AU6436394A

AU6436394A - H2-antagonists as immune stimulants in bacterial infections of cattle or swine

Info

Publication number: AU6436394A
Application number: AU64363/94A
Authority: AU
Inventors: Peter C Canning
Original assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Current assignee: Pfizer Corp SRL
Priority date: 1993-06-15
Filing date: 1994-04-26
Publication date: 1995-01-03
Also published as: CA2165344A1; WO1994028898A1; JPH08506353A; IL109953A0; HUT70766A; EP0703782A1; HU9401775D0

Description

H2-Antagon1 sts as immune stimulants 1n bacterial Infections of cattle or swine.

The present invention relates to the prevention of bacterial infections in cattle and swine by administering an effective amount of certain known compounds previously used as H₂-antagonists. The invention also relates to the prevention or treatment of bacterial infections in cattle and swine by administering said known compounds together with an antibiotic.

The compounds of the invention and their H₂-antagonist activity are disclosed in United States Patents 4,374,843, 4,435,396, 4,560,690, 3,950,333, 4,128,658, 4,283,408, 4,293,557 and 4,375,547, each of which are incorporated by reference.

The present use of these compounds in cattle and swine to prevent bacterial infections is not disclosed.

The invention relates to the prevention of bacterial infections in cattle or swine by administering to a subject an effective amount of a compound of the formula

<¹>

or a pharmaceutically acceptable acid addition salts thereof, wherein X is S or NH; Y is CH, CCH₃ or N; R is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, -(CH₂)_nAr, -NH₂, -NHR, or -NH-COR,, wherein R, is alkyl of 1 to 6 carbon atoms or -(CH₂)_mAr; n is an integer from 2 to 4; m is zero or an integer from 1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or

-(CH₂)_nAr; (2)

wherein R is NHR¹ or NR²R³;

R¹ is (C₇-C₁₂)alkyl, or (C„-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkoxy or trifluoromethyl; and

R² and R³ are each independently (C^C^alkyl or (C₇-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkyl, (C_T-C^alkoxy or trifluoromethyl; or

R² and R³ are taken together with the nitrogen to which they are attached to form a pyrrolidone, piperidine, perhydro-1 H-azepine, or morpholine ring, or a pharmaceutically acceptable acid addition salt thereof; (3)

or a pharmaceutically acceptable acid addition salt thereof, wherein

X is NH and Y is CH or N, or

X is S and Y is CH; R¹ is a straight or branched chain (C₄-C₁₀)alkyl, (R³)₂C₆H₃ or (R³)₂Ar(CH₂)_n wherein n is an integer from 1 to 4, the R³ groups are the same or different and are H, F, Cl, Br, I, CH_3I CH₃O, NO₂, NH₂, OH, CN, COOR⁵, or OCOR⁵ and R⁵ is (C,-C₃)alkyl; and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or imidazolyl group;

R² is H or (C,-C₄)alkyl; or when R¹ and R² are taken together with the nitrogen atom to which they are attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and

R⁴ is H, (C^C^alkyl, NH₂ or CH₂OH;

(4)

wherein A is such that there is formed together with the carbon atom shown an unsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleus being an imidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; X, is hydrogen, lower alkyl, hydroxy, trifluoromethyl, benzyl, halogen, amino or

E '

^ '/

(CH₂)₄Y(CH ₂)_mNHC NHCH₃

in which F is NH or N-cyano; X₂ is hydrogen or when X, is lower alkyl or halogen; k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;

Y is oxygen, sulphur or NH; E is NR₂; R, is hydrogen, lower alkyl, or di-lower alkylamino-lower alkyl; and R₂ is hydrogen, nitro or cyano, or a pharmaceutically acceptable addition salt thereof; with the proviso that X, is

E '

(CH₂)₄Y(CH₂)_mNHC NHCH₃

only when E is NH or N-cyano; (5)

N H R₃

or a physiologically acceptable salt thereof, N-oxide or hydrate thereof in which R, and R₂ which may be the same or different represent hydrogen, lower alkyl, cycloalkyi, lower alkenyl, aralkyi in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or lower alkyl interrupted by an oxygen atom or a group

— N — I R₄

in which R₄ represents hydrogen or lower alkyl; R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;

X is -CH₂-, O or S;

Y represents =S, =O, =NR₅ or =CHR_e;

Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms; R₅ is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo;

R₆ represents nitro, arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy, halo or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 or 2; or when X=S, or -CH₂-, n is zero, 1 or 2;

(6)

wherein R represents a hydrogen atom or a lower alkyl group, R, represents an amino group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono- or di-lower alkylamino group, an arylamine group or an aralkylamino group, R₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each represents an integer of 1-3, or a pharmacologically acceptable acid addition salt thereof;

(7)

- R₄ V I I wherein R, represents a hydrogen atom or a methyl or ethyl group, R₂ and R₃, independently from each other, represent a lower alkyl group, or together form a linear alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a hydroxyl or hydroxymethyl group, and R₄ represents a hydrogen atom or a group of the formula -R₅-Z in which R₅ represents a lower alkylene group, and Z represents a hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino, lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy, benzoyioxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or

(8)

R ³

wherein each of R¹ and R² are individually H or (C^C^alkyl, one of R¹ and R² can be benzyl or benzoyi, and when taken together with the nitrogen to which they are attached, represent piperidino, pyrrolidino or morpholino; except that only one of R¹ and R² can be H when Z is CH₂;

R³ is H or (C C₃)alkyl;

Z is O, S, SO or CH₂; n is 2 or 3 when Z is O, S or SO and n is 1 , 2 or 3 when Z is CH₂;

R⁵ is H or CH₃; m is 1 , 2 or 3;

Q is fl 0=1 — C=0 | | o r | |

C — C=C— wherein A is N-CN, N-NO₂, CH-NO₂, S, O, NH, N-SO₂-aryl, N-SO₂-(C_rC₃)alkyl, N-CO- NH₂, CH-SO₂-aryl or CH-SO₂-CH₃, wherein aryl is phenyl, halo-phenyl, (C₁-C₃)alkylphenyl or (C_T-C^alkyloxyphenyl; and B is NH-R when Q is o=c — c=o

I I — c=c— and NH-R or YR⁴ when Q is R wherein Y is S or O and R is H or R⁴ wherein R⁴ is (C,-C₃)alkyl, (C₃-C₆)cycloalkylmethyl, hydroxy(C,-C₅)alkyl, (C₃-C_β)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the total number of carbons is less than 8; and there is at least a two carbon chain between the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof. In a specific embodiment of the invention said compound is 2-guanidino-4-(2- imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole.

The invention also relates to the prevention of bacterial infections in cattle by administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4- imidazolyl)thiazole, 2-guanidino-4-(2-N-n-hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl- N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine or nizatidine, and the prevention of bacterial infections in swine by administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4- imidazolyl)thiazole,2-guanidino-4-(N-n-hexylamino-4-imidazolyl)thiazole, ranitidine or famotidine. The invention further relates to a combination of an antibiotic and a compound of the formula

(1)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is S or NH; Y is CH, CCH₃ or N; R is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, -(CH₂)_nAr, -NH₂, -NHR, or -NH-COR,, wherein R, is alkyl of 1 to 6 carbon atoms or -(CH₂) r; n is an integer from 2 to 4; m is zero or an integer from 1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or

-(CH₂)_nAr, (2)

wherein

R is NHR¹ or NR²R³;

R¹ is (C₇-C₁₂)alkyl, (C₆-C )pyridylalkyl or (Cn-C^Jphenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkoxy or trifluoromethyl; and

R² and R³ are each independently (C,-C₁₂)alkyl or (C₇-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkyl, (C^CaJalkoxy or trifluoromethyl; or

R² and R³ are taken together with the nitrogen to which they are attached to form a pyrrolidone, piperidine, perhydro-1 H-azepine, or morpholine ring; or a pharmaceutically acceptable acid addition salt thereof;

(3)

or a pharmaceutically acceptable acid addition salt thereof, wherein

X is NH and Y is CH or N, or

X is S and Y is CH;

R¹ is a straight or branched chain (C₄-C₁₀)alkyl, (R³)₂C₆H₃ or (R³)₂Ar(CH₂)_n where n is an integer from 1 to 4, the R³ groups are the same or different and are H, F, Cl, Br, I, CH₃, CH₃O, NO₂, NH₂, OH, CN, COOR⁵, or OCOR⁵ and R⁵ is (C,-C₃)alkyl; and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or imidazolyl group;

R² is H or (C C₄)alkyl; or when R¹ and R² are taken together with the nitrogen atom to which they are attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and

R⁴ is H, (C C₅)alkyl, NH₂ or CH₂OH;

(4)

E '

^<0

(CH₂)₄Y(CH₂)_mNHC

NHCH<

in which E' is NH or N-cyano; X₂ is hydrogen or when X, is lower alkyl or halogen; k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;

E '

(CH₂)₄Y(CH₂)_mNHC

NHCH-

only when E is NH or N-cyano; -lo¬

ts)

or a physiologically acceptable salt thereof, N-oxide or hydrate thereof in which R₁ and R₂ which may be the same or different represent hydrogen, lower alkyl, cycloalkyi, lower alkenyl, aralkyi in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or lower alkyl interrupted by an oxygen atom or a group

— N— I R₄

X is -CH₂-, O or S;

Y represents =S, =O, =NR₅ or =CHR₆;

R_β represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 to 2; or when X=S, or -CH₂-, n is zero, 1 or 2;

(6)

wherein R represents a hydrogen atom or a lower alkyl group, R, represents an amino group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono- or di-lower alkylamino group, an arylamino group, or an aralkylamino group, R₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each represents an integer of 1-3, or a pharmacologically acceptable acid addition salt thereof;

(7)

wherein R, represents a hydrogen atom or a methyl or ethyl group, R₂ and R₃, independently from each other, represent a lower alkyl group, or together form a linear alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a hydroxyl or hydroxy-methyl group, and R₄ represents a hydrogen atom or a group of the formula -R₅-Z in which R₅ represents a lower alkylene group, and Z represents a hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino, lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy, benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof.

(8)

R³

wherein each of R¹ and R² are individually H or (C^O alkyl, one of R¹ and R² can be benzyl or benzoyi, and when taken together with the nitrogen to which they are attached, represent piperidino, pyrrolidino or morpholino; except that only one of R¹ and R² can be H when Z is CH₂; R³ is H or (C,-C₃)εdkyl; Z is O, S, SO or CH₂; n is 2 or 3 when Z is O, S or SO and n is 1 , 2 or 3 when Z is CH₂; R⁵ is H or CH₃; m is 1 , 2 or 3; Q is

R 0=C — C=0

II ^or I I C — c=c— wherein A is N-CN, N-NO₂, CH-NO₂, S, O, NH, N-SO₂-aryl, N-SO₂-(C₁-C₃)alkyl, N-CO- NH₂, N-CO-(C₁-C₃)alk, N-CO₂-(C₁-C₃)alkyl; CH-SO₂-aryl or CH-SO₂-CH₃, wherein aryl is phenyl, halo-phenyl, (C₁-C₃)alkylphenyl or (C^C^alkyloxyphenyl; and B is NH-R when Q is o=c — c=o

— c=c— and NH-R or YR⁴ when Q is

R

wherein Y is S or O and R is H or R⁴ wherein R⁴ is (C,-C₃)alkyl, (C₃-C₆)cycloalkylmethyl, hydroxy(C₁-C₅)alkyl, (C₃-C_β)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the total number of carbons is less than 8; and there is at least a two carbon chain between the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.

In a specific embodiment of the invention said compound is 2-guanidino-4-(2- imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole.

The invention further relates to a combination of an antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2- guanidino-4-(2-N-n-hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2- methyl-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine. The invention yet further relates to the prevention or treatment of bacterial infections in cattle by administering to a subject an effective amount of said combination of said antibiotic and said compound of any one of said formulae I through VIII. In a specific embodiment of such prevention or treatment said compound is 2- guanidino-4-(2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4- imidazolyl)thiazole.

The invention also relates to the prevention or treatment of bacterial infections in cattle by administering to a subject in need of such treatment an effective amount of a combination of an antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-N-n-hexylamino-4- imidazolyl)thiazole, 2-(N-pentyl-N '-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine, and to the prevention or treatment of bacterial infections in swine by administering to a subject an effective amount of a combination of an antibiotic and a compound selected from the group consisting of 2- guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-M-n-hexylamino-4- imidazolyl)thiazole, ranitidine and famotidine.

The above-described compounds of formulae I, II, III, IV, V, VI, VII and VIII are described in, respectively, United States Patents 4,374,843, 4,435,396, 4,560,690, 3,950,333, 4,128,658, 4,283,408, 4,293,557, and 4,375,547. The preparation of these active compounds and their pharmaceutically acceptable salts, if any, is disclosed in these patents. It is noted that the compounds of formulae I to VIII herein are described substantially in accordance with the terminology used in the respective U.S. patents.

The compounds of formulae I to VIII and any pharmaceutically acceptable salts thereof, when used alone, are useful in the prevention of bacterial infections in cattle and swine. The infections may be from a broad spectrum of bacteria, particularly, in cattle, respiratory pathogens, such as Pasteurella haemolvtica. Pasteurella multocida and Haemophilus somnus. and bacteria associated with mastitis: Streptococcus sp.. Staphylococcus sp.. Klebsiella sp.. Escherichia coli.. and Enterobacter sp.. and in swine, respiratory pathogens, such as Actinobacillus pleuropneumoniae. Pasteurella multocida. Mvcoplasma sp.. Haemophilus suis. and Haemophilus parasuis. enteric pathogens, such as Escherichia coli. Salmonella sp.. or Treponema hvodesenteria. and other pathogens, such as Staphylococcus sp.. Streptococcus sp.. Corvnebacterium sp.. Leptospyra sp.. and Ervsipelothrix rhuseopathiae. The compounds of formulae I to VIII and any pharmaceutically acceptable salts thereof, when used in combination with an antibiotic, are useful in the prevention or treatment of bacterial infections in cattle and swine. In such use, each of the active compounds of formulae I to VIII and the antiobiotic agent may be used at a dose similar or equal to the dose used for each agent alone. Since the active compounds and the antibiotic agent are known, the doses for each are known as well. Dependent on the dose for each agent, the ratio of antibiotic to active compound may vary greatly, e.g., from about 0.1 :1 to 50:1. The antibiotics of use in the invention include antibacterial quinolones, such as danofloxacin, enrofloxacin, flumequine, difloxacin, norfloxacin, sarafloxacin, temafloxacin, tosulfloxacin, and ibafloxacin; β-lactams, such as ceftiofur, cefquinome, cefoperazone, cephalexin, cephapirin, cefazolin, ampicillin, amoxicillin, sulbactam-ampicillin, clavulinic acid-amoxicillin, and penicillin G; tetracyclines, such as oxytetracycline, doxycycline, and chlortetracycline; macrolides such as erythromycin, tilmicosin, azithromycin, and tylosin; aminoglycosides, such as pirlimycin, gentamycin, and lincomycin; sulfa combinations, such as baquiloprim/sulfadimethoxine, and trimethoprim/sulfadiazine; and florfenicol.

The compounds of the invention may be administered to the cattle or swine alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form or elixirs or suspensions containing flavoring or coloring agents. They are advantageously contained in an animal feed or drinking water in a concentration of about 5-500 ppm, preferably about 25-100 ppm. They can be injected parenterally, for example, intramusculariy, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic. The compounds can be administered to the cattle or swine intramuscularly or subcutaneously at dosage levels of about 0.1-50 mg/kg/day, advantageously about 0.2-10 mg/kg/day in cattle, for instance 2-10 mg/kg/day, and advantageously about 0.1 to 10 mg/kg in swine, given in single or multiple daily doses.

The activity of compounds of formulae I to VIII against bovine respiratory disease in immunosuppressed calves may be determined as follows. Three to four month old Holstein-Frisian calves free of clinical disease symptoms and weighing about 100 kg are used in these experiments. About five animals are randomly allotted to each treatment on the day of trial initiation. Experimental compounds are administered parenterally 24 hours prior to challenge. All animals except the saline controls are treated once daily for three consecutive days with 0.05 mg/kg of the synthetic corticosteroid dexamethasone (Azium^®) beginning 24 hours prior to challenge. Animals are challenged endotracheally with 50 ml of saline containing 8x10^β cfu of Pasteurella haemolvtica Type 1. All animals are observed daily for symptoms of acute respiratory disease. Body temperatures and illness scores are recorded daily. Animals which die during the course of the study are necropsied and the lungs are removed and examined grossly for pneumonic lesions. The percentage of lung volume exhibiting lesions is recorded. Surviving animals are weighed, euthanized and necropsied 5 days after challenge and the percent lung lesions are recorded. Active compounds reduce the severity of disease in treated animals relative to animals treated with corticosteroid alone.

The prophylactic activity of compounds of formulae I to VIII against naturally induced bovine respiratory disease, may be determined as follows. Animals are transported for about a thousand miles overnight before initiation of the study. Mixed- breed beef cattle free of clinical disease symptoms and weighing about 125 kg are used. Upon arrival, the calves are weighed and mean body temperatures and illness scores measured. Approximately twelve animals are allotted to each treatment. The experimental compounds are administered parenterally as single or multiple doses beginning within 2 to 4 hours of arrival. All animals are observed daily for symptoms of acute respiratory disease. Body temperatures and illness scores are recorded daily. Animals which die during the course of the study are weighed to determine gain or loss and necropsied. The lungs are removed and examined grossly for pneumonic lesions and the percentage of lung volume exhibiting lesions is recorded. Samples of lung tissue are collected for bacteriological culture. Surviving animals are weighed, euthanized and necropsied 10 days after arrival and the percent lung lesions are recorded. Active compounds reduce the incidence and/or severity of disease in treated animals as compared to non-medicated controls.

The therapeutic efficacy of experimental compounds against naturally induced bovine respiratory disease may be determined as follows. Compounds are administered either alone or in conjunction with antibiotics. Animals are transported about 1000 miles overnight before the study is begun, and allotted to treatments upon the onset of clinical disease symptoms. Animals treated with active compounds exhibit a reduction in clinical symptoms relative to the day of allotment. Combination therapy with an antibiotic and an effective immune stimulant results in reduced clinical symptoms and/or a reduction in relapse rates relative to animals treated with antibiotic alone. Mixed-breed beef cattle free of clinical symptoms of disease and weighing about

125 kg are used in these experiments. Upon arrival, the calves are weighed and mean body temperatures and illness scores are determined. During the first seven days after arrival, animals are randomly allotted to treatments when they exhibit a body temperature equal to or more than 104°F and at least one clinical symptom of respiratory disease. Each treatment group contains about 20 animals.

Experimental compounds are typically administered parenterally as either single or multiple doses at the day of allotment.

All animals are observed daily for symptoms of acute respiratory disease. Body temperatures and illness scores are recorded daily. Animals which die during the course of the study are weighed to determine gain or loss and necropsied. The lungs are removed and examined grossly for pneumonic lesions and the percentage of lung volume exhibiting lesions is recorded. Samples of lung tissue are collected for bacteriological culture. Surviving animals are weighed, euthanized and necropsied 10 days after allotment and the percent lung lesions are recorded. The activity of compounds of formulae I to VIII against swine respiratory disease induced by A. pleuropneumoniae may be evaluated as follows. About twenty cross¬ bred swine free of clinical disease symptoms and weighing about 10 kg are randomly allotted to drug treatment groups on the day before the trial starts. Experimental compounds are administered parenterally to the healthy swine immediately before introduction of swine which have been challenged with bacteria. The challenged animals are inoccuiated intranasally with 6 ml of a saline suspension containing about 3 X 10⁷ cfu (colony-forming units) of A. pleuropneumoniae. placed in the pens containing the treated animals, and removed two days later. All treated animals are observed daily for symptoms of respiratory disease, and body temperatures and illness scores are recorded daily. The swine within the experimental treatment groups are euthanized and necropsied. The lungs are removed and examined grossly for pneumonic lesions. The percentage of lung volume exhibiting lesions is recorded. Example 1 The above protocol to determine immune stimulant activity in cattle was used with the test compounds 2-guanidino-4-(N-n-hexylamino-4-imidazolyl)thiazole (CP- 61 ,146), 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole (CP-57,361) and ranitidine. The results of these experiments indicated that animals treated with CP-61 ,146,

CP-57,361 and ranitidine twenty four hours before challenge showed significant protection from infection when compared to controls using Azium. For instance, the treated animals showed a 40 to 60% reduction in mean pneumonic lung volume compared to the Azium controls. Example 2

The prophylactic activities of both single and multiple doses CP-57,361 were determined in naturally infected calves.

Sixty-six calves weighing about 125 kg were shipped about one thousand miles. Upon arrival, thirty six animals were allotted to one of three treatment groups containing 12 calves each. Animals in the first group served as saline controls. Animals in the second group were treated once intramuscularly with 2 mg/kg of CP 57,361 on the day of arrival. Animals in the third treatment group were treated intramuscularly with 2 mg/kg of CP 57,361 once daily for three consecutive days beginning on the day of arrival. Illness scores and body temperatures were recorded daily. The various treatments were started on the day of arrival. Illness scores and body temperatures were recorded daily.

Animals were weighed upon arrival and on the tenth day to assess gain or loss. Half of the animals in each treatment group were euthanized and necropsied on days 11 and 12. Lung lesion scores were recorded and samples for bacteriologic culture were collected.

Saline-treated calves developed moderately severe pneumonia with an overall morbidity rate of about 75%. Both P. haemolvtica and P. multocida were isolated from the lungs of ill animals. These results are consistent with those normally observed for natural infection studies. Results obtained with both regimens of CP 57,361 indicated that these treatments reduced both the incidence and severity of disease relative to the saline controls. Animals treated with CP 57,361 showed a 40% reduction in mean pneumonic lung volume relative to the saline controls. Animals treated with CP 57,361 gained more weight during this study than the non-medicated controls.

All of the medicated animals and particularly those treated with the single dose of CP 57,361 exhibited decreased illness scores relative to the non-medicated controls. Evaluation of the mean daily temperature data indicated the various treatments yielded relatively small reductions relative to the saline controls. Both regimens of CP 57,361 suppressed the temperatures of treated animals relative to the saline controls particularly during the first 5 days.

In summary, this study shows that prophylactic administration of CP-57,361 provides efficacy against natural respiratory disease.

Example 3

The prophylactic efficacy of various doses of CP-57,361 ranging from 1 -4 mg/kg was evaluated using the above test determining the ability of a tested compound to prevent the transmission of A. pleuropneumoniae-induced pneumonia from infected swine to healthy swine. The results of this experiment indicated that swine treated with a single intramuscular injection of CP-57,361 exhibited significantly decreased morbidity relative to swine treated with saline. Morbidity rates for animals treated with CP-57,361 ranged from 5-20% as opposed to 60% for the saline treated swine. Using lung lesion scores as an indicator of disease severity, animals treated with CP-57,361 exhibited a dose-dependent reduction in disease severity relative to the saline-treated swine.

In a subsequent experiment using the above test, the prophylactic efficacy of CP-57,361 and CP-61 ,146 was evaluated using a dose of 4 mg/kg. The compounds were administered as either a single intramuscular injection or by oral gavage. Animals treated with CP-57,361 by either route of administration exhibited significant reductions in morbidity (25%) relative to animals treated with saline (50%). Oral administration of CP-61 ,146 also provided significant protection from infection similar to that observed with CP-57,361.

The prophylactic efficacy of ranitidine, cimetidine, nizatidine, roxatidine and famotidine was also evaluated using the above test by intramuscular administration as a single injection at a dose of 4 mg/kg. The results of this experiment indicated that animals treated with these active agents exhibited reduced morbidity relative to animals treated with saline.

Claims

CLAIMS 1. A method for the prevention of bacterial infections in cattle or swine which comprises administering to a subject an effective amount of a compound of the formula

(1)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is S or NH; Y is CH, CCH₃ or N; R is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, -(CH₂)_nAr, -NH₂, -NHR, or -NH-COR_T , wherein R, is alkyl of 1 to 6 carbon atoms or -(CH^^r; n is an integer from 2 to 4; m is zero or an integer from 1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or

-(CH₂)_nAr; (2)

wherein

R is NHR¹ or NR²R³; R¹ is (C₇-C₁₂)alkyl, (C₈-C pyridylalkyl or (C_{ι r}C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C C₃)alkoxy or trifluoromethyl; and R² and R³ are each independently (C^C^Jalkyl or (C₇-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkyl, (C,-C₃)alkoxy or trifluoromethyl; or

R² and R³ are taken together with the nitrogen to which they are attached to form a pyrrolidone, piperidine, perhydro-1 H-azepine, or morpholine ring, or a pharmaceutically acceptable acid addition salt thereof;

(3)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is NH and Y is CH or N, or

X is S and Y is CH;

R¹ is a straight or branched chain (C₄-C₁₀)alkyl, (R³)₂C₆H₃ or (R³)₂Ar(^CH ₂)_n wherein n is an integer from 1 to 4, the R³ groups are the same or different and are H,

F, Cl, Br, I, CH₃, CH₃O, NO₂, NH₂, OH, CN, COOR⁵, or OCOR⁵ and R⁵ is (C,-C₃)alkyl; and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or imidazolyl group;

R² is H or (C_rC₄)alkyl; or when R¹ and R² are taken together with the nitrogen atom to which they are attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and R⁴ is H, (C,-C₅)alkyl, NH₂ or CH₂OH;

(4)

E '

//

(CH₂)₄Y(CH₂)_mNHC

\

NHCH-

(CH₂)₄Y(CH₂)_mNHC NHCH₃

only when E is NH or N-cyano; (5)

NHR₃ ^V

— — I R₄

in which R₄ represents hydrogen or lower alkyl;

R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;

X is -CH₂-, O or S;

Y represents =S, =O, =NR₅ or =CHR₆; Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;

Rs is H, n^'rtro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo; R_β represents nitro, arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy, halo or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 or 2; or when X=S, or -CH₂-, n is zero, 1 or 2;

(6)

wherein R represents a hydrogen atom or a lower alkyl group, R, represents an amino group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono- or di-lower alkylamino group, an arylamine group or an aralkylamino group, R₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each represents an integer of 1-3, or a pharmacologically acceptable acid addition salt thereof; (7)

0

N— C H ^■ 0 - C H₂- C H₂- C H₂ - N H - C - R₄ V I I

' I

R- R .

wherein R, represents a hydrogen atom or a methyl or ethyl group, R₂ and R₃, independently from each other, represent a lower alkyl group, or together form a linear alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a hydroxyl or hydroxymethyl group, and R₄ represents a hydrogen atom or a group of the formula -R₅-Z in which R₅ represents a lower alkylene group, and Z represents a hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino, lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy, benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or

(8)

R³

wherein each of R¹ and R² are individually H or (^-C^alky!, one of R¹ and R² can be benzyl or benzoyi, and when taken together with the nitrogen to which they are attached, represent piperidino, pyrrolidino or morpholino; except that only one of R¹ and R² can be H when Z is CH₂;

R³ is H or (C₁-C₃)alkyl;

R⁵ is H or CH₃; m is 1 , 2 or 3;

Q is

0 o=c — c=o

II ^or I I c — c=c— wherein A is N-CN, N-NO₂, CH-NO₂, S, O, NH, N-SO₂-aryl, N-SO₂-(C C₃)alkyl, N-CO- NH₂, N-CO-(C_rC₃)alk, N-CO₂-(C-₁-C₃)alkyl; CH-SO₂-aryl or CH-SO₂-CH₃, wherein aryl is phenyl, halo-phenyl, (C₁-C₃)alkylphenyl or (C C₃)alkyloxyphenyl; and B is NH-R when Q is o=c — c=o

— C=C— and NH-R or YR⁴ when Q is

wherein Y is S or O and R is H or R⁴ wherein R⁴ is (C₁-C₃)alkyl, (C₃-C_e)cycloalkylmethyl, ydroxy^, -C₅)alkyl, (C₃-C_β)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the total number of carbons is less than 8; and there is at least a two carbon chain between the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.

2. A method according to claim 1 wherein said compound is 2-guanidino-4- (2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole.

3. A method for the prevention of bacterial infections in cattle which comprises administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4- imidazolyl)thiazole, 2-guanidino-4-(2-N-n-hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl- N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine or nizatidine.

4. A method for the prevention of bacterial infections in swine which comprises administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4- imidazolyl)thiazole, 2-guanidino-4-(2N-n-hexylamino-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine or nizatidine.

5. A composition for the prevention or treatment of bacterial infections in cattle or swine which comprises an antibiotic and a compound of the formula

(1)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is S or NH; Y is CH, CCH₃ or N; R is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, -(CH₂)_nAr, -NH₂, -NHR, or -NH-COR,, wherein R, is alkyl of 1 to 6 carbon atoms or •{CH₂) \r, n is an integer from 2 to 4; m is zero or an integer from 1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or

-(CH₂)_nAr; (2)

wherein

R is NHR¹ or NR²R³;

R¹ is (C₇-C₁₂)alkyl, or (C_{ι r}C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkoxy or trifluoromethyl; and

R² and R³ are each independently (C^C^Jalkyl or (C₇-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkyl, (C^CaJalkoxy or trifluoromethyl; or

(3)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is NH and Y is CH or N, or X is S and Y is CH; R¹ is a straight or branched chain (C₄-C₁₀)alkyl, (R³)₂C₆H₃ or (R³)₂Ar(CH₂)_n where n is an integer from 1 to 4, the R³ groups are the same or different and are H, F, Cl, Br, I, CH₃, CH₃O, NO₂, NH₂, OH, CN, COOR⁵, or OCOR⁵ and R⁵ is (C C₃)alkyl; and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or imidazolyl group;

R² is H or (C^C alkyl; or when R¹ and R² are taken together with the nitrogen atom to which they are attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and

R⁴ is H, (C_rC₅)alkyl, NH₂ or CH₂OH;

(4)

E '

(CH₂)₄Y(CH₂)_mNHC

NHCH-

E '

(CH; )₄Y(CH₂)_mNHC

NHCH-

only when E is NH or N-cyano; (5)

N H R₃

— N— I

R„

in which R₄ represents hydrogen or lower alkyl;

R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;

X is -CH₂-, O or S;

Y represents =S, =O, =NR₅ or =CHR₆;

Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;

R₅ is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo;

R₆ represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 to 2; or when X=S, or -CH₂-, n is zero, 1 or 2;

(6)

(7)

wherein R, represents a hydrogen atom or a methyl or ethyl group, R₂ and R₃, independently from each other, represent a lower alkyl group, or together form a linear alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a hydroxyl or hydroxy-methyl group, and R₄ represents a hydrogen atom or a group of the formula -R₅-Z in which R₅ represents a lower alkylene group, and Z represents a hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino, lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy, benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or (8)

R ³

R³ is H or (C_rC₃)alkyl;

R⁵ is H or CH₃; m is 1 , 2 or 3;

Q is fl o=c — c=o H or | |

C — C=C— wherein A is N-CN, N-NO₂, CH-NO₂, S, O, NH, N-SO₂-aryl, N-SO₂-(C C₃)alkyl, N-CO- NH₂, N-CO-tCTCaJalk, N-CO₂-(C_rC₃)alkyl; CH-SO₂-aryl or CH-SO₂-CH₃, wherein aryl is phenyl, halo-phenyl, (C,-C₃)alkylphenyl or (C C₃)alkyloxyphenyl; and B is NH-R when Q is

0=C — C=0

I I

— C=C— and NH-R or YR⁴ when Q is _fl

wherein Y is S or O and R is H or R⁴ wherein R⁴ is (^-C^alky!, (C₃-C₆)cycloalkylmethyl, hydroxy(C₁-C₅)alkyl, (C₃-C₆)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyi wherein the total number of carbons is less than 8; and there is at least a two carbon chain between the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.

6. A composition according to claim 5 wherein said compound is 2- guanidino-4-(2-imidazolyl)thiazole or 2-(N-benzyl-N '-guanidino)-4-(2-methyl-4- imidazolyl)thiazole.

7. A composition according to claim 5 wherein said antibiotic is a quinolone, β-lactam, tetracycline, macrolide, aminoglycoside, or a sulfa combination.

8. A composition for the prevention or treatment of bacterial infections in cattle or swine which comprises an antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-N-n- hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4- imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.

9. A method for the prevention or treatment of bacterial infections in cattle or swine which comprises administering to a subject an effective amount of a combination of an antibiotic and a compound of the formula

(1)

or a pharmaceutically acceptable acid addition salt thereof, wherein X is S or NH; Y is CH, CCH₃ or N; R is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, -(CH₂)_nAr, -NH₂, -NHR, or -NH-COR,, wherein R, is alkyl of 1 to 6 carbon atoms or -(CH₂)_mAr; n is an integer from 2 to 4; m is zero or an integer from 1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or

-(CH₂)_nAr; (2)

wherein

R is NHR¹ or NR²R³; R is (C₇-C₁₂)alkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkoxy or trifluoromethyl; and

R² and R³ are each independently (C C₁₂)alkyl or (C₇-C₁₂)phenylalkyl, optionally monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C,- C₃)alkyl, (C₁-C₃)alkoxy or trifluoromethyl; or

(3)

R

or a pharmaceutically acceptable acid addition salt thereof, wherein

X is NH and Y is CH or N, or

X is S and Y is CH;

R⁴ is H, (C C_β)aIkyl, NH₂ or CH₂OH; IV

E '

(CH₂)₄Y(CH₂)_mNHC

NHCH-

(CH₂)₄Y(CH₂)_mNHC

NHCH-

only when E is NH or N-cyano; (5)

NHR₃ ^V

— N— I R₄

in which R₄ represents hydrogen or lower alkyl;

R₃ is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl; X is -CH₂-, O or S;

R₆ represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl substituted by alkyl, alkoxy or halo or alkylsulphonyl; m is an integer from 2 to 4; and n is 1 to 2; or when X=S, or -CH₂-, n is zero, 1 or 2; (6)

wherein R represents a hydrogen atom or a lower alkyl group, R, represents an amino group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono- or di-lower alkylamino group, an arylamino group, or an aralkylamino group, R₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each represents an integer of 1-3, or a pharmacologically acceptable acid addition salt thereof; (7)

0

N— C H ^• 0 - C H₂- C H₂ - C H₂- N H - C - R₄ V I I

' I

R- R .

R -

wherein each of R¹ and R² are individually H or (C^C^alkyl, one of R¹ and R² can be benzyl or benzoyi, and when taken together with the nitrogen to which they are attached, represent piperidino, pyrrolidino or morpholino; except that only one of R¹ and R² can be H when Z is CH₂; R³ is H or (C,-C₃)alkyl; Z is O, S, SO or CH₂; n is 2 or 3 when Z is O, S or SO and n is 1 , 2 or 3 when Z is CH₂; R⁵ is H or CH₃; m is 1 , 2 or 3; Q is R 0=C — C=0

II ^or I I

C — C=C— wherein A is N-CN, N-NO₂, CH-NO₂, S, O, NH, N-SO₂-aryl, N-SO₂-(C₁-C₃)alkyl, N-CO- NH₂, N-CO-fC^C^alk, N-CO₂-(C,-C₃)alkyl; CH-SO₂-aryl or CH-SO₂-CH₃, wherein aryl is phenyl, halo-phenyl, (C,-C₃)alkylphenyl or (C^C^alkyloxyphenyl; and B is NH-R when Q is

0=C — C=0

I I

— C=C— and NH-R or YR⁴ when Q is

wherein Y is S or O and R is H or R⁴ wherein R⁴ is (C₁-C₃)alkyl, (C₃-C₆)cycloalkylmethyl, (C₃-C_β)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyi wherein the total number of carbons is less than 8; and there is at least a two carbon chain between the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.

10. A method according to claim 9 wherein said compound is 2-guanidino-4- (2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole.

11. A method for the prevention or treatment of bacterial infections in cattle which comprises administering to a subject in need of such treatment an effective amount of a combination of an antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-N-n- hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4- imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.

12. A method for the prevention or treatment of bacterial infections in swine which comprises administering to a subject an effective amount of a combination of an antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2- methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-M-n-hexylamino-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.

13. A method according to claim 9 wherein said antibiotic is a quinolone, β- lactam, tetracycline, macrolide, aminoglycoside, or a sulfa combination.