WO1996029071A1 - Utilisation de composes antibacteriens - Google Patents

Utilisation de composes antibacteriens Download PDF

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Publication number
WO1996029071A1
WO1996029071A1 PCT/US1996/003778 US9603778W WO9629071A1 WO 1996029071 A1 WO1996029071 A1 WO 1996029071A1 US 9603778 W US9603778 W US 9603778W WO 9629071 A1 WO9629071 A1 WO 9629071A1
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Prior art keywords
compounds
antibacterial
compound
tissue
contact
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PCT/US1996/003778
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English (en)
Inventor
Tomer Sivron
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Ramot University Authority For Applied Research & Industrial Development Ltd.
Dippert, William, H.
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Application filed by Ramot University Authority For Applied Research & Industrial Development Ltd., Dippert, William, H. filed Critical Ramot University Authority For Applied Research & Industrial Development Ltd.
Priority to AU54260/96A priority Critical patent/AU5426096A/en
Publication of WO1996029071A1 publication Critical patent/WO1996029071A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention concerns novel uses of adherent antibacteri ⁇ al compounds in medical treatments.
  • the invention is particularly drawn to the compounds "TA” and its derivatives, such as "Focusin”.
  • the present invention also concerns medical devices coated by these compounds.
  • Myxobacteria are Gram-negative, rod-shaped bacteria commonly found in soil and decay vegetation (Kaiser et al., 1979). Myxobacteria are generally a rich source for antibacterial agents that exhibit a wide range of chemical structures, mode of action and anti-microbial spectrum (Rosenberg and Varon, 1984).
  • M. xanthus TA produces a broad spectrum antibacterial agent when grown under nutritionally limited conditions, during the end of its exponential growth phase.
  • This antibacterial agent disclosed in Rosenberg, U.S. Patent No. 3,973,005, was termed "TA", and is capable of inhibiting growth of a variety of Gram-positive and Gram-negative bacteria (Dworkin & Kaiser, 1985; Rosenberg et al , 1973).
  • the growth inhibition is caused by lysis of growing bacteria as a result of blocking cell wall synthesis at the stage of polymerization of the lipid disaccharide- pentapeptide (Rosenberg et al , 1973; Zafriri et al. , 1981).
  • This mechanism of growth inhibition differs from the mechanism of the ⁇ -lactam antibiotics, which are the major type of antibiotics in use today.
  • strains which have developed resistance to ⁇ -lactams are not resistant to the TA antibacterial agent.
  • TA is a molecule with a molecular weight of 623.4 dalton, and having the molecular formula C 3S H 6] 0 8 N (see below for its structure). TA binds tightly to a variety of tissues and hard surfaces and retains its activity while in the bound form (Manor et al., 1985; Rosenberg et al. , 1984). For example, TA binds to dental hard and soft tissues, which allowed the use of this antibiotic to treat severe gingivitis and to reduce plaque in humans (Manor et al., 1989).
  • One of the disadvantages of the TA antibiotic is that it loses its activity following simultaneous exposure to air and light (Rosenberg et al. , 1982).
  • Focusin an improved derivative of TA, named “Focusin ", has been prepared and found to be more stable and adherent than the parent compound. This derivative is described in Applicant's co-pending Patent Application No. USSN 08/332,964. Focusin was found to have a similar activity spectrum to that of TA although with a somewhat lower specific activity. However, Focusin was found to be much more stable to light and air exposure than the TA antibiotic. Focusin further has a higher aqueous solubility than TA and it also adheres more strongly than TA to a variety of surfaces and is released therefrom more slowly than TA. Like TA, Focusin adheres to soft tissues and hard surfaces, and it retains its bactericidal activity in the bound form.
  • H. pylori infection of the stomach lining is now regarded as one of the major etiological factors in the pathogenesis of inflammation of the stomach lining (gastritis) and of duodenal and gastric ulcers. H. pylori may also be implicated in the development of gastric malignancy such as gastric lymphoma.
  • a panel of experts convened by the U.S. National Institutes of Health has recently noted that aggressive antibiotic regimens can "markedly decrease the recurrence rate of ulcers" (ASM News, 1994).
  • Recurrent tonsillitis is a major cause of morbidity as well as worker and student absenteeism. Approximately 40% of tonsillectomies performed are as a result of recurrent tonsillitis. This disease is usually treated using long term prophylactic systemic antibiotics. Such treatments are not always advisable since they often result in undesirable side effects. Although it would be preferable to prevent bacterial inoculation on the tonsil surface by local application of antibiotics, no treatment has been described as vet which involves coatinq the tonsil surface with an adherent antibiotic substance.
  • an antibacterial compound or a derivative thereof having antibacterial properties and having an inherent ability to adhere to solid or semi-solid substrates.
  • a preferred compound is the antibacterial compound TA having the following formula:
  • a preferred derivative compound is Focusin having the following formula:
  • Me represents a methyl group.
  • antibacterial compound Such adherent antibacterial compounds, and particularly TA and its derivatives, especially Focusin, will at times be referred to herein collectively as "said antibacterial compound”.
  • a method of medical treatment involving the use of said antibacterial compound, wherein the method comprises applying an effective amount of said compound to the surface of a tissue.
  • effective amount should be understood as meaning an amount of said antibacterial compound sufficient to bring about a bactericidal activity.
  • the compound is used to treat diseased tissue.
  • the compound is applied to the gastric mucosa in order to treat gastric inflammations such as gastritis and gastric ulcer, as will be more particularly described below.
  • the compound is applied to the eye for the treatment of eye infections, or to the ear for the treatment of Otitis media.
  • the above antibacterial compound can be applied through other means to other tissues or to the same tissue affected by other diseases which can be advantageously treated by an adhered antibacterial agent which is slowly released over a period of time.
  • the compound is used to prevent a tissue at risk from becoming diseased.
  • the compound is sprayed on the tonsils of a patient suffering from recurring tonsillitis.
  • the said antibacterial compound may be used to prevent bodily odors, e.g. in the armpit, caused by bacteria.
  • a method of preventing infections involving the use of said antibacterial compound comprising coating the surfaces of a medical device which comes into contact with the body with said com- pounds, the surfaces coming into contact with surrounding body tissues or fluids on employment of the device.
  • the medical device is a urinary catheter intended for insertion into the urethra.
  • the external and internal surfaces of the catheter are coated by said antibacterial compound which adheres to the catheter's surface and is slowly released over a period of time, thus inhibiting growth of bacteria at the contact area of the catheter with the surrounding tissue.
  • This slow- release property is especially important in the use of indwelling catheters.
  • the medical device is a stent.
  • contact lenses are coated with said bacterial compound to prevent eye infections frequently caused by the use of such lenses or to treat an existing infection. It will be understood, however, by the skilled man of the art that other medical devices which are wholly or partially inserted into bodily cavities and whose inserted parts come into contact with the surrounding body tissue can also be coated by said antibacterial compounds in accordance with the invention.
  • the present invention also provides a medical device which comes into contact with the body, wherein the surfaces of the device which come into contact with surrounding body tissues or fluids on employment of said device are coated with said antibacterial compound.
  • the present invention further provides an antibacterial conjugate comprising a first said antibacterial compound, and a second non-adherent antimicrobial compound, wherein the conjugate retains the adherent properties of the first antibacterial compounds.
  • the second antimicrobial compound has an activity selected from the group comprising antifungal, antiviral and antibacterial activities.
  • the antimicrobial activity spectrum of the conjugate includes the combined spectrums of each of the component compounds, and the adherent properties of the first antibacterial compound are imparted to the second non-adherent compound.
  • the above conjugate may be used in all of the methods described above for use with said antibacterial compounds.
  • the present invention takes advantage of the inherent adhesive properties of said antibacterial compound which obviate the necessity for using auxiliary means to bind the antibacterial substance to a substrate. Although the said compound strongly adheres to solid or semi solid substrates, it is slowly released from the substrate over a prolonged period of time thereby lengthening the effective period of action. This mode of action is unique in that until now, sustained released properties were, as a rule, achieved by virtue of the choice of an appropriate carrier. Since said antibacterial compound has the unique characteristic of being capable of binding to soft tissue as well as to hard surfaces, this compound can find use both in in situ application to body tissues, as well as with various medical instruments. The wide spectrum of activity exhibited by said compound allows it to be used in the treatment of a large number of bacterial infections.
  • Some examples of diseases potentially and advantageously treatable by said antibacterial compound include otitis media infection of the ears, acute and chronic sinusitis, chronic gingivitis, recurrent tonsillitis, eye infections, burns and other local skin infections.
  • the compound can be applied to the tissue by spraying, or by creams, drops or pills. Since the compound exerts its activity locally, low concentrations are sufficient, lessening the possibility of side effects and lowering the cost of the treatments. The adhesiveness and slow release properties of said compound means that only a small number of treatments at a low frequency will be required.
  • Some examples of solid substrates capable of being coated by said antibacterial compound include plastic and silicone tubing used for catheters and IV lines, as well as stents.
  • the amount of antibiotic required per device e.g. catheter or stent
  • the amount of antibiotic required per device would be very low, making the coating process relatively inexpensive.
  • the direct contact of the coated surfaces with the surrounding tissue, such as the urethra, can result in some of the compound adhering to these tissues, resulting in improved antibacterial protection.
  • Fig. 1 shows the amount of TA ( ⁇ ), Focusin (+) and Ampicillin (*) absorbed to a polystyrene surface, release to a medium within several time intervals;
  • Fig. 2 shows the amount of TA ( ⁇ ) and Focusin (+) absorbed onto polystyrene surfaces, released to a medium within several time intervals
  • Fig. 3 shows the effect of the antibacterial agents' concentration on the ratio of antibiotic bound to polystyrene versus that which was released ("bound/released"): Fig. 3a - TA antibiotic; Fig. 3b - Focusin.
  • Escherichia coli ESS Kan r is a kanamycin resistant strain of
  • E.coli ESS derived by transducing E.coli ESS with Pl :TnV, KanM This strain was used for the standard antibiotic assays.
  • Other strains which were used were the following:
  • Salmonella thyphimorium Erv.>inia herbicolla, Serratia marcescens, Providencia strautii and Proteus vulgaris, Enterobacter,
  • Kleb iella Gr47 Klebsiella pneumoniae, Klebsiella sp., Citrobacter diversus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli K-12, Bacillus suhtilis and Staphylococcus alhus and Mycobacterium smegmatis, Helicohacter pylori. 2. Media and growth conditions
  • E.coli ESS Kan r was maintained by periodic transfer of single colonies for overnight incubation on LB Kan agar at 37°C, followed by further storage at 10°C for 4-6 weeks.
  • LB Kan medium is 1% Tryptone (Difco Laboratories, Detroit Michigan U.S.A.) containing 0.5% Yeast Extract (Difco), 0.5% NaCl (Merck & Co. Inc. Rahway, New Jersey U.S.A.) and 50 ⁇ g/ml Kanamycin monosulfate (Sigma Chemical Company, St. Louis, U.S.A.).
  • LB Kan medium was solidified by 1.5% Bacto agar (Difco).
  • Nutrient Broth agar plates were used.
  • NB medium is 0.8% Nutrient Broth (Difco) containing 0.5% NaCl (Merck).
  • NB was solidified by 1.8% Bacto agar (Difco).
  • the NB plates were overlaid by 3.5 ml NB soft agar (0.9% Bacto agar) mixed with 0.1 ml E.coli ESS Kan r overnight culture.
  • Antibiotic activity against E.coli ESS Kan r was determined by the paper disc filter assay (Loo et al, 1945). Unknown quantities of antibiotic TA or Focusin, dissolved in ethanol, saline or NB were applied to paper disc filters (6 mm diameter; Schleicher and Schull). After allowing the ethanol to evaporate in the hood for about 15 mins, the dry filters were placed on nutrient broth plates which had been overlaid with an overnight culture of E.coli ESS Kan r as described above.
  • the diameter of the zone of inhibition was recorded after 18 hours incubation at 37°C.
  • the concentration of the antibacterial agents were determined from a standard inhibition curve prepared with known quantities of TA and Focusin. 4. Testing for antimicrobial spectrum of TA and Focusin
  • Saturated solutions of TA and Focusin were prepared by adding 1.14 ⁇ g TA and 7 ⁇ g Focusin to 1 ml LB (final cone, of 1% ethanol). About 10 s bacteria of various strains were then added. The control was bacteria in the same medium with no antibacterial agents. The bacteria were introduced at 37°C with shaking at 100 ⁇ m. When the control became turbid, viable cell count was performed on LB agar plates. Growth inhibition is presented as percentage of the no antibiotic control.
  • the antibacterial agents (Focusin and TA) dissolved in ethanol were applied to small polystyrene petri dishes (3 cm diameter) and the ethanol was allowed to evaporate over a period of 15 minutes in a hood. For control, ethanol without the agents was applied to such dishes. To each petri dish, 1 ml of a nutrient broth was added. The petri dishes were then incubated at 37°C at 50 rpm in a shaking device
  • NB was removed and a fresh NB was added.
  • a solution of 100% ethanol was added to the petri dishes in order to extract the residual antibacterial agents that remained stuck to the polystyrene.
  • the E.coli cells Prior to the performance of the disc assay, the E.coli cells were killed by the application of 20 ⁇ of ethanol onto the disc, so as not to disrupt the bioassay.
  • mice Two mice were sacrificed by exposure to ether.
  • the bladder, eyes, intestines, lungs, heart, teeth, liver, spleen and kidneys were removed by dissection.
  • Each experimental set consisted of three test tubes.
  • a piece of each tissue type was placed in each of the three test tubes.
  • the amount of tissue per tube were as follows: bladder Vfe, eye ⁇ _, intestine 1 cm, lung 2, heart Va, fang tooth l ⁇ , liver V3, spleen Vfe and kidney Vi.
  • One test tube contained a control tissue which was treated only with the solvent used for dissolving the antibacterial agent, usually 50% ethanol.
  • the second and third test tubes contained tissues were treated with 4 ⁇ g TA or 20 ⁇ g Focusin, respectively.
  • the tissues were allowed to dry in a hood for 30 mins., and then placed in the test tubes.
  • One milliliter of sterile saline was then added to each test tube and the tubes were then incubated with shaking (50 rpm) at 37°C for one hour.
  • the amount of antibacterial agent that was released to the saline was measured following chloroform extraction by the disc filter assay.
  • the tissues were then transferred to exponentially growing cultures of E.coli ESS in NB at a concentration of 10 5 cells/ml. Incubation was at 37°C and continued for 5 hours, following which the number of viable cells was checked.
  • Focusin was tested in the same manner as that described above (under 6.1) with the exception that the tissues in the test tube were washed four times with a solution of 1 ml sterile saline. Each saline wash was for 1 hour at 37°C. Following incubation, the washing saline solution was added to an exponentially growing cultures of E.coli ESS in a concentration of 10 5 cells/ml.
  • the cultures with the saline wash were incubated al 37°C for 6 hours and then viable cell count was performed in order to estimate the amount of killing by the antibacterial agent that were released from the tissues. After the four washes the tissues were transferred to 10 5 E.coli ESS log cultures and were then incubated for 5 hours. The tissues were transferred in this way for three times, each time the percentage of inhibition by the treated tissue was measured by viable count.
  • Klebsiella pneumoniae 100 96
  • H. pylori which is implicated in gastritis
  • Streptococcus which is implicated in tonsillitis
  • Bacteria such as E. coli and S. albus, which are often implicated in urinary tract infections (UTI)
  • UTI urinary tract infections
  • Kidney 3.9 100 ⁇ 3.8 100
  • the patient having known gastric disease associated with H. pylori will need to be made achlohydric prior to the treatment. This can be done, for example, by giving the patient 20mg of Omeprazole twice a day for 3 days. On the third day, an upper gastrointestinal endoscopy (gastroscopy) is performed. The presence of H. pylori is confirmed by a biopsy CLO test, and the presence of a p ⁇ greater than 6 in the stomach is confirmed by testing a gastric aspirate taken at gastroscopy.
  • the pylorus is blocked off using a Gruntzig balloon.
  • the stomach is then emptied and slightly expanded with air, after which TA or
  • Focusin is sprayed through the endoscope canal in 20 separate squirts, each squirt comprising 0.05ml of TA in a water/alcohol (50:50 V/V) solution of 3mg/ml, as follows:
  • the Gruntzig balloon is deflated and the gastroscope is removed.
  • the residual presence of H. pylori is determined using a C 14 urea breath test.
  • Otis media of the car is one of the most common causes of morbidity in children. Approximately 30% of children with fever seen in regular pediatric practice are diagnosed as suffering from this disease. Eye infections are less frequent, but are nevertheless quite prevalent in both children and adults.
  • antibiotics are generally applied by ear/eye drops 2 to 3 times daily for a period of 1-2 weeks.
  • treatment of the above infections with said antibacte ⁇ rial compound could involve only a single application, due to its inherent adhesiveness and slow release properties.
  • One example of a formulation would be 1-5 mg/ml of said antibacterial compound in 50% DMSO + 1% ethyl alcohol.
  • One embodiment of a therapeutic procedure for the prevention of recurring tonsillitis comprises spraying said antibacterial compound onto the tonsils once every month, for a period of four months.
  • the compound can be sprayed directly onto the tonsils after the patient performs a few deep expirations in order to dry the tonsils of saliva.
  • Each treatment may consist, for example, of spraying a 0.4 ml aliquot of a 2.5 mg/ml solution of antibacterial compound in 50% ethanol.
  • Underarm odor is known to result from, inter alia, axillary odorless precursor molecules such as testosterone being metabolized by axillary bacteria into odorous compounds.
  • Axillary microflora include micrococci, staphyloaocci, anaerobic propionibacteria, and aerobic and anaerobic gram-positive coryneform bacteria. The latter are believed to play an important role in the production of axillary odorous compounds.
  • the compound can be used for the purpose of killing off sensitive axillary bacteria.
  • a Focusin or TA alcoholic solution at a concentration of 5-10 mg/ml is periodically (once every 2-4 weeks) sprayed under the armpits at a dosage of 1-5 mg per spray. Once sprayed, the alcohol evaporates leaving the active compound adhered to the axillary skin.
  • FIG. 3 depicting the effect of the antibacterial agent concentration on the bound/released ratio of the antibiotic to polystyrene.
  • Fig. 3a shows that as the TA concentration increases, the amount of bound TA decreases; against this, as can be seen in Fig. 3b, the Focusin binding showed an increase bound/released ratio with an increase in concentration.
  • the catheter is dipped at room temperature in an alcoholic solution of 2-10 mg/ml of Focusin or TA, so that the entire catheter is coated by 1-5 mg of compound.
  • the active antibacterial compound forms a uniform coating on the inner and outer surfaces of the catheter.
  • the Focusin or TA antibiotic is expected to adhere to the catheter and urethral epithelium for a period of 4-21 days.
  • Standard urethral catheterization including lubrication with Ezracain gel 2%, or other hydrophilic lubricants, and the catheter's balloon is inflated to fix the catheter tip in the bladder.
  • attachment and replacement of the urine collection bag is carried out while maintaining full sterility of the area between the catheter and the urine bag by use of an antiseptic solution.
  • contact lens wear Approximately 20% of eye infections are associated with contact lens wear. A majority of these infections are caused by gram-negative bacteria, and a minority by gram-positive bacteria. The most frequently implicated bacteria are Pseudomonas sp., Staphylococcus epidermidis and Corynebacterium sp. Only about 3% of contact lens associated eye infections are caused by fungi.
  • Contact lenses can be periodically coated with said antibacterial compound so as to avoid contact lens associated eye infections. For example, the lenses may be coated once every 2-4 weeks, preferably by dipping them in a solution containing 1-5 mg of compounds such as Focusin or TA.
  • therapeutic lenses can be coated with said compounds for the pu ⁇ ose of treating an existing eye infection.
  • the lenses will preferably be precoated by dipping (0.1-0.5 mg compound per lens) and distributed as such under medical prescription.
  • an additional novel use of said antibacterial compound is by the chemical attachment of an additional compound.
  • a second, different antibiotic could be linked to Focusin or TA.
  • This second antibiotic which is normally non-adherent and diffusible, will become adherent due to its being conjugated to said antibacterial compound, and will be slowly released together with said compound.
  • the antimicrobial activity spectrum of said antibacterial compound can be greatly expanded by the expedient choice of the second antibiotic. Furthermore, the chance that a bacterial strain will appear that is resistant to the conjugated antimicrobial substance will be very small.
  • the added antibiotic may have antibacterial, antifungal, and/or antiviral properties.
  • An example of a chemical reaction which can be used to conjugate a second antimicrobial compound to said antibacterial compound is a simple procedure in which a ketone group of Focusin or TA is transformed into an enol ether which is bound to the second compound.
  • Antibiotic TA an adherent antibiotic, Biotechnology, 2:796- 799.

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Abstract

Cette invention concerne l'utilisation de composés antibactériens tel que des composés TA, lesquels possèdent des qualités d'adhésion inhérentes et correspondent à la formule (I), ainsi que de leurs dérivés, tel que la Focusine, ces derniers correspondant à la formule (II). Tous ces composés possèdent des qualités inhérentes d'adhésion à des substrats solides ou semi-solides, ces propriétés présentant des avantages dans divers cas de thérapies. Les composés décrits ci-dessus peuvent être utilisés, par exemple, lors d'un procédé de traitement médical durant lequel on applique une quantité suffisante pour être efficace de ces composés à la surface d'un tissu ou à proximité d'un site de tissu malade pouvant être traité à l'aide desdits composés. L'application localisée de ces composés peut également servir à prévenir l'infection du tissu. Ces composés peuvent également servir dans un autre procédé permettant de prévenir les infections, procédé dans lequel on applique un revêtement desdits composés sur les surfaces d'un instrument médical entrant en contact avec le corps. Cette invention concerne également un instrument médical revêtu de ces composés.
PCT/US1996/003778 1995-03-21 1996-03-21 Utilisation de composes antibacteriens WO1996029071A1 (fr)

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US7654997B2 (en) 2004-04-21 2010-02-02 Acclarent, Inc. Devices, systems and methods for diagnosing and treating sinusitus and other disorders of the ears, nose and/or throat
US7771409B2 (en) 2004-04-21 2010-08-10 Acclarent, Inc. Devices, systems and methods useable for treating sinusitis
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