 week 16 period and analyzed for volatile fatty acid content. Thio-17 peptin had no effect on the concentration of acetate, 18 propionate, butyrate or on the concentration of total vola-l9 tile fatty acids in the rumen fluid. Also thiopeptin did not alter feed intake. These data show that thiopeptin does 21 not have any detrimental effect on rumen fermentation or 22 feed intake.
23 In addition, thiopeptin has been tested in cattle 24 in an experimental test similar to the above sheep test designed to show its efficacy in preventing lactic acidosis.
26 Fistulated cattle are dosed with a slurry of finely ground 27 wheat at about 4% of body weight and water (1:2 weight 28 to volume) after a starvation period of 48 hours.

_ 15641 1 A~ in the fistulated sheep test the rumen fluid pH dropped 2 to about 4.0 and blood pH dropped below 7.0 whereupon death 3 occurred in the control animals.
4 When 0.75 or 1.50 mg./~g. of thiopeptin is S administered with the wheat slurry the rumen fluid 6 pH level stabilized at greater than 5 and there was 7 no effect on the blood pH. The control a~imals 8 invariably died at from 25 to 60 hours while the ~9 medicated cattle remained healthy, adjusting ;~ 10 to the high energy feed.
11 Thiostrepton, another sulfur-containing peptide 12 antibiotic has been shown to be equally effective as :1 ~
13 thiopeptin in inhibiting Streptococcus bovis in the 14 in vitro test system. The minimum inhibitory 15 concentration for thiostrepton is 0.016 ~g per ml I~16 in the in vitro test.
i i~17 Lactic acidosis in ruminants can thus now 18 be prevented with this invention by feeding rations 19 containing appropriate levels of thiopeptin or other 20 sulfur-containing peptide antibiotics. This will 21 reduce the incidents of anorexia, rumen disfunction, ,, ~ , .
22 rumenitis, diarrhea, founder, liver abscesses and 23 death in ruminants, and therefore will improve growth :::
24 and Yeed efficiency. This invention will also allow 25 ruminants to be switched more rapidly from a low to a 26 high energy ration and thus reduce the time and cost 27 required to fatten ruminants for market.

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A composition suitable for adding to high energy feed for the prevention of lactic acidosis in ruminants and for shortening the period of adaptation of said ruminants to a high energy feed from a low energy roughage feed which comprises a sulfur-containing peptide antibiotic with a molecular weight in excess of 900 in admixture with an animal feed additive, the amount of antibiotic being from 0.1 to 50% by weight of the feed additive.

2. A concentrated composition of Claim 1, wherein said sulfur-containing peptide antibiotic is thiopeptin or thiostrepton.

3. A concentrated composition of Claim 2, wherein said antibiotic is present to the extent of from 0.5 to 25% by weight.

4. A concentrated composition of Claim 2, wherein said composition is a feed premix for uniform admixture with the animal's daily feed ration.

5. A concentrated therapeutic composition of Claim 2, wherein said composition is a top dressing for the animal's daily feed ration.