Field of the Invention
The invention relates to compositions and methods for the treatment of bacterial infections, parasitic infections and parasitic infestations in animals. More particularly, the invention relates to a composition containing both an antibiotic and parasiticide for use in the treatment of bacterial infections, parasitic infections and parasitic infestations in animals such as cattle, sheep and swine.
Background of the Invention
All references cited herein are hereby incorporated in their entirety by
reference.
Feedlots are in general use with beef cattle in the United States, Canada

they acquired from pastures contaminated with helminth larvae, where the calves grazed prior to their shipment to the feedlot Elimination of external and interna! parasites at this time breaks the cycle of parasitism and prevents their spread to the other animals in the feedlot as calves and other animals are less likely to acquire parasites in the feedlot because they eat feeds that are free of parasites from bunks or mangers.
Without the use of parasiticides, internal and extemal parasites have been one of the most economically-important constraints in raising livestock. The

damage worms cause ranges from decreased productivify of the animals to their death.
First line therapy for the treatment of parasitic worms is often carried out via the administration of an antiparasitic compound. One class of these compounds is avermectins. The avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals.
In addition to the risks of parasitic infestation and widespread infection of cattle or otiier animals in the feediot, the commingling of calves and other livestock from diiferent sources causes the calves and other animals to be exposed to pathogens for which immunity has not developed. The stresses of shipping and change in diet reduces the calves' and other animals' immune defenses. Additionally the poor weather of autumn, when calves and other livestock are usually moved from pastures to feedlots, further increases the risk of illness.

It has become common to administer antimicrobial drugs to calves and other feediot animals at the time of arrival into a feediot, in order to reduce the incidence and severity of respiratory illness in the feediot cattle and other stock.
Without the use of antimicrobial agents, bovine respiratory disease (BRD) has been one of the leading causes of economic loss to the cattle industry throughout the worid. Excessive mortality, reduced weight gains, and the cost of treatment and prevention have placed a heavy burden on the industry.

Bovine respiratory disease (BRD) occurs in both dairy and beef cattle and is one of the leading causes of economic loss to the cattie industry throughout the world. These economic losses are due to excessive mortality, reduced weight gains as well as treatment and prevention costs. BRD is often referred to as the ' "bovine respiratory diseases complex" due to the multifactorial etiology.
The cost of death losses due to respiratory diseases vary around the world. Death losses in the U.S. are estimated to approach $1 billion annually. Losses in various European countries range from $75 to $120 million. Cattle with clinical or sub-clinical BRD do not gain weight or produce milk as well as healthy animals. Beef cattle witti BRD gain less weight, have reduced feed efficiency and often produce a lower grade carcass at slaughter. Perino L.J., Apley M., SoWne Respiratory Disease, in CURRENT VETERINARY THERAPY 4 (FOOD ANIMAL PRACTICE), 4™ ED. 446-455 (Howard J.L„ Smith R.A., eds., 1999). A direct correlation between pulmonary lesions obs^ved st slaughter and reduced weight gains has been established in catte wSi sub-dinicsy infecticms. Whrttem T.E. ef a/., J. Am. Vet. Med. Assoc, 209:S14-S15 (1-^6)-
In addition to the production fosses associated with mortality and morbidity, significant costs are associated with the treatment of BRD due to the costs of various therapeutic agents and the labor required to administer these agents, along with the extra labor to isolate and observe these animals.
The pathogenesis of BRD is thought to be due to the interaction of environmental and physiological stresses coupled with infectious agents. Marinheimia (Pasteurella) haemolytica, Pasteurella multocida and f-iaemophilus

somnus are considered part of the normal flora of the bovine upper respiratory tract. When environmental and physiological stress factors reduce the natural resistance and inhibit the pulmonary defense nr>echanisms these organisms proliferate and colonize the lower respiratory tract. In addition, various bovine viruses such as infectious bovine rhinotrachertis virus (IBRV), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV) and parainfluenza 3 vinjs (PI-3) are known to have immunosuppressive effects in the lung.
Similarly, swine respiratory disease (SRD) also has a muitrfactional etiology. Bacterial infections caused by P. multocida, H. parasuis, Bordetella bronchisepfica, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cl;)olerasuis and Mycoplasma sp. can result In respiratory disease in swine, resulting in significant economic losses. Stresses such as crowding, mixing and moving of pigs and transient viral infections can contribute to the intensification of the disease.
For years antimiatibiai ifierapy has been the mainstay of BRD therapy.

of BRD. NUFLOR©, an 'mjeoabJe fomiulafen of the broad spectrum antibiotic Florfenicol, has emerged as one of the leading antibiotics on a global basis. It is indicated for the treatment and control of BRD associated with M. haemolytica, P. multocida and H. somnus as well as for the prevention of respiratory disease in cattle at high risk of developing BRD associated with these bacteria. NUFLOR® is also indicated for the treatment of bovine interdigital phlegmon (footrot, acute interdigital necrobacillosis, infectious pododermatitis) associated with


be administered subcutaneously as wel! as intramusculariy.
The above mentioned products are typically administered as a single active component formulation - typically by some form of injection, pour on formulation or by oral administration. When the formulation is injectable, there are certain considerations that need to be taken into account Multiple injections at the same or different sites can tead to local inflammation and irrftation. Addrtionally, as the subject to be treated often must be caught and handled, there is an increase in the labor involved in administering the medication. Thus, it would be beneficial to use a formulation that contained both an antibiotic in combination with an antiparasitic agent to remedy the aforementioned problems. Accordingly, there is a need for conveniently administered, stable compositions that can control and prevent the infections associated with bovine respiratory disease and other infectious diseases as well as control and prevent parasitic infections.
Stgnmarv of the Invenlion
The present invsniion provides improved compositions and methods for the treatment of respiratory disease, parasitic infection, parasitic infestation, bacterial infection and other infections of cattle and other animals.
Accordingly, there is disclosed a composition for the treatment of microbial and parasitic infection in an animal comprising
a) a compound selected from the group consisting of
a compound of Formula I;


wherein R is a member selected from the group consisting of methyl or ethyl or a halogenated derivative thereof, dihalogenodeuteriomettiyl, 1-halogeno-1-deuterioethyl, 1,2-dihalogeno-1-deuterioethyl, azidomethyl and methyl sulfonylmethyl;

and Z is hydrogen or an acyi group of a hydrocarboncarboxyJic add having up to 16 carbon atoms or an acyl group of an aminohydrocarboncartraxyiic acid having up to 12 carbon atoms; and the phamnaceutically acceptable salts of said acyl groups; b) an endectocidic compound possessing antiparasitic activity; and
c) a carrier.

There is also disclosed a composition fortiie freatment of a microbial and parasitic infection in an anima! comprising: a) a macrolide antibiotic selected from the group consisting of THmicosin and Tulathromycin; b) an endectocidic compound possessing antiparasitic activity; and c) a carrier.
There is also disclosed a composition for the treatment of a microbial and parasitic infection in an animal comprising: a) a cephalosporin selected from the group consisting of Ceftiofur and Cefquinome; b) an endectocidic compound possessing antiparasitic activity; and c) a carrier.
There is also disclosed a composition for the treatment of a microbial and parasitic infection in an animal comprising: a) a fluorciquinolone antibiotic selected from the group consisting of Enrofloxacin, Danofloxacin and Mari^ofloxacin; b) an endectocidic compound possessing antiparasitic activity; and c) a carrier.
There are also discbsed methods of using the formulations of the present invention to treat bacterid arrd parasitic based infectbns.

The invention provides novel compositions for the treatment of infectious diseases such as bovine respiratory disease in livestock as weW as parasitic infections and infestations. These compositions are formulations comprising an antiparasitic compound, preferably an avermectin, in combination with certain antibacterial drugs, such as, for example, Rorfenico(, Tilmicosin, Tulathromycin, Ceftiofur, Cefqulnome, Enrofloxacin, Marbofloxacin or Danofloxacin.

The following terms will be defined as is known to one of skill In the art. "Acyl" means an H-C(O)-, alky!-C(0)-, aIkenyl-C{OK alkynyl-C(O)-, cycloalkyl-C(0)-, cyc)oaJkenyJ-C(O)-, or cycloa)kynyl-C(O)- group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyf. Preferred acyls contain a lower afkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyi and cyclohexanoyl.
"AlkyJ" means an aliphatic hydrocarbon group, which may be straight or branched, comprising from 1 to about 20 carbon atoms in the chain. Preferred alk^d groups contain from 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alky! groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower aikyi" means a group having from 1 to about 6 carbon atoms in the chain, which rr^y be straight or branched. The term "substituted alkj^" means Itiat the alkyi group r?sy be sitstifeited by on atoms that may be saturated, unsaturated, straight chain, branched chain or cyclic, that may contain aromatic groups and that may be substituted by hydroxyl groups.

Preferred ester derivatives include those derived from dibasic hydrocarboncarboxylates, e.g. the 1-succinate and 1-palmitate esters, which provide water soluble, pharmaceuticafly acceptable cationic salts, e.g. the sodium or potassium salts as well as salts witti amine, e.g. trimethylamine. Also preferred are ester derivatives of amino acids that provide water soluble, pharmaceutically acceptable acid addition salts with mineral or organic acids, e.g. the hydrochloric, or sulfuric acid, or succinic acid addition salts.
As used herein the tenn "pharmaceutically acceptable salts" thus includes salts wherein the acidic hydrogen in the dibasic hydrocarboncarboxylate esters of this invention is replaced with a cation (e.g. sodium D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propyl hemisuccinate) as well as salts wherein the acidic hydrogen forms art add addition salt with an amine (e.g. D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propyl hemisuccinate N-trimethylamine salt). Also included are the add addfiion s^ts formed between mineral or organic

Among the pharmaceutically acceptable cationic salts of the dibasic hydrocarboncarboxylate esters included in Formula I are salts of a\ka\'t and alkaline earth metals (e.g., sodium, potassium, calcium, aluminum) and salts with an amine such as trialkylamines, procaine, dibenzylamine, N-benzyl-beta-phenethylamine, N,N'-dibenzylethylenediam(ne, N-(lower)alkylpiperidines {e.g. N-ethylpiperidine), and N-methyl glucamine.

Preferably R is a haiogenated derivative of methyl or etfiyi, Z Is a hydrogen, X is phenyl, CORi or SO2R1, Ri is methyl, and X" is hydrogen. Most preferably R is CHCI2 or CHF2.
V
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodnjg", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical convereion by metabolic or chemical processes to yie\6 a compound of formula 1 or a satt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.; American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
"Solvate" means a physical association of a compound of this invention -with one or more solvent molecules. This physical assodation involves varying degrees

molecules are incorporated in the crystal latSce of the crystainne solid. "Solvate" encompasses both soiutbn-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a
f
solvate vi^erein the solvent molecule is H2O.
A preferred antibiotic compound is Florfenicol, also known as (D-(threo>-1^p mettiylsulfonyl phenyl-2-dlchloroacetamido-3-fluoro-1-propanoi). Another preferr© antibiotic compound is D-(threo)-1-p-methylsulfonyl phenyi-2-difluoroacetamido-3-

fluoro-1-propanol. Another preferred antibiotic is Thiamphenicol. Processes for the manufacture of these preferred antibiotic compounds, and Intermediates useiijl in such processes, are described in U.S. Patent Nos. 4,311,857; 4,582,918; 4,973,750; 4.876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673; 5,352,832; and 5,663,361. When the antibiotic compound ts Florfenicol, the concentration of FlorfenlcDl typically is from about 10% to about 50% w/v, with the preferred level between about 20% and about 40% wN, even more preferred being at least about 30% w/v.
Another preferred antibiotic compound is Tilmicosin. Tiimicosin is a macrolide antibiotic that Is chemically defined as 20-dihydro-20-deoxy-20-(cis-3,5-dimethy(piperidin-1-yl)-desmycosin and which is reportedly disclosed in U.S. Pat. No. 4,820,695. Also disclosed in U.S. Pat. No. 4,820,695 is an injectable, aqueous formulation comprising 50% (by volume) propylene glycol, 4% (by volume) benzyl alcohol, and 50 to 500 mg/ml of active ingredienL Tilmicosin may be present as the

administered by injection over a 4 day treatment period. Accordingly, Tflmicosin may be used in treatment of, for example, neonatal calf pneumonia and bovine respiratory disease. When Tilmicosin is present, it is present in an amount of about 1% to about 50%, preferably 10% to about 50%, preferably 30%.


administered by injection over a 4 day treatment period. Accordingly, Tilmicosin may be used in treatment of, for example, neonatal calf pneumonia and bovine respiratory disease. When Tilmicosin is present, it is present in an amount of about 1% to about 50%, preferably 10% to about 50%, preferably 30%.
Another suitable antibiotic for use in the present invention is Tulathromycin. Tulathromycin has the following chemical structure:


hexopyranosyl]oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14~hexamethyl-11 -I[3,4,6-trideoxy-3-(dimethylamino)-p-D-xylo-hexopyranosyl]oxy]-, (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R). Tulathromycin may be prepared in accordance with the procedures set forth in U.S. Publication No. 2003/0064939 A1, which is incorporated by reference in its entirety. Tulathromycin may be present in injectable dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. Tulathromycin is most desirably administered in dosages ranging

Tulathromycin may be present in injectable dosage forms at concentration levels ranging from about 5.0% to about 70% by weight
Also preferred antibiotics for use in the present invention include '-ephaiosporins such as, for example, Ceftiofur, Cefquinome, etc. The ;oncentration of the cephalosporin in the formulation of the present invention may 'ary between about 1 mg/ml to 500 mg/ml.
Also preferred antibiotics include fluoroQuinoiones, such as, for example, Enrofioxacin, Danofloxacin, Difloxacin, Orbifloxacin and Marbofloxacin. In the case 3f Enrofioxacin, it may be administered in a concentration of about 100 mg/ml. Danofloxacin may be present in a concentration of about ISO mg/ml.
Other preferred macrolide antibbtlcs include compounds from ttie class of ketolides, or, more specrficatly, the azaiides. Such compounds are described in, for example, U.S. Patent Nos. 6,514,945, 6,472,371, 6,270. 768,6,437,151 and 6,271,255, assigned to Pfizer, and 6,239,112, 5,958,888, assigned to Meriaf, and 6,339,063 and 5,054,434, assigned to Mendc & Co^ afl of vmich are incorporated by reference in Ihelr entirety.

Oxytetracyciine. Other antibiotics may include p-lactams such as penicillins, e.g.. Penicillin, Ampicillin, Amoxicillin, or a combination of Amoxicillin with Clavulanic acid or other beta lactamase inhibitors
Additionally, the present invention may encompass a composition for the treatment of a microbial and parasitic infection in an animal comprisingia) oxytetracyciine; b) an endectocldic compound possessing antiparasitic activity such

as Ivermectin, Doramectin, Abamectin, Selamectin, Emamectin, Eprinomectin, Moxidecttn and Milbemycin; and c) at least one carrier.
Antiparasitic compounds useful within the scope of tlie present invention are preferably comprised of Ihe class of avermectin compounds. As stated above, the avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals. The compositions of the present mvent'ron are useful against both internal parasitic infection and external parasitic infestation.
A preferred compound for use within the scope of the present invention is Ivermectin- Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B1a and less than 20% 22,23-dihydroavermectin Bib- Ivennectin is disclosed in U.S. Pat. No. 4,199,569, hereby incorporated by reference. Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since the mid-1980's.
AbamecSn is an avermsctin that is disacsed in U.S. P^ Ho. 4,310,519, the
entirety of which is incorporated herein fay reference, as avemiectin B1 a/BI b.
Abamectin contains at least 80% of avermectin Big and not more than 20% of
avemnectin B1b.

Another preferred avermectin is Doramectin also known as 25-cycIohexyl-
avermectin Bi. The structure and preparation of Doramectin, is disclosed in U.S.
Pat. No. 5,089,480, which is herein incorporated by reference.
Another preferred avermectin is Moxidectin. Moxidectin, also known as LL-
F28249 alpha is known from U.S. Pat. No. 4,916,154, which is herein incorporated

by reference.
Another preferred avermectin is Selamectin. Selamectin is 25-cyclohexi^-25-de(1-methylpropy!)-5-deoxy-22,23-dihydro-5-(hydroxyimino) avermectin Bi monosaccharide.
Milbemycin, or B-41, is a substance which is isolated from the fermentation broth of a Milbemycin producing strain of Streptomyces. The microorganism, the fermentation conditions and the isolation procedures are more fully described in U.S. Pat. No. 3,950,360 and U.S. Pat. No. 3,984,564.
Emamectin (4"-deoxy-4" epimethylaminoavermectin B.sub.1), which can be prepared as described in U.S. Pat. No. 5,288,710 or 5,399,717, is a mixture of two homologues, 4"-deoxy-4"-epi-methylaminoavermectin B1a and 4"-deoxy-4"-epi- ;- ;, . methylaminoavermectin B1b. Preferably, a salt of Emamectin fs used. Non-limitJng examples of salts of Emamectin which may be used in the present invention include the salts described in U.S. Pat. No. 5,288,710, e.g., salts derived from benzoic acid,

Eprinomectin is chemically known as 4"- epi- Acetyiamino - 4"- deoxy -avermectin Bi. Eprinomectin was specifically developed to be used in all cattle classes and age groups. It was the first avermectin to show broad-spectoim activity against both endo- and ecto- parasites while also leaving minimal residues in meat and milk. It has the additional advantage of being highly potent when delivered topically.

The compositions of the present invention may also further comprise a flukicide. Suitable flukicides Include, for example, Tridabendazole, Fenbendazoie, Albendazole, Ciorsulon and Oxibendazole. It will be appreciated that the above combinations may further include combinations of antibiotic, antiparasitic and anti-fluke active compounds.
The fomnuiations of the present invention may be administered by Injection. In addition to greater convenience and ease of use with a combination product formulation, it is believed that a single daily subcutaneous administration of a combination product in accondance with the present invention wiU promote humane animal care by reducing the numJDer of injections needed to treat animals. By reducing the number of injections, manpower costs also may be significantly reduced. Alternatively, the formulations of the present invention may be administered as a pour on solution. In another embodiment, the fomnuiations of the present invention may be administered, for example, orally, such as a feed additive

Florfenicol is generally soluble in aprotic polar solvents such as a pyrroildone
solvent, or N,N-dimethylacetamide, N,N-dimethylformamide, DMSO, acetone or
glycerol formal. Preferred pyrrolidone solvents are N-methyl-2-pyrroiidone and 2-
pyrrolidone. Accordingly, such an aprotic polar solvent (or a combination of such
solvents) is prefen-ed for use in formulations of the oresent invention that contain

Fiorfenicol or similar antibiotics. Preferably sudi a sotvent is present at atraut 5% to about 80% by weight of the formulation. More preferably such a solvent is present at about 10% to about 35% of the formulation.
Other pharmaceutically acceptable solvents may be present in the formulations of the present invention. Suitable solvents include water, ethano), jsopropanoi, 1 ^-propanediol, glycerin, benzyl alcohol, triacetin dimethylisosorbide, dimethylisosorbide, triacetin, glycol ethers, monothioglycerol, propylene glycol and polyethylene glycol (PEG). Particularly preferred solvents include PEG having an average molecular weight between about 200 and about 400, triacetin, dimethylisosorbide, ethanol, and water, and combinations thereof. These solvents may comprise from 0% to about 75% of the formulation. Preferably they comprise from about 15% to about 60%. More preferably they comprise from about 40% to about 55% of the formulation.

the fomiulations of the present invention include water, ethanol, isopn^panoi, propylene glycol, dimethylisosorbide and triacetin, and oDmbinations thereof.
Other inert ingredients can be added to the present composition, as desired. Such ingredients include preservatives, chelating agents, antioxidants and stabilizers. Exemplary preservatives include methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). Exemplary

chelating agents include edetate sodium. Exemplary antioxidants include butylated hydroxyanisoie and sodium monothoioglycerol.
In order to prepare the composition of the present invention, Vne V6hicle(s) or a portion of the vehide{s), are added to the compounding vessel, followed by the remaining exciplents and the actives. The mixture is mixed until all solids are dissolved. Addrtional solvent to bring the composition to final volume may be added if needed. Additives, such as those fisted above, may also be included in the vessel and mixed into the fonnulation {the order of addition is not critical).
When the antibiotic is Florfenicol, the compositions according to the present invention will generally be administered to cattle at from about 1 mg to about 100 mg of the antibacterial per kilogram of body weight. Preferably the compositions of the present invention will be administered to bovines at from about 20 mg to about 50 mg of the antibacterial per kilogram of body weight. More preferably the dose

Preferably, when the antibiotic is tilmicosin, the dose of Tilmicosin would be about 10 milligrams/kilogram. Tulathromycin is most desirably administered in dosages ranging from about 0.2 mg per kg body weight per day (mg/kg/day) to about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day), and more preferably 1.25, 2.5 or 5 mg/kg as a single dose, although variations will

necessarily occur depending upon the species, weight and condition of the subject being treated.
Preferably, for Ceftiofur hydrochloride, the concentration is about 50 mg/ml. It may be administered as 1 to 2.2 mg/kg of body weight by intramuscular or subcutaneous injection, at 24-hour intervals for 3 to 5 consecutive days.
For singlendose therapy, Enrofloxacin may be administered 7.5 to 12.5 milligrams Enrafioxacin per kilogram of body weight For multiple-day Itierapy it may be administered 2.5 to 5.0 milligrams per kilogram of body weight administered subcutaneously once daily for 3 to 5 days. In the case of Danofloxacin, it may be administered in a concentration of about 180 mg/ml at a dose of 6 mg/kg body weight in a single or multiple dose.
For cattle, administer 10 milligrams per 50 kilograms of the endectocides. It is used in cattle for the treatment and control of gastrointestinal nematodes (adults


When Doramectin is present for use in cattle, administer 200 micrograms per kilogram {10 rniliigrams per 110 pounds) as a single subcutaneous or Intramuscular injection. Doramectin is indicated for the treatment and control of gastrointestinal roundworms, lungworms, eyeworms, gmbs, sucking lice, and mange mites. To control infections and to protect from reinfection with Coopena oncophorQ and Haemonchus placei for 14 days, Ostertagia ostertagi for 21 days, and C, punctata, OesophagostQmum radiatum, and Dictyocaulus vMparus for 28 days after treatment. For swine, administer 300 micrograms per kilogram (10 milligrams per 75 pounds as a single intramuscular injection. It is indicated for treatment and control of gastrointestinal roundworms, lungworms, kidney worms, sucking lice, and mange mites.
Other doses for other antihelminthic compounds may be ascertained by one of ordinary skill in the art.

to treat the animal. The precise dose v\flll depend on tfie stage and severity of the infection, the susceptibility of tiie infecting organism to the composition, and the individual characteristics of the animal species being treated, as will be appreciated by one of ordinary skill in the art.
The compositions according to the present invention are particulariy useful for cattle and other bovids, svwne, and otier large mammals. In addition to the treatment of bovine respiratory disease, the compositions of this invention are also

suitable for the treatment of infectious such as swine respiratory disease, footrot, acute mastitis, pinl^eye {infectious keratoconjunctivitis), acute pneumonia, metritis and enteritis. The dosage regimen for treatment of such diseases would be as described above.
Pinkeye is an acute infectious disease of cattle, sheep and other animals that is characterized by Inflammation of the tissues of the eye, accompanied by nasal discharge, tacrimation and copious ocular discharge. Affected animals may display extreme discomfort, resulting in a drop in milk production; in extreme cases permanent blindness occurs. The disease, which is caused by Moraxella bovis in cattle, is widespread, especially among range and feedlot cattle, and is of great economic importance to the cattle industry.
Footrot {interdigital phlegmon) is an acute infection of the Interdlgitai space that occurs throughout the world in both beef and dairy cattle. Fusobacteiium

Currently, footrot is treated by antibiotic therapy; recommended therapy can involve treatment for up to five days. The use of the formulations of the present invention for the treatment of footrot would be an improvement over presently known treatments because it would provide the proven efficacy of Florfentcol (with fewer administrations). The compositions of the present invention are also useful for the prevention of these diseases in animals at high risk of developing tiiose diseases. For example, the presently-claimed compositions can be

administered to cattle at high risk of developing bovine respiratory disease at the same dosages recommended for treatment of bovine respiratory disease.
The invention will be set forth with more particularity by the following non-limiting examples.
Example 1
A formulation within the scope of the present invention was prepared ccording to procedures customary in the art. The formulation contained the jjlowing concentrations of ingredients as set forth in ihe table below.




Example 2
The formulation prepared in accordance with Example 1 was administered to animals. The following study was conducted using the fomiuiation prepared in accordance with Example 1. 10 calves were administered either the formulation of Example 1 administered as a single subcutaneous injection of Florfenicol dose of 40 mg/kg and an Ivermectin dose of 0.2 mg/kg or the calves were administered a single Iven^ecUn dose of 0.2.mg/kg. Mean serum concentrafcns were detennined. The formulation of Example 1 was also compared against data previously obtained with the administration of commercially available formulations of Florfenicol as a single active agent. The fonnulations of Example 1 achieved acceptable mean serum levels obtained postdose as those obtained wVn the administration of commercially available formulations containing either Florfenicol or Ivemnectin as single active agents.
Although certain presently preferred embodimente of the invention have

Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

WE CLAIM :
1. A composition for the treatment of microbial and parasitic infection in an animal
comprising
a) a compound selected from the group consisting of
a compound of Formula I:

wherein R is a member selected from the group consisting of methyl or ethyl or a
halogenated derivative thereof, dihalogenodeuteriomethyl, 1-halogeno-1-
deuterioethyl, 1,2-dihalogeno-l -deuterioethyl, azidomethyl and
methylsulfonylmethyl;
each of X and X' is a member independently selected from the group consisting of NO2, SO2 R1, SOR, , SR1, SONH2, SO2NH2, SONHR1, S02NHR1, COR1, OR1, R1, CN, halogen, hydrogen, phenyl, and phenyl substituted by halogen, NO2, R1, PO2R1, CONHR,, NHR1, NR1R2 , CONR1R2, OCOR1,or OR,, wherein each of R1 and R2 is a member independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl butyl, t-butyl, isobutyl and phenyl;

and 2 is hydrogen or an acyl group of a hydrocarboncarboxylic acid having up to 16 carbon atoms or an acyl group of an ammohydrocarboncarboxylic acid having up to 12 carbon atoms; and the pharmaceutical acceptable salts of said acyl groups;
b) an endectocidic compound possessing antiparasitic activity; and
c) at least one carrier.
2. The composition as claimed in claim 1, wherein the compound of Formula I is
Florfenicol and the Florfenicol is present in an amount of 10% w/v to
50% w/v.
3. The composition as claimed in claim 1, wherein the endectocidic compound is an avermectin, and wherein the avermectin is a compound selected from the group consisting of Ivermectin, Doramectin, Abamectin, Selamectin, Emamectin, Eprinomectin, Moxidectin and Milbemycin.
4. The composition as claimed in claim 1, wherein the at least one carrier is a solvent.
5. The composition as claimed in claim 4, further comprising a second solvent.
6. A composition for the treatment of a microbial and parasitic infection in an animal comprising:
a) a macrolide antibiotic selected from the group consisting of Tilmicosm and
Tulathromycin ;
b) an endectocidic compound possessing antiparasitic activity; and
c) at least one carrier.
7. The composition as claimed in claim 6, wherein the endectocidic compound is
an avermectin, and wherein the avermectin is a compound selected from the group

consisting of Ivennectin, Doramectin, Abamectin, Selamectin, Emamectin, Eprinomectin, Moxidectin and Milbemycin.
8. The composition as claimed in claim 6, wherein the at least one carrier is a
solvent.
9. A composition for the treatment of a microbial and parasitic infection in an
animal comprising:
a) a cephalosporin selected from the group consisting of Ceftiofur or Cefquinome;
b) an endectocidic compound possessing antiparasitic activity; and
c) at least one carrier.
10. A composition for the treatment of a microbial and parasitic infection in an
animal comprising:
a) afluoroquinolone antibiotic selected from the group consisting of Enrofloxacin,
Danofloxacin and Marbofloxacin;
b) an endectocidic compound possessing antiparasitic activity; and
c) at least one carrier.