Europa,schesP_ MM M II M MM 1 1 M Ml MM M Ml J European Patent Office .ha no © Publication number: 0 384 41 OBI Office europeen, desJ brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 17.05.95 © Int. CI.6: A61 K 31/545, A61 K 31/43, //(A61K31/545,31:43) © Application number: 90103266.4 @ Date of filing: 20.02.90 The file contains technical information submitted after the application was filed and not included in this specification © Antimicrobial composition. ® Priority: 21.02.89 JP 41286/89 9-1, Kamimutsuna 3-chome 14.04.89 JP 94460/89 Okazaki-shi, Aichi (JP) @ Date of publication of application: Inventor: Sanada, Mlnoru, c/o BANYU PHARM. 29.08.90 Bulletin 90/35 CO., LTD. OKAZAKI RES. LABORATORY, © Publication of the grant of the patent: 9-1, Kamimutsuna 3-chome 17.05.95 Bulletin 95/20 Okazaki-shi, Aichi (JP) © Designated Contracting States: Inventor: Nakagawa, Susumu, c/o BANYU CH DE FR GB IT LI NL PHARM. CO., LTD. OKAZAKI RES. LABORATORY, © References cited: 9-1, Kamimutsuna 3-chome EP-A- 0 248 361 Okazaki-shi, Aichi (JP) UNLISTED DRUGS, vol. 37, no. 2, February Inventor: Tanaka, Nobuo, c/o BANYU PHARM. 1985, Chatham, New Jersey, US; "Zienam CO., LTD. 250". 2-3, Nihonbashi Honcho 2-chome Chuo-ku, © Proprietor: BANYU PHARMACEUTICAL CO., Tokyo (JP) LTD. Inventor: Inoue, Matsuhisa 2-3, Nihonbashi Honcho 2-chome 3076-3, Oaza-Tokisawa 00 Chuo-ku, Tokyo (JP) Fujlmi-mura, Seta-gun, @ Inventor: Matsuda, Kouji, c/o BANYU PHARM. Gunma (JP) CO., LTD. OKAZAKI RES. LABORATORY, 00 CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) EP 0 384 410 B1 0 Representative: Klunker . Schmltt-NIIson . HIrsch WInzererstrasse 106 D-80797 Munchen (DE) 2 EP 0 384 410 B1 Description BACKGROUND OF THE INVENTION 5 1 . Field of the Invention The present invention relates to a combination of different kinds of ^-lactam antibiotics as a pharmaceu- tical composition, to the use of the composition for producing a medicament, and to products containing the combination. 70 2. Description of the Related Art Currently, although many kinds of antibiotics have been used for the therapy of various infectious diseases, due to a tendency of pathogenic microorganisms which have encountered antibiotics to acquire a 75 resistance to the antibiotics, usually microorganisms exist which are resistant to a single antibiotic. To resolve this dilemma, attempts have been made to use a combination of more than one antibiotic. For example, the use of a combination of more than one antibiotic has been proposed to enhance an antimicrobial activity against pathogenic microorganisms, for example, gram-positive bacteria such as Staphyrococcus aureus, S. epidermidis, Enterococcus faecalis, etc.; gram negative bacteria such as 20 Citrobacter freundii, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Serratia marcescens, etc.; and glucose non-fermentative gram-negative rods, such as Pseudomonas aeruginosa, P. cepacia, P. maltophilia, Acinetobacter calcoaceticus, etc. Japanese Unexamined Patent Publication (KOKAI) No. 60-126230 and Japanese Examined Patent Publication (KOKOKU) No. 61-37248 describe antimicrobial compositions comprising a combination of 25 penicillin series antibiotic, and penicillin or cephalosporin series antibiotic; Japanese Examined Patent Publication (KOKOKU) No. 62-50448 describes antimicrobial compositions comprising a combination of a synthetic antimicrobial substance and penicillin or cephalosporin series antibiotic; and Japanese Examined Patent Publication (KOKOKU) No. 63-26732 describes antimicrobial compositions comprising a combination of a phosphoric derivative and one of various antimicrobial substances. 30 From EP-A-0 248 361 it is known that combinations of certain cephalosporins and penems exhibit a synergistic effect and may be used for treating bacterial infections. There is a tendency toward an increase in drug-resistant microorganisms isolated from patients suffering from intractable diseases, and there are few antimicrobial compositions which exhibit an effective and sufficient antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), a repre- 35 sentative pathogen of such diseases, and this has led to serious clinical difficulties. It is well known that carbapenem series compounds have a wide antimicrobial spectrum. Known carbapenem series compounds include imipenem (Japanese Examined Patent Publication No. 61-60816), SM-7338 (Japanese Unexamined Patent Publication No. 60-10488), RS-533 (Japanese Unexamined Patent Publication No. 59-51286), but the administering of this carbapenem alone does not provide a sufficient 40 antimicrobial activity against MRSA. Further, although imipenem is often used for the therapy of MRSA infections, it does not provide satisfactory results as MRSA is highly resistant to ^-lactams. All of the above references refer to tests on usual gram-positive bacteria, gram negative bacteria and glucose non-fermetntative gram-negative rods, and do not refer to an evaluation of an acitivity against MRSA. 45 Since there are limitations to the therapy of MRSA infections by a single agent, the use of a combination of an aminoglycoside and a ^-lactam, or a combination of phosphomycin and a ^-lactam has been attempted, but these combinations are not satisfactorily effective. Since an infection with MRSA is representative of intractable infections, the deficiency in effective therapeutic agents must be urgently resolved. 50 SUMMARY OF THE INVENTION Accordingly, the present invention provides an antimicrobial composition comprising a combination of (1) a first ingredient selected from penicillin series compounds, cephalosporin series compounds and 55 pharmaceutically acceptable salts thereof; and (2) a second ingredient selected from carbapenem series compounds and pharmaceutically acceptable salts thereof wherein the penicillin series compound is selected from penicillin G, ampicillin, amoxicillin, mecillinam, pivmecillinam, carbenicillin, carfecillin, carin- dacillin, sulbenicillin, talampicillin, bacampicillin, ticarcillin, piperacillin, ciclacillin and hetacillin, the 3 EP 0 384 410 B1 cephalosporin series compound is selected from cefatrizine, cefamandole, cefuzoname, cefpimizole, cephapirin, cephaloridine, cefsulodin, cefotiam, ceforanide, ceftexzole, cefoxitin, latamoxef, flomoxef, cef- metazole, cefotetan, cefpiramide, cephaloglycin, cephalexin, cefadroxil, cefroxadine, ceferadine, cefaclor and cefoperazone, the carbapenem series compound is selected from imipenem, i.e., (5R,6S,8R)-3-[{2- 5 (formimidoylamino)ethyl}thio] -6-(1 -hydroxyethyl)-7-oxo-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid monohydrate, SM-7338, i.e. (4R,5S,6S,8R,2'S,4'S)-3-[2-(dimethylaminocarbonyl)pyrrolidin-4-ylthio]-6-(1 - hydroxy-ethyl)-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid, and RS-533,i.e. (5R.6S, 8R,4'S)-3-[1-acetimidoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3,2,0]-hept-2-ene-2- carboxylic acid; and said combination providing a synergistic effect over the compounds used alone. io The composition of the present invention is effective against MRSA which is highly resistant to ^-lactam antibiotics. Further developments of the antimicrobial composition of the present invention result from the dependent claims 2 to 10. The present invention also provides products containing a first antibiotic and a second antibiotic, is wherein the first antibiotic is selected from penicillin series compounds, cephalosporin series compounds and pharmaceutically acceptable salts thereof and the second antibiotic is selected from carbapenem series compounds and pharmaceutically acceptable salts thereof, and wherein the penicillin series compound is selected from penicillin G, ampicillin, amoxicillin, mecillinam, pivmecillinam, carbenicillin, carfecillin, carin- dacillin, sulbenicillin, talampicillin, bacampicillin, ticarcillin, piperacillin, ciclacillin and hetacillin, the 20 cephalosporin series compound is selected from cefatrizine, cefamandole, cefuzoname, cefpimizole, cephapirin, cephaloridine, cefsulodin, cefotiam, ceforanide, ceftexzole, cefoxitin, latamoxef, flomoxef, cef- metazole, cefotetan, cefpiramide, cephaloglycin, cephalexin, cefadroxil, cefroxadine, ceferadine, cefaclor and cefoperazone, the carbapenem series compound is selected from imipenem, i.e., (5R,6S,8R)-3-[{2- (formimidoylamino)ethyl}thio] -6-(1 -hydroxyethyl)-7-oxo-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid 25 monohydrate, SM-7338, i.e. (4R,5S,6S,8R,2'S,4'S)-3-[2-(dimethylaminocarbonyl)-pyrrolidin-4-ylthio]-6-(1- hydroxy-ethyl)-4-methyl-7-oxo-1-azabicyclo 3,2,0]hept-2-ene-2-carboxylic acid, and RS-533,i.e. (5R.6S, 8R,4'S)-3-[1-acetimidoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3,2,0]-hept-2-ene-2- carboxylic acid; and said combination providing a synergistic effect over the compounds used alone, the product containing the first antibiotic and the second antibiotic as a combined preparation for separate use 30 or separately administering in the MRSA infection therapy. The present invention further relates to the use of an antimicrobial composition comprising a combina-