WO1996008259A1 - Composition antimicrobienne synergique - Google Patents

Composition antimicrobienne synergique Download PDF

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Publication number
WO1996008259A1
WO1996008259A1 PCT/FI1995/000494 FI9500494W WO9608259A1 WO 1996008259 A1 WO1996008259 A1 WO 1996008259A1 FI 9500494 W FI9500494 W FI 9500494W WO 9608259 A1 WO9608259 A1 WO 9608259A1
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Prior art keywords
bismuth
antibiotic
vancomycin
product according
salt
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PCT/FI1995/000494
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English (en)
Inventor
Timo Juhani Pekkanen
Original Assignee
Orion-Yhtymä Oy
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Publication date
Application filed by Orion-Yhtymä Oy filed Critical Orion-Yhtymä Oy
Priority to AU33885/95A priority Critical patent/AU3388595A/en
Publication of WO1996008259A1 publication Critical patent/WO1996008259A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof

Definitions

  • the present invention relates to synergistic, antimicrobial pharmaceutical compositions and uses thereof for the treatment or prevention of Pseudomonas infections. More particularly the invention relates to synergistic, antimicrobial pharmaceutical compositions for the treatment or prevention of Pseudomonas infections containing a bismuth salt and as an antibiotic agent either a rifamycin antibiotic, a sulfonamide, vancomycin or fusidic acid or pharmaceutically or veterinariiy acceptable salt thereof.
  • antimicrobial agents are subject of continuing research, much of which, in addition to the discovery of new agents, is directed to the discovery of means for the enhancement of the activity of known active agents.
  • Pseudomonas spp. are quite apathogenic to humans, they are very important in causing opportunistic infections particularly in hospitalized patients with severe underlaying illnesses.
  • Ps. aeruginosa the most pathogenic member of this group, is often associated with infections related to injured skin of burned patients, wounds on legs and bedsores. It may also occur in otitis media and in infections of the eye, the joints and the urinary, genitourinary and respiratory tracts.
  • Other infectious strains are Ps. fluoresc ⁇ ns, Ps. putida and Ps. cepacia.
  • Ps. aeruginosa In domestic animals similar infections caused by Pseudomonas spp, mainly Ps. aeruginosa are relatively common. Ps. aeruginosa is an important ⁇ tiologic factor with Staphylococcus aureus in otitis externa in dogs. Mastitis of dairy cows caused by Ps. aeruginosa is often a serious life threatening disease where treatment alternatives are very few.
  • Rifamycin antibiotics such as rifabutin, rifamide, rifamycin sodium, rifapentine, rifaximin and rifampicin are complex macrocyclic antibiotics based on natural products of Streptomyces mediterranei. They inhibit bacterial RNA synthesis by binding to DNA-dependent RNA poiymerase.
  • Rifampicin (chemically 3-4(4-methylpiperazinylimino-methylidene)-rifamycin SV) is an extremely efficient inhibitor of the bacterial enzyme. It inhibits the growth of most gram-positive bacteria, as well as many gram-negative microorganisms and mycobacteria. Although rifamycin antibiotic agents have quite broad spectrum anti-microbial activity, they lack the desired activity against Pseudomonas.
  • Rifampicin is readily absorbed from the gastrointestinal tract. After a single oral dose of 600 mg plasma peak concentrations of 7 to 9 ⁇ g/ml have been reported (Martindale, The Extra Pharmacopoeia, ed. by James E.F. Reynolds, 30th ed., The Pharmaceutical Press, London, 1993, p.199). On the other hand, the ratio of rifampicin concentration at the infection site e.g. in skin blisters to its concentration in serum is 1 :5 (Gerding, D.N. et al., 1991 , in
  • Vancomycin is an amphoteric glycopeptide produced by Streptomyces orientalis. It inhibits the synthesis of bacterial cell wall by inhibiting the peptidoglycan synthesis inside the bacterial cell. Vancomycin is active only against Gram-positive organisms, notably staphylococci, including ⁇ -lactamase-producing and methicillin-resistant strains, and streptococci.
  • Sulphonamides such as sulphadiazine and sulphafurazole, act as inhibitors of folic acid synthesis. They are active against a broad spectrum of bacteria. For example group A streptococci, pneumococci and Neisseria are highly susceptible and staphylococci moderately so. Pseudomonas aeruginosa, however, is usually resistant.
  • Fusidic acid is a steroidal antibiotic produced by the growth of certain strains of Fusidium coccineum. It inhibits bacterial protein synthesis by binding to elongation factor G which is necessary for translocation. Fusidic acid and its salts have been used successiveively in the treatment of staphylococcal infections in human and veterinary medicine especially topically in eye infections and infections of the skin. Fusidic acid and its salts however lack the desired activity against Pseudomonas.
  • Ps. aeruginosa R Bismuth salts such as subsalicylate and subcitrate have been demonstrated to have antibacterial action against some microorganisms, for example Clostridium difficile and Helicobacter pylori (Cornick, N. A. et al.; Reviews of Infectious Diseases, 1990, 12 (suppl. 1), s9 - s10 and Lee S.P.; Scand J. Gastroenterol., 1991 , 26 (suppl. 185), 1 - 6). The mechanism of this antibacterial activity is not known.
  • beta- lactam antibiotics the bacterial cell wall
  • aminogiycosides protein synthesis by binding to the bacterial ribosome
  • rifamycin antibiotics nucleic acid synthesis
  • vancomycin peptidoglycan synthesis
  • sulfoanamides folic acid synthesis
  • fusidic acid and its salts protein synthesis by inhibiting transiocation
  • the activity of rifamycin antibiotics, vancomycin, sulfonamides and/or fusidic acid and its pharmacologically or veterinarily acceptaple salts against Pseudomonas are enhanced by combining a bismuth salt with a rifamycin antibiotic, vancomycin, a sulfonamide or fusidic acid or its pharmacologically or veterinarily acceptaple salt.
  • the present invention also provides a synergistic antimicrobial pharmaceutical composition containing a bismuth salt and a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or pharmacologically or veterinarily acceptable salt thereof.
  • the present invention provides an antimicrobial pharmaceutical o composition
  • a bismuth salt and a rifamycin antibiotic or a bismuth salt and vancomycin or a bismuth salt and a suifonamide or a bismuth salt and fusidic acid or its pharmacologically or veterinarily acceptable salt in an amount having a synergistic effect against Pseudomonas spp.
  • compositions according to the invention include for 5 example granulates, tablets, capsules, dragees, powders, sprays, ointments, gels, emulsions, suspensions and infusions (solutions) and can be administered for example orally, rectally or topically. Both agents are preferably administered concurrently, but the pharmaceutical effect of the present composition will be present if both agents exist concurrently for a 0 certain duration in the body, particularly at the infection site. So, the bismuth salt can be administered separately from or simultaneously with the antibiotic agent. These two agents can be administered via different routes, for example antibiotic agent orally and bismuth salt topically.
  • compositions according to the invention may be 5 formulated and employed in the usual manner.
  • compositions are particularly well-suited for ophthalmic, otic or topical uses (gels, ointments, powders, sprays and aqueous or oily emulsions and suspensions) but could also find other applications.
  • topical use of bismuth salts is preferred. Systemic treatment of infections with bismuth o salts is not recommended because of the possibility of serious side effects.
  • Enhancement of the antibacterial activity of rifamycin antibiotics, vancomycin, sulfonamides and fusidic acid and its pharmaceutically or veterinarily acceptable salt in the treatment of Pseudomonas infections is one of the advantages achieved with the combined use of a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or veterinarily acceptable salt and a bismuth salt.
  • rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or o veterinarily acceptable salt and a bismuth salt When a rifamycin antibiotic or vancomycin or a suifonamide or fusidic acid or its pharmaceutically or o veterinarily acceptable salt and a bismuth salt are used together, they produce a synergistic effect which permits a reduction in the dosage of one or both drugs with achievement of a similar therapeutic effect and the combination produces a more rapid or complete bactericidal effect than could be achieved with either drug alone.
  • compositions according to the present invention are applicable also in the treatment of certain infections caused by either Staphylococcus or Pseudomonas such as hospital infections which in many instances are extremely resistant to antibiotics.
  • the most common hospital infections are the urinary tract and wound infections where the causative 0 agent is often Ps. aeruginosa or S. aureus. Because of the possibility that these two bacteria are simultaneously present in the infection site, the use of the present combination is especially advantageous for the treatment of this kind of infections.
  • otitis externa 5 which is often caused by Ps. aeruginosa or S. aureus. Because of the difficulty of reliable laboratory diagnosis it is advantageous to treat the infection with the present combination which has a good effect on both types of bacteria.
  • the pharmaceutical composition of the present invention exhibit o synergistic antimicrobial activity against Pseudomonas. It has been found that in order to obtain the desired synergistic antimicrobial activity in accordance with the present invention the ratio (by weight) of rifampicin to bismuth subcitrate should be in the range of 1 :1.6 to 1 : 13333, preferably 1 :25 to 1 :200, the ratio (by weight) of vancomycin to bismuth subcitrate should be in 5 the range of 1 :444 to 10:1 , preferably 1 :6 to 1 :2, the ratio (by weight) of sulphadiazine to bismuth subcitrate should be in the range of 1 :2162 to 1:2, preferably 1 :34 to 1 :42 and the ratio (by weight) of sodium fusidate to bismuth subcitrate should be in the range of 1 :512 to 64:1 , preferably 1 :2 to 4:1.
  • (1g BiC contains about 185 mg
  • the preferred bismuth salt used in accordance with the present 5 invention is bismuth subcitrate.
  • Other bismuth salts which may be used include bismuth subnitrate, bismuth subsalicylate.
  • Rifampicin (R ' rf) stock solution was prepared daily in absolute methanol 20 and appropriately diluted with Mueller-Hinton broth.
  • Bismuth subcitrate (BiC) powder was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
  • the MICs ( ⁇ g/ml) of bismuth subcitrate and rifampicin and FIC-indexes at the range of synergism in addition to the lowest MlC-values of rifampicin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of rifampicin/bismuth subcitrate at o the observed range of synergism are presented in table 1.
  • ATCC-43390 1600 32 0.25 - 0.37 0.125/800 1 :400 - 1 :1.6
  • the MIC of rifampicin for Pseudomonas strain EK 81 was determined as above in example 1 but having in the wells of each tray 50, 100, 200, 400 or 800 ⁇ g/ml bismuth subcitrate.
  • ATCC American Type Culture Collection
  • EK Cold of Veterinary Medicine, Helsinki, Finland
  • This strain was choked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
  • Vancomycin (Va) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily.
  • Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
  • Pseudomonas aeruginosa strains were cultivated and the MIC- and
  • FlC-values were determined as described in example 1.
  • the MICs ( ⁇ g/ml) of bismuth subcitrate and vancomycin and FIC- indexes at the range of synergism in addition to the lowest MlC-values of vancomycin when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of vancomycin/ bismuth subcitrate at the observed range of synergism are presented in table 3.
  • the lowest MIC of vancomycin when combined with bismuth subcitrate was 1.8 ⁇ g/ml. This was 5 obtained when the concentration of bismuth subcitrate was 800 ⁇ g/ml.
  • MlC-values of vancomycin were compared with the respective values of vancomycin with bismuth subcitrate, 8 to 278 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
  • the ratio of vancomycin to bismuth subcitrate varied between 1:444 to 10:1 at the observed range of 0 synergism. The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
  • vancomycin is useful antibiotic in the treatment of Pseudomonas infections if it is combined with proper amount of bismuth subcitrate. Also in infections where the simultaneous presence of 5 Pseudomonas and Staphylococci is suspected or when it is not known which of the bacteria are involved the combined use of vancomycin and bismuth subcitrate is advantageous.
  • ATCC-27853 >6400 >500 0.27 - 0.46 31.25/400 1:12.5-10:1
  • ATCC- 14210 6400 >500 0.07 - 0.25 31.25/1600 1:51 -10:1
  • ATCC- 15692 3200 >500 0.125-0.16 31.25/400 1:13-5:1
  • Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
  • Sulphadiazine (SDZ) stock solution was prepared and appropriately diluted with Mueller-Hinton broth daily.
  • Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above.
  • the poor solubility of other bismuth salts prevented their testing. Further, because of the complexity of the synergy assay, only sulphadiazine was chosen for testing.
  • Pseudomonas aeruginosa strains were cultivated and the MIC- and FlC-vaiues determined as decribed in example 1.
  • the MICs ( ⁇ g/ml) of bismuth subcitrate and sulphadiazine and FIC- indexes at the range of synergism in addition t ⁇ the lowest MlC-values of sulphadiazine when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sulphadiazine/ bismuth subcitrate at the observed range of synergism are presented in table 4.
  • the lowest MIC of sulphadiazine when combined with bismuth subcitrate was 0.74 ⁇ g/ml. This was obtained when the concentration of bismuth subcitrate was 1600 ⁇ g/mi.
  • MlC-values of sulphadiazine were compared with the respective values of sulphadiazine with bismuth subcitrate, 32 to 270 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
  • the ratio of sulphadiazine to bismuth subcitrate varied between 1 :2162 to 1 :2 at the observed range of synergism.
  • concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
  • ATCC- 14204 6400 400 0.02 • 0.25 1.48/1600 1 :42 - 1 :1081
  • ATCC-9027 6400 95 0.01 - 0.13 1.48/25 1 :18 - 1 :1081
  • Pseudomonas aeruginosa strains were used in the experiment. Seven were ATCC (American Type Culture Collection) strains isolated from human infections and one was EK (College of Veterinary Medicine, Helsinki, Finland) strain originated from animal infection. This strain was cheked by morphological characteristics and conventional biochemical methods to be Pseudomonas aeruginosa.
  • Sodium fusidate (SF) stock solution was prepared daily in distilled water and appropriately diluted with Mueller-Hinton broth.
  • Bismuth subcitrate (BiC) power was brought into solution with 1 N NaOH and further diluted as above. The poor solubility of other bismuth salts prevented their testing.
  • the MICs ( ⁇ g/ml) of bismuth subcitrate and sodium fusidate and FIC- indexes at the range of synergism in addition to the lowest MlC-values of 5 sodium fusidate when used with bismuth subcitrate and the corresponding concentration of bismuth subcitrate together with the ratios of sodium fusidate/ bismuth subcitrate at the observed range of synergism are presented in table 5.
  • the lowest MIC of sodium fusidate when combined with bismuth subcitrate was 3.6 ⁇ g/m. This was obtained when the concentration of bismuth subcitrate was 800 ⁇ g/ml.
  • MlC-values of sodium fusidate were compared with the respective values of sodium fusidate with bismuth 0 subcitrate, 8 to 444 fold increase in the sensitivity of Ps. aeruginosa strains was observed.
  • the ratio of sodium fusidate to bismuth subcitrate varied between 1 :512 to 64:1 at the observed range of synergism. The concentrations of bismuth subcitrate necessary for synergism were below the corresponding MICs of bismuth subcitrate for these microbes.
  • ATCC-9027 6400 6400 0.03 - 0.26 50/1600 1 :32 - 8:1
  • the MlC-values of sodium fusidate for three Pseudomonas aeruginosa strains were determined as above in example 5 but having in the wells of each tray 50, 100, 200, 400 or 800 ⁇ g/ml bismuth subcitrate.
  • the MlC-values of sodium fusidate and bismuth subcitrate for the strains used in this experiment are: Strain MIC SF ⁇ g/ml MIC BiC ⁇ g/ml
  • a gel formulation according to the present invention is prepared by combining rifampicin (0.001 - 0.1 %) and bismuth subcitrate (0.1 -0.5 %) with a suitable gel base containing for example a carboxyvinyl polymer as a gel former.
  • An ophtalmic formulation according to the present invention is prepared by combining sodium fusidate (0.01 - 0.1 %), bismuth subcitrate (0.1 - 0.5 %) and other necessary ingredients with an aqueous phosphate buffer solution.

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Abstract

Composition antimicrobienne synergique destinée au traitement ou à la prévention d'infections par Pseudomonas et contenant un sel de bismuth et, en tant qu'agent antibiotique, soit un antibiotique de la famille rifamycine, soit de l'acide fusidique ou son sel utilisable dans les domaines pharmaceutique et vétérinaire.
PCT/FI1995/000494 1994-09-12 1995-09-12 Composition antimicrobienne synergique WO1996008259A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33885/95A AU3388595A (en) 1994-09-12 1995-09-12 Synergistic antimicrobial composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9418346A GB2293323A (en) 1994-09-12 1994-09-12 Antibiotics and bismuth salts for treating bacterial infections
GB9418346.4 1994-09-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6362169B1 (en) * 1998-02-24 2002-03-26 Kaneka Corporation Antibacterial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith
US10201518B2 (en) 2016-09-28 2019-02-12 The University Of Hong Kong Bismuth(III) compounds and methods thereof
WO2023063827A1 (fr) * 2021-10-15 2023-04-20 Omnicin Therapeutics B.V. Composition synergique contre pseudomonas aeruginosa

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007842A1 (fr) * 1986-06-17 1987-12-30 Biogen N.V. Combinaisons d'interferons gamma et d'agents anti-inflammatoires ou anti-pyretiques et procede de traitement de maladies
WO1994018967A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Traitements de maladies caracterisees par la neovascularisation
WO1994018968A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Procedes de traitement de l'arteriosclerose

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EP0462631B1 (fr) * 1985-06-13 1996-03-20 Barry James Dr. Marshall Procédés et composés pour le traitement des désordres gastro-instestinaux
CN1057001A (zh) * 1991-07-13 1991-12-18 沈阳市红旗制药厂 肠炎灵胶囊剂的制备方法
CN1080529A (zh) * 1992-06-23 1994-01-12 沈阳市光华兽药厂 杀痢宝的制造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007842A1 (fr) * 1986-06-17 1987-12-30 Biogen N.V. Combinaisons d'interferons gamma et d'agents anti-inflammatoires ou anti-pyretiques et procede de traitement de maladies
WO1994018967A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Traitements de maladies caracterisees par la neovascularisation
WO1994018968A1 (fr) * 1993-02-18 1994-09-01 President And Fellows Of Harvard College Procedes de traitement de l'arteriosclerose

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Title
ACTA PHARM.TURC., vol. 31, no. 2, 1989 pages 49-52, 'Studies on the stability of clotrimazole in simulated gastric and intestinal media' *
NETH.J.PLANT PATHOL., vol. 83, no. 1, 1977 pages 39-47, *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6362169B1 (en) * 1998-02-24 2002-03-26 Kaneka Corporation Antibacterial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith
US10201518B2 (en) 2016-09-28 2019-02-12 The University Of Hong Kong Bismuth(III) compounds and methods thereof
US10624871B2 (en) 2016-09-28 2020-04-21 The University Of Hong Kong Bismuth(III) compounds and methods thereof
WO2023063827A1 (fr) * 2021-10-15 2023-04-20 Omnicin Therapeutics B.V. Composition synergique contre pseudomonas aeruginosa

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GB2293323A (en) 1996-03-27
AU3388595A (en) 1996-03-29
GB9418346D0 (en) 1994-11-02

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