WO1996008259A1 - Synergistic antimicrobial composition - Google Patents
Synergistic antimicrobial composition Download PDFInfo
- Publication number
- WO1996008259A1 WO1996008259A1 PCT/FI1995/000494 FI9500494W WO9608259A1 WO 1996008259 A1 WO1996008259 A1 WO 1996008259A1 FI 9500494 W FI9500494 W FI 9500494W WO 9608259 A1 WO9608259 A1 WO 9608259A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bismuth
- antibiotic
- vancomycin
- product according
- salt
- Prior art date
Links
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 15
- 239000000203 mixture Substances 0.000 title claims description 10
- 230000002195 synergetic effect Effects 0.000 title abstract description 13
- 229960004675 fusidic acid Drugs 0.000 claims abstract description 54
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims abstract description 54
- 150000001621 bismuth Chemical class 0.000 claims abstract description 36
- 230000003115 biocidal effect Effects 0.000 claims abstract description 31
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 26
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 26
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229930189077 Rifamycin Natural products 0.000 claims abstract description 20
- 229960003292 rifamycin Drugs 0.000 claims abstract description 20
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 208000032536 Pseudomonas Infections Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 229960004645 bismuth subcitrate Drugs 0.000 claims description 122
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 claims description 122
- 229960001225 rifampicin Drugs 0.000 claims description 36
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 36
- 108010059993 Vancomycin Proteins 0.000 claims description 35
- 229960003165 vancomycin Drugs 0.000 claims description 35
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims description 35
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 34
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical group C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 23
- 229960004306 sulfadiazine Drugs 0.000 claims description 23
- 241000589516 Pseudomonas Species 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000004599 antimicrobial Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- ZREIPSZUJIFJNP-UHFFFAOYSA-K bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 claims description 3
- 229960000782 bismuth subsalicylate Drugs 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical group O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 claims 1
- RXPAJWPEYBDXOG-UHFFFAOYSA-N hydron;methyl 4-methoxypyridine-2-carboxylate;chloride Chemical compound Cl.COC(=O)C1=CC(OC)=CC=N1 RXPAJWPEYBDXOG-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 description 25
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 230000035945 sensitivity Effects 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 241000295644 Staphylococcaceae Species 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052797 bismuth Inorganic materials 0.000 description 5
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 150000003456 sulfonamides Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 206010021703 Indifference Diseases 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 238000002306 biochemical method Methods 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000000877 morphologic effect Effects 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001243 protein synthesis Methods 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- HWSISDHAHRVNMT-UHFFFAOYSA-N Bismuth subnitrate Chemical compound O[NH+]([O-])O[Bi](O[N+]([O-])=O)O[N+]([O-])=O HWSISDHAHRVNMT-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 206010011409 Cross infection Diseases 0.000 description 2
- 241000305071 Enterobacterales Species 0.000 description 2
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- 108010013639 Peptidoglycan Proteins 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 229960001482 bismuth subnitrate Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960000304 folic acid Drugs 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 206010033072 otitis externa Diseases 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- -1 4-methylpiperazinylimino-methylidene Chemical group 0.000 description 1
- 241001468213 Amycolatopsis mediterranei Species 0.000 description 1
- 241001430312 Amycolatopsis orientalis Species 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 108020004513 Bacterial RNA Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000495778 Escherichia faecalis Species 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000682907 Fusidium Species 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 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 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 102000010562 Peptide Elongation Factor G Human genes 0.000 description 1
- 108010077742 Peptide Elongation Factor G Proteins 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- WANYARLYVUSDSR-UHFFFAOYSA-N Vancomycinic acid Natural products NC(C(O)c1ccc(Oc2cc(cc(Oc3ccc(cc3Cl)C(O)C(N)C(=O)O)c2O)C(N)C(=O)O)c(Cl)c1)C(=O)O WANYARLYVUSDSR-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound 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 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000003771 laboratory diagnosis Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 229950003104 rifamide Drugs 0.000 description 1
- VFYNXKZVOUXHDX-VDPUEHCXSA-N rifamycin b diethylamide Chemical compound CC1=C(O)C(C=2O)=C3C(OCC(=O)N(CC)CC)=CC=2NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]2(C)OC1=C3C2=O VFYNXKZVOUXHDX-VDPUEHCXSA-N 0.000 description 1
- 229940062280 rifamycin sodium Drugs 0.000 description 1
- 229940109171 rifamycin sv Drugs 0.000 description 1
- 229960002599 rifapentine Drugs 0.000 description 1
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 description 1
- 229960003040 rifaximin Drugs 0.000 description 1
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
Definitions
- the present invention relates to synergistic, antimicrobial pharmaceutical compositions and uses thereof for the treatment or prevention of Pseudomonas infections. More particularly the invention relates to synergistic, antimicrobial pharmaceutical compositions for the treatment or prevention of Pseudomonas infections containing a bismuth salt and as an antibiotic agent either a rifamycin antibiotic, a sulfonamide, vancomycin or fusidic acid or pharmaceutically or veterinariiy acceptable salt thereof.
- antimicrobial agents are subject of continuing research, much of which, in addition to the discovery of new agents, is directed to the discovery of means for the enhancement of the activity of known active agents.
- Pseudomonas spp. are quite apathogenic to humans, they are very important in causing opportunistic infections particularly in hospitalized patients with severe underlaying illnesses.
- Ps. aeruginosa the most pathogenic member of this group, is often associated with infections related to injured skin of burned patients, wounds on legs and bedsores. It may also occur in otitis media and in infections of the eye, the joints and the urinary, genitourinary and respiratory tracts.
- Other infectious strains are Ps. fluoresc ⁇ ns, Ps. putida and Ps. cepacia.
- Ps. aeruginosa In domestic animals similar infections caused by Pseudomonas spp, mainly Ps. aeruginosa are relatively common. Ps. aeruginosa is an important ⁇ tiologic factor with Staphylococcus aureus in otitis externa in dogs. Mastitis of dairy cows caused by Ps. aeruginosa is often a serious life threatening disease where treatment alternatives are very few.
- Rifamycin antibiotics such as rifabutin, rifamide, rifamycin sodium, rifapentine, rifaximin and rifampicin are complex macrocyclic antibiotics based on natural products of Streptomyces mediterranei. They inhibit bacterial RNA synthesis by binding to DNA-dependent RNA poiymerase.
- Rifampicin (chemically 3-4(4-methylpiperazinylimino-methylidene)-rifamycin SV) is an extremely efficient inhibitor of the bacterial enzyme. It inhibits the growth of most gram-positive bacteria, as well as many gram-negative microorganisms and mycobacteria. Although rifamycin antibiotic agents have quite broad spectrum anti-microbial activity, they lack the desired activity against Pseudomonas.
- Rifampicin is readily absorbed from the gastrointestinal tract. After a single oral dose of 600 mg plasma peak concentrations of 7 to 9 ⁇ g/ml have been reported (Martindale, The Extra Pharmacopoeia, ed. by James E.F. Reynolds, 30th ed., The Pharmaceutical Press, London, 1993, p.199). On the other hand, the ratio of rifampicin concentration at the infection site e.g. in skin blisters to its concentration in serum is 1 :5 (Gerding, D.N. et al., 1991 , in
- Vancomycin is an amphoteric glycopeptide produced by Streptomyces orientalis. It inhibits the synthesis of bacterial cell wall by inhibiting the peptidoglycan synthesis inside the bacterial cell. Vancomycin is active only against Gram-positive organisms, notably staphylococci, including ⁇ -lactamase-producing and methicillin-resistant strains, and streptococci.
- Sulphonamides such as sulphadiazine and sulphafurazole, act as inhibitors of folic acid synthesis. They are active against a broad spectrum of bacteria. For example group A streptococci, pneumococci and Neisseria are highly susceptible and staphylococci moderately so. Pseudomonas aeruginosa, however, is usually resistant.
- Fusidic acid is a steroidal antibiotic produced by the growth of certain strains of Fusidium coccineum. It inhibits bacterial protein synthesis by binding to elongation factor G which is necessary for translocation. Fusidic acid and its salts have been used successiveively in the treatment of staphylococcal infections in human and veterinary medicine especially topically in eye infections and infections of the skin. Fusidic acid and its salts however lack the desired activity against Pseudomonas.
- Ps. aeruginosa R Bismuth salts such as subsalicylate and subcitrate have been demonstrated to have antibacterial action against some microorganisms, for example Clostridium difficile and Helicobacter pylori (Cornick, N. A. et al.; Reviews of Infectious Diseases, 1990, 12 (suppl. 1), s9 - s10 and Lee S.P.; Scand J. Gastroenterol., 1991 , 26 (suppl. 185), 1 - 6). The mechanism of this antibacterial activity is not known.
- beta- lactam antibiotics the bacterial cell wall
- aminogiycosides protein synthesis by binding to the bacterial ribosome
- rifamycin antibiotics nucleic acid synthesis
- vancomycin peptidoglycan synthesis
- sulfoanamides folic acid synthesis
- fusidic acid and its salts protein synthesis by inhibiting transiocation
- the activity of rifamycin antibiotics, vancomycin, sulfonamides and/or fusidic acid and its pharmacologically or veterinarily acceptaple salts against Pseudomonas are enhanced by combining a bismuth salt with a rifamycin antibiotic, vancomycin, a sulfonamide or fusidic acid or its pharmacologically or veterinarily acceptaple salt.
- the present invention also provides a synergistic antimicrobial pharmaceutical composition containing a bismuth salt and a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or pharmacologically or veterinarily acceptable salt thereof.
- the present invention provides an antimicrobial pharmaceutical o composition
- a bismuth salt and a rifamycin antibiotic or a bismuth salt and vancomycin or a bismuth salt and a suifonamide or a bismuth salt and fusidic acid or its pharmacologically or veterinarily acceptable salt in an amount having a synergistic effect against Pseudomonas spp.
- compositions according to the invention include for 5 example granulates, tablets, capsules, dragees, powders, sprays, ointments, gels, emulsions, suspensions and infusions (solutions) and can be administered for example orally, rectally or topically. Both agents are preferably administered concurrently, but the pharmaceutical effect of the present composition will be present if both agents exist concurrently for a 0 certain duration in the body, particularly at the infection site. So, the bismuth salt can be administered separately from or simultaneously with the antibiotic agent. These two agents can be administered via different routes, for example antibiotic agent orally and bismuth salt topically.
- compositions according to the invention may be 5 formulated and employed in the usual manner.
- compositions are particularly well-suited for ophthalmic, otic or topical uses (gels, ointments, powders, sprays and aqueous or oily emulsions and suspensions) but could also find other applications.
- topical use of bismuth salts is preferred. Systemic treatment of infections with bismuth o salts is not recommended because of the possibility of serious side effects.
- Enhancement of the antibacterial activity of rifamycin antibiotics, vancomycin, sulfonamides and fusidic acid and its pharmaceutically or veterinarily acceptable salt in the treatment of Pseudomonas infections is one of the advantages achieved with the combined use of a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or veterinarily acceptable salt and a bismuth salt.
- rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or o veterinarily acceptable salt and a bismuth salt When a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or o veterinarily acceptable salt and a bismuth salt are used together, they produce a synergistic effect which permits a reduction in the dosage of one or both drugs with achievement of a similar therapeutic effect and the combination produces a more rapid or complete bactericidal effect than could be achieved with either drug alone.
- compositions according to the present invention are applicable also in the treatment of certain infections caused by either Staphylococcus or Pseudomonas such as hospital infections which in many instances are extremely resistant to antibiotics.
- the most common hospital infections are the urinary tract and wound infections where the causative 0 agent is often Ps. aeruginosa or S. aureus. Because of the possibility that these two bacteria are simultaneously present in the infection site, the use of the present combination is especially advantageous for the treatment of this kind of infections.
- otitis externa 5 which is often caused by Ps. aeruginosa or S. aureus. Because of the difficulty of reliable laboratory diagnosis it is advantageous to treat the infection with the present combination which has a good effect on both types of bacteria.
- the pharmaceutical composition of the present invention exhibit o synergistic antimicrobial activity against Pseudomonas. It has been found that in order to obtain the desired synergistic antimicrobial activity in accordance with the present invention the ratio (by weight) of rifampicin to bismuth subcitrate should be in the range of 1 :1.6 to 1 : 13333, preferably 1 :25 to 1 :200, the ratio (by weight) of vancomycin to bismuth subcitrate should be in 5 the range of 1 :444 to 10:1 , preferably 1 :6 to 1 :2, the ratio (by weight) of sulphadiazine to bismuth subcitrate should be in the range of 1 :2162 to 1:2, preferably 1 :34 to 1 :42 and the ratio (by weight) of sodium fusidate to bismuth subcitrate should be in the range of 1 :512 to 64:1 , preferably 1 :2 to 4:1.
- (1g BiC contains about 185 mg
- the preferred bismuth salt used in accordance with the present 5 invention is bismuth subcitrate.
- Other bismuth salts which may be used include bismuth subnitrate, bismuth subsalicylate.
- Rifampicin (R ' rf) stock solution was prepared daily in absolute methanol 20 and appropriately diluted with Mueller-Hinton broth.
- Bismuth subcitrate (BiC) powder was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
- the MICs ( ⁇ g/ml) of bismuth subcitrate and rifampicin and FIC-indexes at the range of synergism in addition to the lowest MlC-values of rifampicin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of rifampicin/bismuth subcitrate at o the observed range of synergism are presented in table 1.
- ATCC-43390 1600 32 0.25 - 0.37 0.125/800 1 :400 - 1 :1.6
- the MIC of rifampicin for Pseudomonas strain EK 81 was determined as above in example 1 but having in the wells of each tray 50, 100, 200, 400 or 800 ⁇ g/ml bismuth subcitrate.
- ATCC American Type Culture Collection
- EK Cold of Veterinary Medicine, Helsinki, Finland
- This strain was choked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
- Vancomycin (Va) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily.
- Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
- Pseudomonas aeruginosa strains were cultivated and the MIC- and
- FlC-values were determined as described in example 1.
- the MICs ( ⁇ g/ml) of bismuth subcitrate and vancomycin and FIC- indexes at the range of synergism in addition to the lowest MlC-values of vancomycin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of vancomycin/ bismuth subcitrate at the observed range of synergism are presented in table 3.
- the lowest MIC of vancomycin when combined with bismuth subcitrate was 1.8 ⁇ g/ml. This was 5 obtained when the concentration of bismuth subcitrate was 800 ⁇ g/ml.
- MlC-values of vancomycin were compared with the respective values of vancomycin with bismuth subcitrate, 8 to 278 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
- the ratio of vancomycin to bismuth subcitrate varied between 1:444 to 10:1 at the observed range of 0 synergism. The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
- vancomycin is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of 5 Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of vancomycin and bismuth subcitrate is advantageous.
- ATCC-27853 >6400 >500 0.27 - 0.46 31.25/400 1:12.5-10:1
- ATCC- 14210 6400 >500 0.07 - 0.25 31.25/1600 1:51 -10:1
- ATCC- 15692 3200 >500 0.125-0.16 31.25/400 1:13-5:1
- Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
- Sulphadiazine (SDZ) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily.
- Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above.
- the poor solubility of other bismuth salts prevented their testing. Further, because of the complexity of the synergy assay, only sulphadiazine was chosen for testing.
- Pseudomonas aeruginosa strains were cultivated and the MIC- and FlC-vaiues determined as decribed in example 1.
- the MICs ( ⁇ g/ml) of bismuth subcitrate and sulphadiazine and FIC- indexes at the range of synergism in addition t ⁇ the lowest MlC-values of sulphadiazine when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sulphadiazine/ bismuth subcitrate at the observed range of synergism are presented in table 4.
- the lowest MIC of sulphadiazine when combined with bismuth subcitrate was 0.74 ⁇ g/ml. This was obtained when the concentration of bismuth subcitrate was 1600 ⁇ g/mi.
- MlC-values of sulphadiazine were compared with the respective values of sulphadiazine with bismuth subcitrate, 32 to 270 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
- the ratio of sulphadiazine to bismuth subcitrate varied between 1 :2162 to 1 :2 at the observed range of synergism.
- concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
- ATCC- 14204 6400 400 0.02 • 0.25 1.48/1600 1 :42 - 1 :1081
- ATCC-9027 6400 95 0.01 - 0.13 1.48/25 1 :18 - 1 :1081
- Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
- Sodium fusidate (SF) stock solution was prepared daily in distilled water and appropriately diluted with Mueller-Hinton broth.
- Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
- the MICs ( ⁇ g/ml) of bismuth subcitrate and sodium fusidate and FIC- indexes at the range of synergism in addition to the lowest MlC-values of 5 sodium fusidate when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sodium fusidate/ bismuth subcitrate at the observed range of synergism are presented in table 5.
- the lowest MIC of sodium fusidate when combined with bismuth subcitrate was 3.6 ⁇ g/m. This was obtained when the concentration of bismuth subcitrate was 800 ⁇ g/ml.
- MlC-values of sodium fusidate were compared with the respective values of sodium fusidate with bismuth 0 subcitrate, 8 to 444 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
- the ratio of sodium fusidate to bismuth subcitrate varied between 1 :512 to 64:1 at the observed range of synergism. The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
- ATCC-9027 6400 6400 0.03 - 0.26 50/1600 1 :32 - 8:1
- the MlC-values of sodium fusidate for three Pseudomonas aeruginosa strains were determined as above in example 5 but having in the wells of each tray 50, 100, 200, 400 or 800 ⁇ g/ml bismuth subcitrate.
- the MlC-values of sodium fusidate and bismuth subcitrate for the strains used in this experiment are: Strain MIC SF ⁇ g/ml MIC BiC ⁇ g/ml
- a gel formulation according to the present invention is prepared by combining rifampicin (0.001 - 0.1 %) and bismuth subcitrate (0.1 -0.5 %) with a suitable gel base containing for example a carboxyvinyl polymer as a gel former.
- An ophtalmic formulation according to the present invention is prepared by combining sodium fusidate (0.01 - 0.1 %), bismuth subcitrate (0.1 - 0.5 %) and other necessary ingredients with an aqueous phosphate buffer solution.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A synergistic, antimicrobial pharmaceutical composition for the treatment or prevention of Pseudomonas infections contains a bismuth salt and as an antibiotic agent either a rifamycin antibiotic or fusidic acid or its pharmaceutically or veterinarily acceptable salt.
Description
SYNERGISTIC ANTIMICROBIAL COMPOSITION
TECHNICAL FIELD OF THE INVENTION
The present invention relates to synergistic, antimicrobial pharmaceutical compositions and uses thereof for the treatment or prevention of Pseudomonas infections. More particularly the invention relates to synergistic, antimicrobial pharmaceutical compositions for the treatment or prevention of Pseudomonas infections containing a bismuth salt and as an antibiotic agent either a rifamycin antibiotic, a sulfonamide, vancomycin or fusidic acid or pharmaceutically or veterinariiy acceptable salt thereof.
BACKGROUND OF THE INVENTION
The use of antimicrobial agents is a subject of continuing research, much of which, in addition to the discovery of new agents, is directed to the discovery of means for the enhancement of the activity of known active agents.
Although Pseudomonas spp. are quite apathogenic to humans, they are very important in causing opportunistic infections particularly in hospitalized patients with severe underlaying illnesses. Ps. aeruginosa, the most pathogenic member of this group, is often associated with infections related to injured skin of burned patients, wounds on legs and bedsores. It may also occur in otitis media and in infections of the eye, the joints and the urinary, genitourinary and respiratory tracts. Other infectious strains are Ps. fluorescβns, Ps. putida and Ps. cepacia.
In domestic animals similar infections caused by Pseudomonas spp, mainly Ps. aeruginosa are relatively common. Ps. aeruginosa is an important θtiologic factor with Staphylococcus aureus in otitis externa in dogs. Mastitis of dairy cows caused by Ps. aeruginosa is often a serious life threatening disease where treatment alternatives are very few.
Because Pseudomonas are naturally very resistant to antibiotics and further, mutations and R-factors make them even more resistant, only few antibiotic agents are effective in the treatment of Pseudomonas infections.
Some new semisynthetic penicillins, cefalosporins and aminoglygosides are
2
currently used in the therapy of Pseudomonas infections and combined use of two anti-microbial agents is preferred in severe infections.
Rifamycin antibiotics, such as rifabutin, rifamide, rifamycin sodium, rifapentine, rifaximin and rifampicin are complex macrocyclic antibiotics based on natural products of Streptomyces mediterranei. They inhibit bacterial RNA synthesis by binding to DNA-dependent RNA poiymerase. Rifampicin (chemically 3-4(4-methylpiperazinylimino-methylidene)-rifamycin SV) is an extremely efficient inhibitor of the bacterial enzyme. It inhibits the growth of most gram-positive bacteria, as well as many gram-negative microorganisms and mycobacteria. Although rifamycin antibiotic agents have quite broad spectrum anti-microbial activity, they lack the desired activity against Pseudomonas.
The activity of rifampicin against some common pathogenic bacteria (MlC:mg/l) is presented below (Antibiotic and Chemotherapy, 1992, 6th edition, edited by Lambert, H.P. and O'Grady F.W., Churchill Livingstone, Great Britain).
Staph. aureus 0.008-0.06
Strep, pyogenes 0.03-0.1
Strep, pneumoniae 0.06-4
M. tuberculosis 0.1-1
H. influenzae 0.5-1
E. coli 8-16
Salmonella 8-16
Ps. aeruginosa 32-64
Rifampicin is readily absorbed from the gastrointestinal tract. After a single oral dose of 600 mg plasma peak concentrations of 7 to 9 μg/ml have been reported (Martindale, The Extra Pharmacopoeia, ed. by James E.F. Reynolds, 30th ed., The Pharmaceutical Press, London, 1993, p.199). On the other hand, the ratio of rifampicin concentration at the infection site e.g. in skin blisters to its concentration in serum is 1 :5 (Gerding, D.N. et al., 1991 , in
Antibiotics in Laboratory Medicine, edited by V. Lorian, Williams & Wilkins. Baltimore, Maryland, USA). So, by administering rifampicin doses sufficiently high to give a microbiologically active (> MIC) concentration against Ps. aeruginosa e.g. in skin blisters serious adverse effects of overdosage, for example hepatic and hematological abnormalities, are likely to occur.
Vancomycin is an amphoteric glycopeptide produced by Streptomyces orientalis. It inhibits the synthesis of bacterial cell wall by inhibiting the peptidoglycan synthesis inside the bacterial cell. Vancomycin is active only
against Gram-positive organisms, notably staphylococci, including β-lactamase-producing and methicillin-resistant strains, and streptococci.
The susceptibility of some pathogenic bacteria to vancomycin (MIC:mg/l) is presented below (Antibiotic and Chemotherapy, 1992, 6th edition, edited by Lambert, H.P. and O'Grady F.W., Churchill Livingstone, Great Britain).
Staph. aureus 0.25-4
Staph. epidermis 0.25-8
Strep, pneumoniae 0.25-1
E. faecalis 0.25-4
C. difficile <0.1-0.5
Enterobacteria R
Ps. aeruginosa R
Sulphonamides such as sulphadiazine and sulphafurazole, act as inhibitors of folic acid synthesis. They are active against a broad spectrum of bacteria. For example group A streptococci, pneumococci and Neisseria are highly susceptible and staphylococci moderately so. Pseudomonas aeruginosa, however, is usually resistant.
Fusidic acid is a steroidal antibiotic produced by the growth of certain strains of Fusidium coccineum. It inhibits bacterial protein synthesis by binding to elongation factor G which is necessary for translocation. Fusidic acid and its salts have been used succesively in the treatment of staphylococcal infections in human and veterinary medicine especially topically in eye infections and infections of the skin. Fusidic acid and its salts however lack the desired activity against Pseudomonas.
The activity of sodium fusidate against some common pathogenic bacteria (MIC:mg/l) is presented below (Antibiotic and Chemotherapy, 1992, 6th edition, edited by Lambert, H.P. and O'Grady F.W., Churchill Livingstone, Great Britain).
Staph. aureus 0.03 - 0.1
Strep, pyogenes 4 - 16
Strep, pneumoniae 2 - 16
M. meningitidis 0.06 - 0.25
Enterobacteria R
Ps. aeruginosa R
Bismuth salts such as subsalicylate and subcitrate have been demonstrated to have antibacterial action against some microorganisms, for example Clostridium difficile and Helicobacter pylori (Cornick, N. A. et al.; Reviews of Infectious Diseases, 1990, 12 (suppl. 1), s9 - s10 and Lee S.P.; Scand J. Gastroenterol., 1991 , 26 (suppl. 185), 1 - 6). The mechanism of this antibacterial activity is not known. It has been suggested that bismuth disrupts bacterial cell integrity causing leakage of intracellular components or displaces magnesium ions, that are important to the integrity of the gram- negative outer membrane, thereby destabilizing the permeability barrier, and enhancing antibiotic permeation (Domenico et al.; Jounal of Antimicrobial Chemotherapy, 1991 , 28, 801-810).
In vitro synergistic activity of the combination of bismuth subcitrate and rifampicin against Helicobacter pylon has been demostrated. (D.L. Van Caekenberghe, J. Breyssens; Antimicrobial Agents and Chemotherapy, 1987, 31/9: 1429-1430). Further, the influence of bismuth subsalicylate and bismuth subnitrate on the antibiotic action of aminogiycosides and some beta-lactam antibiotics against Pseudomonas aeruginosa have been studied (Domenico et al., 1992, Eur. J. Clin. Microbiol. Infect. Dis., 11 : 170-174). However, beta- lactam antibiotics (the bacterial cell wall), aminogiycosides (protein synthesis by binding to the bacterial ribosome), rifamycin antibiotics (nucleic acid synthesis), vancomycin (peptidoglycan synthesis), sulfoanamides (folic acid synthesis) and fusidic acid and its salts (protein synthesis by inhibiting transiocation) differ functionally and structurally from each other. Further, it has also been shown that the antibacterial activity of some antibiotics (e.g. cefoperazone, imipenem and mezlocillin) against Ps. aeruginosa is decreased by bismuth salts (Domenico et al., 1992, Eur. J. Clin. Microbiol. Infect. Dis., 1 : 170-174). Thus, results with one antibiotic cannot be applied to another antibiotic belonging to structurally and/or functionally different group.
DISCLOSURE OF THE INVENTION
In accordance with the present invention the activity of rifamycin antibiotics, vancomycin, sulfonamides and/or fusidic acid and its pharmacologically or veterinarily acceptaple salts against Pseudomonas are enhanced by combining a bismuth salt with a rifamycin antibiotic, vancomycin, a sulfonamide or fusidic acid or its pharmacologically or veterinarily acceptaple salt. The present invention also provides a synergistic antimicrobial pharmaceutical composition containing a bismuth salt and a
rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or pharmacologically or veterinarily acceptable salt thereof.
When bismuth subcitrate was combined with rifampicin or with vancomycin or with sulphadiazine or with sodium fusidate, it was found that the presence of the bismuth salt enhanced the antimicrobial activity of the antibiotic agent against Pseudomonas to an unexpected extent and because of this high-level synergistic action, the effective doses of these substances could be decreased noticeably.
Thus, the present invention provides an antimicrobial pharmaceutical o composition comprising a bismuth salt and a rifamycin antibiotic or a bismuth salt and vancomycin or a bismuth salt and a suifonamide or a bismuth salt and fusidic acid or its pharmacologically or veterinarily acceptable salt, in an amount having a synergistic effect against Pseudomonas spp.
The pharmaceutical compositions according to the invention include for 5 example granulates, tablets, capsules, dragees, powders, sprays, ointments, gels, emulsions, suspensions and infusions (solutions) and can be administered for example orally, rectally or topically. Both agents are preferably administered concurrently, but the pharmaceutical effect of the present composition will be present if both agents exist concurrently for a 0 certain duration in the body, particularly at the infection site. So, the bismuth salt can be administered separately from or simultaneously with the antibiotic agent. These two agents can be administered via different routes, for example antibiotic agent orally and bismuth salt topically.
The pharmaceutical compositions according to the invention may be 5 formulated and employed in the usual manner.
These compositions are particularly well-suited for ophthalmic, otic or topical uses (gels, ointments, powders, sprays and aqueous or oily emulsions and suspensions) but could also find other applications. However, topical use of bismuth salts is preferred. Systemic treatment of infections with bismuth o salts is not recommended because of the possibility of serious side effects.
Nausea and vomiting as well as darkening of the tongue have been reported. Further, the possibility of bismuth encephalopathy exists after prolonged use. (Martindale, The Extra Pharmacopoeia, ed. by James E.F. Reynolds, 30th ed. The Pharmaceutical Press, London, 1993, p. 909).
The pharmaceutical compositions containing the synergistic active combination may also be used in veterinary medicine.
Enhancement of the antibacterial activity of rifamycin antibiotics, vancomycin, sulfonamides and fusidic acid and its pharmaceutically or veterinarily acceptable salt in the treatment of Pseudomonas infections is one of the advantages achieved with the combined use of a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or veterinarily acceptable salt and a bismuth salt. When a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or o veterinarily acceptable salt and a bismuth salt are used together, they produce a synergistic effect which permits a reduction in the dosage of one or both drugs with achievement of a similar therapeutic effect and the combination produces a more rapid or complete bactericidal effect than could be achieved with either drug alone.
5 Further, the compositions according to the present invention are applicable also in the treatment of certain infections caused by either Staphylococcus or Pseudomonas such as hospital infections which in many instances are extremely resistant to antibiotics. The most common hospital infections are the urinary tract and wound infections where the causative 0 agent is often Ps. aeruginosa or S. aureus. Because of the possibility that these two bacteria are simultaneously present in the infection site, the use of the present combination is especially advantageous for the treatment of this kind of infections.
In veterinary clinical praxis a common disease in dogs is otitis externa 5 which is often caused by Ps. aeruginosa or S. aureus. Because of the difficulty of reliable laboratory diagnosis it is advantageous to treat the infection with the present combination which has a good effect on both types of bacteria.
The pharmaceutical composition of the present invention exhibit o synergistic antimicrobial activity against Pseudomonas. It has been found that in order to obtain the desired synergistic antimicrobial activity in accordance with the present invention the ratio (by weight) of rifampicin to bismuth subcitrate should be in the range of 1 :1.6 to 1 : 13333, preferably 1 :25 to 1 :200, the ratio (by weight) of vancomycin to bismuth subcitrate should be in 5 the range of 1 :444 to 10:1 , preferably 1 :6 to 1 :2, the ratio (by weight) of sulphadiazine to bismuth subcitrate should be in the range of 1 :2162 to 1:2,
preferably 1 :34 to 1 :42 and the ratio (by weight) of sodium fusidate to bismuth subcitrate should be in the range of 1 :512 to 64:1 , preferably 1 :2 to 4:1. (1g BiC contains about 185 mg Bi).
The preferred bismuth salt used in accordance with the present 5 invention is bismuth subcitrate. Other bismuth salts which may be used include bismuth subnitrate, bismuth subsalicylate.
The following examples are presented to further illustrate the present invention. They should not be interpreted as limiting the scope of the invention in any way.
ι o EXA PLE 1
Svnerqv study and the enhancement of the antibacterial activity of rifampicin with bismuth subcitrate
Eight Pseudomonas aeruginosa strains were used in the experiment. Five were ATCC (American Type Culture Collection) strains isolated from 1 5 human infections and three were EK (College of Veterinary Medicine,
Helsinki, Finland) strains originated from animal infections. These EK-strains were cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
Rifampicin (R'rf) stock solution was prepared daily in absolute methanol 20 and appropriately diluted with Mueller-Hinton broth. Bismuth subcitrate (BiC) powder was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
After initial cultivation on blood agar at 37 °C typical colonies of the strain to be studied were transferred to Mueller-Hinton broth and incubated
25 20 h at 37 °C. A 10 -3 dilution of the culture with Mueller-Hinton broth was used for the determination of the minimum inhibitory concentration (MIC) by the standard microdilution broth procedure (Amterdam, D.; 1991, Susceptibility Testing of Antimicrobials in Liquid Media. In Antibiotics in Laboratory Medicine, 3th edition, ed. by V. Lorian. Williams & Wilkins,
30 Baltimore, Maryland, USA, pp. 53-105). A 10 "3 dilution of the culture with Mueller-Hinton broth was used also for the synergism studies by the checker board microtiter tray method (G.M. Eliopoulos and R. C. Moellering Jr., 1991. Antimicrobial combinations. In Antibiotics in Laboratory Medicine, 3th edition, ed. by V. Lorian. Williams & Wilkins, Baltimore, Maryland, USA, pp. 432-492).
Synergy was quaπtitatθd by calculating fractional inhibitory concentration index (FIC index) as decribed by Eliopoulos and Moellering. With this method synergy is defined as a FIC index of ≤ 0.5.
Because of the complexity of the synergy assay, only rifampicin was chosen for testing.
The MICs (μg/ml) of bismuth subcitrate and rifampicin and FIC-indexes at the range of synergism in addition to the lowest MlC-values of rifampicin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of rifampicin/bismuth subcitrate at o the observed range of synergism are presented in table 1.
The results in table 1 show that the MlC-values of rifampicin for the tested eight Pseudomonas strains which varied from 8 μg/ml to 32 μg/ml decreased with the presence of bismuth subcitrate to 0.06 - 1 μg/ml. The FIC- indexes were in the range of 0.13 - 0.37 indicating synergism. Further, the 5 obtained FIC-indexes did not indicate indifference or antagonism between rifampicin and bismuth subcitrate. The lowest MIC of rifampicin when combined with bismuth subcitrate was 0.06 μg/ml. This was obtained when bismuth subcitrate concentration was 800 μg/ml. When the MlC-values of rifampicin were compared with the respective values of rifampicin with 0 bismuth subcitrate, 16 to 266 fold increase in the sensitivity of Ps. aeruginosa strains was observed. The ratio of rifampicin to bismuth subcitrate varied between 1 : 13333 - 1 :1.6 at the observed range of synergism. The concentrations of bismuth subcitrate necessary for synergism were far below the corresponding MICs of bismuth subcitrate for the microbes.
5 The present study shows that rifampicin is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of rifampicin and bismuth o subcitrate is advantageous. The results further suggest that in order to achieve synergism against Pseudomonas with rifampicin/bismuth subcitrate mixtures, the concentration of bismuth subcitrate should be higher than the corresponding concentration of rifampicin.
Table t
Strain MIC of BiC MIC of Rif FIC-index at The lowest MIC of Rif Rif /BiC ratios at μg/ml μg/ml the range of with BiC and the the observed synergism corresponding BiC range of concentration μg/ml synergism
ATCC-10145 800 16 0.25 - 0.31 1/200 1 :200 - 1:3
ATCC-14210 6400 16 0.25 - 0.31 0.25/3200 1 :1600 - 1 :25
ATCC- 15692 3200 16 0.16 - 0.27 0.125/1600 1 :3200 - 1 :50
ATCC- 19660 1600 16 0.28 - 0.37 0.125/800 1 :800 - 1:12
ATCC-43390 1600 32 0.25 - 0.37 0.125/800 1 :400 - 1 :1.6
EK-81 > 3200 16 0.25 - 0.37 0.06/800 1 :13333 - 1:3
EK-163 6400 8 0.13 - 0.34 0.06/800 1 :13333- 1 :25
EK-168 > 3200 16 0.25 - 0.37 0.06/800 1 :13333- 1 :6
EXAMPLE 2
Dose response study with rifampicin and bismuth subcitrate
In the study on the possible dose response relationship of the bismuth subcitrate with the sensitivity of Pseudomonas aeruginosa to rifampicin, the MIC of rifampicin for Pseudomonas strain EK 81 was determined as above in example 1 but having in the wells of each tray 50, 100, 200, 400 or 800 μg/ml bismuth subcitrate.
The concentration dependent effect of bismuth subcitrate on the sensitivity of Ps. aeruginosa strain EK-81 to rifampicin is presented in table 2. The MlC-values of rifampicin were determined by the standard microdilution broth procedure.
The results in table 2 show that bismuth subcitrate increased in dose dependent manner the sensitivity of Ps. aueruginosa EK-81 to rifampicin. Without the presence of bismuth subcitrate the MIC-value of rifampicin for strain EK-81 was 16 μg/ml but with bismuth subcitrate concentration of 800 μg/ml the MIC-value was found to be 0.06 μg/ml. Further, even a relatively low concentration of bismuth subcitrate enhanced considerably the activity of
rifampicin against Ps. aeruginosa. The MIC of bismuth subcitrate for Ps. aeruginosa EK-81 was >3200 μg/ml.
Table 2.
BiC μg/ml MIC Rif μg/ml
0 16
50 2
100 1
200 1
400 0.125
800 0.062
EXAMPLE 3
Svnergv study and the enhancement of the antibacterial activity of vancomycin with bismuth subcitrate
Eight Pseudomonas aeruginosa strains were used in the experiment.
Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was choked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
Vancomycin (Va) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily. Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
Pseudomonas aeruginosa strains were cultivated and the MIC- and
FlC-values were determined as described in example 1.
The MICs (μg/ml) of bismuth subcitrate and vancomycin and FIC- indexes at the range of synergism in addition to the lowest MlC-values of vancomycin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of vancomycin/ bismuth subcitrate at the observed range of synergism are presented in table 3.
The results in table 3 show that the tested Pseudomonas aeruginosa strains were quite resistant to vancomycin as well as to bismuth subcitrate. The MIC-value of vancomycin for the tested strains which varied from o 500 μg/ml to 1000 μg/ml decreased with the presence of bismuth subcitrate to 1.8 - 62.5 μg/ml. The FIC-indexes were in the range of 0.06 - 0.5 indicating synergism. Further, the obtained FIC-indexes did not indicate antagonism or indifference between vancomycin and bismuth subcitrate. The lowest MIC of vancomycin when combined with bismuth subcitrate was 1.8 μg/ml. This was 5 obtained when the concentration of bismuth subcitrate was 800 μg/ml. When the MlC-values of vancomycin were compared with the respective values of vancomycin with bismuth subcitrate, 8 to 278 fold increase in the sensitivity of Ps. aeruginosa strains was observed. The ratio of vancomycin to bismuth subcitrate varied between 1:444 to 10:1 at the observed range of 0 synergism.The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
The present study shows that vancomycin is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of 5 Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of vancomycin and bismuth subcitrate is advantageous.
Table 3.
Strain MIC of BiC MICofVa FIC-index at The lowest MIC of Va Va/BiC ratios at μg/ml μg/ml the range of with BiC and the the observed synergism corresponding BiC range of concentration μg/ml synergism
ATCC-27853 >6400 >500 0.27 - 0.46 31.25/400 1:12.5-10:1
ATCC- 14204 6400 1000 0.11 -0.14 12.5/800 1:64-8:1
ATCC- 14210 6400 >500 0.07 - 0.25 31.25/1600 1:51 -10:1
ATCC- 15692 3200 >500 0.125-0.16 31.25/400 1:13-5:1
ATCC- 19660 1600 500 0.28 - 0.5 62.5/400 1:6-1:1.6
ATCC-10145 800 500 0.15-0.375 62.5/400 1:6-5:1
ATCC-9027 6400 500 0.13-0.19 1.8/800 1 :444 - 12
EK-81 >3200 1000 0.06-0.13 7.8/800 1:102- 1:1
EXAMPLE 4
Svnerφv study and the enhancement of the antibacterial activity of sulDhadiazine with bismuth subcitrate
Eight Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
Sulphadiazine (SDZ) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily. Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing. Further, because of the complexity of the synergy assay, only sulphadiazine was chosen for testing.
Pseudomonas aeruginosa strains were cultivated and the MIC- and FlC-vaiues determined as decribed in example 1.
The MICs (μg/ml) of bismuth subcitrate and sulphadiazine and FIC- indexes at the range of synergism in addition tϋ the lowest MlC-values of sulphadiazine when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sulphadiazine/ bismuth subcitrate at the observed range of synergism are presented in table 4.
The results in table 4 show that the tested Pseudomonas aeruginosa strains were quite resistant to sulphadiazine as well as to bismuth subcitrate. The MlC-values of sulphadiazine for the tested eight strains which varied from 95 μg/ml to 400 μg/ml decreased with the presence of bismuth subcitrate to 0.74 - 5.9 μg/ml. The FIC-indexes were in the range of 0.01 - 0.28 indicating synergism. Further, the obtained FIC-indexes did not indicate antagonism or indifference between sulphadiazine and bismuth subcitrate. The lowest MIC of sulphadiazine when combined with bismuth subcitrate was 0.74 μg/ml. This was obtained when the concentration of bismuth subcitrate was 1600 μg/mi. When the MlC-values of sulphadiazine were compared with the respective values of sulphadiazine with bismuth subcitrate, 32 to 270 fold increase in the sensitivity of Ps. aeruginosa strains was observed. The ratio of sulphadiazine to bismuth subcitrate varied between 1 :2162 to 1 :2 at the observed range of synergism.The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
The present study shows that sulphadiazine is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of
Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of sulphadiazine and bismuth subcitrate is advantageous.
Table 4.
Strain MIC of BiC MIC of FIC-index at The lowest MIC of SDZ/BiC ratios at μg nl SDZ the range of SDZ with BiC and the the observed μg/ml synergism corresponding BiC range of concentration μg/ml synergism
ATCC-27853 > 6400 380 0.25 - 0.28 1.48/25 1 :18 - 1 :1081
ATCC- 14204 6400 400 0.02 • 0.25 1.48/1600 1 :42 - 1 :1081
ATCC- 14210 6400 190 0.04 - 0.25 0.74/1600 1:2 - 1:2162
ATCC- 15692 3200 190 0.04 • 0.26 2.97/800 1 :4 - 1269
ATCC- 19660 1600 190 0.05 - 0.28 5.9/25 1 :4 - 1 :136
ATCC- 10145 800 400 0.06 - 026 5.9/200 1 -2 - 1 :34
ATCC-9027 6400 95 0.01 - 0.13 1.48/25 1 :18 - 1 :1081
EK-81 > 6400 200 0.03 - 0.26 1.48/1600 1 :42 - 1 :1081
EXAMPLE 5
Svnerαv study and the enhancement of the antibacterial activity of sodium fusidate with bismuth subcitrate
Eight Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
Sodium fusidate (SF) stock solution was prepared daily in distilled water and appropriately diluted with Mueller-Hinton broth. Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
Because of the complexity of the synergy assay, only sodium fusidate was chosen for testing.
Pseudomonas aeruginosa strains were cultivated and the MIC- and FlC-values were determined as described in example 1.
The MICs (μg/ml) of bismuth subcitrate and sodium fusidate and FIC- indexes at the range of synergism in addition to the lowest MlC-values of 5 sodium fusidate when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sodium fusidate/ bismuth subcitrate at the observed range of synergism are presented in table 5.
The results in table 5 show that the tested Pseudomonas aeruginosa o strains were quite resistant to sodium fusidate as well as to bismuth subcitrate. The MlC-values of sodium fusidate for the tested eight strains which varied from 1600 μg/ml to 6400 μg/ml decreased with the presence of bismuth subcitrate to 3.6 - 200 μg/ml. The FIC-indexes were in the range of 0.02 - 0.31 indicating synergism. Further, the obtained FIC-indexes did not indicate 5 antagonism or indifference between sodium fusidate and bismuth subcitrate.
The lowest MIC of sodium fusidate when combined with bismuth subcitrate was 3.6 μg/m. This was obtained when the concentration of bismuth subcitrate was 800 μg/ml. When the MlC-values of sodium fusidate were compared with the respective values of sodium fusidate with bismuth 0 subcitrate, 8 to 444 fold increase in the sensitivity of Ps. aeruginosa strains was observed. The ratio of sodium fusidate to bismuth subcitrate varied between 1 :512 to 64:1 at the observed range of synergism.The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
5 The present study shows that sodium fusidate is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of fusidic acid or its o pharmaceutically or veterinarily acceptable salt and bismuth subcitrate is advantageous.
Table 5.
Strain MIC of BiC MICof SF FIC-index at The lowest MIC of SF SF/BiC ratios at μg/ml μg/ml the range of with BiC and the the observed synergism corresponding BiC range of concentration μg/ml synergism
ATCC-27853 > 6400 1600 0.05 - 0.26 3.6/800 1 :512 - 4:1
ATCC- 14204 6400 1600 0.09 - 0.26 6.25/1600 1256 - 4:1
ATCC-14210 6400 >3200 0.14 - 0.19 50/1600 1256 - 4:1
ATCC-15692 3200 >3200 0.02 - 0.27 6.25/1600 1:16 - 8:1
ATCC- 19660 1600 1600 0.03 - 0.31 100/400 1:4 - 16:1
ATCC-10145 800 1600 0.14 - 0.31 100/200 12 - 64:1
ATCC-9027 6400 6400 0.03 - 0.26 50/1600 1 :32 - 8:1
EK-81 > 3200 1600 0.09 - 0.13 6.25/1600 1:512 - 4:1
EXAMPLE 6
Dose response study with sodium fusidate and bismuth subcitrate
In the study on the possible dose response relationship of the bismuth subcitrate with the sensitivity of Pseudomonas aeruginosa to sodium fusidate, the MlC-values of sodium fusidate for three Pseudomonas aeruginosa strains were determined as above in example 5 but having in the wells of each tray 50, 100, 200, 400 or 800 μg/ml bismuth subcitrate.
The effect of the increasing concentration of bismuth subcitrate on the MICs of sodium fusidate for strains ATCC 25004, ATCC 10145 and ATCC 14204 determined by the standard microdilution broth procedure are presented in table 6.
The results in table 6 show that bismuth subcitrate increased in dose dependent manner the sensitivity of the three Ps. aeruginosa strains to sodium fusidate. Further, even a relatively low concentration of BiC enhanced considerably the activity of sodium fusidate against Ps. aeruginosa and
increase in the sensitivity of Pseudomonas to sodium fusidate by bismuth subcitrate increases with increasing concentration of bismuth subcitrate.
The MlC-values of sodium fusidate and bismuth subcitrate for the strains used in this experiment are: Strain MIC SF μg/ml MIC BiC μg/ml
ATCC-25004 3200 6400
ATCC-10145 1600 800
ATCC-14204 1600 6400
Table 6.
BiC MIC of SF μg/ml μg/ml ATCC-25004 ATCC-10145 ATCC-14204
50 200 100 100
100 100 -
200 100 50 100
400 50 625 50
800 25 625
EXAMPLE 7,
A αel containing rifampicin and bismuth subcitrate for the treatment of wounds
A gel formulation according to the present invention is prepared by combining rifampicin (0.001 - 0.1 %) and bismuth subcitrate (0.1 -0.5 %) with a suitable gel base containing for example a carboxyvinyl polymer as a gel former.
EXAMPLE 8.
Eve drops containing sodium fusiriatβ and bismuth subcitrate
An ophtalmic formulation according to the present invention is prepared by combining sodium fusidate (0.01 - 0.1 %), bismuth subcitrate (0.1 - 0.5 %) and other necessary ingredients with an aqueous phosphate buffer solution.
Claims
1. A product which is an antimicrobial pharmaceutical composition 5 comprising (i) an antibiotic agent which is a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof and (ii) a bismuth salt for use in the treatment of a Pseudomonas infection.
2. A product comprising (i) an antibiotic agent which is a rifamycin o antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof and (ii) a bismuth salt as a combined preparation for simultaneous, separate or sequential use in the treatment of a Pseudomonas infection.
3. A product according to claim 1 or 2 wherein the bismuth salt is 5 bismuth subcitrate, bismuth subsalicylate or bismuth nitrate.
4. A product according to claim 3 wherein the bismuth salt is bismuth subcitrate.
0 5. A product according to any one of claims 1 to 4 wherein the antibiotic agent is rifampicin.
6. A product according to any one of claims 1 to 4 wherein the antibiotic agent is sodium fusidate. 5
7. A product according to any one of claims 1 to 4 wherein the antibiotic agent is sulphadiazine.
8. A product according to any one of claims 1 to 4 wherein the antibiotic o agent is vancomycin.
9. A product according to any one of claims 1 to 5 comprising a rifamycin antibiotic wherein the weight ratio of a rifamycin antibiotic to bismuth salt is in the range of from 1 :13333 to 1 :1.6 5
10. A product according to claim 6 wherein the weight ratio of sodium fusidate to bismuth salt is in the range of from 1 :512 to 64:1
11. A product according to claim 7 wherein the weight ratio of sulphadiazine to bismuth salt is in the range of from 1 :2162 to 1 :2.
5 12. A product according to claim 8 wherein the weight ratio of vancomycin to bismuth salt is in the range of from 1 :444 to 10:1.
13. A product according to any one of claims 1 to 12 wherein the bismuth salt is in a form suitable for administration simultaneously with the antibiotic o agent.
14. A product according to any one of claims 1 to 12 wherein the bismuth salt is in a form suitable for administration separately from the antibiotic agent.
5 15. Use of a bismuth salt and an antibiotic agent which is a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof in the manufacture of a medicament for use in the treatment of a Pseudomonas infection.
0 16. A method of treatment or prevention of a Pseudomonas infection comprising administering to a subject an effective amount of an antibiotic agent which is a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof and an effective amount of a bismuth salt. 5
17. A pharmaceutical or veterinary formulation comprising as active ingredients an antibiotic agent which is a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof, and a bismuth salt formulated for pharmaceutical or veterinary o use respectively.
18. Use of a bismuth salt to enhance the antimicrobial activity of an antibiotic agent which is a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or a pharmaceutically or veterinarily acceptable salt thereof 5 against Pseudomonas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU33885/95A AU3388595A (en) | 1994-09-12 | 1995-09-12 | Synergistic antimicrobial composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9418346.4 | 1994-09-12 | ||
| GB9418346A GB2293323A (en) | 1994-09-12 | 1994-09-12 | Antibiotics and bismuth salts for treating bacterial infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996008259A1 true WO1996008259A1 (en) | 1996-03-21 |
Family
ID=10761199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FI1995/000494 WO1996008259A1 (en) | 1994-09-12 | 1995-09-12 | Synergistic antimicrobial composition |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3388595A (en) |
| GB (1) | GB2293323A (en) |
| WO (1) | WO1996008259A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6362169B1 (en) * | 1998-02-24 | 2002-03-26 | Kaneka Corporation | Antibacterial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith |
| US10201518B2 (en) | 2016-09-28 | 2019-02-12 | The University Of Hong Kong | Bismuth(III) compounds and methods thereof |
| WO2023063827A1 (en) * | 2021-10-15 | 2023-04-20 | Omnicin Therapeutics B.V. | Synergistic composition against pseudomonas aeruginosa |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987007842A1 (en) * | 1986-06-17 | 1987-12-30 | Biogen N.V. | Combinations of gamma interferons and anti-inflammatory or anti-pyretic agents and methods for treating diseases |
| WO1994018968A1 (en) * | 1993-02-18 | 1994-09-01 | President And Fellows Of Harvard College | Methods for treating arteriosclerosis |
| WO1994018967A1 (en) * | 1993-02-18 | 1994-09-01 | President And Fellows Of Harvard College | Treatments for diseases characterized by neovascularization |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE318144T1 (en) * | 1985-06-13 | 2006-03-15 | Barry James Marshall | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF GASTROINTESTINAL CONDITIONS, CONTAINING BISMUT AND AN ANTIMICROBIAL AGENT |
| CN1057001A (en) * | 1991-07-13 | 1991-12-18 | 沈阳市红旗制药厂 | The preparation method of anti-enteritis capsule |
| CN1080529A (en) * | 1992-06-23 | 1994-01-12 | 沈阳市光华兽药厂 | The manufacture method of dysentery medicine (Salibao) |
-
1994
- 1994-09-12 GB GB9418346A patent/GB2293323A/en not_active Withdrawn
-
1995
- 1995-09-12 WO PCT/FI1995/000494 patent/WO1996008259A1/en active Application Filing
- 1995-09-12 AU AU33885/95A patent/AU3388595A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987007842A1 (en) * | 1986-06-17 | 1987-12-30 | Biogen N.V. | Combinations of gamma interferons and anti-inflammatory or anti-pyretic agents and methods for treating diseases |
| WO1994018968A1 (en) * | 1993-02-18 | 1994-09-01 | President And Fellows Of Harvard College | Methods for treating arteriosclerosis |
| WO1994018967A1 (en) * | 1993-02-18 | 1994-09-01 | President And Fellows Of Harvard College | Treatments for diseases characterized by neovascularization |
Non-Patent Citations (2)
| Title |
|---|
| ACTA PHARM.TURC., vol. 31, no. 2, 1989 pages 49-52, 'Studies on the stability of clotrimazole in simulated gastric and intestinal media' * |
| NETH.J.PLANT PATHOL., vol. 83, no. 1, 1977 pages 39-47, * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6362169B1 (en) * | 1998-02-24 | 2002-03-26 | Kaneka Corporation | Antibacterial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith |
| US10201518B2 (en) | 2016-09-28 | 2019-02-12 | The University Of Hong Kong | Bismuth(III) compounds and methods thereof |
| US10624871B2 (en) | 2016-09-28 | 2020-04-21 | The University Of Hong Kong | Bismuth(III) compounds and methods thereof |
| WO2023063827A1 (en) * | 2021-10-15 | 2023-04-20 | Omnicin Therapeutics B.V. | Synergistic composition against pseudomonas aeruginosa |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9418346D0 (en) | 1994-11-02 |
| GB2293323A (en) | 1996-03-27 |
| AU3388595A (en) | 1996-03-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Muroi et al. | Antibacterial activity of anacardic acid and totarol, alone and in combination with methicillin, against methicillinresistant Staphylococcus aureus | |
| Michalopoulos et al. | The revival of fosfomycin | |
| MANGI et al. | Development of meningitis during cephalothin therapy | |
| Gonzalez et al. | Pefloxacin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use | |
| JP6101010B2 (en) | Treatment of diseases associated with the use of antibiotics | |
| JP2025507179A (en) | Use of SU3327 in the manufacture of a drug for enhancing the antibacterial infection effect of polymyxin | |
| US4749568A (en) | Rubradirin treatment of methicillin-resistant staph | |
| Khan et al. | A review-ceftriaxone for life | |
| US3949077A (en) | Synergistic antibiotic compositions | |
| Kafetzis et al. | Isepamicin versus amikacin for the treatment of acute pyelonephritis in children | |
| WO1996008259A1 (en) | Synergistic antimicrobial composition | |
| Lasemi et al. | Complications of antibiotic therapy and introduction of nanoantibiotics | |
| Alikhani et al. | An unreported clindamycin adverse reaction: wrist monoarthritis | |
| AU2002334074A1 (en) | Allicin | |
| EP1435928A1 (en) | Allicin | |
| Tissi et al. | In vivo efficacy of azithromycin in treatment of systemic infection and septic arthritis induced by type IV group B Streptococcus strains in mice: comparative study with erythromycin and penicillin G | |
| Ekwo et al. | Effect of clindamycin on aminoglycoside activity in a murine model of invasive Escherichia coli infection | |
| Kim et al. | Update on azithromycin and cardiac side effects | |
| Louie et al. | Comparative in-vitro susceptibilities of Pseudomonas aeruginosa, Xanthomonas maltophilia, and Pseudomonas spp. to sparfloxacin (CI-978, AT-4140, PD131501) and reference antimicrobial agents | |
| GB2292884A (en) | Rifamycin & bismuth salts for treating bacterial infections | |
| JPH01180825A (en) | Agent for infectious disease | |
| Birnbaumer et al. | The new antibiotics | |
| Reyes et al. | Studies of in vitro synergy between several beta-lactam and aminoglycoside antibiotics against endocarditis strains of Pseudomonas aeruginosa | |
| Webbs et al. | Cefoxitin therapy for bacterial endocarditis | |
| Sirisanthana et al. | Effect of clavulanic acid on the in vitro synergism between carbenicillin and gentamicin against Serratia marcescens |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AT AU BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KZ LT LU LV MK MX NO NZ PL PT RO RU SE SI SK UA US UZ |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |