CA1038759A - Mixtures of cephalosporin and penicillin type antibiotics - Google Patents
Mixtures of cephalosporin and penicillin type antibioticsInfo
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- CA1038759A CA1038759A CA221,406A CA221406A CA1038759A CA 1038759 A CA1038759 A CA 1038759A CA 221406 A CA221406 A CA 221406A CA 1038759 A CA1038759 A CA 1038759A
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- penicillin
- salt
- antibacterial composition
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- animals
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Abstract
ANTIBACTERIAL COMPOSITION FOR ANIMALS
Abstract of the Disclosure:
An antibacterial composition for animals comprising cephalosporin compound of the formula:
wherein R1 is a substituted or unsubstituted heterocyclic group, or its salt and a penicillin compound of the formula:
Abstract of the Disclosure:
An antibacterial composition for animals comprising cephalosporin compound of the formula:
wherein R1 is a substituted or unsubstituted heterocyclic group, or its salt and a penicillin compound of the formula:
Description
~L~3~3~5~ ::
The present invention relates to ~n antibacterial composition for animalsO More partlcularly, it relates to an antibacterial composition comprising a cephalosporin com~ound or it~ salt ~nd a penicillin compound or its salt.
Cephalosporin compounds an~ penicillin co~pounds-and their salts have been known as antibiotics having a wide range of antibacterial spectrum.
A~ the results of the extensive s-tudyings of the pre3ent inventors~ it has been newly found ~hat some speci~
~ic cephalosporin compounds or their salts exhibit a synergis-tic antibacterial activities by combining with some penicillin compounds or their salts, th~t is, the combination of the ~ -cephalosporin compounds or their salt with t'ne penicillin com-pounds or their salts shows a strong antibacterial activity -against pathogenic bacteria in animals other than human,~par-~ticularly gr~m-ne~ative bacteria such as Citrobacter and Proteus, ~against which the ceph~losporin compounds and penicillin com~
pounds show no or litt~e antibacterial activit~, when they are u6ed each alone, and against the cephalosporin compounds- and penicillin compounds-resistant bacteria.
- ~ An object of the present inven~ion i~ to provide an antibacterial composition for animals comprisine a cephalo-8porin compound or its salt an~ a penicillin compound or its salt useful against pathogenic bacteria in animals, against whiCh the cephalosporin compound or the penicillin compour.d alone i3 not eff~ctive.
~ nothcr ob~ect o~ the invention is to provide an antibacterlal composltion 40r animal~ useful a~ain~t the cephalo-8porin co~pound- or penicillin co~pound-r~istant bacteria.
A further ob~ect OL th~ invent~on is to provide an
The present invention relates to ~n antibacterial composition for animalsO More partlcularly, it relates to an antibacterial composition comprising a cephalosporin com~ound or it~ salt ~nd a penicillin compound or its salt.
Cephalosporin compounds an~ penicillin co~pounds-and their salts have been known as antibiotics having a wide range of antibacterial spectrum.
A~ the results of the extensive s-tudyings of the pre3ent inventors~ it has been newly found ~hat some speci~
~ic cephalosporin compounds or their salts exhibit a synergis-tic antibacterial activities by combining with some penicillin compounds or their salts, th~t is, the combination of the ~ -cephalosporin compounds or their salt with t'ne penicillin com-pounds or their salts shows a strong antibacterial activity -against pathogenic bacteria in animals other than human,~par-~ticularly gr~m-ne~ative bacteria such as Citrobacter and Proteus, ~against which the ceph~losporin compounds and penicillin com~
pounds show no or litt~e antibacterial activit~, when they are u6ed each alone, and against the cephalosporin compounds- and penicillin compounds-resistant bacteria.
- ~ An object of the present inven~ion i~ to provide an antibacterial composition for animals comprisine a cephalo-8porin compound or its salt an~ a penicillin compound or its salt useful against pathogenic bacteria in animals, against whiCh the cephalosporin compound or the penicillin compour.d alone i3 not eff~ctive.
~ nothcr ob~ect o~ the invention is to provide an antibacterlal composltion 40r animal~ useful a~ain~t the cephalo-8porin co~pound- or penicillin co~pound-r~istant bacteria.
A further ob~ect OL th~ invent~on is to provide an
- 2 - ~ `
~3~7S~ :
antibacterial composition for nnimals having an excell0nt bac~
tericidal rate an~ enhanced therapeutic and preventive effects.
A still further object of the invention is to pro-~ide an antibacterial compo~it~on u~eful for treating or pre~
venting animal disea~es induced by pathogenic bacteria, par-ticularly ma~titi~ in cow or other animals.
These and other objects of the in~ention will be ;.
apparent from the description hereinafter.
: The antibacterial composition of the present inven~
tion comprises a combination o~ a cephalosporin compound o~
the formula~
., ~ ~' .
70 N 2 ~ ~
~_~" ~,L_-N \ ~ H2 ~-Rl .
- 1 . .-: .
- - ~OOH .
wherein ~ is a substituted or unsubstituted heterocyclic group, or its salt and a penicillin compound of the formula~
S CH~
COOH
wherein R2 is an acyl group, or its salt. . 1`
The heterocyclic group (Rl) in the above cephalo-~porln compound (I) i~ a 5 or 6-membered heterocyclic group including at lea~t one nitrogen atom and includes, for.e~ample.
thiadiazolyl, o~adiazolyl, thiazolyl and tetrazolyl which may be substituted bg an alkyl group having 1 to 4 carbon atoms.
Preferred heterocyclic group i~ 1,3,4-thiadiazol-2-yl, 5-methyl-~ 4-thiadiazol-2-yl, 5-methgl 1,3,4-oxadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,3,4-triazol-2 yl and l-methyltetrazol-5-yl. The tetrazolylacetamido.group at 7 position o~ cephalo-_ ~ _ .. ..... . .. .
.. ..
. ~ , . .
~3~759 8porin compound (I) includes (tetrazol-1-yl)aoetamido and (tetrazol-2-yl)acetamido The ~alts of the cephalosporin compounds (I) include ~hysiologically acceptable salts, such as a metal salt (e.g.
sodium, potassium or calcium salt); ammonium salt, an amine salt (e.g. trimethylamine, triethylamine, procaine or dibenzyl-amine ~alt), a salt with a basic amino acid, or the like which are a conventional salt of cephalosporin compounds.
Pre~erred examples of the cephalosporin compounds (I) are 7-(tetrazol-l-yl)acetamido-3-(5-~ethyl~1,394-thla_ diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (i.e.
cefazolin), j-(tetrazol-l-yl)acetamido-3-(1,3,4-thiadiazo1-2-yl)thiomethyl-3-cephem-4-carboxylic acid (hereinafter, re-~erred to ss ~R-10123) and 7-(tetrazol-1-yl~acetam1do-3-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (hereinafter, referrea to aæ FR-10675) and the1r salts. Among such cephalosporir.s, cefasolin sodium is known æs~ni~ue anti-biotics and marked world-widely.
The pen}cill1n compounds (II~ include natursl peni- ~
oillin~ and semi-synthetic penicillins. And, as ths acyl group o~ the penicillin compounds (II), there are msntioned, ~or ex amp-e, an alkanoyl and alkenyl ha~ing 2 to 8 carbon atoms which may be æubstituted by amino, carbo~y or aryloxy whic~ may be , 8ubstituted by hydroxy, halogen or nitro (e.g. 2-pentenylcarbonyl, n-heptylcarbonyl, caproyl, 4-amino-4-carbo~ybutyryl, a-phenoxy-butyryl, a-phenoxypropionyl or p-chlorophenoxyacetyl); a phenyl-acetyl wherein the phenyl eroup may be substituted by hydroxy or methoxy and the acetyl ~roup may be ~ubstituted by amino, carboxy or 8u1~0 at the a-po8ition (e,g. phenylacetyl, p-hydroxy-phenylacetyl, a-amino-(p-hydroxyphenyl)acetyl, a-~ulfo-phenyl .... . . ............ . . . . . . .
,~' ' l!
. , .
acetyl, u-carboxy-phenyla~etyl, 2,6-dimethoxyphenylacetyl or a~aminophenylacetyl) and a heterocyclic carbonyl wherein the heterocyclic group may be ~ubstituted by a lower alkyl or aryl wherein the aryl group may be ~ubstituted by a halogen (e.g.
(5-methyl-3-phenyl-isoxazol-4-yl)carbonyl7 [3-(o-chlorophenyl~
5-methylisoxazol-4~yl]carbonyl~ [3-(2,6-dichlorophenyl)-5 methyliso~azol-4~yl]carbonyl, (5-methyl-~-phenylisoxazol-4-yl~carbonyl or [3-(6-~luoro~2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl).
Representative examples o~ the natural penicillins may be penicillin G, ~ X, penicillin F, penicillin ~, 3-pentenylpenicillin, dihydropenicillin F, penicillin N, isopenicillir. ~, penicillin V, or the like. Representative ex~
amples of the semi-synthetic penicillins may be carbenicilline : :' .
(i.e. a-carboxybenzylpenicillin), cloxacillin (i.e. ~3-(o-chloro-phenyl)-5-methyl-4-isoxazolyl]penicillin), dicloxacillin (i.e.
~ -(296-dichlornphenyl-5-methyl-4-i~oxazolyl]penicillin), o~a-cilline (i.e, (5-methyl-3-phenyl-4-isoxazolyl)penicillin), methi-c~llin (i.e. (2,6 dimethoxyphenyl)penicil-in), propicillin (i.e.
a-phenoxypropylpenicillin) 9 phenethicillin (i.e. a-phenoxyethyl-penicillin)9 ampicillin (i.e. D(-)-a-aminobenzylpenicillin), ~luclo~acillin ~i.e. [3-(6-fluoro-2-chlorophenyl)-5-methyl-4-iso~azolyl]penicillin), sulbenicill1n (i.e. a-sulfo-phenylacet-amidopenicillin), amoxycillin (i.e. D(-)-a-amino-(p-hydroxyphenyl)-acetamidopenicilIin~, or the like and their ~alts. ~;
The salt~ of the pen~cillin compound~ (II) are exempli~~ied the same examples as those of cephalosporin compound (I).
Preferred combinations of the cephalosporin compound~
and the penicillin compounds are a combination of a cephalo-~porin compound ~elected from the group consisting of cefazolin, 5 -- .
- '' . , , ;, .
37~ :
FR-10123 and FR-10675 and a penicillin compound selected from the group consistin~ oL carbenicillin, cloxacillin, di-cloxacillin, oxacillin, methicillin, propicillin, phenethi-cillin, ampicillin, fluclo~acillin, amoxycillin and sulbeni-~illin. The most preferr~d eombinations are ce~azolin/carbeni-cillin, cefa7.01in/clo~acillin, cefazolin/dicloxacillin~ FR-10123/
~lucloxacil~in and ~R-10675Jamoxycillin.
- The ratio of the cephalosporin compound or its salt and the penicillin compound or its salt in the present anti-bacterial composition may vary with the compounds to be combined respectively, the ~ind~ o~ the bacteria and the symptoms of the infected animals to which the present composition i9 applied, but may usually be in a range of 1 1 to 1 : 10 by weight, pre- ~ -~erably 1 : i to 1 : 4 by weight. --~
... . : . .. . . .
The antibacterial composition of the present inven-tion is useful for treætin6 and preventing diseases induced by pathogenic bacterla in anlma~ls other than human, for instance, poultry, domes~ic animals, pet animals, or experimental ani-mals (e.g. chicken, turke~, duc~., quail, cow, cattle, horse, -~ pig, hog, dog, sheep, goat, mink, canary, macaw, mouse, rat or - rabbit).
.
~ he present antib~cterial composition may be applied to the animals in conventional forms which the conventional cephalosporin preparations and penicillin preparations are a~plied to. ~or instance, it is preferably applied in a form o~ in~ection, and for treating mastiti~ in cow or other ani-male, it i3 preferably a~plied in a form of infusion. It may be also be applied locally in a form of a powder or an oint-ment. When u3ed a~ an in~ection or infusion, it may be u~ed in admi~ture with a solid or liquid carrier or diluent .~hich "
~ i3~759 i~ u~ually u~ed for the conventional antibiotic injections or infusions. The most preferred carrier or diluent is water~
vegitable oils, ~ara~fin~ or the like. ~lhen used a~ an oint-ment, it may be used in admixture with conventional oint~ent bases.
The dosage o~ the pre~ent composition Jill vary with the kinds of the cephalosporin compounds and the penicillin , . ..
compounds and the mixed ratio thereof as well as the ~inds and ~
. , , , , ~ , the severity of the infection. For instance, for treating ~ov-vine mastiti~ during lactation drying period, it may be adminis-tered in a dose of about 200 mg/quarter.
The antibacterial activities and the preventing effec-:
tiveness aga~nst bacteial infection of the present compositon are illustrated by the following experimental tests in vitro and in VlVO.
~t 1 _, ~
~ynergi~tic activity of cefazolin and cloxacillin .. - :
against pathogen isolated from milk o~ cow suffering from mastitis , , ~ .
i~ the inhibitory concentration test in ~itro~
In a heart infusion medium containing a prescribed amount of cloxacillin and cefazolin sodi~n (hereinafter, re-~erred to merely as "aefazolin" was inoculated each pathogen ~/ -ln a concentration of about 105 cells/ml, and it was.cultured at 375C ~or ~0 hours, and then the growth of the test micro-or~anism3 wa~ mea~ured. The result~ are shoT~n in the follow-ing table In the tables, the symbol "+" means that the test microoreani~m ~rew and the symbol "-" means that the test microor~an~sm did not erow.
~:3387~ :
Table_l ~Escherichia coli, strain 4U-58-2L~) .
Cloxacillin (mcg/ml) ____l_____ . . :
5 _ _ _ _ . .
f _ _ :~
12.5 - ~ - ~ _ ::~
6.25 + + .+ _ ;
. o + _ _ L~ . ~ ~ .
:
0 0.39 0,78 1.56 -Cefazolin ~mcg/ml) Table 2 (Escherichia coli, strain 8-29-RB) .
,... - .
Cloxacillin (mcg/ml) _ .
100 ~ __ _ .-~ _ ~
~ ~ 50 : ~ ~ _ _ _ _ _ _ .
+ * r-~~~ ~ ~ I;
12.5 + + + _ _ _, ~ ..
6.25 + ~ + _ _
~3~7S~ :
antibacterial composition for nnimals having an excell0nt bac~
tericidal rate an~ enhanced therapeutic and preventive effects.
A still further object of the invention is to pro-~ide an antibacterial compo~it~on u~eful for treating or pre~
venting animal disea~es induced by pathogenic bacteria, par-ticularly ma~titi~ in cow or other animals.
These and other objects of the in~ention will be ;.
apparent from the description hereinafter.
: The antibacterial composition of the present inven~
tion comprises a combination o~ a cephalosporin compound o~
the formula~
., ~ ~' .
70 N 2 ~ ~
~_~" ~,L_-N \ ~ H2 ~-Rl .
- 1 . .-: .
- - ~OOH .
wherein ~ is a substituted or unsubstituted heterocyclic group, or its salt and a penicillin compound of the formula~
S CH~
COOH
wherein R2 is an acyl group, or its salt. . 1`
The heterocyclic group (Rl) in the above cephalo-~porln compound (I) i~ a 5 or 6-membered heterocyclic group including at lea~t one nitrogen atom and includes, for.e~ample.
thiadiazolyl, o~adiazolyl, thiazolyl and tetrazolyl which may be substituted bg an alkyl group having 1 to 4 carbon atoms.
Preferred heterocyclic group i~ 1,3,4-thiadiazol-2-yl, 5-methyl-~ 4-thiadiazol-2-yl, 5-methgl 1,3,4-oxadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,3,4-triazol-2 yl and l-methyltetrazol-5-yl. The tetrazolylacetamido.group at 7 position o~ cephalo-_ ~ _ .. ..... . .. .
.. ..
. ~ , . .
~3~759 8porin compound (I) includes (tetrazol-1-yl)aoetamido and (tetrazol-2-yl)acetamido The ~alts of the cephalosporin compounds (I) include ~hysiologically acceptable salts, such as a metal salt (e.g.
sodium, potassium or calcium salt); ammonium salt, an amine salt (e.g. trimethylamine, triethylamine, procaine or dibenzyl-amine ~alt), a salt with a basic amino acid, or the like which are a conventional salt of cephalosporin compounds.
Pre~erred examples of the cephalosporin compounds (I) are 7-(tetrazol-l-yl)acetamido-3-(5-~ethyl~1,394-thla_ diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (i.e.
cefazolin), j-(tetrazol-l-yl)acetamido-3-(1,3,4-thiadiazo1-2-yl)thiomethyl-3-cephem-4-carboxylic acid (hereinafter, re-~erred to ss ~R-10123) and 7-(tetrazol-1-yl~acetam1do-3-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (hereinafter, referrea to aæ FR-10675) and the1r salts. Among such cephalosporir.s, cefasolin sodium is known æs~ni~ue anti-biotics and marked world-widely.
The pen}cill1n compounds (II~ include natursl peni- ~
oillin~ and semi-synthetic penicillins. And, as ths acyl group o~ the penicillin compounds (II), there are msntioned, ~or ex amp-e, an alkanoyl and alkenyl ha~ing 2 to 8 carbon atoms which may be æubstituted by amino, carbo~y or aryloxy whic~ may be , 8ubstituted by hydroxy, halogen or nitro (e.g. 2-pentenylcarbonyl, n-heptylcarbonyl, caproyl, 4-amino-4-carbo~ybutyryl, a-phenoxy-butyryl, a-phenoxypropionyl or p-chlorophenoxyacetyl); a phenyl-acetyl wherein the phenyl eroup may be substituted by hydroxy or methoxy and the acetyl ~roup may be ~ubstituted by amino, carboxy or 8u1~0 at the a-po8ition (e,g. phenylacetyl, p-hydroxy-phenylacetyl, a-amino-(p-hydroxyphenyl)acetyl, a-~ulfo-phenyl .... . . ............ . . . . . . .
,~' ' l!
. , .
acetyl, u-carboxy-phenyla~etyl, 2,6-dimethoxyphenylacetyl or a~aminophenylacetyl) and a heterocyclic carbonyl wherein the heterocyclic group may be ~ubstituted by a lower alkyl or aryl wherein the aryl group may be ~ubstituted by a halogen (e.g.
(5-methyl-3-phenyl-isoxazol-4-yl)carbonyl7 [3-(o-chlorophenyl~
5-methylisoxazol-4~yl]carbonyl~ [3-(2,6-dichlorophenyl)-5 methyliso~azol-4~yl]carbonyl, (5-methyl-~-phenylisoxazol-4-yl~carbonyl or [3-(6-~luoro~2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl).
Representative examples o~ the natural penicillins may be penicillin G, ~ X, penicillin F, penicillin ~, 3-pentenylpenicillin, dihydropenicillin F, penicillin N, isopenicillir. ~, penicillin V, or the like. Representative ex~
amples of the semi-synthetic penicillins may be carbenicilline : :' .
(i.e. a-carboxybenzylpenicillin), cloxacillin (i.e. ~3-(o-chloro-phenyl)-5-methyl-4-isoxazolyl]penicillin), dicloxacillin (i.e.
~ -(296-dichlornphenyl-5-methyl-4-i~oxazolyl]penicillin), o~a-cilline (i.e, (5-methyl-3-phenyl-4-isoxazolyl)penicillin), methi-c~llin (i.e. (2,6 dimethoxyphenyl)penicil-in), propicillin (i.e.
a-phenoxypropylpenicillin) 9 phenethicillin (i.e. a-phenoxyethyl-penicillin)9 ampicillin (i.e. D(-)-a-aminobenzylpenicillin), ~luclo~acillin ~i.e. [3-(6-fluoro-2-chlorophenyl)-5-methyl-4-iso~azolyl]penicillin), sulbenicill1n (i.e. a-sulfo-phenylacet-amidopenicillin), amoxycillin (i.e. D(-)-a-amino-(p-hydroxyphenyl)-acetamidopenicilIin~, or the like and their ~alts. ~;
The salt~ of the pen~cillin compound~ (II) are exempli~~ied the same examples as those of cephalosporin compound (I).
Preferred combinations of the cephalosporin compound~
and the penicillin compounds are a combination of a cephalo-~porin compound ~elected from the group consisting of cefazolin, 5 -- .
- '' . , , ;, .
37~ :
FR-10123 and FR-10675 and a penicillin compound selected from the group consistin~ oL carbenicillin, cloxacillin, di-cloxacillin, oxacillin, methicillin, propicillin, phenethi-cillin, ampicillin, fluclo~acillin, amoxycillin and sulbeni-~illin. The most preferr~d eombinations are ce~azolin/carbeni-cillin, cefa7.01in/clo~acillin, cefazolin/dicloxacillin~ FR-10123/
~lucloxacil~in and ~R-10675Jamoxycillin.
- The ratio of the cephalosporin compound or its salt and the penicillin compound or its salt in the present anti-bacterial composition may vary with the compounds to be combined respectively, the ~ind~ o~ the bacteria and the symptoms of the infected animals to which the present composition i9 applied, but may usually be in a range of 1 1 to 1 : 10 by weight, pre- ~ -~erably 1 : i to 1 : 4 by weight. --~
... . : . .. . . .
The antibacterial composition of the present inven-tion is useful for treætin6 and preventing diseases induced by pathogenic bacterla in anlma~ls other than human, for instance, poultry, domes~ic animals, pet animals, or experimental ani-mals (e.g. chicken, turke~, duc~., quail, cow, cattle, horse, -~ pig, hog, dog, sheep, goat, mink, canary, macaw, mouse, rat or - rabbit).
.
~ he present antib~cterial composition may be applied to the animals in conventional forms which the conventional cephalosporin preparations and penicillin preparations are a~plied to. ~or instance, it is preferably applied in a form o~ in~ection, and for treating mastiti~ in cow or other ani-male, it i3 preferably a~plied in a form of infusion. It may be also be applied locally in a form of a powder or an oint-ment. When u3ed a~ an in~ection or infusion, it may be u~ed in admi~ture with a solid or liquid carrier or diluent .~hich "
~ i3~759 i~ u~ually u~ed for the conventional antibiotic injections or infusions. The most preferred carrier or diluent is water~
vegitable oils, ~ara~fin~ or the like. ~lhen used a~ an oint-ment, it may be used in admixture with conventional oint~ent bases.
The dosage o~ the pre~ent composition Jill vary with the kinds of the cephalosporin compounds and the penicillin , . ..
compounds and the mixed ratio thereof as well as the ~inds and ~
. , , , , ~ , the severity of the infection. For instance, for treating ~ov-vine mastiti~ during lactation drying period, it may be adminis-tered in a dose of about 200 mg/quarter.
The antibacterial activities and the preventing effec-:
tiveness aga~nst bacteial infection of the present compositon are illustrated by the following experimental tests in vitro and in VlVO.
~t 1 _, ~
~ynergi~tic activity of cefazolin and cloxacillin .. - :
against pathogen isolated from milk o~ cow suffering from mastitis , , ~ .
i~ the inhibitory concentration test in ~itro~
In a heart infusion medium containing a prescribed amount of cloxacillin and cefazolin sodi~n (hereinafter, re-~erred to merely as "aefazolin" was inoculated each pathogen ~/ -ln a concentration of about 105 cells/ml, and it was.cultured at 375C ~or ~0 hours, and then the growth of the test micro-or~anism3 wa~ mea~ured. The result~ are shoT~n in the follow-ing table In the tables, the symbol "+" means that the test microoreani~m ~rew and the symbol "-" means that the test microor~an~sm did not erow.
~:3387~ :
Table_l ~Escherichia coli, strain 4U-58-2L~) .
Cloxacillin (mcg/ml) ____l_____ . . :
5 _ _ _ _ . .
f _ _ :~
12.5 - ~ - ~ _ ::~
6.25 + + .+ _ ;
. o + _ _ L~ . ~ ~ .
:
0 0.39 0,78 1.56 -Cefazolin ~mcg/ml) Table 2 (Escherichia coli, strain 8-29-RB) .
,... - .
Cloxacillin (mcg/ml) _ .
100 ~ __ _ .-~ _ ~
~ ~ 50 : ~ ~ _ _ _ _ _ _ .
+ * r-~~~ ~ ~ I;
12.5 + + + _ _ _, ~ ..
6.25 + ~ + _ _
3.13 + + + _ ~ :
:--O, + L~ +_ , +
. 0: .3g0.7~ 1~56 3.13 Cefazolin (mcg/ml) ~ .
: ~ .
~:
, , ,, :
. .
, ;'. . .
10;3B759 ¦:
Table 3(Proteus mirabllis, strain 48-~2~F) :
Cloxacillin ~
(m4go/ml) _ _ _ I ; ' ~:
200 _ + _ _ _ . ~
100 + + ~__ _ , `,',,~
5o + + ~ ;
~ , }, .
+ + ~ + _ . ~
__ . ' ,~
12.5+ + + + _ ~ -:
...
6.25 + + + + _ ::~
_~ . .,:' . , O ,+ ,+ ~ + + . ,~ '",'' 0 0.78 1.56 3.1~ 6.25 ~-Cefa~olin (mcg/ml) Test 2 ~ ~ Synerglstic activ1ty of cefazolin and~cloxacillin :~ against pathogen isolated from dogs suffering from diarrhea in : the inhibitory concentration~test in vitro: : ,~
In the aame manner as described in Test 5, the test ~as~carried out with Salmonella spp.~isolated from rectum feces ;~
of diarrhea dogs. ~he results are shown i.n the following tables. .~: :
almonella t2~____ rium, strain Dl55) Cloxacillin :~
(mcg/ml) r--~ I .
200 + _ _ I _ _ _ : ~ - _ '~.: ,100 , + +_ _ _ ; - , '~
: . 50 + ~ + + _ j _ "
25 + + + + _ .
,. -- ., f 12,5 ~ + I + ~ +
6.25 + + + ~ .
i ~,;
, O + + + I + ~ , .
. __ l :
0 0.20.39 0.78 1.56 Cefezolin (mcg/ml) :
,,, , , ,; ,~", .', _ 9 _ ~;
',, ' .' " . , , , ~ , . .
~:
,, 1 i ,'' ,' ~ ' , ' , ,. . . .
-~ ~~38~7S9 :-Table 5 (~almonella enteritidi~, ~train 1892) Cloxacillin ( ms_/m ) 12.5 ~ + + +
6.25 + + + + `
~ ' . O _ __ _ . ''~'-"':' 0 0,78 1.56 3.1 Cefazolin (mcg/ml) Test Effects on the ex~perimentally infected mice: -ICR male mlce of 4 weeks age (10 mice per~one group) ~were used. A prescribed amount of the pathogenic bacteria :~ , .
suspended in~5 ~,' mucin was lnoculated intraperitoneally. One hour after the inoculation, the antibiotics as~ mentioned in the ~ollowing table were administered subcutaneously, and ~;~
; ~hen-the inhibitory effects thereof were measured. The re- ~ - =
sults are shown in the following table. 1~;
.
!:
;
1"'-~
` ' ~',:
''" "
. . , - 1~ - ., ' '''''' ' ' ''' ' ' , ~,......... .
~"' ' ''' '' , Table 6 ~ 75g _ _ . ~ , ., ED~o m~/mouse ~
, _ Micro- Cbalenge Calbeni- ¦
or~anisms dose Cillin ~ lcefa~olin Calbeni-inoculated (cell~/mouse) Cef~lzol nl c 1 n Escherich~a . ::
c~ strain ~.6 X 105 1.12 1.60 3.85 :
_ _ ~ . . . . _ Proteus 1.2 :C 108 ¦ 0.60 ¦ 0~90 ¦ 1.11 -~
~train-5~26 j . . . ..
C trob traln~ 8.1 X 10 ¦ 12.~ l > 20 ¦ .
815 ~
. Citrobact~r , .
spp., strainl 4.8 X 104 3.28 7 11 > 20 . .
,; .
As made clear from the above results, the synergistic : -i~hibitory activity of carbeniclllin sodium and cefazolin ~as .
also confirmed by in vivo test~ . v . . :~
-~ Test 4 Synergistic activity of cefazolin and cloxacillin against pathogen isolated from milk of cow su~fereing from .
ma~titis in the inhibitory concentration test in ~vitro:
.
In the same manner as described in Test 5, the test . wa~ oarried out with Serratia epp., strain 22 being resistant ;~
to cephalosporins and penicillins and Staph~lococcus aureus~ .-~train 7 originated bovine mastitisO The results are shown ir the followina table-. ~
`.
. .
-ç
. _ r .' . I
; .
37~9 Table_7 (Serratia spp., ~train 22) Clo~acillin ( ~COgO/n`'l ) _ _ l ~ ~ , . ~
200 + + _ _ _ _ ~ _ _ _ ~ I _.
100 ~. + ~ I - ! -__ _ _ __ 5 + ~ + I + I _ _ _ _ ~
I _ ~ ~ ~
25 + + I ~ + l + +
__ ~
~2.5 rL ¦ + ¦ + + + ¦ Lr _ _ __ __ 6.~5 + ¦ + + rL ~Lr ¦ -Lr ¦ + ¦ _ ¦ .
~ ~ ~ I _ . ~ , o~r ~lL~rL ¦ ~ ¦ + ~ ~ ¦ + +
------ - ~ - - ~ --0 . 6.2512.5 25 50 100 200 400 . 800 Cefaæolin (mcg/ml) .. . . ~ . , T~ble 8 (Staph~ococcus aureus~ strain 7) ~ :
Cloxacillin tmcg/ml) , -0 2 + ~ + I _ _ -~-:
~ . , I _~ - ,_ - .' .-- C).l + 1 + 1 + ~ + I .
: ~ :
0-05 + ¦ -Lr ¦ + ~ ~
.~ ~ . _. ~ ~ ~ __ I I `' - 0.025 + ¦ ~ ¦ + ¦ ~rL + I +
~ ~ - -t - t-- I - -------r- l :
. - O ' + I + I + I t + I
0, 0.025 0.05 0.1 0.2 0.4 ..
- Cefazolin (mcg/ml) - ~ est 5 ' The synergistlc activity of FR-10123 and flucloxacil- .
lin against Serratia spp,, ~train 22 isolated from bovine mastitis ~-was tested in the same manner as described in Test 1, wherein the pathogen wa~ lnoculated in the medium in a concen~ration of 105 cells/ml. The result3 are shown in the following Table.
, - 12 - -., ~
7S~
Table 9 (S~E~ 5p~. 9 ~train 22) Flucloxacillin (mcg/ml~ ~ _ I
200 ~ ~ _ 100 ~=_ = ., ~0 ~ ~
~ _ I I ., I +_ I + _l + I + I + ~ ~ ~
12 5 + + I + l ~ l + l +
i , 6.25 + ~ I + I ~ + I + I ~
~ __ _ _ j I , o .+ + l + l ~ + l + + l ~ ~ + .
_~ ~ _................ ;
~: 0 6.25 12.5 25 50 100 200 400 800 : :
~R-10123 (mcg~ml) Tes~ 6 .
- The syner~istic activity o~ FR-10675 and amo~ycil-lin against Sta~hvlococcus aureus, strain ~ isolated from mil~
o~ ~ow suffering from mastitis was tested in the same manner -~
~ . . - , as described in ~`est 1, wherein the pathogen was inoculated in ~ ~:
: the medium in a concentration o~ 106 cells/.ml. The results are .
: : shown in the following Table.
Table 10: (5ta~hvl-ococcus auIeus~ strain 8) Amoxycillin :
(mcg/ml) - 6.25 _ _ 3 .13 ~ + + _ _ .56 _ ~ + +
0c78 + + + + . . .
0.39 + + ~ ~. .
_ _ O +. ~ + + .-~ - .
,. _ ._ . ...
g 0.1 0.2 0.39 ' FR-10675 (mcg/ml) .. ~ :
The antibact~rial compo3ition~ of the present in- :
~entlon are illu~trated by the follouing ~xample.
: 3 il7S9 ~ ~
- Exam~le 1 Cefnzolin sodium 100 m~
Cloxacillin 100 mg ~anette llax SX (tradename) 50 mg Soft paraffin 100 mg Brilliant b~ue ~CF 25 mg :;
~h~ above ingredients were mixed ~ith liquid paraf-fin to give a total weight of 3 g per infusion preparation.
xample 2 Cefazolin sodium 40 mg .~:
Clo~acillin 150 mg ¦ ;
~anette Wa~ SX (tradename) 50 mg~
- Soft paraffin 100 mg rilliant blue ~C~ 25~mg - ~he above ingredients were mi~ed with liquid paraf~
~, :fin to give a total weight of 3 g per infu~ion preparation.
,, ~. , : ' - ' ' .
: - 14 -~" :''''''' '''T
.",
:--O, + L~ +_ , +
. 0: .3g0.7~ 1~56 3.13 Cefazolin (mcg/ml) ~ .
: ~ .
~:
, , ,, :
. .
, ;'. . .
10;3B759 ¦:
Table 3(Proteus mirabllis, strain 48-~2~F) :
Cloxacillin ~
(m4go/ml) _ _ _ I ; ' ~:
200 _ + _ _ _ . ~
100 + + ~__ _ , `,',,~
5o + + ~ ;
~ , }, .
+ + ~ + _ . ~
__ . ' ,~
12.5+ + + + _ ~ -:
...
6.25 + + + + _ ::~
_~ . .,:' . , O ,+ ,+ ~ + + . ,~ '",'' 0 0.78 1.56 3.1~ 6.25 ~-Cefa~olin (mcg/ml) Test 2 ~ ~ Synerglstic activ1ty of cefazolin and~cloxacillin :~ against pathogen isolated from dogs suffering from diarrhea in : the inhibitory concentration~test in vitro: : ,~
In the aame manner as described in Test 5, the test ~as~carried out with Salmonella spp.~isolated from rectum feces ;~
of diarrhea dogs. ~he results are shown i.n the following tables. .~: :
almonella t2~____ rium, strain Dl55) Cloxacillin :~
(mcg/ml) r--~ I .
200 + _ _ I _ _ _ : ~ - _ '~.: ,100 , + +_ _ _ ; - , '~
: . 50 + ~ + + _ j _ "
25 + + + + _ .
,. -- ., f 12,5 ~ + I + ~ +
6.25 + + + ~ .
i ~,;
, O + + + I + ~ , .
. __ l :
0 0.20.39 0.78 1.56 Cefezolin (mcg/ml) :
,,, , , ,; ,~", .', _ 9 _ ~;
',, ' .' " . , , , ~ , . .
~:
,, 1 i ,'' ,' ~ ' , ' , ,. . . .
-~ ~~38~7S9 :-Table 5 (~almonella enteritidi~, ~train 1892) Cloxacillin ( ms_/m ) 12.5 ~ + + +
6.25 + + + + `
~ ' . O _ __ _ . ''~'-"':' 0 0,78 1.56 3.1 Cefazolin (mcg/ml) Test Effects on the ex~perimentally infected mice: -ICR male mlce of 4 weeks age (10 mice per~one group) ~were used. A prescribed amount of the pathogenic bacteria :~ , .
suspended in~5 ~,' mucin was lnoculated intraperitoneally. One hour after the inoculation, the antibiotics as~ mentioned in the ~ollowing table were administered subcutaneously, and ~;~
; ~hen-the inhibitory effects thereof were measured. The re- ~ - =
sults are shown in the following table. 1~;
.
!:
;
1"'-~
` ' ~',:
''" "
. . , - 1~ - ., ' '''''' ' ' ''' ' ' , ~,......... .
~"' ' ''' '' , Table 6 ~ 75g _ _ . ~ , ., ED~o m~/mouse ~
, _ Micro- Cbalenge Calbeni- ¦
or~anisms dose Cillin ~ lcefa~olin Calbeni-inoculated (cell~/mouse) Cef~lzol nl c 1 n Escherich~a . ::
c~ strain ~.6 X 105 1.12 1.60 3.85 :
_ _ ~ . . . . _ Proteus 1.2 :C 108 ¦ 0.60 ¦ 0~90 ¦ 1.11 -~
~train-5~26 j . . . ..
C trob traln~ 8.1 X 10 ¦ 12.~ l > 20 ¦ .
815 ~
. Citrobact~r , .
spp., strainl 4.8 X 104 3.28 7 11 > 20 . .
,; .
As made clear from the above results, the synergistic : -i~hibitory activity of carbeniclllin sodium and cefazolin ~as .
also confirmed by in vivo test~ . v . . :~
-~ Test 4 Synergistic activity of cefazolin and cloxacillin against pathogen isolated from milk of cow su~fereing from .
ma~titis in the inhibitory concentration test in ~vitro:
.
In the same manner as described in Test 5, the test . wa~ oarried out with Serratia epp., strain 22 being resistant ;~
to cephalosporins and penicillins and Staph~lococcus aureus~ .-~train 7 originated bovine mastitisO The results are shown ir the followina table-. ~
`.
. .
-ç
. _ r .' . I
; .
37~9 Table_7 (Serratia spp., ~train 22) Clo~acillin ( ~COgO/n`'l ) _ _ l ~ ~ , . ~
200 + + _ _ _ _ ~ _ _ _ ~ I _.
100 ~. + ~ I - ! -__ _ _ __ 5 + ~ + I + I _ _ _ _ ~
I _ ~ ~ ~
25 + + I ~ + l + +
__ ~
~2.5 rL ¦ + ¦ + + + ¦ Lr _ _ __ __ 6.~5 + ¦ + + rL ~Lr ¦ -Lr ¦ + ¦ _ ¦ .
~ ~ ~ I _ . ~ , o~r ~lL~rL ¦ ~ ¦ + ~ ~ ¦ + +
------ - ~ - - ~ --0 . 6.2512.5 25 50 100 200 400 . 800 Cefaæolin (mcg/ml) .. . . ~ . , T~ble 8 (Staph~ococcus aureus~ strain 7) ~ :
Cloxacillin tmcg/ml) , -0 2 + ~ + I _ _ -~-:
~ . , I _~ - ,_ - .' .-- C).l + 1 + 1 + ~ + I .
: ~ :
0-05 + ¦ -Lr ¦ + ~ ~
.~ ~ . _. ~ ~ ~ __ I I `' - 0.025 + ¦ ~ ¦ + ¦ ~rL + I +
~ ~ - -t - t-- I - -------r- l :
. - O ' + I + I + I t + I
0, 0.025 0.05 0.1 0.2 0.4 ..
- Cefazolin (mcg/ml) - ~ est 5 ' The synergistlc activity of FR-10123 and flucloxacil- .
lin against Serratia spp,, ~train 22 isolated from bovine mastitis ~-was tested in the same manner as described in Test 1, wherein the pathogen wa~ lnoculated in the medium in a concen~ration of 105 cells/ml. The result3 are shown in the following Table.
, - 12 - -., ~
7S~
Table 9 (S~E~ 5p~. 9 ~train 22) Flucloxacillin (mcg/ml~ ~ _ I
200 ~ ~ _ 100 ~=_ = ., ~0 ~ ~
~ _ I I ., I +_ I + _l + I + I + ~ ~ ~
12 5 + + I + l ~ l + l +
i , 6.25 + ~ I + I ~ + I + I ~
~ __ _ _ j I , o .+ + l + l ~ + l + + l ~ ~ + .
_~ ~ _................ ;
~: 0 6.25 12.5 25 50 100 200 400 800 : :
~R-10123 (mcg~ml) Tes~ 6 .
- The syner~istic activity o~ FR-10675 and amo~ycil-lin against Sta~hvlococcus aureus, strain ~ isolated from mil~
o~ ~ow suffering from mastitis was tested in the same manner -~
~ . . - , as described in ~`est 1, wherein the pathogen was inoculated in ~ ~:
: the medium in a concentration o~ 106 cells/.ml. The results are .
: : shown in the following Table.
Table 10: (5ta~hvl-ococcus auIeus~ strain 8) Amoxycillin :
(mcg/ml) - 6.25 _ _ 3 .13 ~ + + _ _ .56 _ ~ + +
0c78 + + + + . . .
0.39 + + ~ ~. .
_ _ O +. ~ + + .-~ - .
,. _ ._ . ...
g 0.1 0.2 0.39 ' FR-10675 (mcg/ml) .. ~ :
The antibact~rial compo3ition~ of the present in- :
~entlon are illu~trated by the follouing ~xample.
: 3 il7S9 ~ ~
- Exam~le 1 Cefnzolin sodium 100 m~
Cloxacillin 100 mg ~anette llax SX (tradename) 50 mg Soft paraffin 100 mg Brilliant b~ue ~CF 25 mg :;
~h~ above ingredients were mixed ~ith liquid paraf-fin to give a total weight of 3 g per infusion preparation.
xample 2 Cefazolin sodium 40 mg .~:
Clo~acillin 150 mg ¦ ;
~anette Wa~ SX (tradename) 50 mg~
- Soft paraffin 100 mg rilliant blue ~C~ 25~mg - ~he above ingredients were mi~ed with liquid paraf~
~, :fin to give a total weight of 3 g per infu~ion preparation.
,, ~. , : ' - ' ' .
: - 14 -~" :''''''' '''T
.",
Claims (14)
1. An antibacterial composition for animals comprising a cephalosporin compound of the formula:
wherein R1 is a substituted or unsubstituted 5- or 6-membered heterocyclic group including at least one nitrogen atom or a salt thereof and a penicillin compound of the formula:
wherein R2 is an acyl group selected from the group consisting of heterocyclic carbonyl, phenylacetyl, alkanoyl of 2 to 8 carbon atoms and alkanoyl of 2 to 8 carbon atoms, said acyl group being substituted or unsubstituted or a salt thereof.
wherein R1 is a substituted or unsubstituted 5- or 6-membered heterocyclic group including at least one nitrogen atom or a salt thereof and a penicillin compound of the formula:
wherein R2 is an acyl group selected from the group consisting of heterocyclic carbonyl, phenylacetyl, alkanoyl of 2 to 8 carbon atoms and alkanoyl of 2 to 8 carbon atoms, said acyl group being substituted or unsubstituted or a salt thereof.
2. The antibacterial composition for animals according to claim 1, wherein said cephalosporin compound and said penicillin compound are present in a ratio of 1:1 to 1:10, by weight.
3. The antibacterial composition for animals according to claim 1 or 2, wherein R1 is a member selected from the group consisting of 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,3,4-triazol-2-yl, and 1-methyltetrazol-5-yl.
4. The antibacterial composition for animals according to claim 1, wherein the cephalosporin compound is a member selected from the group consisting of Cefazolin, 7-(tetrazol-1-yl)acetamido-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, 7-(tetrazol-1-yl)acetamido-3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and salts thereof.
5, The antibacterial composition according to claim 1 or 2, wherein R2 is alkanoyl or alkenoyl having 2 to 8 carbon atoms, and is unsubstituted or substituted by amino, carboxy or aryloxy, said aryloxy being unsubstituted or substituted by hydroxy, halogen or nitro, a phenylacetyl wherein the phenyl group is unsubstituted or substituted by hydroxy or methoxy and the acetyl group is unsubstituted or substituted by amino, carboxy or sulfo at the .alpha.-position, and a hetero-cyclic carbonyl wherein the heterocyclic group is unsub-stituted or substituted by a lower alkyl or aryl wherein the aryl group is unsubstituted or substituted by halogen.
6. The antibacterial composition for animals according to claim 1 or 2, wherein R2 is a member selected from the group consisting of 2-pentenylcarbonyl, n-heptylcarbonyl, caproyl, 4-amino-4-carboxybutylcarbonyl, .alpha.-phenoxybutyr .alpha.-phenoxypropionyl, p-chlorophenoxyacetyl, phenylacetyl, p-hydroxyphenylacetyl, .alpha.-amino-(p-hydroxyphenyl)acetyl, .alpha.-sulfo-phenylacetyl, .alpha.-carboxyphenylacetyl, 2,6-dimethoxy-phenylacetyl, .alpha.-amino-phenylacetyl, (5-methyl-3-phenylisoxazol-4-yl)carbonyl, [3-(o-chlorophenyl)-5-methylisoxazol-4-yl]-carbonyl, [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]-carbonyl, (5-methyl-3-phenylisoxazol-4-yl)carbonyl and [3-(6-fluoro-2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl.
7. The antibacterial composition for animals according to claim 1, wherein the penicillin compound is a member selected from the group consisting of penicillin G, penicillin X, penicillin F, penicillin K, 3-pentenylpenicillin, dihydro-penicillin F, penicillin N, isopenicillin N, penicillin V, carbenicillin, cloxacillin, dicloxacillin, oxacillin, methicillin, propicillin, phenethicillin, ampicillin, flucloxacillin, amoxycillin and sulbenicillin.
8. The antibacterial composition for animals according to claim 2, wherein the cephalosporin compound is a member selected from the group consisting of Cefazolin, 7-(tetrazol-1-yl)acetamido-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid, 7-(tetrazol-1-yl)acetamido-3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and salts thereof; and the penicillin compound is a member selected from the group consisting of penicillin G, penicillin X, penicillin F, penicillin K, 3-pentenylpenicillin, dihydro-penicillin F, penicillin N, isopenicillin M, penicillin V, carbenicillin, cloxacillin, dichloracillin, oxacillin, methi-cillin, propicillin, phenethicillin, ampicillin, flucloxa-cillin, amoxycillin and sulbenicillin.
9. The antibacterial composition for animals according to claim 1, 4 or 8, wherein the cephalosporin compound or a salt thereof and the penicillin compound or a salt thereof are present in a ratio of 1:1 to 1:4 by weight.
10. An antibacterial composition for animals comprising cefazolin a salt thereof and carbenicillin or a salt thereof in a ratio of 1:1 to 1:4 by weight.
11. An antibacterial composition for animals comprising cefazolin or a salt thereof and cloxacillin or a salt thereof in a ratio of 1:1 to 1:4 by weight.
12. An antibacterial composition for animals comprising cefazolin or a salt thereof and dicloxacillin or a salt thereof in a ratio of 1:1 to 1:4 by weight.
13. An antibacterial composition for animals comprising 7-(tetrazol-1-yl)acetamido-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid or a salt thereof and flucloxacillin or a salt thereof in a ratio of 1:1 to 1:4 by weight.
14. An antibacterial composition for animals comprising 7-(tetrazol-1-yl)acetamido-3-(1-methyltetrazol-5-yl)-thio-methyl-3-cephem-4-carboxylic acid or a salt thereof and amoxy-cillin or a salt thereof in a ratio of 1:1 to 1:4 by weight.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3500874A JPS5813526B2 (en) | 1974-03-27 | 1974-03-27 | Grasshopper's garden |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038759A true CA1038759A (en) | 1978-09-19 |
Family
ID=12430047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA221,406A Expired CA1038759A (en) | 1974-03-27 | 1975-03-06 | Mixtures of cephalosporin and penicillin type antibiotics |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5813526B2 (en) |
| CA (1) | CA1038759A (en) |
| DK (1) | DK132675A (en) |
| IT (1) | IT1036078B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54126735A (en) * | 1978-03-24 | 1979-10-02 | Toyama Chem Co Ltd | Bactericidal composition for medical use |
| JPS59126251U (en) * | 1983-02-15 | 1984-08-25 | ミノルタ株式会社 | Copy machine |
| JPS6036646U (en) * | 1983-08-22 | 1985-03-13 | 京セラミタ株式会社 | Shell type electrostatic copying machine |
| JPH0582374U (en) * | 1992-04-08 | 1993-11-09 | 元実 原田 | Clothes cover |
-
1974
- 1974-03-27 JP JP3500874A patent/JPS5813526B2/en not_active Expired
-
1975
- 1975-02-25 IT IT6748475A patent/IT1036078B/en active
- 1975-03-06 CA CA221,406A patent/CA1038759A/en not_active Expired
- 1975-03-26 DK DK132675A patent/DK132675A/da not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS50126816A (en) | 1975-10-06 |
| IT1036078B (en) | 1979-10-30 |
| JPS5813526B2 (en) | 1983-03-14 |
| DK132675A (en) | 1975-09-28 |
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