CA1119098A - Antibacterial composition for medical use - Google Patents
Antibacterial composition for medical useInfo
- Publication number
- CA1119098A CA1119098A CA000332598A CA332598A CA1119098A CA 1119098 A CA1119098 A CA 1119098A CA 000332598 A CA000332598 A CA 000332598A CA 332598 A CA332598 A CA 332598A CA 1119098 A CA1119098 A CA 1119098A
- Authority
- CA
- Canada
- Prior art keywords
- beta
- medical use
- antibacterial composition
- lactamase
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An antibacterial composition for medical use comprising a cephalosporin or a pharmaceutically accep-table salt thereof and a .beta.-lactamase-inhibiting compound having a .beta.-lactam ring. The composition exhibits synergistic effect which is much greater than the sum of antibacterial effects of each component used alone.
An antibacterial composition for medical use comprising a cephalosporin or a pharmaceutically accep-table salt thereof and a .beta.-lactamase-inhibiting compound having a .beta.-lactam ring. The composition exhibits synergistic effect which is much greater than the sum of antibacterial effects of each component used alone.
Description
1 This inventior, relates to novel antibacterial compositions for medical use. More particularly, it relates to antibacterial compositions for medical use comprising cephalosporins represented by the formula [I]:
0~0 C2H5-N N-CONH-CH-CONH ~ 1 [I]
0~ ~\CH2R
COOH
R
wherein Rl represents an acetoxy, 5-(1-methyl-1,2,3,4-tetrazolyl)thio or 2-(5-methyl-1,3,4-thiadiazolyl)-thio group and R2 represents a hydrogen. atom or a hydroxyl group, or pharmaceutically acceptable salts thereof and ~-lactamase-inhibiting compounds having a ~-lactam ring.
The cephalosporins represented by the formula [I] and pharmaceutically acceptable salts thereof, which were developed by the present inventors, are useful substances having excellent characteristics such as a broad antibacterial spectrum.
The present inventors have found as a result of extensive studies that when a cephalosporin represented .~ : .
~11909~
1 by the formula [I] or a pharmaceutically acceptable salt thereof is mixed with a ~-lactamase-inhibiting compound having a ~-lactam ring, the latter makes it difficult for the cephalosphorins represented by the formula [I] and pharmaceutically acceptable salts thereof to be affected by ~-lactamase, and the resulting composi-tion exhibits a synergistic effect on the antibacterial activity.
An object of this invention is to provide an antibacterial composition having a pronounced antibac-terial activity against Gram-negative bacteria existing even in a large population, especially against Escherichia coli, Proteus species, Klebsiella pneumoniae and Pseudomonas aeruginosa.
Another object of this invention is to provide an antibacterial composition active to those pathogenic bacteria which are resistant to conventional penicillins or cephalosporins.
A further object of this invention is to provide an antibacterial composition capable of enhancing the bactericidal speed and therapeutic effectiveness.
- Other objects and advantages of this invention will become apparent from the following description.
According to this invention, there is provided an antibacterial composition for medical use comprising a cephalosporin represented by the formula [I] or a pharmaceutically acceptable salt thereof and a ~-lactamase-inhibiting compound having a ~-lactam ring.
' .
1 The above-mentioned pharmaceuticaily acceptable salts are those which are commonly used as cephalosporin salts, including salts with metals such as sodium, potassium and calcium, ammonium salt and salts with amines such as procaine, N,N-dibenzylethylenediamine and the like.
The ~-lactamase-inhibiting compounds having a ~-lactam ring used in this invention include ~-lactamse-inhibiting penicillins and cephalosporins and clavulanic acids. The ~-lactamase-inhibiting penicillins and cephalosporins are, for example, Cloxacillin, Dicloxacillin, Oxacillin, Flucloxacillin, Methicillin, Cefoxitin and 7~ cyanomethylthioacetamido)-7~-methoxy-3-[5-(1-methyl-1,2,3,4~tetrazolyl)thiomethyl]-Q3-cephem-4-carboxylic acid and pharmaceutically acceptable saltsthereof. These pharmaceutically acceptable salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [I].
And the clavulanic acids include, for example, the compound which is represented by the following formula and pharmaceutically acceptable salts thereof:
~/
N -~
COOH
..
, ~ ~
1~19098 1 These pharmaceutically acceptable salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [I].
The suitable ratio of the cephalosporin repre-sented by the formula [I] to the ~-lactamase-inhibiting compound having a ~-lactam ring in the composition of this invention varies to some degrees depending on the type of target pathogenic bacteria or symptoms, but is generally in the range of form 1 : 0.04 to-l : 5 (in terms of weight ratio or potency ratio), preferably 1 : 0.1 to 1 : 1.5 (in terms of weight ratio or potency ratio).
In this invention, the type of ~-lactamse-inhibiting compounds having a ~-lactam ring may be properly selected according to particular pathogenic bacteria.
The antibacterial composition for medical use according to this invention is used preferably as a parenteral injection, although it can be used in other dosage forms and through other administration routes similarly to known antibiotics such as conventional penicillins and cephalosporins. It can also be used in the-form of ointment and preparation for rectal administration.
When used as an injection, the antibacterial composition of this invention can be mixed with solid or liquid carriers or diluents which are conventionally used in injections of known antibiotics. Of the carriers, sterilized water is most frequently used.
' ~
l The antibacterial composition of this invention may, of course, be in the form of powder which can be dissolved in suitable vehicles such as sterilized water, glucose solution and physiological saline solution for use as an injection.
In administering the antibacterial composition of this invention as an injection to man, intravenous inejction (including drip infusion) or intramuscular injection is generally suitable.
The dosage of the antibacterial composition of this invention is properly selected in accordance with the ratio between the cephalosporin represented by the formula [I] and the ~-lactamase-inhibiting compound having a ~~lactam ring, age of the patient, and the type or symptoms of the infectious disease. The suitable dose of an injection ranges generally from 0.5 to lO g potency per day for adults, but the dose is not limited thereto.
In administering the antibacterial composition of this invention as an intramuscular injection, it can be used together with those drugs which are usually used in injections such as analgesics, for example, lidocaine hydrochloride.
The efficacy of the antibacterial composition of this invention is illustrated below with reference to Test Examples and the accompanying drawings which are diagrammatic representation of the test results. In the drawings, Fig. l shows antibacterial activities of sodium 7-[D(~ -(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-1 p-hydroxyphenylacetamide]-3-[5-(1-methyl-1,2,3,4-tetra-zolyl)thiomethyl]-~3-cephem-4-carboxylate (referred to hereinafter as T-1551 Na) and Methicillin sodium against Escherichia coli TK-3, which is clinically isolated strain, Fig. 2 shows those of T-1551 Na and Methicillin sodium against Klebsiella pneumoniae Y-4 which is clinically isolated strain, Fig. 3 shows those of T-1551 Na and potassium clavulanate against Escherichia coli GN 6299 which is clinically isolated strain, Fig. 4 shows those of T-1551 Na and potassium clavulanate against Klebsiella pneumoniae GN 69 which clinically isolated strain, and Fig. 5 shows those of T-1551 Na and potassium clavulanate against Pseudomonas aeruginosa GN 3345 which is clinically isolated strain.
Test Example 1 Growth-inhibition test on clinically isolated strain Heart Infusion agar containing a prescribed amount of Methicillin sodium or T-1551 Na was inoculated with the test bacterium at a rate of about 108 cells/ml.
After incubation for 18 hours at 37C., the growth of the test bacterium was inspected. The results of test were as shown in Tables 1, 2 and 3. In each table, (+) means that the test bacterium grew and (-) means that the test bacterium did not grow. From Tables 1, 2 and 3, it is apparent that the combination of Methicillin sodium and T-1551 Na exhibits a synergistic effect on the inhibi-tion of growth of the pathogenic bacteria.
- .: ~
Table 1 Escherichia coli TK-3 strain (~g/mQ) 3200 _ _ - _ 1600 _ - - - + __ = __ _ ~ 800 _ _ _ _ +_ + + + + +
400 _ _ _ _ + + + + + +
200 - - - - __ _ _ __ o 10 0 _ _ _ _ _ _ _ _ + _ 25 _ + + + + + + + + +
12.5 _ + + + + + + + + +
_ __ O + + + + + + + + + +
200 100 50 25 12.5 6.25 3.13 1.56 0.78 0 (~g/mQ) T-1551 Na .
111~098 Table 2 Klebsiella pneumoniae Y-4 s~rain (~g/mQ) 1600 r~ ~ ~ ~ ~ ~
~o 400 _ _ _ + + + + + + +
ul ~ 200 _ + + + + + + + +
~ 100 _ _ + + + + + + + +
~ 5 _ _ .
_ _ + + + + + + + +
12.5 - _ + + + + + + +
200 100 50 25 12.5 6.25 3.13 1.56 o.78 0 (~g/mQ) T-1551 Na .
11 ~9098 Table 3 Pseudomonas aeruginosa S-lll strain (~g/mQ) 3200 _ _ _ _ _ t _ -t _ =
1600 _ _ _ _ _ + + + + +
800 _ _ _ _ _ _ 400 _ _ _ + + + + + + +
200 - __ - _ _ _ _ + - t rl 100 _ _ _ + + + + + + +
_ _ _ + + + + + + +
_ _ t t + + + + + t +
12.5 + + + + . + + + + + +
O + + .+ + + + + I + + +
200 100 50 25 12.5 6.25 3.13 1.56 0.78 - 0 (~g/mQ) T-1551 Na _ 9 _ ' ' '.
111~098 1 Test Example 2 ~-Lactamase specific activity The ~-lactamase activity was assayed by the iodometric assay method at 30C, following the procedure of Perret [C.J. Perret, "Iodometric Assay of Penicillinase", Nature, 174, 1012-1013 (1954)], except that a 0.1 molar phosphate buffer solution (pH 7.0) was used in place of the 0.2 molar phosphate buffer solution (pH 6.5). One unit of ~-lactamase activity corresponds to the quantity of ~-lactamase which decomposes 1 ~mole/hour of T-1551 Na in a 0.1 molar phosphate buffer solution (pH 7.0) containing 8 mmoles of the substrate.
In Table 4, there are shown ~-lactamase specific activities of Escherichia coli TK-3 strain, Klebsiella pneumoniae Y-4 strain and Pseudomonas aeruginosa S-lll strain.
Table 4 _ Strain ~-Lactamase activity (unit/mg dry weight) Escherichia coli TK-3 53 Klebsiella pneumoniae Y-4 30 Pseudomonas aeru~inosa S-lll 5.2 1119()98 1 Test Example 3 Antibacterial activity against clinically isolated strains The following test was performed to examine whether or not the synergistic effect of the present composition confirmed by the growth inhibition test in Test Examp]e 1 is accompanied by an antibacterial effect.
A pathogenic bacterium was inoculated at a rate of about 108 cells/ml into a Nutrient broth containing T-1551 Na (50 ~g/ml) alone, T-1551 Na (25 ~g/ml) plus Methicillin sodium (25 ~g/ml) or Methicillin sodium (50 ~g/ml) alone. The inoculated broth was incubated at 37C and the number of live cells in the culture broth was determined at predetermined time intervals.
The test results are as shown in Figs. 1 and
0~0 C2H5-N N-CONH-CH-CONH ~ 1 [I]
0~ ~\CH2R
COOH
R
wherein Rl represents an acetoxy, 5-(1-methyl-1,2,3,4-tetrazolyl)thio or 2-(5-methyl-1,3,4-thiadiazolyl)-thio group and R2 represents a hydrogen. atom or a hydroxyl group, or pharmaceutically acceptable salts thereof and ~-lactamase-inhibiting compounds having a ~-lactam ring.
The cephalosporins represented by the formula [I] and pharmaceutically acceptable salts thereof, which were developed by the present inventors, are useful substances having excellent characteristics such as a broad antibacterial spectrum.
The present inventors have found as a result of extensive studies that when a cephalosporin represented .~ : .
~11909~
1 by the formula [I] or a pharmaceutically acceptable salt thereof is mixed with a ~-lactamase-inhibiting compound having a ~-lactam ring, the latter makes it difficult for the cephalosphorins represented by the formula [I] and pharmaceutically acceptable salts thereof to be affected by ~-lactamase, and the resulting composi-tion exhibits a synergistic effect on the antibacterial activity.
An object of this invention is to provide an antibacterial composition having a pronounced antibac-terial activity against Gram-negative bacteria existing even in a large population, especially against Escherichia coli, Proteus species, Klebsiella pneumoniae and Pseudomonas aeruginosa.
Another object of this invention is to provide an antibacterial composition active to those pathogenic bacteria which are resistant to conventional penicillins or cephalosporins.
A further object of this invention is to provide an antibacterial composition capable of enhancing the bactericidal speed and therapeutic effectiveness.
- Other objects and advantages of this invention will become apparent from the following description.
According to this invention, there is provided an antibacterial composition for medical use comprising a cephalosporin represented by the formula [I] or a pharmaceutically acceptable salt thereof and a ~-lactamase-inhibiting compound having a ~-lactam ring.
' .
1 The above-mentioned pharmaceuticaily acceptable salts are those which are commonly used as cephalosporin salts, including salts with metals such as sodium, potassium and calcium, ammonium salt and salts with amines such as procaine, N,N-dibenzylethylenediamine and the like.
The ~-lactamase-inhibiting compounds having a ~-lactam ring used in this invention include ~-lactamse-inhibiting penicillins and cephalosporins and clavulanic acids. The ~-lactamase-inhibiting penicillins and cephalosporins are, for example, Cloxacillin, Dicloxacillin, Oxacillin, Flucloxacillin, Methicillin, Cefoxitin and 7~ cyanomethylthioacetamido)-7~-methoxy-3-[5-(1-methyl-1,2,3,4~tetrazolyl)thiomethyl]-Q3-cephem-4-carboxylic acid and pharmaceutically acceptable saltsthereof. These pharmaceutically acceptable salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [I].
And the clavulanic acids include, for example, the compound which is represented by the following formula and pharmaceutically acceptable salts thereof:
~/
N -~
COOH
..
, ~ ~
1~19098 1 These pharmaceutically acceptable salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [I].
The suitable ratio of the cephalosporin repre-sented by the formula [I] to the ~-lactamase-inhibiting compound having a ~-lactam ring in the composition of this invention varies to some degrees depending on the type of target pathogenic bacteria or symptoms, but is generally in the range of form 1 : 0.04 to-l : 5 (in terms of weight ratio or potency ratio), preferably 1 : 0.1 to 1 : 1.5 (in terms of weight ratio or potency ratio).
In this invention, the type of ~-lactamse-inhibiting compounds having a ~-lactam ring may be properly selected according to particular pathogenic bacteria.
The antibacterial composition for medical use according to this invention is used preferably as a parenteral injection, although it can be used in other dosage forms and through other administration routes similarly to known antibiotics such as conventional penicillins and cephalosporins. It can also be used in the-form of ointment and preparation for rectal administration.
When used as an injection, the antibacterial composition of this invention can be mixed with solid or liquid carriers or diluents which are conventionally used in injections of known antibiotics. Of the carriers, sterilized water is most frequently used.
' ~
l The antibacterial composition of this invention may, of course, be in the form of powder which can be dissolved in suitable vehicles such as sterilized water, glucose solution and physiological saline solution for use as an injection.
In administering the antibacterial composition of this invention as an injection to man, intravenous inejction (including drip infusion) or intramuscular injection is generally suitable.
The dosage of the antibacterial composition of this invention is properly selected in accordance with the ratio between the cephalosporin represented by the formula [I] and the ~-lactamase-inhibiting compound having a ~~lactam ring, age of the patient, and the type or symptoms of the infectious disease. The suitable dose of an injection ranges generally from 0.5 to lO g potency per day for adults, but the dose is not limited thereto.
In administering the antibacterial composition of this invention as an intramuscular injection, it can be used together with those drugs which are usually used in injections such as analgesics, for example, lidocaine hydrochloride.
The efficacy of the antibacterial composition of this invention is illustrated below with reference to Test Examples and the accompanying drawings which are diagrammatic representation of the test results. In the drawings, Fig. l shows antibacterial activities of sodium 7-[D(~ -(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-1 p-hydroxyphenylacetamide]-3-[5-(1-methyl-1,2,3,4-tetra-zolyl)thiomethyl]-~3-cephem-4-carboxylate (referred to hereinafter as T-1551 Na) and Methicillin sodium against Escherichia coli TK-3, which is clinically isolated strain, Fig. 2 shows those of T-1551 Na and Methicillin sodium against Klebsiella pneumoniae Y-4 which is clinically isolated strain, Fig. 3 shows those of T-1551 Na and potassium clavulanate against Escherichia coli GN 6299 which is clinically isolated strain, Fig. 4 shows those of T-1551 Na and potassium clavulanate against Klebsiella pneumoniae GN 69 which clinically isolated strain, and Fig. 5 shows those of T-1551 Na and potassium clavulanate against Pseudomonas aeruginosa GN 3345 which is clinically isolated strain.
Test Example 1 Growth-inhibition test on clinically isolated strain Heart Infusion agar containing a prescribed amount of Methicillin sodium or T-1551 Na was inoculated with the test bacterium at a rate of about 108 cells/ml.
After incubation for 18 hours at 37C., the growth of the test bacterium was inspected. The results of test were as shown in Tables 1, 2 and 3. In each table, (+) means that the test bacterium grew and (-) means that the test bacterium did not grow. From Tables 1, 2 and 3, it is apparent that the combination of Methicillin sodium and T-1551 Na exhibits a synergistic effect on the inhibi-tion of growth of the pathogenic bacteria.
- .: ~
Table 1 Escherichia coli TK-3 strain (~g/mQ) 3200 _ _ - _ 1600 _ - - - + __ = __ _ ~ 800 _ _ _ _ +_ + + + + +
400 _ _ _ _ + + + + + +
200 - - - - __ _ _ __ o 10 0 _ _ _ _ _ _ _ _ + _ 25 _ + + + + + + + + +
12.5 _ + + + + + + + + +
_ __ O + + + + + + + + + +
200 100 50 25 12.5 6.25 3.13 1.56 0.78 0 (~g/mQ) T-1551 Na .
111~098 Table 2 Klebsiella pneumoniae Y-4 s~rain (~g/mQ) 1600 r~ ~ ~ ~ ~ ~
~o 400 _ _ _ + + + + + + +
ul ~ 200 _ + + + + + + + +
~ 100 _ _ + + + + + + + +
~ 5 _ _ .
_ _ + + + + + + + +
12.5 - _ + + + + + + +
200 100 50 25 12.5 6.25 3.13 1.56 o.78 0 (~g/mQ) T-1551 Na .
11 ~9098 Table 3 Pseudomonas aeruginosa S-lll strain (~g/mQ) 3200 _ _ _ _ _ t _ -t _ =
1600 _ _ _ _ _ + + + + +
800 _ _ _ _ _ _ 400 _ _ _ + + + + + + +
200 - __ - _ _ _ _ + - t rl 100 _ _ _ + + + + + + +
_ _ _ + + + + + + +
_ _ t t + + + + + t +
12.5 + + + + . + + + + + +
O + + .+ + + + + I + + +
200 100 50 25 12.5 6.25 3.13 1.56 0.78 - 0 (~g/mQ) T-1551 Na _ 9 _ ' ' '.
111~098 1 Test Example 2 ~-Lactamase specific activity The ~-lactamase activity was assayed by the iodometric assay method at 30C, following the procedure of Perret [C.J. Perret, "Iodometric Assay of Penicillinase", Nature, 174, 1012-1013 (1954)], except that a 0.1 molar phosphate buffer solution (pH 7.0) was used in place of the 0.2 molar phosphate buffer solution (pH 6.5). One unit of ~-lactamase activity corresponds to the quantity of ~-lactamase which decomposes 1 ~mole/hour of T-1551 Na in a 0.1 molar phosphate buffer solution (pH 7.0) containing 8 mmoles of the substrate.
In Table 4, there are shown ~-lactamase specific activities of Escherichia coli TK-3 strain, Klebsiella pneumoniae Y-4 strain and Pseudomonas aeruginosa S-lll strain.
Table 4 _ Strain ~-Lactamase activity (unit/mg dry weight) Escherichia coli TK-3 53 Klebsiella pneumoniae Y-4 30 Pseudomonas aeru~inosa S-lll 5.2 1119()98 1 Test Example 3 Antibacterial activity against clinically isolated strains The following test was performed to examine whether or not the synergistic effect of the present composition confirmed by the growth inhibition test in Test Examp]e 1 is accompanied by an antibacterial effect.
A pathogenic bacterium was inoculated at a rate of about 108 cells/ml into a Nutrient broth containing T-1551 Na (50 ~g/ml) alone, T-1551 Na (25 ~g/ml) plus Methicillin sodium (25 ~g/ml) or Methicillin sodium (50 ~g/ml) alone. The inoculated broth was incubated at 37C and the number of live cells in the culture broth was determined at predetermined time intervals.
The test results are as shown in Figs. 1 and
2, and it was confirmed that the antibacterial activity had increased by the joint use of T-1551 Na and Methicillin sodium. The minimum inhibitory concentration of T-1551 Na or Methicillin sodium against Escherichia coli TK-3 strain or Kleosiella pneumoniae Y-4 strain was greater than 800 ~g/ml in each case.
Test Example 4 Effect of combined use on experimental infection in mice Male mice (5 mice per group) of the ICR strain, 4 weeks of age, were peritoneally inoculated with the prescribed number of pathogenic bacteria suspended in 1 5% mucin. After one hour and two hours following the inoculation, test preparations shown in Table 5 were subcuataneously administered to examine the protection effect. The results obtained were as shown in Table 5, wherein the protection effect was expressed in terms of ED50-Table 5 Challenge ED50, mg/mouse bacterium dose Methicillin T-155' cillin mouse) Na (2 : 1) Na Na K. pneumoniae 5.7 x 107 4.8 >26.8 >50 - Y-53 1.0 x 107 1.66 >10.0 >46.6 As is apparent from Table 5, the synergistic effect of the combined use of T-1551 Na and Methicillin sodium on the inhibition of pathogenic bacteria growth, which had been found in vitro, was recognized also by the experiment of protection of animal from infection.
Text Example 5 The same operation as in Test Example 1 was repeated, except that the Methicillin sodium was replaced by potassium clavulanate and the test bacteria were replaced by those shown in Tables 6~ 7 and 8, to obtaln the results shown n T~bles 6, 7 and 8.
~119~)98 Table 6 Escherichia coli GN 6299 strain (~g/mQ) Potasslum 6 L ~ ~ ~ t clavula- ~ _ _ _ _ _ _ _ nate 1.6 _ _ _ _ _ _ _ _ _ 0.4 O
800 200 50 12.5
Test Example 4 Effect of combined use on experimental infection in mice Male mice (5 mice per group) of the ICR strain, 4 weeks of age, were peritoneally inoculated with the prescribed number of pathogenic bacteria suspended in 1 5% mucin. After one hour and two hours following the inoculation, test preparations shown in Table 5 were subcuataneously administered to examine the protection effect. The results obtained were as shown in Table 5, wherein the protection effect was expressed in terms of ED50-Table 5 Challenge ED50, mg/mouse bacterium dose Methicillin T-155' cillin mouse) Na (2 : 1) Na Na K. pneumoniae 5.7 x 107 4.8 >26.8 >50 - Y-53 1.0 x 107 1.66 >10.0 >46.6 As is apparent from Table 5, the synergistic effect of the combined use of T-1551 Na and Methicillin sodium on the inhibition of pathogenic bacteria growth, which had been found in vitro, was recognized also by the experiment of protection of animal from infection.
Text Example 5 The same operation as in Test Example 1 was repeated, except that the Methicillin sodium was replaced by potassium clavulanate and the test bacteria were replaced by those shown in Tables 6~ 7 and 8, to obtaln the results shown n T~bles 6, 7 and 8.
~119~)98 Table 6 Escherichia coli GN 6299 strain (~g/mQ) Potasslum 6 L ~ ~ ~ t clavula- ~ _ _ _ _ _ _ _ nate 1.6 _ _ _ _ _ _ _ _ _ 0.4 O
800 200 50 12.5
3.1 o.8 0.2 0 (~g/mQ) T-1551 Na ~ ~9098 Table 7 Klebsiella pneumoniae GN 69 strain (~g/mQ) 100 ~ ' ~
6.25 - - - - - - _ _ _ Potassium _ _ _ _ _ _ _ _ clavula- _ _ _ nate 1 ~ ~ ~
800 200 50 12.5 ; .
]
. ~
3.1 o.8 0.2 0 (~g/mQ) T-1551 Na - - .
11190g8 Table 8 Pseudomonas aeruginosa GN 3345 strain (~g/mQ) _ 100 _ _ _ _ _ _ + + + +
a~ _ _ , _ _ _ _ _ + 25 - - _ = - _ + + + +
__ _ __ ___ 12.5 _ _ _ _ _ ~ t + + +
3 ~ ~ ~ ~
800 200 50 12.5 3.1 0 T-1551 Na (~g/mQ) ~119098 1 Test Example 6 The same operation as in Test Example 3 was repeated, except that the Methicillin sodium was replaced by potassium clavulanate, the pathogenic bacteria were replaced by those shown in Figs. 3 to 5, and they were inoculated at a rate of 106 cells/ml instead of 10 cells/mol, to obtain the results shown in Figs. 3, 4 and 5.
The test results described in the foregoing Test Examples 1 to 6 are typical of the pharmacological activity of the antibacterial composition of this invention. When other ~-lactamase-inhibiting compounds having a ~-lactam ring such as Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Cefoxitin, and 7~-(D-~-cyanomethylthioacetamido)-7~-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid, and sodium salts thereof, there were obtained results similar to those obtained with Methicillin sodium and potassium clavulanate.
And when other cephalosporins represented by the formula [I] than T-1551 Na were used, there were obtained effects similar to those obtained with T-1551 Na.
From the foregoing description, it is under-standable that the antibacterial composition for medical use according to this invention is expected to be ef~ective in the therapy of various diseases, the causative organisms of which are bacteria sensitive to the respective penicil-lins and cephalosporins. Especially, the composition of ~19098 l this invention will be highly useful in the therapy of various diseases including, for example, those in the medical department and urological department which are casued by the bacteria~ sensitive to the cephalosporins represented by the formula [I~ or pharmaceutically acceptable salts thereof, particularly belonging to Gram-negative bacteria, (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus species, etc.).
The present invention is illustrated below with reference to Examples which are merely illustrative and not limitative.
Example l Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(l-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 500 mg
6.25 - - - - - - _ _ _ Potassium _ _ _ _ _ _ _ _ clavula- _ _ _ nate 1 ~ ~ ~
800 200 50 12.5 ; .
]
. ~
3.1 o.8 0.2 0 (~g/mQ) T-1551 Na - - .
11190g8 Table 8 Pseudomonas aeruginosa GN 3345 strain (~g/mQ) _ 100 _ _ _ _ _ _ + + + +
a~ _ _ , _ _ _ _ _ + 25 - - _ = - _ + + + +
__ _ __ ___ 12.5 _ _ _ _ _ ~ t + + +
3 ~ ~ ~ ~
800 200 50 12.5 3.1 0 T-1551 Na (~g/mQ) ~119098 1 Test Example 6 The same operation as in Test Example 3 was repeated, except that the Methicillin sodium was replaced by potassium clavulanate, the pathogenic bacteria were replaced by those shown in Figs. 3 to 5, and they were inoculated at a rate of 106 cells/ml instead of 10 cells/mol, to obtain the results shown in Figs. 3, 4 and 5.
The test results described in the foregoing Test Examples 1 to 6 are typical of the pharmacological activity of the antibacterial composition of this invention. When other ~-lactamase-inhibiting compounds having a ~-lactam ring such as Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Cefoxitin, and 7~-(D-~-cyanomethylthioacetamido)-7~-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid, and sodium salts thereof, there were obtained results similar to those obtained with Methicillin sodium and potassium clavulanate.
And when other cephalosporins represented by the formula [I] than T-1551 Na were used, there were obtained effects similar to those obtained with T-1551 Na.
From the foregoing description, it is under-standable that the antibacterial composition for medical use according to this invention is expected to be ef~ective in the therapy of various diseases, the causative organisms of which are bacteria sensitive to the respective penicil-lins and cephalosporins. Especially, the composition of ~19098 l this invention will be highly useful in the therapy of various diseases including, for example, those in the medical department and urological department which are casued by the bacteria~ sensitive to the cephalosporins represented by the formula [I~ or pharmaceutically acceptable salts thereof, particularly belonging to Gram-negative bacteria, (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus species, etc.).
The present invention is illustrated below with reference to Examples which are merely illustrative and not limitative.
Example l Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(l-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 500 mg
4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 4 ml of a solution containing 0.5% (W/V) o~ lidocaine hydrochloride to obtain an injectable solution to be diluted when used.
Example 2 Sterilized sodium 7-~D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- l g 4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency i~l9~)98 1 The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an in~ectable solution.
Example 3 Sterilized sodium 7-[D(~ -(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydrox~phenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 1 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved in 20 ml of a 5% glucose solution to obtain an injectable solution.
Example 4 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 2 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved in 250 ml 10 of a transfusion to obtain a drip infusion.
Example 5 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 250 mg 4-carboxylate ... potency Sterilized Methicillin sodium ... 250 mg potency 1~19098 1 The above ingredients were dissolved in 20 ml of a physiological saline solution to obtain an injec-table solution.
Example 6 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido~~3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of distilled water and freeze-dried in a usual manner to obtain a composition. This composition was dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 7 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterilized Cloxacillin sodium ... 500 mg potency The abo~e ingredients were dissolved in 20 ml of physiological saline solution to obtain an injec-table solution.
1~19098 1 Example 8 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido~-3-[5-(l-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- l g 4-carboxylate ... potency Sterilized Dicloxacillin sodium ... 500 mg - potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 2 Sterilized sodium 7-~D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- l g 4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency i~l9~)98 1 The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an in~ectable solution.
Example 3 Sterilized sodium 7-[D(~ -(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydrox~phenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 1 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved in 20 ml of a 5% glucose solution to obtain an injectable solution.
Example 4 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 2 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved in 250 ml 10 of a transfusion to obtain a drip infusion.
Example 5 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem- 250 mg 4-carboxylate ... potency Sterilized Methicillin sodium ... 250 mg potency 1~19098 1 The above ingredients were dissolved in 20 ml of a physiological saline solution to obtain an injec-table solution.
Example 6 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido~~3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of distilled water and freeze-dried in a usual manner to obtain a composition. This composition was dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 7 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterilized Cloxacillin sodium ... 500 mg potency The abo~e ingredients were dissolved in 20 ml of physiological saline solution to obtain an injec-table solution.
1~19098 1 Example 8 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido~-3-[5-(l-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- l g 4-carboxylate ... potency Sterilized Dicloxacillin sodium ... 500 mg - potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
5 Example 9 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterilized Oxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an inejctable solution.
Example 10 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterlized Cefoxitin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an 1 injectable solution.
Example 11 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterilized Flucloxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline soluton to obtain an inejctable solution.
Example 12 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-acetoxymethyl- 1 g ~3-cephem-4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 13 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-. 1 g ~3-cephem-4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency 1119~)98 1 The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 14 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]- 1 g ~3-cephem-4-carboxylate ... potency Sterilized potassium clavulanate ... 300 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
:: : .
: . , ~ : .
:
Example 10 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterlized Cefoxitin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an 1 injectable solution.
Example 11 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem- 1 g 4-carboxylate ... potency Sterilized Flucloxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline soluton to obtain an inejctable solution.
Example 12 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-acetoxymethyl- 1 g ~3-cephem-4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 13 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-. 1 g ~3-cephem-4-carboxylate ... potency Sterilized Methicillin sodium ... 500 mg potency 1119~)98 1 The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 14 Sterilized sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]- 1 g ~3-cephem-4-carboxylate ... potency Sterilized potassium clavulanate ... 300 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
:: : .
: . , ~ : .
:
Claims (17)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antibacterial composition for medical use comprising as active ingredients a cephalosporin represented by the formula:
[I]
wherein R1 represents an acetoxy, 5-(1-methyl-1,2,3,4-tetrazolyl)thio or 2-(5-methyl-1,3,4-thiadiazolyl)thio group and R2 represents a hydrogen atom or a hydroxyl group, or a pharmaceutically acceptable salt thereof and a .beta.-lactamase-inhibiting compound having a .beta.-lactam ring.
[I]
wherein R1 represents an acetoxy, 5-(1-methyl-1,2,3,4-tetrazolyl)thio or 2-(5-methyl-1,3,4-thiadiazolyl)thio group and R2 represents a hydrogen atom or a hydroxyl group, or a pharmaceutically acceptable salt thereof and a .beta.-lactamase-inhibiting compound having a .beta.-lactam ring.
2. An antibacterial composition for medical use according to Claim 1, wherein the .beta.-lactamase-inhibiting compound having a .beta.-lactam ring is a .beta.-lactamase-inhibiting penicillin or a pharmaceutically acceptable salt thereof.
3. An antibacterial composition for medical use according to Claim 1, wherein the .beta.-lactamase-inhibiting compound having a .beta.-lactam ring is a .beta.-lactamase-inhibiting cephalosporin or a pharmaceutically acceptable salt thereof.
4. An antibacterial composition for medical use according to Claim 1, wherein the .beta.-lactamase-inhibiting compound having a .beta.-lactam ring is a clavulanic acid or a pharmaceutically acceptable salt thereof.
5. An antibacterial composition for medical use according to Claim 2, wherein the .beta.-lactamase-inhibiting penicillin is Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Flucloxabillin, or a pharmaceutically acceptable salt thereof.
6. An antibacterial composition for medical use according to Claim 3, wherein the .beta.-lactamase-inhibiting cephalosporin is Cefoxitin, 7.beta.-(.alpha.-cyanomethylthioacetamido)-7.alpha.-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
7. An antibacterial composition for medical use according to Claim 4, wherein in the formula [I], R1 repre-sents a 5-(1-methyl-1,2,3,4-tetrazolyl)thio group and R2 represents a hydroxyl group.
8. An antibacterial composition for medical use according to Claim 5, wherein in the formula [I], R1 represents a 5-(1-methyl-1,2,3,4-tetrazolyl)thio group and R2 represents a hydroxyl group.
9. An antibacterial composition for medical use according to Claim 6, wherein in the formula [I], R1 represents a 5-(1-methyl-1,2,3,4-tetrazolyl)thio group and R2 represents a hydroxyl group.
10. An antibacterial composition for medical use according to Claim 1, wherein the mixing ratio (in terms of weight ratio or potency ratio) of the .beta.-lactamase-inhibiting compound having a .beta.-lactam ring to the cephalosporin represented by the formula [I] or the pharmaceutically acceptable salt thereof is from 0.1 to 1.5.
11. An antibacterial composition for medical use according to Claim 2, wherein the mixing ratio (in terms of weight ratio or potency ratio) of the .beta.-lactamase-inhibiting penicillin to the cephalosporin represented by the formula [I] or the pharmaceutically acceptable salt thereof is from 0.1 to 1.5.
12. An antibacterial composition for medical use according to Claim 3, wherein the mixing ratio (in terms of weight ratio or potency ratio) of the .beta.-lactamase-inhibiting cephalosporin to the cephalosporin represented by the formula [I] or the pharmaceutically acceptable salt thereof is from 0.1 to 1.5.
13. An antibacterial composition for medical use according to Claim 4, wherein the mixing ratio (in terms of weight ratio or potency ratio) of the clavulanic acid or pharmaceutically acceptable salt thereof to the cephalosporin represented by the formula [I] or the pharmaceutically acceptable salt thereof is from 0.1 to 1.5.
14. An antibacterial composition for medical use according to Claim 11, wherein the .beta.-lactamase-inhibiting penicillin is Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Flucloxacillin, or a sodium salt thereof.
15. An antibacterial composition for medical use according to Claim 12, wherein the .beta.-lactamase-inhibiting cephalosporin is Cefoxitin, 7.beta.-(.alpha.-cyanomethylthioacetamido)-7.alpha.-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or a sodium salt thereof.
16. An antibacterial composition for medical use according to Claim 13, wherein the clavulanic acid or phamaceutically acceptable salt thereof is clavulanic acid or potassium clavulanate.
17. An antibacterial composition for medical use according to Claim 1, 14 or 15 ar 16, wherein the composi-tion is in the form of an injection.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA000332598A CA1119098A (en) | 1979-07-26 | 1979-07-26 | Antibacterial composition for medical use |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA000332598A CA1119098A (en) | 1979-07-26 | 1979-07-26 | Antibacterial composition for medical use |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1119098A true CA1119098A (en) | 1982-03-02 |
Family
ID=4114792
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000332598A Expired CA1119098A (en) | 1979-07-26 | 1979-07-26 | Antibacterial composition for medical use |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1119098A (en) |
-
1979
- 1979-07-26 CA CA000332598A patent/CA1119098A/en not_active Expired
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Neu et al. | Antibacterial activity of ceftriaxone (Ro 13-9904), a beta-lactamase-stable cephalosporin | |
Aswapokee et al. | A sulfone β-lactam compound which acts as a β-lactamase inhibitor | |
US4956179A (en) | Antibacterial combination of penicillin and cephalosporin | |
Tsuchiya et al. | Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin: in vitro and in vivo antibacterial activities | |
US4199566A (en) | Antibacterial composition for medical use | |
Maugh | A New Wave of Antibiotics Builds: New β-lactams active against resistant organisms are about to flood the market, but some physicians and hospitals may drown | |
US4428936A (en) | Antibacterial composition for medical use | |
CA1119098A (en) | Antibacterial composition for medical use | |
Eykyn | Use and control of cephalosporins. | |
Clarke et al. | Ro 13-9904 and GR 20263, two new cephalosporins with broad-spectrum activity: an in vitro comparison with other B-actam antibiotics | |
Aswapokee et al. | In vitro activity and beta-lactamase stability of BL-S786 compared with those of other cephalosporins | |
Jones et al. | Beta-lactamase hydrolysis and inhibition studies of the new 1-carbacephem LY163892 | |
EP2124935B1 (en) | Antibacterial combination and its use | |
US5049384A (en) | Antibacterial composition for medical use and a process for the preparation thereof | |
IE47856B1 (en) | Antibacterial composition for medical use | |
Clarke et al. | In-vitro activity of ceftazidime compared with other β-lactam antibiotics | |
Counts et al. | Comparative in vitro activity of the new oral cephalosporin cefixime | |
HIkida et al. | In-vitro antibacterial activity of L-105, a new cephalosporin | |
Clarke et al. | Antibacterial activity of the cephamycin cefotetan: an in-vitro comparison with other β-actam antibiotics | |
Axelrod et al. | Cephradine levels in human aqueous humor | |
Turck | Introduction: Cephalosporins and Related Antibiotics: An Overview | |
NO792370L (en) | PROCEDURE FOR THE PREPARATION OF A CEPHALOSPORIN DERIVATIVE | |
CA1336412C (en) | Pharmaceutical composition having synergistic effect | |
Theron, EJ & Nel | Treatment of septic burns with a third-generation cephalosporin (cefatriaxon) | |
HU181974B (en) | Process for producing pharmaceutical compositions of antibacterial activity containing cepheme-carboxylic acid derivatives and beta-lactamase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |