[go: up one dir, main page]

WO1996008258A1 - Composition antimicrobienne - Google Patents

Composition antimicrobienne Download PDF

Info

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
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/FI1995/000493
Other languages
English (en)
Inventor
Timo Juhani Pekkanen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orion Oyj
Original Assignee
Orion Yhtyma 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 Yhtyma Oy filed Critical Orion Yhtyma Oy
Priority to AU33884/95A priority Critical patent/AU3388495A/en
Publication of WO1996008258A1 publication Critical patent/WO1996008258A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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.

Landscapes

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

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 Ceased 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
GB9418345.6 1994-09-12
GB9418345A GB2292884A (en) 1994-09-12 1994-09-12 Rifamycin & bismuth salts for treating bacterial infections

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 Ceased 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
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
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
ATE81010T1 (de) * 1985-06-13 1992-10-15 Barry James Marshall Zusammensetzungen zur behandlung von magendarmst¯rungen.
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
GB2292884A (en) 1996-03-13
GB9418345D0 (en) 1994-11-02

Similar Documents

Publication Publication Date Title
JP2676080B2 (ja) 非抗バクテリア性テトラサイクリン組成物
MANGI et al. Development of meningitis during cephalothin therapy
RU2560846C1 (ru) Фармацевтические композиции, содержащие сулбактам и ингибитор бета-лактамазы
JPH0780774B2 (ja) 薬剤組成物
Yeldandi et al. In-vitro and in-vivo studies of trimethoprim-sulphamethoxazole against multiple resistant Staphylococcus aureus
Hoppe et al. Comparison of erythromycin ethylsuccinate and co-trimoxazole for treatment of pertussis
Scheld et al. Comparison of netilmicin with gentamicin in the therapy of experimental Escherichia coli meningitis
Guerrant et al. Nosocomial bloodstream infections caused by gentamicin-resistant gram-negative bacilli
Elwell et al. In vitro and in vivo efficacy of the combination trimethoprim-sulfamethoxazole against clinical isolates of methicillin-resistant Staphylococcus aureus
Kuenzi et al. Postantibiotic effect of roxithromycin, erythromycin, and clindamycin against selected gram-positive bacteria and Haemophilus influenzae
Figueredo et al. Synergy of ciprofloxacin with fosfomycin in vitro against Pseudomonas isolates from patients with cystic fibrosis
JPH07188030A (ja) 薬剤の製造のためのモエノマイシンおよびその誘導体並びにこれらを含有する薬剤
Yogev et al. In vitro activity of antibiotics alone and in combination against Actinobacillus actinomycetemcomitans
CN109481439A (zh) 包含抗菌剂和他唑巴坦的组合物
CN1054745C (zh) 抗菌组合物
WO1996008258A1 (fr) Composition antimicrobienne
US3949077A (en) Synergistic antibiotic compositions
Fremaux et al. In-vitro antibacterial activity of RP 59500, a semisynthetic streptogramin, against Streptococcus pneumoniae
Iravani et al. Effects of changes in pH, medium, and inoculum size on the in vitro activity of amifloxacin against urinary isolates of Staphylococcus saprophyticus and Escherichia coli
CN112438989B (zh) 一种非抗生素类抗菌组合物及其应用
Day et al. Increased susceptibility of Pseudomonas aeruginosa to ciprofloxacin in the presence of vancomycin
VilmGnyi et al. Clarithromycin pharmacokinetics after oral administration with or without fasting in crossbred beagles
WO1996008259A1 (fr) Composition antimicrobienne synergique
Ekwo et al. Effect of clindamycin on aminoglycoside activity in a murine model of invasive Escherichia coli infection
EP2771016B1 (fr) Primycine et ses constituants pour une utilisation destinée au traitement ou à la prévention d'infections provoquées par des pathogènes spécifiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KZ LT LU LV MK MX NO NZ PL PT RO RU SE SI SK UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase