DE2733642A1 - ANTIBIOTIC AGENTS - Google Patents

Description

Bayer Aktiengesellschaft

Central Patents Department. Trademarks and licenses

509 Leverkusen. Bayerwerk

PG / AB

July 1977

Antibiotics

The present invention relates to new antibiotic synergistic active ingredient combinations from ß-lactam antibiotics on the one hand and the synergistic clavulanic acid or its pharmaceutically acceptable salts or esters, especially their sodium salt, on the other hand.

It is known (DT-OS 2 517 316) that clavulanic acid is able to exert an inhibitory effect on β-lactamases. It is also known and experimentally proven that the minimum inhibitory concentrations of ampicillin, amoxicillin, carbenicillin and benzylpenicillin can be considerably reduced by clavulanic acid as a synergist (see DT-OS 2 517 316, Example 42 and 44).

From the data given it can be seen that on average the mixture of ampicillin with clavulanic acid is the has the best antibiotic effectiveness.

It has now been found that the new combination of active ingredients from (1) penicillins or cephalosporins of the general formula:

809886 / 02U

R ₁ -CO-NH-CH-CO-NH ^

I i ' ^Y

¹ <^ - N "

R ₂ O "

in which 0 ^ _n H

R ₁ iiir hm Ί; -, c: -: ₃ -Sc ₂ -U ^ n-, V ^ri vj-,

C O, O.

-, C ₂ H ₅ -N N- and | \ -N N-,

R ₂ for phenyl, p-hydroxyphenyl and furyl,

• ^ / CH ₃ R ₃ for H, OCH ₃ and OC _a H ₅ sceht, where Y / ^C \ CH

^ -CH

\ «^ COOII

CH,
ι -

^ C-CH ₂ -T is where T is -C-CO-CH ₃ ,

C.
COOH

-0-CO-NH ₂ , -S-Al ₃ JLl ₄ , -S-IL ₁ ^, -S-IL _N Jfi

ϊ ι

R, R4

and R _{4 is} H, CH ₃ , -CH ₂ -COOH, -CH ₂ -SO ₃ H or -CH ₂ -CH ₂ -N (CHj) ₂ ,

or their pharmaceutically usable salts, in particular the sodium salts, as well as their various crystal and hydrate forms and (2) clavulanic acid of the formula II:

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BATH ORIGINAL

CH ₂ OH
/ τι

COCH

or their pharmaceutically acceptable salts or in In vivo cleavable esters, in particular their sodium salt, have a particularly high antibiotic effectiveness.

Examples of ß-lactam antibiotics of the formula I preferably used as component (1) are:

D- J.Π, imidazo 1 id in-2-oxo-1-yl) -carbonylamineq7 "benzylpenci 11 in, D-« C / 7 3-methylsulfonyl-2-oxo-imidazoIidin-1-yl) -ca r bony 1 am ino7-benzyl penic il lin, D-dL / J ~ (4-methyl-5-oxo-1,2-diazol-3-yn-2-yl) -carbonylaminoy-benzylpenicillin, O-JL [\ 3-Furfurylideneamino-2-oxo-imidazolidin-1-yl) -carbonyI-amineq7 ~ p-hydroxybenzylpenicillin, D-oC / 74-ethyl-2,3-dioxopiperazino-1-yl) -carbonylaminoy-benzylpenicillin and D. -oC / "(4-ethyl-2, 3-dioxo-piperaz ino-l-yl) -car bony I ami no / -p-hydroxy-benzyl-penic ill in, D-6-ß - <(_- 2 ^ "(4-Ethyl-2, 4-dioxopiperaζino-l-yl) -carbonylamino ^ -phenylacetamidoj-e-ou -methoxy- ponic i ll-.ric acid, O-6 - ^ - f'2 £ ( j> -FurfuryIidenamino-Zo :: oi: n: da:; oliili; ily L) -Ci-bü. '. Yioi.ii;. ^ /' - p-nydroxypheriylac9tac: ic: o j-6-c: -. " net hoxy-penicillanic acid, D-7-β j_-2 / "; 3-Furlury Iidenamino- ■ 2-oxo-inidazolid Ln-l-yi" -cr.rconyl ^ r.inoZ-i ^ rP-yl-acatamidoi -7 - '".'-.'- ^r .e ti: jxy-cep'':alosp'jrc: i3 Jure, D ---, i-" J -1 £ {^ -λβ thy 1-2 , 3-o ic χα-ri:; cr j. '. Ino-I-yl ] - ■ ::'. R -cor.y J :::.: r. : Jy-hy droy.yi: ^r r.er.yle.co ta.T.icio S 6-u-zsj thoxy-pCT.icillar.säv.re, IJ-7 - Γ '> - /' (: '-Furf urylid9r: -: r.ino-2-oxoimidazo Li JL: il-yl Jc.-irhor.yl.'. ITiiicJ'-phyriylacecariiiol-7 - «- ;. '^ - ti.üxy-Ctrp: i ^: cijf, ο: '- "ϋ".:;ί..ί.:' _ uiul 1—7 -.- ^ '—'2L ( ^ -Cycloprocyl— 2-fIXO- in; c.izolidiri-l -yl) -cL'.rLony J l ': ü LioZ-phciiyj. ice t a.Tj ido. * - 7-CC-LIt. ¹ Llioxy-ct. ·: ·. :: .-. 1 o ;; pora.:j;i ire.

The Π-lactam antibiotics named and their pharmaceuticals Usable salts are known /s.Z. B. DT-OS 2 104 S8O,

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BATH ORIGINAL

DT-OS 2 152 967, DT-OS 2 525 541, DT-OS 2 525 541, 2 519 4ΟΟ, U.S. Patent 3,974,2887.

Clavulanic acid and its pharmaceutically acceptable salts and in vivo cleavable esters are described in DT-OS 2,517,316.

For example, it has been found that the invention Active ingredient combination of D - <^. / T3-methylsulfonyl-2-oxoimidazolidin-1-yl) -carbonylamineq7-benzylpenicill in with clavulanic acid with regard to its antibiotic effectiveness of an active ingredient combination of ampicillin and clavulanic acid, as it is described as particularly effective in DT-OS 2 517 316, is surprisingly strongly superior, and it is against E.coli F14, E.coli Münster, Klebsiella 1857 and Proteus morg. 932 about 3 times better, against E. coli T7, E. coli A 261 and Proteus vulg. 1017 about 6 times better, against Klebsiella 57 USA about 12 times better and against Proteus morg. 11O2 / II1 about 19O times better than the active ingredient combination of Offenlegungsschrift No. 2,517,316, consisting of Ampicillin and clavulanic acid.

It must also be surprising that the antibacterial effectiveness of the active ingredient combination according to the invention is essential is higher than the sum of the effects of the individual active ingredients. So there is a real synergistic effect before. The active ingredient combinations are therefore a valuable addition to pharmacy.

The weight ratios of the active ingredients (1) and (2) can fluctuate in relatively large ranges, namely from the ratio (1) to (2) like 1 to 10 up to the ratio (1) to

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(2) as 10 to 1. The range (1) to (2) is preferred as 1 to 5 to 5 to 1, the range is very particularly preferred 1 to 3 to 3 to 1.

The invention also relates to medicaments containing an active ingredient combination from a penicillin or cephalosporin of the general formula I or a pharmaceutically usable salt thereof and clavulanic acid or its pharmaceutically acceptable salts or esters. The sodium salts are preferred. In the case of the esters of clavulanic acid, the methyl and ethyl esters are preferred.

The present invention includes such drug formulations, which can be used parenterally, locally or orally. Parenteral and oral, very particularly, are preferred parenteral application forms. Accordingly, the use forms preferably comprise sterile formulations suitable for injection or infusion purposes.

Mixtures of clavulanic acid or its salts or esters with the penicillins or cephalosporins mentioned, for example D- _t -il ^ / l3-methylsulfonyl-2-oxo-imidazolidin-1-yl) -carbonylamino7-benzylpenicillin sodium, can be used in a formulated single dose per person , with a total amount of 0.5 to 10 g. About 0.5 g to 30 g of the active ingredient mixture can be administered per person on one treatment day. However, these are not restrictive information; because the single dose and the dosing intervals vary greatly with the severity of the infection.

In addition to clavulanic acid or its esters or salts, e.g. B. their Sodium salt, including several of the penicillins or cephalosporins mentioned, e.g. B. D- - / ~ (3-methylsulfonyl-2-oxo-imidazoli-

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din-l-ylJ-carbonylaminoZ-benzylpenicillin-sodium and D ^ Lr- £ ~ ( imidazolidin-2-oxo-l-yl) -carbonylamimjT-benzylpenicillin. However, those medicaments are preferred which, in addition to clavulanic acid or its esters or salts, contain only one penicillin.
The medicaments according to the invention have a strong antimicrobial activity while being well tolerated.

The medicaments according to the invention are against a very wide range of microorganisms effective. With their help, e.g. gram-negative and gram-positive bacteria and combats bacteria-like microorganisms and prevents the diseases caused by these pathogens, to be improved and / or cured.

The inventive active ingredient mixtures are particularly beneficial against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and chemotherapy of local and system; see infections in the Suitable for human and veterinary medicine that are caused by these pathogens.

For example, local = and / or systemic diseases treats and / or prevents v / ground caused by the following pathogens or by mixtures of the following Pathogen causes v / ground:

I icrococcaceae, such as staphylococci, e.g., Staphylococcus aureus, Staph. epidermidis (Staph. = Staphylococcus);

Lactobacteriaceae, such as streptococci, for example Streptococcus pyogenes, a- or v /. β-hemolytic streptococci, non (y) -herolytic streptococci, Str. viridans, Str. faecaiis (enterococci) and Diplococcus pneuir.oniae (pneuirococci) (Str. = Streptococcus);

Nei-sseriaceae, such as Neisserien, e.g. M.raeningitidis (Keningokokkcn), N. catarrhalis (N. = Neisseria); Le A 18 220 80 9

Coryriebacteriaceae, such as Corynebacteria, for example Corynebacterium diphtherine, C. pycgenes, C. acnes (C. = Corynebacterium);

Enterotacteriaceae, v / ie Escherichiae bacteria of the Coli group, Escherichia-3fkterien, e.g. Eschsrichia coil, Er; l; vrobactc; r-33kterien, e.g. 5. E.cerc-ieries, E.cloacae, Klebsiella-Bakterier., E.g. K.pn ^ uToniae, Serratia, e.g. Scrratia iiar'cesccns (E. = En-srobacter) (K. = Klebsiella), Froteae-bacteria of the Proteus- Group, Proteus, e.g. Proteus Yul ^ ari s, Pr.ir.orfsnii, Pr.re tt £ c-ri, Pr.niirabilis (Fr. = Proteus), Providencia z.3. P: -ovi.ienci = sp., Sclr.onelleae, Salnivonelia bacteria, e.g. Salmonella paratyphi A and B, S.typhi, S.enteritidis, S.cholerae suis, S.typhimurium (S. = Salmonella), Shigella- Bacteria, for example Shigella dysenteriae, Sh.sonnei (Sh. = Shigelln);

Pseudomonadaceae, such as Pseudoconas bacteria, for example Pseudomonas aeruginosn, Aeromonas bacteria, for example Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas);

Parvobacteriaceae or Brucellaceae, v / ie Pasteurella bacteria, eg Pasteurelie irultocida, Past.pseudotuberculosis (Past. - Pasteurella), Heinsophilus bacteria, eg Haemophilas influenzao.

Bacteroidacea, such as Bacteroides bacteria, e.g., Bacteroides fragilis.

Bacillaceae, such as aerobic spore formers, e.g., Bacillus ar.tnracis, B.subtilia, B.cereus (3rd = Bacillus), anaerobic Spore-forming chlostridia, e.g. Clostridium perfringens, Cl.tetani (Cl. = Clostridium);

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The above list of pathogens is only exemplary and in no way restrictive.

As diseases caused by the active ingredient combinations according to the invention to know how to prevent, improve and / or be cured, for example:

Diseases of the respiratory tract and the pharynx; Ot: .tis; Pharyngitis; Pneu.Tioniε; Peritonitis; Pyelonephritis; Cystitis; Endocarditis; System infections; Bronchitis; Arthritis.

The present invention includes pharmaceutical preparations, In addition to non-toxic, inert pharmaceutically suitable carriers, clavulanic acid ur: d one or more Penicillins or cephalosporins and methods according to the invention for the production of these preparations.

The present invention also includes pharmaceutical preparations i: i Dosing seii-h: iten. This means that the Preparations are in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules, their A fraction or a mixture of active ingredients. Multiples of one Single dose. The dosage units can be, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a Single dose included. A single dose contains; preferably the amount of active ingredient administered in one application and which is usually a whole, a half, or a third of a quarter of a daily dose.

Among non-toxic, inert, pharmaceutically acceptable Carriers are solid, semi-solid or liquid diluents, To understand fillers and forming aids of all kinds.

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BATH ORIGINAL

Preferred pharmaceutical preparations are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes. Ointments, gels, creams, Called lotions, powders and sprays.

Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. starches, milk sugar, Cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethyl cellulose, alginates, Gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g., paraffin, and (f) absorption accelerators, e.g. 3. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and etonite; and (i) lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be mixed with the usual, optionally containing opacifying agents Coverings and sheaths be provided and also be composed in such a way that they only contain the active ingredient (s) or preferably in a certain part of the intestinal tract, optionally with a delay, in which case the embedding materials e.g. polymer substances and waxes can be used.

The active compound mixtures according to the invention can, if appropriate, be mixed with one or more of the abovementioned carriers also be in microencapsulated form.

In addition to the active ingredient mixture, suppositories can contain the usual water-soluble or water-insoluble carriers,

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eg polyethylene glycols, fats, eg cocoa fat, and higher esters (eg C ₁₄ alcohol with C ₁₆ fatty acid) and mixtures of these substances.

Ointments, pastes, creams and gels can contain the usual carrier substances in addition to the active substance mixture, e.g. animal ones and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can contain the usual carrier substances in addition to the active ingredient mixture, e.g. lactose, talc, Silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual propellants, e.g. chlorofluorocarbons contain.

In addition to the active substance mixture, solutions and emulsions can contain the usual carriers such as solvents and solubilizers and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3-butylene glycol, dimethylformamide, Oils, especially cottonseed oil, peanut oil, corn oil, Olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active substance mixture, suspensions can be the usual ones Carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and

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Sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, Contains bentonite, agar-agar and tragacanth or mixtures or substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving agents Contains additives, e.g. peppermint oil and eucalyptus oil, and sweeteners e.g. saccharin.

The therapeutically effective combinations of active ingredients should be used in the pharmaceutical preparations listed above preferably in a concentration of from about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture to be available.

In addition to the active ingredient mixtures according to the invention, the pharmaceutical preparations listed above can also contain further ones contain active pharmaceutical ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. by mixing the active ingredient mixture with pharmaceutical Usable carriers and additives.

The present invention also includes the use of Mixtures of active ingredients according to the invention and of pharmaceutical preparations which contain two or more according to the invention Contain active ingredients in human and veterinary medicine for the prevention, improvement and / or healing of the above Diseases.

The active ingredient mixtures or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously and intramuscularly.

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In general, it has proven to be advantageous both in human and in veterinary medicine to use the method according to the invention Mixture of active ingredients in total amounts of about 1.5 to about 60, preferably 1.5 to 15 g / person per 24 hours, if necessary, to be administered in the form of several, e.g. 3, single doses to achieve the desired results. A single dose contains the active ingredient mixture or mixtures according to the invention preferably in amounts of about 0.1 to about 20 g, in particular 0.1 to 1.5 g / human. However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the type and severity of the Disease, the type of preparation and application of the drug and the period or interval within to which the administration takes place. So in some cases it may be sufficient with less than the above mentioned amount of active ingredient mixture get along, while in other cases the above-mentioned amount of active ingredient exceeded must become. Determining the optimal dosage and type of application of the active ingredient mixture required in each case can easily be done by any skilled person on the basis of their specialist knowledge.

In the case of use as a feed additive, the new active ingredient mixtures in the usual way together with the Feed or with feed preparations or with the drinking water are given. This can prevent infection by gram negative or gram positive bacteria and also a better one Utilization of the feed can be achieved.

The new active ingredient combinations are characterized by strong antibacterial effects that have been tested in vivo and in vitro and by oral absorbability.

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The effectiveness of the active ingredient combination according to the invention can be exemplified by the following in vitro test demonstrated:

example

Comparison of the MIC of the active ingredient combination according to the invention from the penicillin D-a / j3-methylsulfonyl-2-oxo-imidazolidinl-yl) carbonylamineq7-benzylpenicillin sodium and the sodium salt of clavulanic acid (combination A) with the MIC of the active ingredient combination of the sodium salts of Ampicillin and clavulanic acid (combination B) according to laid-open specification No. 2,517,316.

Method: The minimum inhibitory concentrations in the Tube dilution test determined. Reading was made after 24 hours. Both combinations (A and B) were each equal amounts by weight of penicillin and clavulanic acid combined. The numbers in the The following table shows the lowest still effective amount of the respective penicillin (in combination A or B), in U / ml that was still effective against the specified bacterium. In column F it is indicated to how many times the active ingredient combination A according to the invention is better in each case for the individual germs than that at the time the technical combination B.

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Tabel

MIC

Germ Combination A Combination B F.
(approx.) E. coli T 7 U / ml:
(Penicillin) U / ml:
(Penicillin) 6.1 E. coli A 261 2.1 12.8 5.8 E. coli F IA 1.1 6.4 3.0 E.coli Munster A, 2 12.8 2.9 Klebs. 57 USA 1.1 3.2 11.6 Klebs. 1857 1.1 12.8 3.0 Prot.morg. 932 ^, 2 12.8 2.9 Prot.vulg. 1017 17.0 49.7 5.8 Prot.morg.1102 / III 1.1 6.4 189 <0.53 100.3

Method: Determination of the minimum inhibitory concentration in the tube dilution test, reading after 24 hours; there were equal amounts of weight combined; the MIC numbers in the table indicate the lowest effective amount.

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Claims (6)

Claims 1. Antibiotic agent, characterized by a content of an active ingredient combination consisting of (1) ß-lactam antibiotics of formula I: R ₃ R ₁ -CO-NH- in which 0 0 R ₁ Är Ki} ϊ-, CK ₃ -SO ₂ -I ^ N-, and / CH ₃ R ₂ ; for phenyl, ρ-hydroxyphenyl and furyl, / ₃ R _{3 represents} H, OCH ₃ and OC ₂ H ₅ s, where Y / ^C > ^ CH ^X C CH. ι ~ ^and p-CH ₂ -T COOH -0-CO-NH ₂ , - k — n ^X C00H means where T is -0-CC-CH ₃ , , - :; i: —i: , -S-Il ..J *, -ZX ₁ Jk stands Ϊ V R ₄ ^R 4 and R _{4 is} H, CH ₃ , -CH ₂ -COCH, -CH ₂ -SO ₃ H or -CH ₂ -CH ₂ -N (CH ₃ ) _a , Le A 18 22Ο - 15 - 80988ß / 02U or their pharmaceutically usable salts, in particular the sodium salts, as well as their various Crystal and hydrate forms and (2) clavulanic acid of formula II ^ L 0 CH ₂ OH o ^ ^'K' Y COCH or their pharmaceutically acceptable salts or esters which can be cleaved in vivo, in particular their sodium salt . 2. Antibiotic agent according to claim 1, which is a ß-lactam antibiotic from the group D- J. At Imidazo lid in- 2-oxo-1 i'l) -cavbonylaminoZ-benzylpencillin, D-oC / 7 3-methylsulfonyl-2-oxo-imidazolindin-1-yl) -carbony 1 amino7-benzylpenicillin, D -OIL ^ ~ (4-Metyl-5-oxo-1,2-diazo1-3-yn-2-yl) -carbonylamino ^ -benzylpenicillin, D-JL / 73-furfurylideneamino-2-oxo-ifludazolidin-1-yl ) -carbonylaminoy-p-hydroxybenzylpenicillin, Dc, C / 14-ethyl-2, 3-dioxopiperazino-1-yl) -carbonylaminoy-benzylpenicillin and D-oC / ~ (4-ethyl-2, 3-dioxo-piperaz ino- l-yl) -carbonyIamino7 ~ p-hydroxybenzyl-penicillin, D-6-ß - ^ _- 2 / "(4-Sthyl-2,4-dioxopiperazino-l-yl) -carbonylamineiZ-phenylacetamidoJ-6 -« / -methoxyper.icillic acid, D-6-ß- {~ 2zf (3-FuriuryIidenaraino-2-o;: o- 5-a-ciethoxy-penicillanic acid, D-7-ß | _-2Z "(3-FurfuryIidenanino-2-oxo-inida2olidin-1-yl) -c?: Rbonyla-ino7-fur-2-yl-acatasidoj-7 -> :: -. ethoxy-cephalospcranic acid, D- £ -3- | _-2 / "(4-ethyl-2, 3- aicy.o-zi ^ er2rAnc-l-yl] -czztor.ylsrr-r .? r? - ^ - y £ roxy ~ Sr. =: r.ylacet &z> iao V £ --cx - e-thcxy-por-icillar.sav.: 'e, D-7-ß i-2 / "(J-Furf urylider. ^: R.ir.o- T-oC -.- niecJioxy-cephalosiJoranoic acid and / or I) -7-βi-2 ^ [3-cyclopropyl 2-oxc) -imi (l <izc) lidin-l-yl) -carbonylamino7-phenylacetamidoJ- Lc ^ JV U 22O - 16 - 809ΠΠΓ) / 021Α BATH ORIGINAL 7-oL-methoxy-cephalosporanic acid or a pharmaceutical usable salt, in particular the sodium salt, of the compounds mentioned. 3. Antibiotic agent according to claims 1 and 2, characterized in that the active ingredient combination The weight ratio of (1) to (2) is between 1:10 and 10: 1, preferably between 1: 5 and 5: 1. 4. Process for the preparation of an antibiotic agent, characterized in that components (1) and (2) according to claim 1 and pharmaceutically suitable carriers and / or additives mixed with one another. 5. A method for the treatment of diseases caused by bacteria, characterized in that combinations of active substances are used according to claim 1 applied to humans or animals suffering from these diseases. 6. Use of an antibiotic agent according to claim 1 in the treatment of bacteria-induced Diseases. Le A 18 220 - 17 - 809886 / 02U