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WO1996008258A1 - Composition antimicrobienne - Google Patents

Composition antimicrobienne Download PDF

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Publication number
WO1996008258A1
WO1996008258A1 PCT/FI1995/000493 FI9500493W WO9608258A1 WO 1996008258 A1 WO1996008258 A1 WO 1996008258A1 FI 9500493 W FI9500493 W FI 9500493W WO 9608258 A1 WO9608258 A1 WO 9608258A1
Authority
WO
WIPO (PCT)
Prior art keywords
rifampicin
bismuth
bismuth salt
rifamycin
antibiotic
Prior art date
Application number
PCT/FI1995/000493
Other languages
English (en)
Inventor
Timo Juhani Pekkanen
Original Assignee
Orion-Yhtymä Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orion-Yhtymä Oy filed Critical Orion-Yhtymä Oy
Priority to AU33884/95A priority Critical patent/AU3388495A/en
Publication of WO1996008258A1 publication Critical patent/WO1996008258A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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 antimicrobial pharmaceutical compositions and uses thereof for the treatment or prevention of staphylococcus infections. More particularly the invention relates to anti ⁇ microbial pharmaceutical compositions containing a bismuth salt and a rifamycin antibiotic agent for the treatment or prevention of staphylococcus infections.
  • Staphylococcus aur ⁇ us is encountered as a normal inhabitant of human skin and mucous membranes. However, it is responsible for a variety of clinical disorders in man and in animals ranging from pustules to fulminating septicemia.
  • rifamycin antibiotic agents such as rifabutin, rifamide, rifamycin sodium, rifapentine, rifaximin and rifampicin are complex macrocyclic antibiotics based on natural products of Streptomyces m ⁇ diterranei. They inhibit bacterial RNA synthesis by binding to DNA-dependent RNA polymerase.
  • 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.
  • Rifamycin antibiotics especially rifampicin
  • rifampicin have been used frequently for therapy of selected staphylococcal infections in animals and humans.
  • In vitro rifampicin is extremely active against staphylococci, the growth is usually inhibited by rifampicin concentrations ⁇ 0.03 ⁇ g/ml.
  • mutants resistant to rifampicin can be detected both in vitro and in vivo amongst most of the bacteria usually sensitive to rifampicin.
  • S. aur ⁇ us has a propensity to rapidly acquire resistance to rifampicin after exposure to the agent as monotherapy.
  • the resistance is usually the result of one-step mutation which alters the ⁇ -subunit of RNA-polymerase, reducing its binding affinity for rifampicin.
  • the rapid development of resistance when rifampicin is used alone is a serious problem and greatly limits the usefulness of rifampicin in the treatment of e.g. 5. aureus infections.
  • the successive use of rifampicin in e.g. serious staphylococcal infections depends on the elimination of resistant variants present in the bacterial population.
  • Colloidal bismuth subcitrate and bismuth subsalicylate have been found to be useful in combination with ⁇ itroimidazole by preventing the development of aquired nitroimidazole resistance of H ⁇ licobact ⁇ r pylori (Axon, A. T. R., J. Gastroenterol. Hepatol., 1991, 6/2, 131 - 137).
  • the purpose of this invention is to overcome the problem of rapid development of rifampicin resistance in Staphylococcus by combining a bismuth salt with a rifamycin antibiotic agent. Further the purpose of this invention is to prepare antimicrobial pharmaceutical compositions containing a rifamycin antibiotic and a bismuth salt and thereby to inhibit the development of resistance.
  • the present invention provides an antimicrobial pharmaceutical composition
  • a rifamycin antibiotic agent and a bismuth salt in an amount suppressing the development of rifampicin resistance in Staphylococcus.
  • Staphylococcus infections which may be treated are preferably local rather than systemic infections and include e.g. S. aureus and 5. epidermis.
  • compositions according to the invention include for example granulates, tablets, capsules, dragees, powders, ointments, gels, emulsions, suspensions and infusions (solutions) and can be administered for example orally, rectally, topically or by bladder infusion. Both agents are preferably administered concurrently, but the pharmaceutical effect of the present composition will be present if both agents exist concurrently for a certain duration in the body, particularly at the infection site.
  • the second of the two agents to be administered may be administered within the metabolic half life at the infection site of the first agent to be administered. So, the bismuth salt can be administered sequentially, separately or simultaneously with the rifamycin antibiotic. These two agents can be administered via different routes, for example rifamycin antibiotic orally and bismuth salt topically.
  • compositions according to the invention may be formulated and employed in the usual manner. These compositions are particularly well-suited for ophthalmic, otic or topical uses (gels, ointments, powders, sprays and aqueous or oily emulsions and suspensions), but could also find other applications.
  • topical use of bismuth salts is preferred. Systemic treatment of infections with bismuth salts is not recommended because of the possibility of serious side effects. Nausea and vomiting as well as darkening of the tongue have been reported. Further, the possibility of bismuth encephalopathy exists after prolonged use (Martindal ⁇ , The Extra
  • the concentration of a bismuth salt in a pharmaceutical preparation containing also rifampicin should be in the range of 5 - 3000 ⁇ g/ml e.g. 5 to 400 ⁇ g/ml. The effect is not concentration dependent and at low bacterial densities even a relatively low bismuth salt concentration may be sufficient.
  • the weight ratio of a bismuth salt to rifamycin is preferably between 1 :0.0003 - 1 :50 e.g. 1 :0.0003 to 1 :20, particularly 1 :0.0003 to 1:0.625.
  • compositions containing the active combination may also be used in veterinary medicine.
  • compositions according to the present invention are applicable also in the treatment of certain infections caused by either Staphylococcus or Ps ⁇ udomonas 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 agent is often Ps. aeruginosa or S. aureus. Because of the possibility that these two bacteria are simultaneously present at the infection site, the use of the present combination is especially advantageous for the treatment of this kind of infections / these kinds of infection.
  • FRI-1104 was obtained from Food Research Institute (FRI), Madison, USA and strains 2 - 12 (ATCC-12600, ATCC-8096, ATCC-25923, ATCC-25178, ATCC-8095, ATCC-27664, ATCC-13565, ATCC-19095, ATCC-14458, ATCC- 27154 and ATCC-6538) were obtained from American Type Culture Collection (ATCC), Maryland, USA. All strains were tested by the broth microdilution method for sensitivity of rifampicin. The minimum inhibitory concentration (MIC) was for all strains ⁇ 0.008 ⁇ g/ml. The strains were similarily tested for their sensitivity of bismuth subcitrate. The MIC for strain 5 was found to be 800 ⁇ g/ml and for the others the MIC-values were ⁇ 3200 ⁇ g/ml.
  • the success rate of developing rifampicin resistance after exposure to rifampicin, rifampicin together with bismuth subcitrate, bismuth subcitrate or nil was performed by suspending S. aureus organisms to a density of about 1- 10 10 cfu/ml in Mueller-Hinton (MH) broth containing 0.1 ⁇ g/ml rifampicin, 0.1 ⁇ g/ml rifampicin together with 400 ⁇ g/ml bismuth subcitrate, 400 ⁇ g/ml bismuth subcitrate or no additions, respectively.
  • MH Mueller-Hinton
  • the results are summarized in tables 1 and 2.
  • the first column (rif) in both tables shows the log cfu/ml of the 12 strains of S. aureus resistant to either 0.1 ⁇ g/ml (table 1) or 1 ⁇ g/ml (table 2) rifampicin recovered after exposure to 0.1 ⁇ g/ml rifampicin for 18 h over the log cfu/ml of total viable organisms.
  • the second column (rif+bic) shows correspondingly the log cfu/ml of the resistant organisms over the log cfu/ml of the total viable organisms after exposure to 0.1 ⁇ g/ml rifampicin together with 400 ⁇ g/ml bismuth subcitrate.
  • the third column (bic) shows the log cfu/ml of the rifampicin resistant staphylococci over the log cfu/ml of the total viable organisms after exposure to 400 ⁇ g/ml bismuth subcitrate only.
  • the fourth column (nil) shows the log cfu/ml of the rifampicin resistant organisms over the log cfu/ml of the total viable organisms after exposure only to MH-broth.
  • the MIC-values were obtained with an inoculum of 10 5 cfu/ml while the initial bacterial density in the exposure studies was about 10 10 cfu/ml.
  • the exposure of bismuth subcitrate alone did not significantly affect the total number of vialble organisms or have any clear effect on the number of rifampicin resistant organisms.
  • the comparison of the second (rif+bic) and the fourth (nil) columns in the tables shows that among most of the strains (except perhaps strains 11 and 12) the development of new resistant organisms was possibly totally inhibited by bismuth subcitrate.
  • bismuth subcitrate The effects of bismuth subcitrate were measured by using a maximum bismuth subcitrate concentration of 400 ⁇ g/ml on a bacterial density of about 10 10 cfu/ml. Higher concentrations were avoided because they could have generally suppressed the growth of staphylococci. To have an effect on the development of resistance bismuth salt must apparently react with the individual bacteria. The concentration of bismuth salt that is required for the effect seen thus obviously depends also on the number of bacteria in the study medium. Further, even relatively low bismuth subcitrate concentrations can suppress the emergence of resistance among staphylococci if the density of bacteria in the study system is low enough. Table 1.
  • a topical ointment or gel formulation according to the present invention is prepared by combining rifampicin (0.005 %) and bismuth subcitrate (0.02%) with an appropriate ointment or gel base and with necessary additives.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On peut traiter ou prévenir des infections par staphylocoques par l'administration séquentielle, séparée ou simultanée d'un sel de bismuth et d'un antibiotique de la famille rifamycine. La résistance à la rifamycine est inhibée.
PCT/FI1995/000493 1994-09-12 1995-09-12 Composition antimicrobienne WO1996008258A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33884/95A AU3388495A (en) 1994-09-12 1995-09-12 Antimicrobial composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9418345A GB2292884A (en) 1994-09-12 1994-09-12 Rifamycin & bismuth salts for treating bacterial infections
GB9418345.6 1994-09-12

Publications (1)

Publication Number Publication Date
WO1996008258A1 true WO1996008258A1 (fr) 1996-03-21

Family

ID=10761198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI1995/000493 WO1996008258A1 (fr) 1994-09-12 1995-09-12 Composition antimicrobienne

Country Status (3)

Country Link
AU (1) AU3388495A (fr)
GB (1) GB2292884A (fr)
WO (1) WO1996008258A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100572090B1 (ko) * 1998-02-24 2006-04-17 액티브 바이오틱스 인코포레이티드 상승작용이 있는 항균제 조성물, 그것을 함유하는 의약 및 소화기질환 치료제, 그들의 제조 방법, 및 그에 관련된 제제
RU2632766C1 (ru) * 2016-07-26 2017-10-09 Общество с ограниченной ответственностью "Медико-инженерный центр + 16" Антимикробный тимпанальный шунт

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000147A1 (fr) * 1993-06-28 1995-01-05 Merck & Co., Inc. INHIBITEURS DE L'ISOZYME 1 DE LA 4-AZA-PREGNANE 5α-REDUCTASE

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3650787T2 (de) * 1985-06-13 2006-11-16 Dr. Barry James Marshall Pharmazeutische Zusammensetzung zur Behandlung gastrointestinaler Beschwerden, die Wismut und ein antimikrobielles Mittel enthält
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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000147A1 (fr) * 1993-06-28 1995-01-05 Merck & Co., Inc. INHIBITEURS DE L'ISOZYME 1 DE LA 4-AZA-PREGNANE 5α-REDUCTASE

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J.CLIN.ENDOCRINOL.METAB., vol. 70, no. 4, 1990 pages 1136-41, 'Effects of finasteride (MK-906), a 5-alpha reductase inhibitor, on circulating androgens in male volunteers' *
METABOLISM, vol. 39, no. 9, 1990 pages 919-24, 'HDL response to 5-alpha dihydrotestosterone and testosterone in Macaca Fascicularis: a hormone-responsive primate model for the study of atherosclerosis' *
PHARMACOMETRICS, vol. 47, no. 3, 1994 'Androgen Osaterone Acetate (TZP-4238)' *

Also Published As

Publication number Publication date
AU3388495A (en) 1996-03-29
GB9418345D0 (en) 1994-11-02
GB2292884A (en) 1996-03-13

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