AT392903B - Pharmaceutical preparation containing a cephalosporin and a penem antibiotic - Google Patents

Abstract

Pharmaceutical preparation with synergistic antibacterial activity, containing a) a cephalosporin derivative of the general formula I or its physiologically tolerated salts or esters and b) a penem antibiotic of the general formula II or its physiologically tolerated salts or esters, process for the production of a preparation of this type and its use for treating bacterial infections. <IMAGE>

Description

AT 392 903 B

It is known that antibiotics from the class of the cephalosporins, such as. B. Ccfotaxim, cefodizime or cefpiroma, excellent for the treatment of bacterial infections, but that the antibaclerial activity against certain gram-positive and gram-negative aerobic, especially anacrobe germs may not be sufficient.

Antibiotics from the peneme group, such as. B. 5R.6S-6- (IR-hydroxyelhyl) -3- (4-carbamoyl-phenoxy) -7-oxo-4-thia-l-azabicyclo known from EP-A1-0 170 028 [3.2.0 ] hept-2-en-carboxylic acid, have an antibacterial activity that kills many pathogens against which cephalosporins are not very effective.

From ΕΡΆ-0 120 613 it is known that synergistic effects can occur between certain penems and penicillins or cephalosporins. Compared to the penem-cephalosporin combinations described there, the preparations according to the invention are distinguished by a significantly higher antibacterial activity.

Furthermore, from US-A-4,560,550 penems are known which, as can be seen from tables 1 and 10 of the patent, have a very low antibaclerial activity. As a rule, this is 1 O-potency less than the intrinsic activity of the penem compounds used in the present combination. The penems according to the United States Palentschrift act only synergistically with other ß-lactam antibiotics, since they are ß-lactamase inhibitors. This synergism is therefore limited to germs whose resistance to ß-lactam antibiotics is based on the formation of a ß-lactamase. Therefore, no synergistic effect can be found if the resistance of the germs is based on a different mechanism.

However, the penems from the preparations according to the invention surprisingly also have a synergistic activity with β-lactams if the germs do not form β-lactamase. This can be seen from Table 7 below, in which streptococci of Serogruppc D are inhibited significantly better by a mixture of HRE 664 and cefotaxime than is the case for the individual components. Table A describes this again for HRE 664.

In experiments with a character representative of the streptococci of serogroup D (Streptococcus faecalis D-1), this surprising effect could also be demonstrated for other examples (Table B).

This can also be observed in a representative of the clinically important group of methicillin-resistant staphylococci (MRS A), whose resistance to β-lactams is not based on a lactamase, as Table C shows.

The synergistic antibacterial effect against germs which do not form β-lactamase, which is achieved with the preparations according to the invention, can therefore be regarded as surprising and inventive.

It has now been found that cephalosporins in combination with certain penems surprisingly have a clearly synergistic antibacterial effect.

The invention therefore relates to pharmaceutical preparations with synergistic antibaktcricllcr effectiveness, containing a cephalosporin and a penile antibiotic, which are characterized in that

(a) a cephalosporin derivative of the general formula I

(I). wherein

Rj can represent hydrogen, Cj-C ^ alkyl or carboxy-C ^ -C ^ alkyl and the group = N-ORj in syn-position,

Rj the meaning of hydrogen, methyl, methoxy, vinyl, acetoxymethyl, carbamoyloxymethyl, of -CH2S-X, with X =

-2-

AT 392 903 B with Y = hydrogen, Cj-C ^ alkylthio, Cj-C4-alkoxy or Cj-Cj-cycloalkyl of -CH2-Qy of

or

wherein the condensed rings are also in the 3,4 position and can also be interrupted by oxygen, from

-CH

or

of thienopyridinio-methyl, furopyridinio-methyl or of 5-melhyl-tetrazol-2-yl-methyl, and R3 for hydrogen, a physiologically compatible cation, a physiologically compatible ester residue or - if in R2 the structure -CHj-N ^ occurs - stands for a negative charge, or a modified formula, in which -CH2- instead of -C (= N-OR j) -, or an N-acyl-phcnylglycine-ccphalosporin and

(b) a penem antibiotic of the general formula II

OH

-3-

AT 392 903 B -CH2-0-C0NH2, -S- (CH2) 2-0-C0NH2 or -S- (CH2) 3-S02NH2 and R4 represents hydrogen, a physiologically compatible cation or a physiologically compatible ester residue, if appropriate be in a separate order.

Aminolhiazole cephalosporins used according to the invention and their physiologically tolerable salts or esters are described, for example, in DE-A-27 02 501.27 13 272.27 15 385.28 10 922.29 21 316.29 22 036, in EP-A-0 064 740, in US-A-4 278 793.4 501 739, in GB-A-2 105 334 and GB-A-2 105 335. However, other cephalosporins such as e.g. B. N-acyl-phcnylglycine cephalosporins into consideration or those of the formula (I) · in which instead of the group -C (= N-ORj) - the group -CH2- is.

Penem antibiotics of the formula (II) are described, for example, in EP-A-0 069 377, EP-A-0170 028, GB-A-85.20631, EP-A-121 502, GB-PS 2 097 786 and BE-PS 898 603.

Rj in formula (I) is Cj-C ^ alkyl, z. B. methyl, ethyl, propyl, preferably methyl.

Rj stands for carboxy-Cj-C4-alkyl, z. B. carboxymethyl, carboxyethyl, carboxypropyl, preferably the rest -CH2-COOH, but especially the rest

- C-COOH of interest.

Of the substituted pyridinium-methyl radicals listed above, 2,3-cyclopentcno- and 2,3-cyclohexenopyridinium-methyl, as well as 4-methylthio-, 4-cyclopropyl- and 3-methoxy-pyridinium-methyl, are also preferred 3,4-cyclopenteno and 3,4-cyclohexenopyridinium methyl.

Of particular interest according to the invention are those compounds of the formula I in which Rj is methyl and R2 is -CH2-OCOCH3 (cefotaxime),

(Cefodizim), (Ceftriaxon), (Cefmenoxim) or (Cefpirom), or R | stands for -CH2COOH and R2 for -CH = CH2 (cefixime), the cefodizime, cefpirom, ceftriaxone, in particular cefotaxime, again being a preferred position within this group.

If R2 stands for a -CH2-pyridinium compound, the carboxyl group is present as the inner salt (-COO ^) in the general formula (I).

Particularly interesting cephalosporin derivatives include aminothiazole cephalosporins which contain -CH2- instead of -C (= N-ORj) -, cefotiam and N-

Acyl-phenylglycine-cephalosporins the cefoperazone. -4-

AT 392 903 B

The penem anubiotics are of the general formula II

OH

ao,

-CH2-0-C0NH2. -S- (CH2) 2-0-C0NH2 or -S- (CH2) 3-S02NH2 and R4 for hydrogen, a physiologically compatible cation or a physiologically compatible ester residue. Of the substituted phenoxy and phenyl substituents listed above, the radicals are preferred

the 4-carbamoyl-phenoxy radical (HRE 664) is particularly noteworthy

According to the invention, a combination of cefodizime or cefpirome, but especially of cefotaxime and the penem HRE 664, is particularly interesting. R3 and R4 can represent hydrogen or a physiologically compatible cation, such as, for. B. a

Alkalization, preferably potassium or sodium, in particular sodium, or other known, physiologically compatible salts with alkaline earth metal or organic ammonium ions (see, for example, US Pat. No. 4,278,793). R3 and R4 can furthermore stand for a physiologically compatible ester residue which is particularly interesting for enteral application, such as, for. B. for an acyloxymelhyl or acyloxyethyl radical having 2 to 12, preferably 2 to 6 carbon atoms in the acyl part, preferably acetoxymethyl, 1 '- (acetoxy) ethyl or pivaloyloxymethyl, for 5-methyl-1,3-dioxalen-2-one -4-yl-methyl, or also for other, physiologically compatible esters, as described for example in EP-Al-0170028.

The production of the components of the active ingredient combination which are considered according to the invention is described, for example, in the patent rights mentioned above.

The combination of cephalosporins and compounds according to the invention has a strong antibacterial action and is therefore particularly well suited for the treatment of bacterial infections. What is essential is the fact that the action of the two components does not behave additively, but rather an unexpected, strong synergistic effect.

Even with germs against which a single component alone has no significant antibacterial effect, a synergistic effect can be observed in combinations. -5-

AT 392 903 B

The preparations according to the invention thus detect a spectrum of germs at low minimum inhibitory concentrations which cannot be achieved by the individual components.

For the reasons mentioned, the preparation according to the invention is superior to the individual components in the treatment of bacterial infections. It allows lower dosages of the individual components S to be delivered and nevertheless achieves better therapy success.

The invention also relates to a process for the preparation of such a preparation, which is characterized in that a) a cephalosporin derivative of the formula (I) or its physiologically tolerable »! Salts or esters and b) a penem antibiotic of the formula (Π) or its physiologically tolerable salts or esters 10 together with (a) physiologically acceptable carrier (s) and optionally other auxiliaries or additives in a suitable dosage form.

The invention further relates generally to pharmaceutical products which, side by side, in unmixed form a) a cephalosporin derivative of the formula (I) or its physiologically tolerable salts or esters and 15 b) a penem antibiotic of the formula (Π) or its physiologically tolerable salts or Contain esters as a combination preparation for simultaneous, separate or graduated use in the treatment of bacterial infections.

The doses of the cephalosporin derivative and the penem antibiotic in the preparations according to the invention are preferably chosen so that the individual components would not yet have a sufficient or full effect. The daily dose of the combinations according to the invention (sum of the individual components) is between about 1 to 16 g, preferably about 4 to 8 g. The ratio of the individual components in the combination can be between approximately 1: 9 and 9: 1, preferably between approximately 1: 5 and 5: 1. The dose in an administration unit can be chosen, for example, between 50 and 200 mg.

Since the production of the cephalosporin component is generally less complex and therefore also cheaper than the production of the penem antibiotic, a combination according to the invention is preferred for this reason alone, in which the cephalosporin content is higher than that of the penem.

The preparation according to the invention »! or products can be administered parenterally or orally »i. Parenteral administration is preferred.

The combinations of the active substances which can be used chemotherapeutically can be used for the production of pharmaceutical preparations which contain an effective amount of the active substances, together with carriers, and which are suitable for enteral and parenteral administration. For example, injectable solutions are preferably isotonic aqueous solutions or suspensions, which can be sterilized and can contain auxiliaries, such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or 35 buffer substances. The pharmaceutical preparations according to the invention, which, if desired, may contain other chemotherapeutically valuable substances, are used, for. B. made by conventional methods.

For parenteral application, the combination according to the invention is preferably dissolved immediately before use in sterile water or - if necessary - in a buffer solution, such as, for example, a phosphate-40 or carbonate buffer, as is usually used for these purposes, and then applied

The following examples serve to illustrate the invention.

Example 1 45 Effect of the combination of the sodium salt of 5R, 6S-6- (1R-hydroxyethyl) -3- (4-cafbamoylphenoxy) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -carboxylic acid (HRE 664, referred to in the table as (1)) and the sodium salt of cefotaxime (2) against gram-positive and gram-negative test strains. To determine the synergism, mixtures of the compound (1) with the compound (2) were prepared in a ratio of 1: 1.1: 2 and 1: 3. The MIC values were checked in comparison to the individual substances 50

TateUs.1 55 germ (1) alone staph. SG 511 0.062 Staph. 285 0.062 Staph. 503 0.062 60 class a »og. 1082E 0.5 Citrob. 82 Cull. 1 MIC in mg / 1 (2) (1): (2) alone 1: 1 1: 2 1: 3 2 0.125 0.125 0.125 2 0.125 0.125 0.125 2 0.125 0.125 0.125 1 0.5 0.5 0.5 2 0 .5 0.5 0.25 -6-

AT 392 903 B

Example 2

Effect of the combination of (1) and (2) against clinical isolates with resistance to the cephalosporin component.

Table 2 MIC in me / 1

Germ (1) (2) (1) l (2) alone alone 1: 1 1: 2 1: 3 staph. 789 4 64 4 4 8 Staph. 22130 2 32 4 4 4 Strept D 756 8 64 4 4 4 Strept DEder 8 64 4 4 4 Strept faecium D 8 64 8 16 8 Citrob. 2901 8 64 4 4 4 Ent cl. M 423 4 64 2 2 4 Ent cl. M 447 16 64 16 8 8 Ent cl. P99 2 64 2 2 2 Example 3 Effect of the combination of (1) and (2) on anaerobic Germs Table 3 MIC in me / 1 (1) (2) (1) l (2) Germ alone alone 1: 1 1: 2 1: 3 B. fragilis 312 0.125 128 0.125 0.25 0.25 B. fragilis 960 0.125 16 0.125 0.125 0.125 B. fragilis 17 390 0.25 8 0.25 0.5 0.25 B. fragilis 18 125 0.25 2 0.25 0.25 0.25 B. ovatus 103 0.125 64 0.125 0.125 0.125 B. vulgatus 1446 0.125 64 0.125 0.125 0.125 B. thetaiotaomicron 123 0.125 64 0.125 0.125 0.125 Sph. varius 5262 0.25 64 0.5 1 1 Cl. tetani 19406 0.25 8 0.5 0.5 0.5

Example 4

The combination of the potassium salt of the penem compound 5R, 6S-3- (2-carbamoyloxyethylthio) -6- (lR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2- En-carboxylic acid (3) with the compound (2) was tested in 3 strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. laMsi FIC values of a combination of the

Penems strain (3) with the cephalosporin (2) E. coli 2136E 0.5 E. coli 2137E 0.751 E. coli 2138E 0.5 Citrobacter freundii 8090 0.281 -7-1

The FIC value of 0.75 suggests an over-additive effect.

AT 392 903 B

Example 5

The combination of the potassium salt of the penem compound 5R, 6S-6- (lR-hydroxy-ethyl) -3- (4-formamidophenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2- en-2-caibonic acid (4) with the compound (2) was tested in 3 strains of E. coli and a strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FlC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

IateUsi

Strain FIC values of a combination of the penem (4) with the cephalosporin (2) E. coli 2136E 0.5 E. coli 2137E 0.375 E. coli 2138E 0.5 Citrobacter freundii 8090 0.091

Example 6

The combination of the sodium salt of the penem compound 5R, 6S-3- (3-carbamoylphenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2- en-2-carboxylic acid (5) with the compound (2) was tested in 3 strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of I show an additive interaction.

Table 6 FIC values of a combination of the

Penems strain (5) with the cephalosporin (2) E. coli 2136E 0375 E. coli 2137E 0.5 E. coli 2138E 0375 Citrobacter freundii 8090 0.125

Example 7

Cephalosporins, as given above as an example, usually have less activity against gram-positive germs such as staphylococci and against gram-negative anaerobic germs than against gram-negative aerobic pathogens (see also Seibert et al., Infection, Volume 11 (1983) 5,275-279).

Penems, on the other hand, generally have better antibacterial activity against gram-positive cocci and anaerobes than against gram-negative germs (see also Bauemfeind, J. Antimicrob. Chemother. 15,111,1985).

For the example of a combination of one part of penem and three parts of cephalosporin, Table 7 shows a superiority of the antibacterial activity of the combination over the individual components. The combination preparation compensates for the weakness in the antibacterial spectrum of both preparations and thus has a broader antibacterial spectrum, which makes it particularly suitable for therapy of bacterial infections without prior isolation of the pathogen

Table 7 MIC in mg / 1 HRE664 cefotaxime (1): (2)

Stamm_ (1) (2) _1: 3

Strept D 756 8 64 4 Strept D Eder 8 64 4 Strept D 21777 8 64 4 Strept D 26777 8 64 4 Citrob. 2901 8 64 4 -8- AT 392 903 B continued Table 7

Strain HRE664 (1) MIC in mg / 1 cefotaxime (2) (1): (2) 1: 3 Citrob. 82 Cull. 1 2 0.25 Ent. cl. M 447 16 64 8 Ent cl. 2240 Cull. 2 0.062 0.015 E. coli 2139E 1 0.031 0.015 Kl. Pneu. 1976E 1 0.062 0.031 B. vulgatus 1446 0.125 64 0.125 B. distasonis 1366 0.25 0.125 0.125 Example 8 The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (4-carbamoylphenoxy) -7 -oxo-4 azabicyclo [3.2.0] hept-2-en-2-carboxylate (6) with cefotaxime was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, HC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index E. coli 2136E 0.312 E. coli 2137E 0312 E. coli 2138E 0349 Citrobacter freundii 8090 0.094

Example 9

The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-methyl-sulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (6) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). According to this, FIC values i 0.5 are characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.379 E. coli 2137E 0.5 E. coli 2138E 0382 Citrobacter freundii 8090 0.5

Example 10

The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (7) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0379 E. coli 2137E 0320 E. coli 2138E 0374 Citrobacter freundii 8090 0.047 -9-

AT 392 903 B

Example 11

The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (8) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional 5 inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 10th

Strain HC index E. coli 2136E 0379 E. coli 2137E 0379 15 E. coli 2138E 0379 Citrobacter freundii 8090 0312

Peispigi 12

The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7-oxo-4-thia-l-20 azabicyclo [3.2.0] hept-2-en-2- Carboxylate (9) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 25th

Strain FIC index 30 E. coli 2136E 0383 E. coli 2137E 0383 E. coli 2138E 0.185 Citrobacter freundii 8090 0.0935 35

Example 13

The combination of sodium 5R, 6S-3- (4-cyanophenoxy) -6- (IR-hydroxyetbyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (10) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional 40 inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 45

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 035 50 E. coli 2138E 035 Citrobacter freundii 8090 0.75

Example 14

The combination of the sodium salt of 5R, 6S-6- (lR-hydroxyethyl) 3- (4-carbamoyl-phenoxy) -7-oxo-4-thia-55 l-azabicyclo [3.2.0] hept-2-ene-carboxylic acid (1) with cefodizime (11) was tested on three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -10- 60

AT 392 903 B HC index

Strain E. coli 2136E 0.49 E. coli 2137E 0.5 E. coli 2138E 0.37 Citrobacter freundii 8090 0.186

Example 15

The combination of sodium 5R, 6S-6- (1R-hydroxyethyl) -3- (4-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (6) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; firactional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.155 E. coli 2137E 0.498 E. coli 2138E 0.374 Citrobacter freundii 8090 0.375

Example 16

The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (7) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; firactional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. HC index

Strain E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.249 Citrobacter freundii 8090 0.140

Example 17

The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (9) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. The fractional inhibitory concentration (FIC index) was determined as a measure of the synergistic activity according to Berenbaum, J. Infect Dis . 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.125 E. coli 2137E 0.187 E. coli 2138E 0.375 Citrobacter freundii 8090 0.093

Example 18

The combination of sodium 5R, 6S-3- (4-cyanophenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-lazabicyclo [3.2.0] hept-2-en-2-carboxylate (10) with cefodizime (11) was found in three strains of E. coli and one -11-

AT 392 903 B

Strain of Citrobacter freundii tested As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.373 E. coli 2138E 0.498 Citrobacter freundii 8090 0.062

Example 19 The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (8) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. The "fiactional inhibitory concentration" was used as a measure of the synergistic activity. (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.498 E. coli 2137E 0.498 E. coli 2138E 0.624 Citrobacter freundii 8090 0.281

Example 20 The combination of sodium 5R, 6S-3- (3-carbamoylphenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (5) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.496 E. coli 2138E 1 Citrobacter freundii 8090 0.187

Example 21 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (2-carbamoyloxyethylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 Carboxylate (3) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). According to this, FIC values of £ 0.5 are characteristic of synergistic activity, FIC values of 1 show an additive interaction.

Strain HC index E. coli 2136E 0.498 E. coli 2137E 0.498 E. coli 2138E 0.5 Citrobacter freundii 8090 0.249 -12-

AT 392 903 B

Example 22 The combination of potassium 5R, 6S-6- (IR-hydroxyethyl) -3- (4-formamidophenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (4) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive intraction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.75 E. coli 2138E 0.5 Citrobacter freundii 8090 0.125

Example 23 The combination of the sodium salt of 5R, 6S-6- (IR-hydroxyethyl) -3- (4-carbamoylphenoxy) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylic acid (1) with cefpirom (12) was tested in three strains of E. coli and one strain of Citrobacter freundii. The fractional inhibitory concentration (FIC index) was determined according to Berenbaum as a measure of the synergistic activity. J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.66 E. coli 2138E 0.315 Citrobacter freundii 0.5

Example 24 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (6) with cefpirome (12) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.374 E. coli 2137E 0.249 E. coli 2138E 0.187 Citrobacter freundii 8090 0.126 P.eispig.1.25 The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (lR- hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (7) with cefpirome (12) was found in three strains of E. coli and one strain of Citrobacter freundii tested. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -13-

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Strain HC index E. coli 2136E 0.629 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 8090 0.126

Example 26 The combination of potassium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7 * oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (9) with cefpirome (12) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain HC index E. coli 2136E 0.125 E. coli 2137E 0.5 E. coli 2138E 0.186 Citrobacter freundii 8090 0.258

Example·!? The combination of sodium 5R, 6S-3- (4-cyanophenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (10) with cefpiroma (12) was tested on three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). According to this, FIC values of £ 0.5 are characteristic of synergistic activity, FIC values of 1 show an additive interaction.

Strain HC index E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 8090 0.062

Example 28 The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (8) with cefpirome (12) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, HC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain HC index E. coli 2136E 0.75 E. coli 2137E 0.62 E. coli 2138E 0.5 Citrobacter freundii 8090 0.5

Example 29 The combination of sodium 5R, 6S-3- (3-carbamoyl-phenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azäbicyclo [3.2.0] hept-2-ene -2-carboxylate (5) with cefpirome (12) was found in three strains of E. coli and one -14- 5

AT 392 903 B

Citrobacter fireundii strain tested. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). According to this, FlC values i 0.5 are characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 10 E. coli 2137E 0.75 E. coli 2138E 0.372

Citrobacter fireundii 8090 0.390

Example, 3Q 15 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (2-carbamoyloxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (3) with cefpirome (12) was tested in three strains of E. coli and one strain of Citrobacter fireundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index 25 E. coli 2136E 0.366 E. coli 2137E 0.496 E. coli 2138E 0.372 Citrobacter freundii 8090 0.366 30 Example 31 The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-formamidophenyl ) -7-oxo-4-thia-l-azabicyclo [3.2.] Hept-2-en-2-carboxylate (4) with cefjpirom (12) was tested in three strains of E. coli and one strain of Citrobacter fireundii as The measure for the synergistic activity was the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After 35, FIC values are &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index 40 E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.312 45 Citrobacter fireundii 8090 0.125 Example 3? The combination of the sodium salt of 5R, 6S-6- (lR-hydroxyethyl) -3- (4-carbamoyl-phenoxy) -7-oxo4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylic acid (1) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional 50 inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 55 strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.379 E. coli 2138E 0.75 60 Citrobacter fireundii 8090 0.075 -15-

AT 392 903 B

Bgia &gt; ¥, .33,

The combination of sodium 5R, 6S-6- (1R-hydroxyethyl) -3- (4-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (6) with ceftriaxone (13) was tested on three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.498 E. coli 2138E 0.374 Citrobacter freundii 8090 0.187

Example 34

The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (7) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.75 Citrobacter freundii 8090 0.091 B.eisoieL35 The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3 - (3-methylsulfmylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (9) with ceftriaxone (13) was found in three strains of E. coli and one Strain of Citrobacter freundii tested As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain HC index E. coli 2136E 0.125 E. coli 2137E 0.75 E. coli 2138E 0.077 Citrobacter freundii 8090 0.034

Example 36

The combination of sodium 5R, 6S-3- (4-cyanophenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (10) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -16-

AT 392 903 B

Strain FIC index 5 E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 8090 0.182 10 Example 37 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) - 3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (8) with ceftriaxone (13) was found in three strains of E. coli and a strain of Citrobacter freundii tested The fractional inhibitory concentration (FIC index) was determined as a measure of the synergistic activity according to Berenbaum, J. Infect. Dis. 137 ¢ 1978), 122-136. After that 15, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index 20 E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 0.186 25

Example 38

The combination of sodium 5R, 6S-3- (3-carbamoyl-phenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (5) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional 30 inhibitory concentraüon &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 35 strain FIC index E. coli 2136E 0.318 E. coli 2137E 0.31 E. coli 2138E 0.75 40 Citrobacter freundii 8090 0.06

EXAMPLE 39

The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (2-carbamoyloxyethylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (3) with ceftriaxone (13) was tested on three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentraüon &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 50 strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.75 55 E. coli 2138E 0.629 Citrobacter freundii 8090 0.0625

Example 40

The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-formamidophenyl) -7-oxo-4-thia-l-60 azabicyclo [3.2.0] hept-2-en-2- Carboxylate (4) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional -17-

AT 392 903 B inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.125 E. coli 2138E 0.5 Citrobacter freundii 8090 0.372

Example 41 The combination of the sodium salt of 5R, 6S-6- (IR'-hydroxyethyl) -3- (4-carbamoylphenoxy) -7-oxo4-thia-l-azabicyclo [3.2.0] hept-2-en-2 -carboxylic acid (1) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). According to this, FIC values of £ 0.5 are characteristic of synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.49 E. coli 2137E 0.5 E. coli 2138E 0.372 Citrobacter freundii 0.077

Example 42 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (6) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.312 E. coli 2137E 0.375 E. coli 2138E 0.374 Citrobacter freundii 8090 0.312

Example 43 The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (7) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.498 E. coli 2137E 0.5 E. coli 2138E 0.374 Citrobacter freundii 8090 0.077 -18-

AT 392 903 B

Example 44 The combination of potassium 5R, 6S-6- (1R-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-en-2 carboxylate (9) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.75 E. coli 2138E 0.5 Citrobacter freundii 8090 0.125

Example 45 The combination of sodium 5R, 6 $ -3- (4-cyanophenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en- 2-carboxylate (10) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). According to this, FIC values <, 0.5 are characteristic of synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 1 E. coli 2137E 0.375 E. coli 2138E 0.375 Citrobacter freundii 8090 0.186

Example 46 The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (8) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of I show an additive interaction.

Strain FIC index E. coli 2136E 0.63 E. coli 2137E 0.75 E. coli 2138E 0.5 Citrobacter freundii 8090 0.265

Example 47 The combination of sodium 5R, 6S-3- (3-carbamoyl-phenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (5) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. The fractional inhibitory concentration (FIC index) was determined according to Berenbaum as a measure of the synergistic activity. J. Infect Dis. 137 ¢ 1978), 122-136. After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -19-

AT 392 903 B

Strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 8090 0.186

Example 48

The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (2-carbamoyloxyethylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (3) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. cou 2137E 0.498 E. coli 2138E 0.498 Citrobacter freundii 8090 0.124 Example 49 The combination of potassium 5R, 6S-6- (IR-hydroxyethyl) -3- (4-formamidophenyl ) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (4) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.5 E. coü 2138E 0.624 Citrobacter freundii 8090 0.156 Example 50 The combination of sodium 5R, 65-6- (lR-hydroxyethyl) -3- (4th -carbamoyl-phenoxy) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-caiboxylate (1) with cefoperazone (15) was found in three strains of E. coü and one strain tested by Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. Strain FIC index E. coü 2136E 0.5 E. coü 2137E 0.5 E. coü 2138E 0.278 Citrobacter freundü 8090 0.09

Example 51

The combination of sodium 5R, 6S-6- (1R-hydroxyethyl) -3- (4-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (6) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity,

AT 392 903 B inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 5 strain FIC index 0.25 0.75 0.498 0.056

E. coli 2136E E. coli 2137E 10 E. coli 2138E

Citrobacter freundii 8090

Example 52

The combination of sodium 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-1-15 azabicyclo [3.2.0] hept-2-en-2- Carboxylate (7) with cefoperazone (15) was found in three strains of E. coli and one

Strain of Citrobacter freundii tested As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. 20th

Strain FIC index E. coli 2136E 0.75 25 E. coli 2137E 0.75 E. coli 2138E 0.374 Citrobacter freundii 8090 0.077

Example 53 30 The combination of potassium 5R, 6S-6- (1R-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en- 2-caiboxylate (9) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). According to this, FIC values <, 0.5 are characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index 40 E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.75 Citrobacter freundii 8090 0.312 45 Example 54

The combination of sodium 5R, 6S-3- (4-cyanophenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (10) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis 137 (1978), 122-136. After 50 are FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.25 E. coli 2138E 0.28 Citrobacter freundii 8090 0.091 -21- 60

AT 392 903 B

Example 55 The combination of sodium 5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (8) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). According to this, FIC values of £ 0.5 are characteristic of synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.75 E. coli 2137E 0.75 E. coli 2138E 0.373 Citrobacter freundii 8090 0.281

Example 56 The combination of sodium 5R, 6S-3- (3-carbamoylphenyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (5) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.31 E. coli 2137E 0.374 E. coli 2138E 0.308 Citrobacter freundii 8090 0.124

Example 57 The combination of sodium 5R, 6S-6- (lR-hydroxyethyl) -3- (2-carbamoyloxyethylthio) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 Caiboxylate (3) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.563 E. coli 2137E 1 E. coli 2138E 0.5 Citrobacter freundii 8090 0.366

Example 58 The combination of potassium 5R, 6S-6- (lR-hydroxyethyl) -3- (4-formidophenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (4) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -22-

AT 392 903 B

Strain FIC index 5 E. coli 2136E 0.75 E. coli 2137E 0.75 E. coli 2138E 0.372 Citrobacter freundii 8090 0.248 10

Example 59

The combination of sodium 5R, 6S-3- (4-formamido-phenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2 carboxylate (16) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional IS inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). According to this, FIC values 5 0.5 are characteristic of a synergistic activity, HC values of 1 show an additive interaction. 20 strain HC index E. coli 2136E 0.383 E. coli 2137E 0.5 25 E. coli 2138E 0.374 Citrobacter freundii 8090 0.122

Example 60 30 The combination of sodium 5R, 6S-3- (4-formamido-phenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2- en-2-carboxylate (16) with cefodizime (11) was tested on three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, HC values &lt; 0.5 characteristic of a synergistic activity, HC values of 1 show an additive interaction.

Strain HC index 40 E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.125 Citrobacter freundii 8090 0.047 45 Example 61 The combination of sodium 5R, 6S-3- (4-formamido-phenoxy) - 6- (lR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (16) with cefpirome (12) was found in three strains of E. coli and a 50 strain of Citrobacter freundii tested. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (HC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, HC values &lt; 0.5 characteristic of a synergistic activity, HC values of 1 show an additive interaction. 55 strain HC index E. coli 2136E 0.5 E. coli 2137E 0.5 60 E. coli 2138E 0.5 Citrobacter freundii 8090 0.273 -23-

AT 392 903 B

Example 62 The combination of sodium 5R, 6S-3- (4-formamido-phenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (16) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FlC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.36 Citrobacter freundii 8090 0.122

Example 63 The combination of sodium 5R, 6S-3- (4-formamido-phenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l azabicyclo [3.2.0] hept-2-en- 2-carboxylate (16) with cefotiam (14) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.374 E. coli 2138E 0.374 Citrobacter freundii 8090 0.257

Example 64 The combination of sodium 5R, 6S-4- (4-formamido-phenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylate (16) with cefoperazone (15) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.75 E. coli 2138E 0.5 Citrobacter freundii 8090 0.093

Example 65 The combination of sodium 5R, 6S-3- (carbamoyloxymethyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (17) with cefotaxime (2) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction. -24-

tribe

AT 392 903 B FIC index E. coli 2136E 0.5 E. coli 2137E 0.37 E. coli 2138E 0.5 Citrobacter freundii 8090 0.122

Example 66 The combination of sodium 5R, 6S-3- (carbamoyloxymethyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (17) with cefodizime (11) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.5 E. coli 2137E 0.5 E. coli 2138E 0.75 Citrobacter freundii 8090 0.125

Example 67 The combination of sodium 5R, 6S-3- (carbamoyloxymethyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (17) with Ceipirom (12) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.37 E. coli 2137E 0.5 E. coli 2138E 0.5 Citrobacter freundii 8090 0.062

Example 68 The combination of sodium 5R, 6S-3- (carbamoyloxymethyl) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate (17) with ceftriaxone (13) was tested in three strains of E. coli and one strain of Citrobacter freundii. As a measure of the synergistic activity, the &quot; fractional inhibitory concentration &quot; (FIC index) determined according to Berenbaum, J. Infect. Dis. 137: 122-136 (1978). After that, FIC values &lt; 0.5 characteristic of a synergistic activity, FIC values of 1 show an additive interaction.

Strain FIC index E. coli 2136E 0.375 E. coli 2137E 0.125 E. coli 2138E 0.5 Citrobacter freundii 8090 0.093 -25-

AT 392 903 B

Example 69

Preparation of a parenteral preparation 1.5 g of cefotaxime (2) and 0.5 g of HRE 664 (1) are injected in 10 ml of water. solved and then applied. Depending on the solubility ratios, similar quantitative ratios also apply to the other exemplary embodiments described above.

Connections of the examples

5R, 6S-6- (lR-hydroxyethyl) -3- (4-carbamoylphenoxy) -7-oxo-4-thia-l-azabicyclo [3.2.0] hcpt-2-cn-2-carboxylic acid (sodium salt)

OH

5R, 6S-3- (2-carbamoyloxyelhylthio) -6- (lR-hydroxyclhyl) -7-oxo-4-thia-l-azabicyclo [3.2.0) hcpt-2-cn-2-carboxylic acid (potassium salt)

5R, 6S-6- (IR-hydroxyethyl) -3- (4-formamidophenyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (potassium salt)

5R, 6S-3- (3-CarbamoyI-phenyI) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (sodium salt) -26- (6)

AT 392 903 B

OH

5R, 6S-6- (IR-hydroxyethyl) -3- (4-methylsulfinyl-phenyl) -7-oxo4-thia-l-azabicyclo [3.2.0] hcpt-2-cn-2-carboxylic acid (sodium salt)

OH

so3

CD 5R, 6S-3- (4-methylsulfinylphenoxy) -6- (IR-hydroxyethyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-cn-2-carboxylic acid (sodium salt )

5R, 6S-6- (IR-hydroxyethyl) -3- (3-sulfamoyl-propyllhio) -7-oxo-4-ihia'l-azabicyclol3.2.0] hcpt-2-cn-2 · carboxylic acid (sodium salt)

OH

soch3 (?) 5R, 6S-6- (lR-hydroxyethyl) -3- (3-methylsulfinylphenyl) -7-oxo-4-lhia-l-azabicyclo [3.2.0] hept-2-cn-2- carboxylic acid (potassium salt)

OH

(10) 5R, 6S-3- (4-cyanophenoxy) -6- (lR-hydn &gt; xyelhyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-en-2-carboxylic acid (Sodium salt) -27-

5 AT 392 903 B

10 5R, 6S-3- (4-formamido-phenoxy) -6- (IR-hydroxycthyl) -7-oxo-4-thia-l-azabicyclo [3.2.0] hcpt-2-ene-2-carboxylic acid (sodium salt) 15 20

Η H

(2) 25 30

Cefotaxime (sodium salt)

Η H

N-r-CH.

ch2cooh (11) 35 cefodizime (sodium salt) 40 H. N-r-

(12) 45

Cefpirom 50

Η H N- • C-CONIl * —ΐ · S. H3C \ 55 n2 »\ 2 ^ S- 60 ceftriaxone (disodium salt)

N “OCH COONa

ONa O -28- (13)

AT 392 903 B 10

Η H CH2-CONH

N - N (14) ch3

Cefotiam 15 20

Η H

N N CH '4 1 N_ CH. (15) 25 cefooerazone (sodium salt) 30

OH

(17) 35 5R16S-3- (carbamoyloxymcthyl) -6- (IR-hydroxycthyl) -7-oxo-4-lhia-l-azabicylo [3.2.0Jhcpt-2-cn-2-carboxylic acid (sodium salt) 40

TafaelteA 45 strain HRE664 (1) MIC in mg / 1 cefotaxime (2) (1): (2) 1: 3 50 StrepL D 756 8 64 4 Strept. D Eder 8 64 4 Strept. D 21777 8 64 4 Strept. D 26777 8 64 4 55 -29- 60

Claims (3)

AT 392 903 B Table B Streptococcus faecalis Dl MHK in mg / 1 FIC Index No. of the Penems Penem Cefotaxim (2) (see p. 46) 1 5 4 3 16 16 16 8 4 4 4 4 0.65 0.43 0.43 0.43 Table C Staph. aureus 3066 (MRSA) MIC in mg / 1 No. of penem (see p. 46/47) Penem cefotaxime (2) mixture of 8 parts of CTX and 2 parts of penem 3 8 64 4 9 16 64 8 4 16 64 8 5 16 64 8 8 16 64 4 PATENT CLAIMS 1. Pharmaceutical preparation with synergistic antibacterial activity, containing a cephalosporin and one, characterized in that (a) a cephalosporin derivative of the general formula I C - CONH N-OR1 Η H where Rj can be hydrogen, CrC4-alkyl or carboxy-C ^ -C ^ -alkyl and the group = N-ORj is in the syn-position, -30- (I). AT 392 903 B 1 * 2 the meaning of hydrogen, methyl, methoxy, vinyl, acetoxymethyl, carbamoyloxymethyl, of -ch2s-x, withX = with Y = hydrogen, Cj-C ^ alkylthio, CpC ^ -alkoxy or C ^ -C ^ -cycloalkyl (+ &gt; γλ of -CH2-N where the fused rings are also in 3,4-position and can also be interrupted by oxygen, from of thienopyridinio-methyl, furopyridinio-methyl or of 5-methyl-tetrazol-2-yl-melhyl, and R3 for hydrogen, a physiologically compatible cation, a physiologically compatible ester residue or - if in R2 the structure -CH2-N (+ * occurred · represents a negative charge, or a modified formula, in which -CH2- instead of -C (= N-ORj) -, or an N-acyl-phcnylglycine-ccphalosporin and (b) a penem antibiotic of the general formula II 0H 31- wherein Zfor AT 392 903 B -CH2-0-C0NH2, -S- (CH2) 2-0-C0NH2 or -S- (CH2) 3-S02NH2 and R4 represents hydrogen, a physiologically compatible cation or a physiologically compatible ester, optionally in a separate arrangement . 2. A process for the preparation of a preparation according to claim 1, characterized in that a) a cephalosporin derivative of the general formula (1) according to claim 1 or its physiologically tolerable salts or esters and b) a penem antibiotic of the general formula (II) according to Claim 1 or its physiologically tolerable salts or esters together with a physiologically tolerable carrier and optionally other auxiliaries or additives in a suitable dosage form 3. Pharmaceutical preparation according to claim 1, characterized in that it side by side in unmixed form a) a cephalosporin derivative of the general formula (I) according to claim 1 or its physiologically tolerable salts or esters and b) a penem antibiotic of the general formula (II) according to claim 1 or its physiologically compatible salts or esters and a combination ion preparation for simultaneous, separate or staggered use in the treatment of bacterial infections. -32-