IE47856B1 - Antibacterial composition for medical use - Google Patents
Antibacterial composition for medical useInfo
- Publication number
- IE47856B1 IE47856B1 IE50179A IE50179A IE47856B1 IE 47856 B1 IE47856 B1 IE 47856B1 IE 50179 A IE50179 A IE 50179A IE 50179 A IE50179 A IE 50179A IE 47856 B1 IE47856 B1 IE 47856B1
- Authority
- IE
- Ireland
- Prior art keywords
- medical use
- antibacterial composition
- use according
- pharmaceutically acceptable
- lactamase
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 46
- 230000000844 anti-bacterial effect Effects 0.000 title claims description 44
- 150000003839 salts Chemical class 0.000 claims description 30
- 229930186147 Cephalosporin Natural products 0.000 claims description 24
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 24
- 102000006635 beta-lactamase Human genes 0.000 claims description 24
- 229940124587 cephalosporin Drugs 0.000 claims description 24
- 230000002401 inhibitory effect Effects 0.000 claims description 24
- 150000001780 cephalosporins Chemical class 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000003460 beta-lactamyl group Chemical group 0.000 claims description 10
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical group [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 9
- 125000004149 thio group Chemical group *S* 0.000 claims description 9
- 229930182555 Penicillin Natural products 0.000 claims description 8
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 8
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 claims description 6
- 229960002682 cefoxitin Drugs 0.000 claims description 5
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims description 4
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 4
- 229960004273 floxacillin Drugs 0.000 claims description 4
- 229960003085 meticillin Drugs 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229960003324 clavulanic acid Drugs 0.000 claims description 3
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 claims description 3
- 229960003326 cloxacillin Drugs 0.000 claims description 3
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 claims description 3
- 229960001585 dicloxacillin Drugs 0.000 claims description 3
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 claims description 3
- 229960001019 oxacillin Drugs 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 3
- 229940049954 penicillin Drugs 0.000 claims 3
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 125000003831 tetrazolyl group Chemical group 0.000 claims 1
- 239000011734 sodium Substances 0.000 description 40
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 description 23
- MGFZNWDWOKASQZ-UMLIZJHQSA-M methicillin sodium Chemical compound [Na+].COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 MGFZNWDWOKASQZ-UMLIZJHQSA-M 0.000 description 22
- 229940019826 methicillin sodium Drugs 0.000 description 22
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 17
- 229910052708 sodium Inorganic materials 0.000 description 17
- 239000004615 ingredient Substances 0.000 description 14
- 229940102223 injectable solution Drugs 0.000 description 13
- 239000002504 physiological saline solution Substances 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 241000588747 Klebsiella pneumoniae Species 0.000 description 8
- 244000052616 bacterial pathogen Species 0.000 description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 5
- 150000002960 penicillins Chemical class 0.000 description 5
- -1 1 - methyl - 1,2,3,4 - tetrazolyl Chemical group 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 241000588722 Escherichia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YBPAYPRLUDCSEY-UHFFFAOYSA-N 2-(4-hydroxyphenyl)acetamide Chemical compound NC(=O)CC1=CC=C(O)C=C1 YBPAYPRLUDCSEY-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 2
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960003016 cefoxitin sodium Drugs 0.000 description 1
- SCLZRKVZRBKZCR-SLINCCQESA-M cloxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl SCLZRKVZRBKZCR-SLINCCQESA-M 0.000 description 1
- 229960003026 cloxacillin sodium Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960003994 oxacillin sodium Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- VDUVBBMAXXHEQP-ZTRPPZFVSA-M sodium;(2s,6r)-3,3-dimethyl-6-[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)SC21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 VDUVBBMAXXHEQP-ZTRPPZFVSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
This invention relates to novel antibacterial compositions for medical use. More particularly, it relates in a first aspect to antibacterial compositions for medical use comprising as active ingredients a cephalosporin represented by the formula 0 )— C ,Hf -tl N-CONH-CH-CONH Π j— N [Ij COOH wherein R^ represents an acetoxy, 5-(l-methyl-l,2,3,4tetrazolyl) thio or 2-(5- methyl- 1,3,4 - thiadazolyl) - thio group and o R represents a hydroxyl group, or pharmaceutically acceptable 10 salts thereof and a β - lactamase - inhibiting compound haying a B - lactam ring.
In a second aspect of the invention there is provided an antibacterial composition for medical use comprising as an active ingredient a cephalosporin represented by the formula: [I] and wherein represents an acetoxy, -(1- methyl - 1,2,3,4 - tetrazolyl) thio or 2-(5- methyl - 1,3,4 - thiadiazolyl) thio group j. r2 represents a hydrogen atom, or a pharmaceutically acceptable salt thereof, characterized in that said composition additionally includes a p - lactamase - inhibiting compound having a β - lactam ring selected from a clavulanic acid, Cefoxitin, and 7b - (a - cyanomethylthioacetamido) - 7a - methoxy - 3 10 J> - (1 - methyl - 1,2,3,4 - tetrazolyl) thiomethyl] - Δ3 - cephem - 4 - carboxylic acid or a pharmaceutically acceptable salt of any one of the B - lactamase - inhibiting compounds.
The cephalosporins represented by the formula (I) and pharmaceutically acceptable salts thereof, which are developed by the present inventors, are useful substances having excellent characteristics such as a broad antibacterial spectrum.
The present inventors have found as a result of extensive studies that when a cephalosporin represented by the formula [I] or a pharmaceutically acceptable salt thereof is mixed with a 0-lactamase-inhibiting compound having a 0-lactam ring, the latter makes it difficult for the cephalosporins represented by the formula [I] and pharmaceutically acceptable salts thereof to be affected by 0-lactamase, and the resulting composition exhibits a synergistic effect on the antibacterial activity.
An object of this invention is to provide an 10 antibacterial composition having .a pronounced, antibacterial activity against Gram-negative bacteria existing even in a large population, especially against Escherichia coli, Proteus species, Klebsiella pneumoniae and Pseudomonas aeruginosa.
Another object of this invention is to provide an antibacterial composition active to those pathogenic bacteria which are resistant to conventional penicillins or cephalosporins.
A further object of this invention is to provide an antibacterial composition capable of enhancing the bactericidal speed and therapeutic effectiveness.
Other objects and advantages of this invention will become apparent from the following description.
The above-mentioned pharmaceutically acceptable salts are those which are commonly used as cephalosporin salts, including salts with metals such as sodium, potassium and calcium, ammonium salt and salts with amines such as procaine, N,N-dibenzylethylenediamine and the like.
The β-lactamase-inhibiting compounds having a β-lactam ring used in this invention include β-lactamase inhibiting penicillins and cephalosporins and clavulanic acids. The β-lactamase-inhibiting penicillins and cephalosporins are, for example, Cloxacillin, Dicloxacillin, Oxacillin, Flucloxacillin, Methicillin, Cefoxitin and 7B-(a-cyanomet hylthioacetamido)-7a-methoxy-3-[5-(1o methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ -cephem-1!carboxylic acid and pharmaceutically acceptable salts thereof. These pharmaceutically acceptable salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [X].
And the clavulanic acids include, foi’ example, the compound which is represented by the following formula and pharmaceutically acceptable salts thereof: H These pharmaceutically acceptable' salts have the same meanings as mentioned above as to salts of the cephalosporins represented by the formula [I].
The suitable ratio of the cephalosporin represented by the formula [I] to the β-lactamase-inhibiting compound having a β-lactam ring in the composition of this invention varies to some degrees depending on the type of target pathogenic bacteria or symptoms, but is generally in the range of form 1 : 0.04 to. 1 : 5 (in terms of weight ratio or potency ratio), preferably 1 : 0.1 to 1 : 1.5 (in terms of weight ratio or potency ratio).
In this invention, the type of 6-lactam.ase inhibiting compounds having a β-lactam ring may be properly selected according to particular pathogenic bacteria.
The antibacterial composition for medical use according to this invention is used preferably as a parenteral injection, although it can be used in other dosage forms and through other administration routes similarly to known antibiotics such as conventional penicillins and cephalosporins. It can also be used in the form of ointment and preparation for rectal administration.
When used as an injection, the antibacterial composition of this invention can be mixed with solid or liquid carriers or diluents which are conventionally used in injections of known antibiotics. Of the carriers, sterilized water is most frequently used.
The antibacterial composition of this invention may, of course, be in the form of powder which can be dissolved in suitable vehicles such as sterilized water, glucose solution and physiological saline solution for use as an injection.
In administering the antibacterial composition of this invention as an injection to man, Intravenous injection (including drip infusion) or intramuscular injection is generally suitable.
The dosage of the antibacterial composition of this invention is properly selected in accordance with the ratio between the cephalosporin represented by the formula [I] and the β-lactamase-inhibiting compound having a g-lactam ring, age of the patient, and the type or symptoms of the Infectious disease. The suitable dose of an injection ranges generally from 0.5 to 10 g potency per day for adults, but the dose ic not limited thereto.
In administering the antibacterial composition of this invention as an intramuscular injection, it can be used together with those drugs which are usually used in injections such as analgesics, for example, lidocaine hydrochloride.
The efficacy of the antibacterial composition of this invention Is Illustrated below with reference bo Test Examples and the accompanying drawings which are diagrammatic representation of the test results. In the drawings, Fig. 1 shows antibacterial activities of sodium 7-[D(-)-α~(4-ethyl-2,3-dloxo-l-piperazinylearbonylamino)7 p-hydroxyphenylacetamide]-3-[5-(l-methyl-l,'2,3,4-tetrazolyl)thiomethyl]-A -cephem-4-carboxylate (referred to hereinafter as T-1551 Na) and Methicillin sodium against a Escherichia coli TK-3, which is/clinically isolated strain, Pig. 2 shows those of T-1551 Na and Methicillin sodium a against Klebsiella pneumoniae Y-4 which is/clinically isolated strain, Fig. 3 shows those of T-1551 Na and potassium clavulanate against Escherichia coli GN 6299 a which is/clinically Isolated strain, Fig. 4 shows those of T-1551 Na and potassium clavulanate against Klebsiella is a pneumoniae GN 69 which/clinically isolated strain, and Fig. 5 shows those of T-1551 Na and potassium clavulanate a against Pseudomonas aeruginosa GN 3345 which is/clinically isolated strain.
Test Example 1 Growth-inhibition test on clinically isolated strain Heart Infusion agar containing a prescribed amount of Methicillin sodium or T-1551 Na was inoculated β with the test bacterium at a rate of about 10 cells/ml.
After incubation for 18 hours at 37°C., the growth of the test bacterium was inspected. The results of test were as shown in Tables 1, 2 and 3· In each table, (+) means that the test bacterium grew and (-) means'that the test bacterium did not grow. From Tables 1, 2 and 3, it is apparent that the combination of Methicillin sodium and T-1551 Na exhibits a synergistic effect on the inhibition of growth of the pathogenic bacteria.
Table 1 Escherichia coll TK-3 strain Methicillin sodium (ug/mfc) 3200 1600 800 400 200 100 12.5 - - - - + + + + + + - - - - + + + + + + - - - - + + + + + + - - - - + + + + + + - - - - + + + + + + - - - + + + + + + + - - - + + + + + + 4* - + + + + + + + + + - + + + + + + + + + + + + + + + + + + 4· 200 100 50 25 12.5 6.25 3.13 1.56 0.78 0 (ug/mi.) T-1551 Na Table 2 Klebsiella pneumoniae Y-4 strain (pg/mfc) ι—! ι—! •H •H Λ P S 3200 1600 800 400 200 100 12.5 200 100 50 25 12.5 6.25 3.13 1-56 0.78 0 (pg/mA) T-1551 Na Table 3 Pseudomonas aeruginosa S-lll strain (Vg/m$.) Methicillin sodium 3200 1600 800 400 200 100 12.5 200 100 50 25 12.5 6.25 3.13 1-56 0.78 0 (ug/mfc) T-1551 Na Test Example 2 β-Lactamase specific activity The β-lactamase activity was assayed by the iodometric assay method at 30°C, following the procedure of Perret [C.J. Perret, Iodometric Assay of Penicillinase, Nature, 174, 1012-1013 (1954)], except that a 0.1 molar phosphate buffer solution (pH 7·0) was used in place of the 0.2 molar phosphate buffer solution (pH 6.5)· One unit of β-lactamase activity corresponds to the quantity of β-lactamase which decomposes 1 pmole/hour of T-1551 Na in a 0.1 molar phosphate buffer solution (pH 7.0) containing 8 mmoles of the substrate.
In Table 4, there are shown β-lactamase specific activities of Escherichia coli TK-3 strain, Klebsiella pneumoniae Y-4 strain and Pseudomonas aeruginosa S-lll strain.
Table 4 Strain β-Lactamase activity (unit/mg dry weight) Escherichia coli TK-3 53 Klebsiella pneumoniae Y-4 30 Pseudomonas aeruginosa S-lll 5-2 Test Example 3 Antibacterial activity against clinically isolated strains The following test was performed to examine whether or not the synergistic effect of the present composition confirmed by the growth inhibition test in Test Example 1 is accompanied by an antibacterial effect.
A pathogenic bacterium was inoculated at a g rate of about 10 cells/ml into a Nutrient broth containing T-1551 Na (50 pg/ml) alone, T-1551 Na (25 pg/ml) plus Methicillin sodium (25 pg/ml) or Methicillin sodium (50 ug/ml) alone. The inoculated broth was incubated at 37°C and the number of live cells in the culture broth was determined at predetermined time intervals.
The test results are as shown in Figs. 1 and 2, and it was confirmed that the antibacterial activity had increased by the joint use of T-1551 Na and Methicillin sodium. The minimum inhibitory concentration of T-1551 Na oi· Methicillin sodium against Escherichia coll TK-3 strain or Klebsiella pneumoniae Y-4 strain was greater than 800 ug/ml in each case.
Test Example 4 Effect of combined use on experimental infection in mice Male mice (5 mice per group) of the ICR strain, weeks of age, were perltotieally inoculated with the prescribed number of pathogenic bacteria suspended in % mucin. After one hour and two hours following the inoculation, test preparations shown in Table 5 were subcutaneously administered to examine the protection effect. The results obtained were as shown in Table 5, wherein the protection effect was expressed in terms of Εϋ^θ.
Table 5 Infectious bacterium Challenge dose (cells/ mouse)ED50 mg/mouse T-1551 Na+ Methicillin Na (2 : 1) T-1551 Na Methi- cillin Na K. pneumoniae 5-7 x 107 4.8 >26.8 >50 K. pneumoniae Ϊ-53 1.0 x 107 1.66 >10.0 >46.6 As is apparent from Table 5, the synergistic effect of the combined use of T-1551 Na and Methicillin sodium on the inhibition of pathogenic bacteria growth, which had been found by vitro, was recognized also by the experimental of protection from infection.
Text Example 5 The same operation as in Test Example 1 was 15 repeated, except that the Methicillin sodium was replaced by potassium clavulanate and the test bacteria were replaced by those shown in Tables 6, 7 and 8, to obtain the results shown in Tables 6, 7 and 8. 800 200 50 12-5 - - - - - - - - - - - + - - - - - + - - - - - + - - - - - + - - - - - - - - - - + - - - - - - - - + + + - - + + + + + + + + + 3.1 0.8 0.2 0 (pg/mi.) T-1551 Na 7 8 5 6 Table 7 Klebsiella pneumoniae GN 69 strain (pg/mi.) 100 - - - - - - - - - - - - - - - - 25 - - - - - - - - - - - - - - - - 6.25 - - - - - - - - Potassium clavula- - - - - - - - - nate 1.6 - - - - - - - - - - - - - - - 0.4 - - - - - - - - - - - - - - - - 0 - - + + + + + + 800 200 50 12.5 - - - - - - - - - - - - - - - - - + - - - - - + - - - - - + - - - - - + - - - - - + - - - - - + - - - - + + - - + + + + + + + + + + 3.1 0.8 0.2 0 (pg/mS.) T-1551 Na 478S6 (ug/m£) Potassium clavulanate Table 8 Pseudomonas aeruginosa GN 33^5 strain - - - - - - + + + + - - - - - - + + + + - - - - - - + + + - - - - - - + + + + - - - - - + + + + + - - - - - + + + + + - - - - - + + + + + - - - - - + + + + + - - - - - + + + + + - - - - + + + + + + - - + + + + + + + + 800 200 50 12.5 3.1 0 T-1551 Na (pg/mA) 7 8 5 6 Test Example 6 The same operation as in Test Example 3 was repeated, except that the Methicillin sodium was replaced by potassium clavulanate, the pathogenic bacteria were replaced by those shown in Figs. 3 to 5, and they were 6 8 inoculated at a rate of 10 cells/ml instead of 10 cells/mol, to obtain the results shown in Figs. 3, 4 and 5.
The test results described in the foregoing Test Examples 1 to 6 are typical of the pharmacological activity of the antibacterial composition of this invention. When other β-lactamase-inhibiting compounds having a 8-lactam ring such as Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Cefoxitin, and 7g-(D-acyanomethylthioacetamido)-7a-methoxy-3-[5-(1-methyl1j 2,3,4-tetrazolyl)thlomethyl]-A^-cephem-4-carboxylic acid, and sodium salts thereof, there were obtained results similar to those obtained with Methicillin sodium and potassium clavulanate.
And when other cephalosporins represented by the formula [I] than T-1551 Na were used, there were obtained effects similar to those obtained with T-1551 Na.
From the foregoing description, it is understandable that the antibacterial composition for medical use according to this invention is expected to be effective in the therapy of various diseases, the causative organisms of which are bacteria sensitive to the respective penicillins and cephalosporins. Especially, the composition of this invention will be highly useful in the therapy of various diseases including, for example, those in the medical department and urological department which are caused by the bacteria, sensitive to the cephalosporins represented by the formula [I] or pharmaceutically acceptable salts thereof, particularly belonging to Gram-negative bacteria, (Escherichia coll, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus species, etc.).
The present invention is illustrated below 10 with reference to Examples which are merely illustrative and not limitative.
Example 1 Sterilized sodium 7-[D(-)-a-(4-ethyl2,3-dioxo-l-piperazinylearbonylamino)-phydroxyphenylacetamido]-3-C5-(l-methyl1,2,3,4-tetrazolyl)thiomethylj-A3-cephem- 500 mg 4-carboxylate — potency Sterilized Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 4 ml of a solution containing 0.5% (W/V) of lidocaine hydrochloride to obtain an injectable solution to be diluted when used.
Example 2 Sterilized sodium 7-CD(-)-a-(4-ethyl2,3-dloxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-[5-(l-methyl1,2,3,4-tetrazolyl)thiomethylj-A3-eephem- 1 g 4-carboxylate ,.. potency Sterilized Methicillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 3 Sterilized sodium 7-[D(-)-a-(4-ethyl2,3-dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]~3-[5-(l-methyl1,2,3,4-tetrazolyDthiomethylj-A3-cephem- 1 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved in 20 ml of a 5% glucose solution to obtain an injectable solution.
Example 4 J5 Sterilized sodium 7-[D(-)-a-(4-ethyl2,3-dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-[5-(l-methyll,2,3,4-tetrazolyl)thiomethylj-A3-cephem- 2 g 4-carboxylate ... potency Sterilized Methicillin sodium ... 1 g potency The above ingredients were dissolved of a transfusion to obtain a drip infusion.
Example 5 Sterilized sodium 7-[D(-)-a-(4-ethyl25 2,3-dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-[5-(l-niethyl1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem4-carboxylate Sterilized Methicillin sodium in 250 ml 250 mg potency 250 mg potency 478S6 The above ingredients were dissolved in 20 ml of a physiological saline solution to obtain an injectable solution.
Example 6 Sterilized sodium 7-[D(-)-n-(4~ethyl2,3-dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-[5-(l-methyll,2a3,4-tetrazolyl)thiomethylj-43-cephem- 1 g 4-carboxylate ... potency Methicillin sodium ... 5θθ mg potency The above ingredients were dissolved in 20 ml of distilled water and freeze-dried in a usual manner to obtain a composition. This composition was dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 7 Sterilized sodium 7-ED(-)-a-(4-ethyl2,3-dioxo-l-piperazinylcarbonylamino)p-hydroxyphenylacetamido]-3-[5-(l-methyll,2J3,4-tetrazolyl)thiomethyl]-A3-cephem- 1 g 4-carboxylate ... potency Sterilized Cloxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 8 Sterilized sodium 7-(D(-)-a-(4-ethyl-2,3dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-C5-(l-methyll^jSjit-tetrazolylJthiomethylj-AS-cephem- 1 g 4-carboxylate ... potency Sterilized Dicloxaeillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 9 Sterilized sodium 7-(D(-)-a-(4-ethyl-2,3dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-(5-(1-methyll,2,3>4-tetrazolyl)thiomethylj-A3-cephem- 1 g 4-carboxylate ... potency Sterilized Oxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 10 Sterilized sodium 7-(D(-)-a-(4-ethyl-253dioxo-l-piperazinylcarbonylamino)-phydroxyphenylacetamido]-3-(5-(1-methyllj>2,3>4-tetrazolyl)thiomethyl]-h3-cephem- 1 g 4-carboxylate ... potency Sterilized Cefoxitin sodium . . , 500 mg potency The above ingredients were dissolved in ml of physiological saline solution to obtain an injectable solution.
Example 11 Sterilized sodium 7-[D(-)-a-(4-ethyl-2,3dioxo-l-piperazinylcarbonylamino)-?hydroxyphenylac etamido]-3-[5-(1-methyll,2,3,4-tetrazolyl)thiomethylj-A3-cephem- 1 g 4-carboxylate ... potency Sterilized Flucloxacillin sodium ... 500 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 12 Sterilized sodium 7-[D(-)-a-(4-ethyl2,3-dioxo-l-piperazinylearbonylamino)-phydroxyphenylacetamido]-3'Q-(1-f«ethyll,2,3,4-tetrazolyl)thiomethylj - Δ^- cephem-4carboxylate Sterilized Methicillin sodium The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution. g .,. potency ... 5θθ mg potency Example 13 Sterilized sodium 7-[D(-)-a-(4-ethyl2,3-dioxo-l-piperazinylcarbonylamino)n-hvdroxvDheny lac etamido ]-3-[ 5-(1-methyl1.2,3,4 - tetrazolyl) thioniethylj- Δ3 - cephem - 1 g - carboxylate ' ‘' P°tency Sterilized Methicillin sodium ... 500 mg potency 47836 The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Example 14 Sterilized sodium 7-[D(-)-<*-(4-ethyl2,3-dioxo-l-piperazinylcarbonylamino)p-hydroxyphenylacetamido]-3-[5-(lmethyl-l32,3,4-tetrazolyl)thiomethyl]A3-cephem-4-carboxyiate Sterilized potassium clavulanate g potency 300 mg potency The above ingredients were dissolved in 20 ml of physiological saline solution to obtain an injectable solution.
Claims (20)
1. An antibacterial composition for medical use comprising as active ingredients a cephalosporin represented by the formula: wherein R 1 represents an acetoxy, 5-(l-methyl-l,2,3,4tetrazolyl)thio or 2-(5-methyl-l,3,4-thiadiazolyl)thio group and R represents a hydroxyl group, or a pharmaceutically acceptable salt thereof and 10 a β-laetamase-inhibiting compound having a β-laetam ring.
2. An antibacterial composition for medical use according to Claim 1, wherein the β-lactamaseinhibiting compound having a β-lactam ring is a βlactamase-inhibiting penicillin or a pharmaceutically 15 acceptable salt thereof.
3. An antibacterial composition for medical use according to Claim 1, wherein the β-lactamase-inhibiting compound having a β-lactam ring is a β-lactamaseinhiblting cephalosporin or a pharmaceutically acceptable 20 salt thereof.
4. An antibacterial composition for medical use according to Claim 1, wherein the β-lactamase-inhibiting compound having a β-lactam ring is a clavulanle acid or a pharmaceutically acceptable salt thereof.
5. An antibacterial composition for medical use according to Claim 2, wherein the β - lactamase-inhibiting penicillin is Cloxacillin, Dicloxacillin, Oxacillin, Methicillin, Flucloxacillin, or a pharmaceutically acceptable salt thereof.
6. An antibacterial composition for medical use according to Claim 3, wherein the Β-lactamase-inhibiting cephalosporin is Cefoxitin, 7β-(α - cyanomethylthioacetamido)-7a -methoxy-3r- Ί 3 [5-(1-methyl-1,2,3,4-tetrazolyl)thicmethylJ -Δ - cephem - 4 carboxylic acid or a pharmaceutically acceptable salt thereof.
7. An antibacterial composition for medical use according to any one of Claims 4 to 6, wherein in the formula I, R^ represents a 5-(l-methyl-l,2,3,4-tetrazolyl)thio group.
8. An antibacterial composition for medical use according to any one of Claims 1 to 6, wherein the mixing ratio (in terms of the weight ratio or potency ratio) of the β-lactamase-inhibiting compoung having a β-lactam ring to the cephalosporin represented by the formula I or a pharmaceutically acceptable salt thereof is from 0.1 to 1.5.
9. An antibacterial composition for medical use according to Claim 5 or 8 wherein the pharmaceutically acceptable salt of the β - lactamase - inhibiting penicillin is a sodium salt.
10. An antibacterial composition for medical use according to Claim 6 or 8 wherein the pharmaceutically acceptable salt of the β - lactamase - inhibiting cephalosporin is a sodium salt.
11. An antibacterial composition for medical use according to claim 4 or 8 wherein the pharmaceutically acceptable salt of clavulanic acid is a potassium salt.
12. An antibacterial composition for medical use according to claim 1, 9, 10 or 11 wherein the composition is in injectable form.
13. An antibacterial composition for medical use according to claim 1 and substantially as hereinbefore set forth with reference to 5 the foregoing examples.
14. An antibacterial composition for medical use comprising as an active ingredient a cephalosporin represented by the formula: wherein R represents an acetoxy, 5-(1- methyl - 1,2,3,4 10 tetrazolyl) thio or 2-(5- methyl - 1,3,4 - thiadiazolyl) thio group and R 1 * 3 4 represents a hydrogen atom, or a pharmaceutically acceptable salt thereof, characterized in that said composition additionally includes a β - lactamase - inhibiting compound having a β - lactam ring selected from a clavulanic acid, Cefoxitin and 15. 7β - (a - cyanomethylthioacetamido) - 7a - methoxy - 3 5-(1- methyl - 1,2,3,4 - tetrazolyl) thiomethyl] - a 3 - cephem 4 - carboxylic acid or a pharmaceutically acceptable salt of any one of the β - lactamase - inhibiting compounds.
15. An antibacterial composition for medical use according to Claim 20 14 wherein is a 5-(1- methyl - 1,2,3,4 - tetrazolyl) thio group. 4-78 5 6
16. An antibacterial composition for medical use wherein the mixing ratio (in terms of weight ratio or potency) of the β - lactamase inhibiting compound having a β - lactam ring to the cephalosporin of Formula I or a pharmaceutically acceptable salt thereof is from 5 0.1 to 1.5.
17. An antibacterial composition for medical use according to any one of claims 14 to 16 wherein the pharmaceutically acceptable salt is a sodium salt.
18. An antibacterial composition for medical use according to any one 10 of Claims 14 to 16 wherein the pharmaceutically acceptable clavulanate acid salt is potassium clavulanate.
19. An antibacterial composition for medical use according to any one of claims 14 to 16 wherein the composition is in injectable form.
20. An antibacterial composition for medical use according to 15 Claim 14 and substantially as hereinbefore set forth, with reference to the foregoing examples.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE50179A IE47856B1 (en) | 1979-07-24 | 1979-07-24 | Antibacterial composition for medical use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE50179A IE47856B1 (en) | 1979-07-24 | 1979-07-24 | Antibacterial composition for medical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE47856B1 true IE47856B1 (en) | 1984-07-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE50179A IE47856B1 (en) | 1979-07-24 | 1979-07-24 | Antibacterial composition for medical use |
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| Country | Link |
|---|---|
| IE (1) | IE47856B1 (en) |
-
1979
- 1979-07-24 IE IE50179A patent/IE47856B1/en not_active IP Right Cessation
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