ANTIBACTERIAL COMPOSITION FOR MEDICAL USE

COMPOSE ANTIBACTERIEN A USAGE MEDICAL

English 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.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
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]
<IMG>
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
23

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
24

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.
26

Description

1119098
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.
'
.

- 1119098
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.
' ~

1119098
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)-

1119098
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.
- .: ~

1119098
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
-- 7 --
.

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
-- 8 --
.

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
-- 10 --

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

1119098
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)
- 15 -

~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
- 16 -

~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
- 18 -

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.
- 19 -

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
- 20 -

1119098
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
- 21 -

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.
- 22 -
:: : .
: . , ~ : .
: