WO2014033561A1 - Antibacterial compositions - Google Patents
Antibacterial compositions Download PDFInfo
- Publication number
- WO2014033561A1 WO2014033561A1 PCT/IB2013/053867 IB2013053867W WO2014033561A1 WO 2014033561 A1 WO2014033561 A1 WO 2014033561A1 IB 2013053867 W IB2013053867 W IB 2013053867W WO 2014033561 A1 WO2014033561 A1 WO 2014033561A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- acceptable derivative
- mecillinam
- beta
- pharmaceutical composition
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 62
- 230000000844 anti-bacterial effect Effects 0.000 title description 5
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 48
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 44
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 229940024554 amdinocillin Drugs 0.000 claims description 93
- BWWVAEOLVKTZFQ-ISVUSNJMSA-N chembl530 Chemical compound N(/[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)=C\N1CCCCCC1 BWWVAEOLVKTZFQ-ISVUSNJMSA-N 0.000 claims description 93
- 238000000034 method Methods 0.000 claims description 89
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 62
- 229960003324 clavulanic acid Drugs 0.000 claims description 62
- 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 62
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 57
- 229960002129 cefixime Drugs 0.000 claims description 31
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 claims description 31
- 239000003781 beta lactamase inhibitor Substances 0.000 claims description 23
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 23
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 22
- 229960003022 amoxicillin Drugs 0.000 claims description 20
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 20
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 20
- 230000003115 biocidal effect Effects 0.000 claims description 13
- 229960005090 cefpodoxime Drugs 0.000 claims description 12
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims description 12
- 229960001668 cefuroxime Drugs 0.000 claims description 12
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims description 12
- -1 carbapenems Chemical class 0.000 claims description 9
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 9
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 9
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 7
- 229960002182 imipenem Drugs 0.000 claims description 7
- 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 claims description 7
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 claims description 4
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 claims description 4
- 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 description 4
- 229960005361 cefaclor Drugs 0.000 claims description 4
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims description 4
- 229960003719 cefdinir Drugs 0.000 claims description 4
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims description 4
- 229960004069 cefditoren Drugs 0.000 claims description 4
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 claims description 4
- 229960002580 cefprozil Drugs 0.000 claims description 4
- 229950009592 cefquinome Drugs 0.000 claims description 4
- 235000019371 penicillin G benzathine Nutrition 0.000 claims description 4
- 229930182555 Penicillin Natural products 0.000 claims description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 3
- 229960003644 aztreonam Drugs 0.000 claims description 3
- 229940041011 carbapenems Drugs 0.000 claims description 3
- 150000002961 penems Chemical class 0.000 claims description 3
- 150000002960 penicillins Chemical class 0.000 claims description 3
- JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 claims description 2
- FMZXNVLFJHCSAF-DNVCBOLYSA-N (6R,7R)-3-[(4-carbamoyl-1-pyridin-1-iumyl)methyl]-8-oxo-7-[(1-oxo-2-thiophen-2-ylethyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CC=3SC=CC=3)[C@H]2SC1 FMZXNVLFJHCSAF-DNVCBOLYSA-N 0.000 claims description 2
- XSPUSVIQHBDITA-KXDGEKGBSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(5-methyltetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-KXDGEKGBSA-N 0.000 claims description 2
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 claims description 2
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims description 2
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 claims description 2
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims description 2
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 claims description 2
- 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 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims description 2
- 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 2
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 claims description 2
- 229930195708 Penicillin V Natural products 0.000 claims description 2
- 229960000723 ampicillin Drugs 0.000 claims description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 2
- 229960004328 azidocillin Drugs 0.000 claims description 2
- ODFHGIPNGIAMDK-NJBDSQKTSA-N azidocillin Chemical compound C1([C@@H](N=[N+]=[N-])C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 ODFHGIPNGIAMDK-NJBDSQKTSA-N 0.000 claims description 2
- 229960003623 azlocillin Drugs 0.000 claims description 2
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin 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)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 claims description 2
- 229960002699 bacampicillin Drugs 0.000 claims description 2
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 claims description 2
- 229960002536 benzathine benzylpenicillin Drugs 0.000 claims description 2
- 229940095744 benzathine phenoxymethylpenicillin Drugs 0.000 claims description 2
- BVGLIYRKPOITBQ-ANPZCEIESA-N benzylpenicillin benzathine Chemical compound C=1C=CC=CC=1C[NH2+]CC[NH2+]CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 BVGLIYRKPOITBQ-ANPZCEIESA-N 0.000 claims description 2
- 229960003169 biapenem Drugs 0.000 claims description 2
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 claims description 2
- 229960003669 carbenicillin Drugs 0.000 claims description 2
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims description 2
- 229960000717 carindacillin Drugs 0.000 claims description 2
- JIRBAUWICKGBFE-MNRDOXJOSA-N carindacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(=O)OC=1C=C2CCCC2=CC=1)C1=CC=CC=C1 JIRBAUWICKGBFE-MNRDOXJOSA-N 0.000 claims description 2
- UIMOJFJSJSIGLV-JNHMLNOCSA-N carumonam Chemical compound O=C1N(S(O)(=O)=O)[C@H](COC(=O)N)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 UIMOJFJSJSIGLV-JNHMLNOCSA-N 0.000 claims description 2
- 229960000662 carumonam Drugs 0.000 claims description 2
- 229960003972 cefacetrile Drugs 0.000 claims description 2
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 claims description 2
- 229960004841 cefadroxil Drugs 0.000 claims description 2
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 claims description 2
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 claims description 2
- 229950004030 cefaloglycin Drugs 0.000 claims description 2
- 229950005258 cefalonium Drugs 0.000 claims description 2
- 229960003866 cefaloridine Drugs 0.000 claims description 2
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 claims description 2
- 229960000603 cefalotin Drugs 0.000 claims description 2
- 229960003012 cefamandole Drugs 0.000 claims description 2
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims description 2
- 229960004350 cefapirin Drugs 0.000 claims description 2
- 229960002420 cefatrizine Drugs 0.000 claims description 2
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims description 2
- HGXLJRWXCXSEJO-GMSGAONNSA-N cefazaflur Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(F)(F)F)[C@H]2SC1 HGXLJRWXCXSEJO-GMSGAONNSA-N 0.000 claims description 2
- 229950004359 cefazaflur Drugs 0.000 claims description 2
- 229960005312 cefazedone Drugs 0.000 claims description 2
- VTLCNEGVSVJLDN-MLGOLLRUSA-N cefazedone Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3C=C(Cl)C(=O)C(Cl)=C3)[C@H]2SC1 VTLCNEGVSVJLDN-MLGOLLRUSA-N 0.000 claims description 2
- 229960001139 cefazolin Drugs 0.000 claims description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims description 2
- 229960001817 cefbuperazone Drugs 0.000 claims description 2
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 claims description 2
- 229960002966 cefcapene Drugs 0.000 claims description 2
- HJJRIJDTIPFROI-NVKITGPLSA-N cefcapene Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 HJJRIJDTIPFROI-NVKITGPLSA-N 0.000 claims description 2
- HOGISBSFFHDTRM-GHXIOONMSA-N cefdaloxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/O)\C1=CSC(N)=N1 HOGISBSFFHDTRM-GHXIOONMSA-N 0.000 claims description 2
- 229950006550 cefdaloxime Drugs 0.000 claims description 2
- 229960002100 cefepime Drugs 0.000 claims description 2
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 claims description 2
- 229960004041 cefetamet Drugs 0.000 claims description 2
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 claims description 2
- 229960003791 cefmenoxime Drugs 0.000 claims description 2
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 claims description 2
- 229960003585 cefmetazole Drugs 0.000 claims description 2
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 claims description 2
- 229960002025 cefminox Drugs 0.000 claims description 2
- JSDXOWVAHXDYCU-VXSYNFHWSA-N cefminox Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC[C@@H](N)C(O)=O)OC)CC=1CSC1=NN=NN1C JSDXOWVAHXDYCU-VXSYNFHWSA-N 0.000 claims description 2
- 229960001958 cefodizime Drugs 0.000 claims description 2
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 claims description 2
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to antibacterial compositions and methods of treating or controlling bacterial infections.
- Beta-lactam antibiotics have historically remained the mainstay of therapy for the management of wide range of serious Gram- negative infections.
- beta- lactam antibiotic agents In general, there are four primary mechanisms by which bacteria can overcome beta- lactam antibiotic agents. These mechanisms include production of beta-lactamases, decreased expression of outer membrane proteins, efflux pumps and mutations in the active site of Penicillin Binding Proteins (PBPs). Production of beta-lactamases is the most dominant mechanism of resistance to this class of antibiotic. Introduction of extended spectrum beta- lactam antibiotic agents during 1980s were responded by Gram negative organisms with the production of Extended Spectrum Beta-lactamases (ESBLs).
- ESBLs Extended Spectrum Beta-lactamases
- the ESBLs are heterogenous group of plasmid mediated enzymes, now numbering more than 890, (Bush et al, Critical Care 2010; 14:224) imparting various degrees of resistance to broader spectrum of beta- lactam antibiotic agents including third and fourth generation cephalosporins.
- E. coli and Klebsiella account for the majority of the pathogens expressing ESBLs in most parts of the world. AmpC hyperproducing E. coli and Klebsiella are recognized worldwide as important nosocomial pathogens and have also been associated with hospital acquired urinary tract infections, blood stream infections and other severe infections such as intra-abdominal infections and sepsis.
- ESBL producing organisms Given the ability of ESBL producing organisms to hydrolyze several beta-lactam antibiotic agents, it is not surprising that antibiotic choice for infections with such organisms is seriously reduced. Furthermore, plasmid-bearing genes encoding ESBLs frequently also carry genes encoding resistance to quinolones, aminoglycosides and trimethoprim- sulphamethaxozole. Invariably, injectable agents such as carbapenems are employed since there are no effective oral options available. Current oral options such as quinolones and oral cephalosporins are ineffective in tackling quinolone and ESBL resistance respectively which coexists in many clinical isolates. Therefore ESBL including Class A and C effective oral options are urgently needed.
- compositions and methods for the treatment or control of bacterial infections are provided.
- compositions useful for the treatment or control of bacterial infections comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for increasing antibiotic effectiveness of a beta-lactam antibiotic agent in a subject comprising coadministering said beta-lactam antibiotic agent with effective amounts of: (a) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (b) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof, exhibits unexpectedly improved and synergistic antibacterial efficacy, even against highly resistant ESBL producing bacteria.
- infection includes presence of microbes, including bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject.
- infection in addition to referring to the presence of bacteria also refers to normal flora which, are not desirable.
- infection includes infection caused by bacteria.
- treat refers to administering a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes.
- prophylactic treatment refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection.
- therapeutic treatment refers to administering treatment to a subject already suffering from infection.
- treat also refers to administering compositions or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection or one or more symptoms of the bacterial infection, or (ii) retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial infections, or (iv) suppress the clinical manifestation of a bacterial infection, or (v) suppress the manifestation of adverse symptoms of the bacterial infections.
- control generally refers to preventing, reducing, or eradicating infection or inhibiting the rate and extent of such infection, or reducing the microbial population, such as a microbial population present in or on a body or structure, surface, liquid, subject, etc, wherein such prevention or reduction in the infection or microbial population is statistically significant with respect to untreated infection or population. In general, such control may be achieved by increased mortality amongst the microbial population.
- an effective amount refers to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject.
- a therapeutically or pharmaceutically effective amount of an antibiotic agent or a pharmaceutical composition is the amount of the antibiotic agent or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media).
- the effective or pharmaceutically effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, characteristics of the subject (for example height, weight, sex, age and medical history), severity of infection and the particular type of the antibiotic used.
- a therapeutically or prophylactically effective amount is that amount which would be effective to prevent a microbial (e.g. bacterial) infection.
- administration includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or it's active ingredients or other pharmaceutically active ingredients to the site of the infection.
- the method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition or the type/nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject.
- Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
- a pharmaceutical composition comprising more than one ingredients (active or inert)
- one of way of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder etc.) and then administering the dosage form.
- the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic effect.
- growth refers to a growth of microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria).
- the term also includes maintenance of on-going metabolic processes of a microorganism, including processes that keep the microorganism alive.
- ⁇ refers to ability of a treatment or a composition or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject.
- antibiotic effectiveness refers to the ability of the composition or the beta- lactam antibiotic agent to prevent or treat the microbial (e.g. bacterial) infection in a subject.
- compositions refers to a compound or material used to facilitate administration of a compound, for example, to increase the solubility of the compound.
- Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin.
- Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils.
- various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J.
- antibiotic agent refers to any substance, compound or a combination of substances or a combination of compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment.
- antibiotic agent also refers to compounds capable of decreasing infectivity or virulence of bacteria.
- pharmaceutically acceptable derivative as used herein is meant to include any pharmaceutically acceptable salt, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers or adducts of a compound of the present invention which, upon administration to the subject, is capable of providing (directly or indirectly) the parent compound.
- pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated herein by reference, describes various pharmaceutically acceptable salts in details.
- subject refers to vertebrate or invertebrate, including a mammal.
- subject includes human, animal, a bird, a fish, or an amphibian.
- Typical, non-limiting examples of a “subject” includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
- beta-lactam antibiotic agent refers to compounds with antibiotic properties and containing a beta-lactam nucleus in their molecular structure.
- beta-lactamase refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring.
- beta-lactamase includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta- lactam antibiotic, either partially or completely.
- beta-lactamase inhibitor refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.
- beta-lactam antibiotic and “beta-lactamase inhibitor” includes their pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or their any other pharmaceutically acceptable derivatives.
- composition useful for the treatment or control of bacterial infections comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- methods for increasing antibiotic effectiveness of a beta-lactam antibiotic agent in a subject comprising coadministering said beta-lactam antibiotic agent with effective amounts of: (a) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (b) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
- compositions and methods according to the invention include at least one beta- lactam antibiotic agent.
- the beta-lactam antibiotic agent is selected from the group consisting of penicillins, penems, carbapenems, cephems, and monobactams.
- the beta-lactam antibiotic agent is a penicillin compound.
- penicillin compounds include amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, meticillin, nafcillin or a pharmaceutically acceptable derivative thereof.
- the beta-lactam antibiotic agent is a penem compound.
- penem compounds include faropenem or a pharmaceutically acceptable derivative thereof.
- the beta-lactam antibiotic agent is a carbapenem compound.
- carbapenem compounds include the biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, or a pharmaceutically acceptable derivative thereof.
- the beta-lactam antibiotic agent is a cephem compound.
- the cephem compounds include cephalosporins, cephamycins, and carbacephems.
- Typical, non-limiting examples of cephem compounds include cefazolin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, ceft
- the beta-lactam antibiotic agent is a monobactam compound.
- monobactam compounds include aztreonam, tigemonam, carumonam, nocardicin A, or a pharmaceutically acceptable derivative thereof.
- the beta-lactam antibiotic agent is amoxicillin or a pharmaceutically acceptable derivative thereof.
- the beta-lactam antibiotic is cefixime, cefuroxime, cefpodoxime, cefaclor, cefprozil, cefdinir, cefditoren or a pharmaceutically acceptable derivative thereof.
- compositions and methods according to the invention include a beta-lactamase inhibitor.
- beta-lactamase inhibitors include sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
- the beta-lactamase inhibitor is clavulanic acid or its pharmaceutically acceptable salt (for example, potassium or a sodium salt).
- mecillinam is present as pivmecillinam (also known as mecillinam pivoxil).
- the amount of each component in the composition and methods according to the invention can vary widely depending on the requirements.
- the beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg. In some other embodiments, the beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
- compositions useful for the treatment or control of bacterial infections comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- amoxicillin or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
- clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
- a pharmaceutical composition useful for the treatment or control of bacterial infections comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- cefixime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
- clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
- a pharmaceutical composition useful for the treatment or control of bacterial infections comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- cefuroxime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
- clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
- composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of:
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof,
- a method for the treatment or control of bacterial infections comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
- cefpodoxime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg. In some other embodiments, clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
- the pharmaceutical composition and/or other pharmaceutically active ingredients according to the invention may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site.
- the method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject.
- the microorganism e.g. bacteria
- compositions to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
- compositions or active ingredients thereof are administered orally.
- compositions according to the invention can be formulated into various dosage forms wherein the active ingredients may be present either together (e.g. as an admixture) or as separate components.
- the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture.
- the composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form can be administered in several ways. In one possible way, the ingredients can be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components can be separately administered in appropriate proportions so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
- the active ingredients can be administered to a subject in several ways depending on the requirements.
- the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject.
- the active ingredients are administered separately.
- the invention further provides for combining separate pharmaceutical compositions in kit form.
- the kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like.
- the kit comprises directions for the administration of the separate components.
- the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals.
- the active ingredients are administered separately, they may be administered simultaneously or sequentially.
- compositions or the active ingredients according to the present invention may be formulated into a variety of dosage forms.
- dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
- compositions and methods disclosed herein are useful in treating or controlling bacterial infections.
- compositions and methods disclosed herein are particularly effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known beta-lactam antibiotic or their known compositions.
- Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like.
- infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.
- compositions and methods according to the invention are also effective in treating or controlling bacterial infections that are caused by bacteria producing one or more beta- lactamase enzymes.
- the ability of compositions and methods according to the present invention to treat such resistant with typical beta-lactam antibiotics represents a significant improvement in the art.
- Table 1 detail results of the activity study using a combination of amoxicillin + clavulanic acid and mecillinam against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
- MIC value for each of Clavulanic acid and Mecillinam when used alone was > 64 mcg/ml.
- MIC value for Mecillinam in combination with Clavulanic acid (4mcg/ml) was 16 mcg/ml.
- Table 2 provides data demonstrating surprising effect of the combination according to the invention on the killing of highly resistant ESBL producing pathogen (K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL).
- bacterial cultures continued growth in control (drug free) and in the presence of drugs (for example, amoxicillin, clavulanic acid and mecillinam alone), indicating no antibacterial activity.
- drugs for example, amoxicillin, clavulanic acid and mecillinam alone
- Table 3 provides data demonstrating surprising effect of the combination on the killing of another highly resistant ESBL producing pathogen (K. pneumoniae B 43 strain producing SHV and TEM ESBLs).
- Table 3 Cidal activity of a combination comprising Amoxicillin, Clavulanic acid and Mecillinam against K. pneumoniae B 43 strain producing SHV and TEM ESBLs.
- Table 4 provides data demonstrating surprising effect of the combination (Cefixime + Clavulanic acid + Mecillinam) against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
- the combination (Cefixime + Clavulanic acid + Mecillinam) has pharmacodynamics to Carbapenem (for example, Imipenem).
- Table 5 provides data demonstrating surprising effect of the combination (Cefixime + Clavulanic acid + Mecillinam) against K. pneumoniae B 43 strain producing SHV and TEM ESBLs.
- the combination (Cefixime + Clavulanic acid + Mecillinam) exhibits potent activity against ESBL producing strain causing 99% reduction in the count at the end of 8 hrs, where a carbapenem (for example, Imipenem) fails to kill consistently.
- Table 6 provides data demonstrating surprising effect of a combination (Cefpodoxime + Clavulanic acid + Mecillinam) against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
- Tables 1 to 7 indicate that a combination comprising at least one beta-lactam antibiotic agent, at least one beta-lactamase inhibitor and mecillinam or a pharmaceutically acceptable derivative can be effectively used in treating or controlling bacterial infections (even those being caused by bacteria producing one or more beta- lactamase enzymes) in a subject.
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Abstract
A pharmaceutical composition useful for the treatment or control of bacterial infections is disclosed.
Description
ANTIBACTERIAL COMPOSITIONS
FIELD OF THE INVENTION
The invention relates to antibacterial compositions and methods of treating or controlling bacterial infections.
BACKGROUND OF THE INVENTION
The accelerated emergence of antibiotic resistance among the widely prevalent pathogens is the most serious threat to the management of infectious diseases. For Gram negatives, resistance to beta-lactam, fluoroquinolone and aminoglycoside class of antibiotic agents is currently posing a considerable challenge to clinicians. Beta-lactam antibiotics have historically remained the mainstay of therapy for the management of wide range of serious Gram- negative infections.
In general, there are four primary mechanisms by which bacteria can overcome beta- lactam antibiotic agents. These mechanisms include production of beta-lactamases, decreased expression of outer membrane proteins, efflux pumps and mutations in the active site of Penicillin Binding Proteins (PBPs). Production of beta-lactamases is the most dominant mechanism of resistance to this class of antibiotic. Introduction of extended spectrum beta- lactam antibiotic agents during 1980s were responded by Gram negative organisms with the production of Extended Spectrum Beta-lactamases (ESBLs). The ESBLs are heterogenous group of plasmid mediated enzymes, now numbering more than 890, (Bush et al, Critical Care 2010; 14:224) imparting various degrees of resistance to broader spectrum of beta- lactam antibiotic agents including third and fourth generation cephalosporins.
ESBL producing Enterobacteriaceae are causing a worldwide epidemic of urinary tract infections in community and inpatient settings as well as severe infections in hospital populations. Their prevalence varies from one country to another and from institution to institution. E. coli and Klebsiella account for the majority of the pathogens expressing ESBLs in most parts of the world. AmpC hyperproducing E. coli and Klebsiella are recognized worldwide as important nosocomial pathogens and have also been associated with hospital acquired urinary tract infections, blood stream infections and other severe infections such as intra-abdominal infections and sepsis.
Given the ability of ESBL producing organisms to hydrolyze several beta-lactam antibiotic agents, it is not surprising that antibiotic choice for infections with such organisms is seriously reduced. Furthermore, plasmid-bearing genes encoding ESBLs frequently also carry genes encoding resistance to quinolones, aminoglycosides and trimethoprim- sulphamethaxozole. Invariably, injectable agents such as carbapenems are employed since
there are no effective oral options available. Current oral options such as quinolones and oral cephalosporins are ineffective in tackling quinolone and ESBL resistance respectively which coexists in many clinical isolates. Therefore ESBL including Class A and C effective oral options are urgently needed.
SUMMARY OF THE INVENTION
Accordingly, there are provided pharmaceutical compositions and methods for the treatment or control of bacterial infections.
In one general aspect, there are provided pharmaceutical compositions useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In yet another general aspect, there are provided methods for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for increasing antibiotic effectiveness of a beta-lactam antibiotic agent in a subject, said method comprising coadministering said beta-lactam antibiotic agent with effective amounts of: (a) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (b) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the following description including claims.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the inventions as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.
The inventors have surprisingly discovered that a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof, exhibits unexpectedly improved and synergistic antibacterial efficacy, even against highly resistant ESBL producing bacteria.
The term "infection" as used herein includes presence of microbes, including bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject. As such, the term "infection" in addition to referring to the presence of bacteria also refers to normal flora which, are not desirable. The term "infection" includes infection caused by bacteria.
The term "treat", "treating" or "treatment" as used herein refers to administering a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from infection. The term "treat", "treating" or "treatment" as used herein also refers to administering compositions or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection or one or more symptoms of the bacterial infection, or (ii) retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial infections, or (iv) suppress the clinical
manifestation of a bacterial infection, or (v) suppress the manifestation of adverse symptoms of the bacterial infections.
The term "control" or "controlling" as used herein generally refers to preventing, reducing, or eradicating infection or inhibiting the rate and extent of such infection, or reducing the microbial population, such as a microbial population present in or on a body or structure, surface, liquid, subject, etc, wherein such prevention or reduction in the infection or microbial population is statistically significant with respect to untreated infection or population. In general, such control may be achieved by increased mortality amongst the microbial population.
The term "effective amount" as used herein refers to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject. For example, a therapeutically or pharmaceutically effective amount of an antibiotic agent or a pharmaceutical composition is the amount of the antibiotic agent or the pharmaceutical composition required to produce a desired therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or in vitro studies (e.g. in agar or broth media). The effective or pharmaceutically effective amount depends on several factors, including but not limited to, the microorganism (e.g. bacteria) involved, characteristics of the subject (for example height, weight, sex, age and medical history), severity of infection and the particular type of the antibiotic used. For prophylactic treatments, a therapeutically or prophylactically effective amount is that amount which would be effective to prevent a microbial (e.g. bacterial) infection.
The term "administration" or "administering" includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or it's active ingredients or other pharmaceutically active ingredients to the site of the infection. The method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition or the type/nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash. In case of a pharmaceutical composition comprising more than one ingredients (active or inert), one of way of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder etc.) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients
reach beneficial therapeutic levels such that the composition as a whole provides a synergistic effect.
The term "growth" as used herein refers to a growth of microorganisms and includes reproduction or population expansion of the microorganism (e.g. bacteria). The term also includes maintenance of on-going metabolic processes of a microorganism, including processes that keep the microorganism alive.
The term, "effectiveness" as used herein refers to ability of a treatment or a composition or one or more pharmaceutically active ingredients to produce a desired biological effect in a subject. For example, the term "antibiotic effectiveness" of a composition or a beta- lactam antibiotic agent refers to the ability of the composition or the beta- lactam antibiotic agent to prevent or treat the microbial (e.g. bacterial) infection in a subject.
The term "synergistic" or "synergy" as used herein refers to the interaction of two or more agents so that their combined effect is greater than their individual effects.
The term ""pharmaceutically inert ingredient" or "carrier" or "excipient" refers to a compound or material used to facilitate administration of a compound, for example, to increase the solubility of the compound. Solid carriers include, e.g., starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid carriers include, e.g., sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.
The term "antibiotic agent" as used herein refers to any substance, compound or a combination of substances or a combination of compounds capable of: (i) inhibiting, reducing or preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the environment. The term "antibiotic agent" also refers to compounds capable of decreasing infectivity or virulence of bacteria.
The term "pharmaceutically acceptable derivative" as used herein is meant to include any pharmaceutically acceptable salt, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers or adducts of a compound of the present invention which, upon administration to the subject, is capable of providing (directly or indirectly) the parent compound.
In general, the pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated herein by reference, describes various pharmaceutically acceptable salts in details.
The term "subject" as used herein refers to vertebrate or invertebrate, including a mammal. The term "subject" includes human, animal, a bird, a fish, or an amphibian. Typical, non-limiting examples of a "subject" includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
The term "beta-lactam antibiotic agent" as used herein refers to compounds with antibiotic properties and containing a beta-lactam nucleus in their molecular structure.
The term "beta-lactamase" as used herein refers to any enzyme or protein or any other substance that breaks down a beta-lactam ring. The term "beta-lactamase" includes enzymes that are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta- lactam antibiotic, either partially or completely.
The term "beta-lactamase inhibitor" as used herein refers to a compound capable of inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.
A person of skills in the art would appreciate that various compounds described herein (including, for example, the beta-lactam antibiotic and the beta-lactamase inhibitor) can exist and are often used as their pharmaceutically acceptable derivatives such as salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or other pharmaceutically acceptable derivatives. A reference to compounds discussed herein, therefore, is intended to include such pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or their any other pharmaceutically acceptable derivatives. For example, the terms "beta-lactam antibiotic", and "beta-lactamase inhibitor" includes their pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or their any other pharmaceutically acceptable derivatives.
In one general aspect, there are provided pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In another general aspect, there are provided methods for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
In a further general aspect, there are provided methods for increasing antibiotic effectiveness of a beta-lactam antibiotic agent in a subject, said method comprising coadministering said beta-lactam antibiotic agent with effective amounts of: (a) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (b) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
The compositions and methods according to the invention include at least one beta- lactam antibiotic agent. In some embodiments, the beta-lactam antibiotic agent is selected from the group consisting of penicillins, penems, carbapenems, cephems, and monobactams.
In some other embodiments, the beta-lactam antibiotic agent is a penicillin compound. Typical, non-limiting examples of penicillin compounds include amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, meticillin, nafcillin or a pharmaceutically acceptable derivative thereof.
In some other embodiments, the beta-lactam antibiotic agent is a penem compound. Typical, non-limiting examples of penem compounds include faropenem or a pharmaceutically acceptable derivative thereof.
In some embodiments, the beta-lactam antibiotic agent is a carbapenem compound. Typical, non-limiting examples of carbapenem compounds include the biapenem, ertapenem,
doripenem, imipenem, meropenem, panipenem, or a pharmaceutically acceptable derivative thereof.
In some embodiments, the beta-lactam antibiotic agent is a cephem compound. In general, the cephem compounds include cephalosporins, cephamycins, and carbacephems. Typical, non-limiting examples of cephem compounds include cefazolin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, ceftazidime, cefoperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline fosamil, ceftiofur, cefquinome, cefovecin or a pharmaceutically acceptable derivative thereof.
In some other embodiments, the beta-lactam antibiotic agent is a monobactam compound. Typical, non-limiting examples of monobactam compounds include aztreonam, tigemonam, carumonam, nocardicin A, or a pharmaceutically acceptable derivative thereof.
In some embodiments, the beta-lactam antibiotic agent is amoxicillin or a pharmaceutically acceptable derivative thereof. In some other embodiments, the beta-lactam antibiotic is cefixime, cefuroxime, cefpodoxime, cefaclor, cefprozil, cefdinir, cefditoren or a pharmaceutically acceptable derivative thereof.
The compositions and methods according to the invention include a beta-lactamase inhibitor. Typical, non-limiting examples of such beta-lactamase inhibitors include sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof. In some embodiments, the beta-lactamase inhibitor is clavulanic acid or its pharmaceutically acceptable salt (for example, potassium or a sodium salt).
In some embodiment, mecillinam is present as pivmecillinam (also known as mecillinam pivoxil).
The amount of each component in the composition and methods according to the invention can vary widely depending on the requirements.
In some embodiments, the beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
In some other embodiments, the beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, mecillinam or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, there is provided a pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some embodiments, amoxicillin or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
In some other embodiments, clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, mecillinam or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, there is provided a pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a
pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some embodiments, cefixime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
In some other embodiments, clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, mecillinam or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, there is provided a pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a
pharmaceutical composition comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some embodiments, cefuroxime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
In some other embodiments, clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, mecillinam or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, there is provided a pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of:
(a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof,
(b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
In some embodiments, cefpodoxime or a pharmaceutically acceptable derivative thereof in the compositions and methods according to invention is present in an amount of about 0.1 mg to about 3000 mg.
In some other embodiments, clavulanic acid or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In some embodiments, mecillinam or a pharmaceutically acceptable derivative thereof in the composition and methods according to the invention is present in an amount of about 0.1 mg to about 3000 mg.
In the methods, the pharmaceutical composition and/or other pharmaceutically active ingredients according to the invention may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site. The method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject. Some non-limiting examples of administering the composition to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
In some embodiments, the compositions or active ingredients thereof are administered orally.
The compositions according to the invention can be formulated into various dosage forms wherein the active ingredients may be present either together (e.g. as an admixture) or as separate components. When the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture. The composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form can be administered in several ways. In one possible way, the ingredients can be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components can be separately administered in appropriate proportions so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
Similarly, in the methods according to the invention, the active ingredients can be administered to a subject in several ways depending on the requirements. In some embodiments, the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject. In some other embodiments, the active ingredients are administered separately. Since the invention contemplates that the active ingredients agents may be administered separately, the invention further provides for combining separate pharmaceutical compositions in kit form. The kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such
separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals. When the active ingredients are administered separately, they may be administered simultaneously or sequentially.
The pharmaceutical composition or the active ingredients according to the present invention may be formulated into a variety of dosage forms. Typical, non-limiting examples of dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
In general, the pharmaceutical compositions and method disclosed herein are useful in treating or controlling bacterial infections. Advantageously, the compositions and methods disclosed herein are particularly effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known beta-lactam antibiotic or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like. Other non-limiting examples of infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.
Surprisingly, the compositions and methods according to the invention are also effective in treating or controlling bacterial infections that are caused by bacteria producing one or more beta- lactamase enzymes. The ability of compositions and methods according to the present invention to treat such resistant with typical beta-lactam antibiotics represents a significant improvement in the art.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.
EXAMPLES
The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or
illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.
The efficacy of compositions and methods in treating or controlling bacterial infections was studied. In a typical study, overnight grown bacterial cultures were diluted appropriately and inoculated on the agar media containing doubling dilutions of the antibiotic. Observation for growth or no growth was performed after 16-20 hours of incubation at 35 + 2°C in ambient air. The overall procedure was performed as per Clinical and Laboratory Standards Institute (CLSI) recommendations (Clinical and Laboratory Standards Institute (CLSI), performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, M 100 - S20, Volume 30, No. 1, 2010). The results of these studies are summarized in Tables 1 - 3.
Table 1 detail results of the activity study using a combination of amoxicillin + clavulanic acid and mecillinam against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
As seen from the data given in Table 1, each of amoxicillin and mecillinam have much higher MIC values indicating their lower antibiotic effectiveness, when used alone. A combination comprising amoxicillin + clavulanic acid and mecillinam + clavulanic acid showed moderate enhancement in the antibiotic effectiveness as compared when these were used alone. Surprisingly, the combination of amoxicillin + clavulanic acid + mecillinam exhibited substantially lower MIC value of 1 mcg/ml.
MIC value for each of Clavulanic acid and Mecillinam when used alone was > 64 mcg/ml. MIC value for Mecillinam in combination with Clavulanic acid (4mcg/ml) was 16 mcg/ml.
Table 2 provides data demonstrating surprising effect of the combination according to the invention on the killing of highly resistant ESBL producing pathogen (K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL). As can be seen, bacterial cultures continued growth in control (drug free) and in the presence of drugs (for example, amoxicillin, clavulanic acid and mecillinam alone), indicating no antibacterial activity. In contrast, a combination comprising amoxicillin, clavulanic acid and mecillinam showed potent cidality bringing about 99 to 99.99% killing in 2 to 8 hours.
Initial bacterial count (at 0 hours) was 6.65 log CFU/ml
Table 3 provides data demonstrating surprising effect of the combination on the killing of another highly resistant ESBL producing pathogen (K. pneumoniae B 43 strain producing SHV and TEM ESBLs).
Table 3. Cidal activity of a combination comprising Amoxicillin, Clavulanic acid and Mecillinam against K. pneumoniae B 43 strain producing SHV and TEM ESBLs.
Bacterial count
Sr. Combination (Log CFU/ml)
2 hours 6 hours 8 hours
1. Control (No active ingredient) 7.95 8.97 9
2. Amoxicillin (8 mcg/rnl) 7.8 8.8 9
3. Clavulanic acid (4 mcg/rnl) 8.1 8.7 9
4. Mecillinam (4 mcg/rnl) 7.74 8.69 8.89
5. Amoxicillin (8 mcg/rnl) + Clavulanic acid (4
8.16 8.60 9 mcg/rnl)
6 Amoxicillin (8 mcg/rnl) + Mecillinam (4 mcg/rnl) 7.57 8.49 8.90
7. Mecillinam (4 mcg/rnl) + Clavulanic acid (4
7.16 6.95 7.2 mcg/rnl)
8. Amoxicillin (4 mcg/rnl) + Clavulanic acid (4
7.02 4.74 4.24 mcg/rnl) + Mecillinam (4 mcg/rnl)
9. Amoxicillin (8 mcg/rnl) + Clavulanic acid (4
6.39 4.60 3.84 mcg/ml)+ Mecillinam (4 mcg/rnl)
10. Imipenem (2mcg/ml) 5.4 3.9 3.8
Initial bacterial count (at 0 hours) was 7.04 log CFU/ml
Table 4 provides data demonstrating surprising effect of the combination (Cefixime + Clavulanic acid + Mecillinam) against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL. As can be seen, the combination (Cefixime + Clavulanic acid + Mecillinam) has pharmacodynamics to Carbapenem (for example, Imipenem).
Table 4. Cidal activity of a combination comprising Cefixime, Clavulanic acid and Mecillinam against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL
Bacterial count
Sr. Combination (Log CFU/ml)
2 hours 4 hours 8 hours
1. Control (No active ingredient) 8.60 8.74 8.92
2. Cefixime (2 mcg/rnl) 8.11 8.30 9
3. Clavulanic acid (4 mcg/rnl) 8.4 8.65 8.9
4. Mecillinam (2 mcg/ml) 7.95 8.33 8.90
5. Cefixime (1 mcg/ml) + Clavulanic acid (4 mcg/ml) 6.47 5.60 3.13
6. Cefixime (2 mcg/ml) + Clavulanic acid (4 mcg/ml) 6.09 4.39 3.10
7. Mecillinam (2 mcg/ml) + Clavulanic acid (4
8.04 8.1 8.17 mcg/ml)
8. Cefixime (1 mcg/ml) + Mecillinam (2 mcg/ml) 7.74 8.07 8.84
9. Cefixime (2 mcg/ml) + Mecillinam (2 mcg/ml) 7.69 8.09 8.97
10. Cefixime (1 mcg/ml) + Clavulanic acid (4 mcg/ml)
4.21 3.30 2.50 + Mecillinam (2 mcg/ml)
11. Cefixime (2 mcg/ml) + Clavulanic acid (4 mcg/ml)+
4.09 3 2.32 Mecillinam (2 mcg/ml)
12. Imipenem (1 mcg/ml) 4.87 3.39 2.84
Initial bacterial count (at 0 hours) was 7.43 log CFU/ml
Table 5 provides data demonstrating surprising effect of the combination (Cefixime + Clavulanic acid + Mecillinam) against K. pneumoniae B 43 strain producing SHV and TEM ESBLs. As can be seen, the combination (Cefixime + Clavulanic acid + Mecillinam) exhibits potent activity against ESBL producing strain causing 99% reduction in the count at the end of 8 hrs, where a carbapenem (for example, Imipenem) fails to kill consistently.
Table 5. Cidal activity of a combination comprising Cefixime, Clavulanic acid and Mecillinam against K. pneumoniae B 43 strain producing SHV and TEM ESBLs.
Bacterial count
Sr. Combination (Log CFU/ml)
2 hours 4 hours 8 hours
1. Control (No active ingredient) 8.20 8.60 8.92
2. Cefixime (2 mcg/ml) 8.16 8.47 8.84
3. Clavulanic acid (4 mcg/ml) 8.1 8.56 8.85
4. Mecillinam (2 mcg/ml) 8.39 8.60 8.90
5. Cefixime (1 mcg/ml) + Clavulanic acid (4 mcg/ml) 7.54 5.92 6.47
6. Cefixime (2 mcg/ml) + Clavulanic acid (4 mcg/ml) 7.60 7.60 5.77
7. Mecillinam (2 mcg/ml) + Clavulanic acid (4
8.06 7.97 7.17 mcg/ml)
8. Cefixime (1 mcg/ml) + Mecillinam (2 mcg/ml) 7.87 8.27 8.23
9. Cefixime (2 mcg/ml) + Mecillinam (2 mcg/ml) 8.47 8.17 8.39
10. Cefixime (1 mcg/ml) + Clavulanic acid (4 mcg/ml)
6.60 5.11 4.47 + Mecillinam (2 mcg/ml)
11. Cefixime (2 mcg/ml) + Clavulanic acid (4 mcg/ml)+
6.13 5.09 4.27 Mecillinam (2 mcg/ml)
12. Imipenem (1 mcg/ml) 6.37 5.69 6.60
Initial bacterial count (at 0 hours) was log 7.43 CFU/ml
Table 6 provides data demonstrating surprising effect of a combination (Cefpodoxime + Clavulanic acid + Mecillinam) against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
Initial bacterial count (at 0 hours) was 7.27 log CFU/ml
Table 7 provides data demonstrating surprising effect of a combination (Cefuroxime + Clavulanic acid + Mecillinam) against K. pneumoniae ATCC 700603 strain producing SHV 18 ESBL.
Initial bacterial count (at 0 hours) was 7.27 log CFU/ml
The data provided in Tables 1 to 7, indicate that a combination comprising at least one beta-lactam antibiotic agent, at least one beta-lactamase inhibitor and mecillinam or a pharmaceutically acceptable derivative can be effectively used in treating or controlling bacterial infections (even those being caused by bacteria producing one or more beta- lactamase enzymes) in a subject.
Claims
1. A pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
2. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
3. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) at least one beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof, (b) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
4. A method for increasing antibiotic effectiveness of a beta-lactam antibiotic agent in a subject, said method comprising co-administering said beta-lactam antibiotic agent with effective amounts of: (a) at least one beta-lactamase inhibitor or a pharmaceutically acceptable derivative thereof, and (b) mecillinam or a pharmaceutically acceptable derivative thereof, wherein the beta-lactam antibiotic agent is not mecillinam or a pharmaceutically acceptable derivative thereof.
5. A pharmaceutical composition according to Claim 1 or a method according to any of the Claims 2 to 4, wherein the beta-lactam antibiotic agent is selected from the group consisting of penicillins, penems, carbapenems, cephems, and monobactams.
6. A pharmaceutical composition according to Claim 1 or a method according to Claims 2 to 4, wherein the beta-lactam antibiotic is selected from amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, meticillin, nafcillin, faropenem, biapenem,
ertapenem, doripenem, imipenem, meropenem, panipenem, cefazolin, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, ceftazidime, cefoperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline fosamil, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, carumonam, nocardicin A.
7. A pharmaceutical composition according to Claim 1 or a method according to Claims 2 to 4, wherein the beta-lactam antibiotic is selected from amoxicillin, cefixime, cefuroxime, cefpodoxime, cefaclor, cefprozil, cefdinir, cefditoren or a pharmaceutically acceptable derivative thereof.
8. A pharmaceutical composition according to Claim 1 or a method according to Claims 2 to 4, wherein the beta-lactamase inhibitor is selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
9. A pharmaceutical composition according to Claim 1, wherein beta-lactam antibiotic agent or a pharmaceutically acceptable derivative thereof is present in an amount of about 0.1 mg to about 3000 mg.
10. A pharmaceutical composition according to Claim 1, wherein the beta- lactamase inhibitor or a pharmaceutically acceptable derivative thereof is present in an amount of about 0.1 mg to about 3000 mg.
11. A pharmaceutical composition according to Claim 1, wherein mecillinam or a pharmaceutically acceptable derivative thereof is present in an amount of about 0.1 mg to about 3000 mg.
12. A pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
13. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically
acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
14. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) amoxicillin or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
15. A pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
16. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
17. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefixime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
18. A pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
19. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
20. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefuroxime or a pharmaceutically acceptable derivative
thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
21. A pharmaceutical composition useful for the treatment or control of bacterial infections, the composition comprising effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
22. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
23. A method for the treatment or control of bacterial infections, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising effective amounts of: (a) cefpodoxime or a pharmaceutically acceptable derivative thereof, (b) clavulanic acid or a pharmaceutically acceptable derivative thereof, and (c) mecillinam or a pharmaceutically acceptable derivative thereof.
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| NZ706734A NZ706734A (en) | 2012-09-03 | 2013-05-13 | Pharmaceutical compositions useful for the treatment or control of bacterial infections |
| US14/433,883 US20150258072A1 (en) | 2012-09-03 | 2013-05-13 | Antibacterial compositions |
| EP13732248.3A EP2934523A1 (en) | 2012-09-03 | 2013-05-13 | Antibacterial compositions |
| AU2013308128A AU2013308128B2 (en) | 2012-09-03 | 2013-05-13 | Antibacterial compositions |
| CN201380057333.1A CN104768547A (en) | 2012-09-03 | 2013-05-13 | Antibacterial compositions |
| ZA2015/02275A ZA201502275B (en) | 2012-09-03 | 2015-04-07 | Antibacterial compositions |
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| EP (1) | EP2934523A1 (en) |
| CN (1) | CN104768547A (en) |
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| WO2016081452A1 (en) * | 2014-11-17 | 2016-05-26 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
| US10500191B2 (en) | 2015-07-09 | 2019-12-10 | Washington University | Compositions and methods of use of antibacterial drug combinations |
| US10800778B2 (en) | 2016-09-16 | 2020-10-13 | Entasis Therapeutics Limited | Beta-lactamase inhibitor compounds |
| US11046694B2 (en) | 2017-05-08 | 2021-06-29 | Entasis Therapeutics, Inc. | Compounds and methods for treating bacterial infections |
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| CN106518702B (en) * | 2015-09-10 | 2019-03-22 | 北京大学 | Aspergillomarasmine element A and its derivative, synthetic method and application |
| WO2022198378A1 (en) * | 2021-03-22 | 2022-09-29 | 广州新创忆药物临床研究有限公司 | β-LACTAMASE INHIBITOR COMPOSITION WITH STABLE QUALITY, USE THEREOF AND METHOD THEREFOR |
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| AU5863894A (en) * | 1993-01-22 | 1994-08-15 | Smithkline Beecham Plc | Pharmaceutical formulations comprising clavulanic acid alone or in combination with other beta-lactam antibiotics |
| US5994340A (en) * | 1997-08-29 | 1999-11-30 | Synphar Laboratories, Inc. | Azetidinone derivatives as β-lactamase inhibitors |
| IT1317735B1 (en) * | 2000-01-26 | 2003-07-15 | Nicox Sa | SALTS OF ANTIMICROBIAL AGENTS. |
| CN1969846A (en) * | 2006-04-04 | 2007-05-30 | 陈旭良 | Pharmaceutical composition of mecillinam sodium and beta-lactamase inhibitor |
| CN101129382B (en) * | 2006-08-25 | 2013-12-25 | 天津和美生物技术有限公司 | Antibiotic compound containing beta-lactam antibiotic and buffering component |
| CN101003539A (en) * | 2007-01-16 | 2007-07-25 | 广东中科药物研究有限公司 | Trometamol salt in compound of cillin category, and preparation method |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016081452A1 (en) * | 2014-11-17 | 2016-05-26 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
| CN107108624A (en) * | 2014-11-17 | 2017-08-29 | 恩塔西斯治疗有限公司 | Combination treatment for treating drug resistant bacterial infections |
| US9968593B2 (en) | 2014-11-17 | 2018-05-15 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
| AU2015350128B2 (en) * | 2014-11-17 | 2019-05-16 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
| US10376499B2 (en) | 2014-11-17 | 2019-08-13 | Entasis Therapeutics Limited | Combination therapy for treatment of resistant bacterial infections |
| EA033829B1 (en) * | 2014-11-17 | 2019-11-29 | Entasis Therapeutics Ltd | Combination therapy for treatment of resistant bacterial infections |
| US10500191B2 (en) | 2015-07-09 | 2019-12-10 | Washington University | Compositions and methods of use of antibacterial drug combinations |
| US11559514B2 (en) | 2015-07-09 | 2023-01-24 | Washington University | Compositions and methods of use of antibacterial drug combinations |
| US10800778B2 (en) | 2016-09-16 | 2020-10-13 | Entasis Therapeutics Limited | Beta-lactamase inhibitor compounds |
| US11046694B2 (en) | 2017-05-08 | 2021-06-29 | Entasis Therapeutics, Inc. | Compounds and methods for treating bacterial infections |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2889793C (en) | 2017-09-26 |
| RU2646798C2 (en) | 2018-03-07 |
| CA2889793A1 (en) | 2014-03-06 |
| US20150258072A1 (en) | 2015-09-17 |
| CN104768547A (en) | 2015-07-08 |
| RU2015124175A (en) | 2017-01-10 |
| ZA201502275B (en) | 2016-11-30 |
| EP2934523A1 (en) | 2015-10-28 |
| AU2013308128A1 (en) | 2015-04-30 |
| AU2013308128B2 (en) | 2017-11-02 |
| NZ706734A (en) | 2016-05-27 |
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