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WO2005018701A1 - Compositions antimicrobiennes synergiques et procedes d'inhibition de la formation de biofilms - Google Patents

Compositions antimicrobiennes synergiques et procedes d'inhibition de la formation de biofilms Download PDF

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Publication number
WO2005018701A1
WO2005018701A1 PCT/CA2004/001477 CA2004001477W WO2005018701A1 WO 2005018701 A1 WO2005018701 A1 WO 2005018701A1 CA 2004001477 W CA2004001477 W CA 2004001477W WO 2005018701 A1 WO2005018701 A1 WO 2005018701A1
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WO
WIPO (PCT)
Prior art keywords
composition
catheter
group
iron
ovotransferrin
Prior art date
Application number
PCT/CA2004/001477
Other languages
English (en)
Inventor
Srinivasa Madhyastha
Original Assignee
Kane Biotech Inc.
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
Priority claimed from CA002452032A external-priority patent/CA2452032C/fr
Priority claimed from US10/781,464 external-priority patent/US7314857B2/en
Application filed by Kane Biotech Inc. filed Critical Kane Biotech Inc.
Publication of WO2005018701A1 publication Critical patent/WO2005018701A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/50—Isolated enzymes; Isolated proteins
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/044—Proteins; Polypeptides; Degradation products thereof
    • A61L29/048—Other specific proteins or polypeptides not covered by A61L29/045 - A61L29/047
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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

  • This invention relates to synergistic antimicrobial compositions which inhibit biofilm formation on or in medical devices such as catheters as well as other devices.
  • Biofilms are medically and industrially important because they can accumulate on a wide variety of substrates and are resistant to antimicrobial agents and detergents. Microbial biofilms develop when microorganisms irreversibly adhere to a surface and produce extracellular polymers that facilitate adhesion and provide a structural matrix. Therefore inhibiting adhesion to surfaces is important. This surface may be inert, non-living material or living tissue.
  • Biof ⁇ lm-associated microorganisms behave differently from planktonic (freely suspended) organisms with respect to growth rates and ability to resist antimicrobial treatments and therefore pose a public health problem.
  • Many chronic infections that are difficult or impossible to eliminate with conventional antibiotic therapies are known to involve biofilms.
  • a partial list of the infections that involve biofilms includes: otitis media, prostatitis, vascular endocarditis, cystic fibrosis pneumonia, meliodosis, necrotising faciitis, osteomyelitis, peridontitis, biliary tract infection, struvite kidney stone and host of nosocomial infections (Costerton, J.W., et al., Science, 284:1318-1322, 1999).
  • Biofilms on indwelling medical devices may be composed of gram-positive or gram-negative bacteria or yeasts. Bacteria commonly isolated from these devices include the gram-positive Enterococcus faecalis (E.faecalis), Staphylococcus epidermidis (S. epidermidis) , Staphylococcus aureus (S. aureus), Streptococcus viridans (St. viridans); and the gram- negative Escherichia coli (E.coli), Klebsiella pneumoniae (K. pneumoniae), Proteus mirabilis (P. mirabilis) and Pseudomonas aeruginosa (P.
  • aeruginosa (Oonlw ⁇ , R.M., Emerging Infectious Diseases, 7:277-281, 2001).
  • the organisms most commonly isolated from urinary catheter biofilms are Staphylococcus epidermidis, Enter ococcus faecalis, E. coli, Proteus mirabilis, Pseudomonas aeruginosa and Klebsiella pneumoniae.
  • Urinary catheters and central venous catheters are notorious examples of infection prone devices.
  • Catheter-associated urinary tract infection is the most common nosocomial infection. Each year, more than 1 million patients in US hospitals acquire such an infection.
  • Catheter- associated urinary tract infection is the second most common cause of nosocomial infections (Maki, D.G. and P.A. Tambyah., Emerging Infectious Diseases, 7:1-6, 2001).
  • antimicrobial agents are of varying chemical composition and can include chelating agents (EDTA, EGTA, DTP A, etc.), cationic polypeptides (protamine, polylysine, lysozyme, etc.), surfactants (SDS, Tween- 80TM, surfactin, etc.), quaternary ammonium compounds (benzalkonium chloride, tridodecyl methyl ammonium chloride, didecyl dimethyl ammonium chloride, etc.).
  • chelating agents EDTA, EGTA, DTP A, etc.
  • cationic polypeptides protamine, polylysine, lysozyme, etc.
  • surfactants SDS, Tween- 80TM, surfactin, etc.
  • quaternary ammonium compounds benzalkonium chloride, tridodecyl methyl ammonium chloride, didecyl dimethyl ammonium chloride, etc.
  • the iron- sequestering glycoproteins such as lactoferrin from milk and ovotransferrin (conalbumin) from egg white are iron-binding glycoproteins, which inhibit the growth of certain bacteria by making iron unavailable for bacterial metabolism (Bezkorovainy, A., Adv. Exp. Med. Biol. 135:139-154, 1981).
  • the main methods of antimicrobial catheter preparation include immersion or flushing, coating, drug-polymer conjugate and impregnating (Tunny, M.M., et al., Rev. Med. Microbiol., 74: 195-205, 1996).
  • suitable catheters can be treated by immersion immediately prior to placement, which offers flexibility and control to clinicians in certain situations.
  • Several studies have examined the clinical efficacy of catheters coated with antimicrobial agents. Polyurethane catheters coated with minocycline and EDTA showed potential in reducing recurrent vascular catheter-related infections (Raad, 1. 1, et al., Clinical Infectious Diseases, 25: 149-151, 1997).
  • Minocycline and rifampin coatings have been shown to significantly reduce the risk of catheter- associated infections (Raad, LI. et al., Crit. Care Med., 26: 219-224, 1998).
  • Minocycline coated onto urethral catheters has been shown to provide some protection against colonization (Darouiche, R.O., et al., Int. J. Antimicrob. Ag. 8: 243-247,1997).
  • Johnson, et al. described substantial in vitro antimicrobial activity of a commercially available nitrofurazone coated silicone catheter (Johnson, J.R., et al., Antimicrob. Agents. Chemother. 43: 2,990-2,995,1999).
  • silver-containing compounds as antimicrobial coatings for medical devices has been widely investigated.
  • Silver-sulfadiazine used in combination with chlorhexidine has received particular interest as a central venous catheter coating (Stickler, D.J., Curr. Opin. Infect. Dis., 13:389-393, 2000; Darouiche, R.O., et al., New Eng. J. Med., 340: 1-8,1999).
  • the loading of antimicrobial agents into medical devices by immersion or coating technologies has the advantage of being relatively simple. However, the limited mass of drug that can be incorporated may be insufficient for a prolonged antimicrobial effect, and the release of the drug following clinical insertion of the device is rapid and relatively uncontrolled.
  • a means of reducing these problems is by direct incorporation of the antimicrobial agent into the polymeric matrix of the medical device at the polymer synthesis stage or at the device manufacture stage.
  • Rifampicin has been incorporated into silicone in an attempt to prevent infection of cerebrospinal fluid shunts with some success (Schierholz, J.M., et al., Biomaterials, 18: 839-844,1997), and hexetidine in PVC was observed to decrease bacterial colonization (Jones, D.S., et al., Pharm. Res., 19: 818-824,2002).
  • Iodine has also been incorporated into medical device biomaterials.
  • Coronary stents have been modified to have antithrombogenic and antibacterial activity by covalent attachment of heparin to silicone with subsequent entrapment of antibiotics in cross-linked collagen bound to the heparinised surface (Fallgren, C, et al., Zent.Fur Bakt.-hit. J. Med. Micro. Vir., Paraotol. Infect. Dis., 287:19-31,1998).
  • Charter, E.A., et al. disclosed a composition consisting of avidin, ovotransferrin, chicken immunoglobulins, chitosan, polylysine, protamine, nisin, EDTA, rosemary, cinnemaldehyde, allicin and eugenol for inhibiting the growth of microoraganisms on fruit, vegetable, turfgrass and other plant systems by the application of specific enzymes either alone or in combination with fungicidally active agents (US Pat. Application No. 20020001582, 2002).
  • Welle, C.J., et al. disclosed the method of preparing a kit for flushing a medical device.
  • the kit includes a solution containing an antibiotic, an anticoagulant (protamine sulfate) and an antithrombotic agent or chelating agent useful for preventing infections caused by bacterial growth in catheters.
  • an antibiotic an anticoagulant (protamine sulfate) and an antithrombotic agent or chelating agent useful for preventing infections caused by bacterial growth in catheters.
  • Budny, J.A. et al. discloses various antimicrobial agents for anchoring to biofilms (US Patent Application No. 20020037260, 2002).
  • Raad, et al, in US Patent No. 5,362,754 (1994) disclosed that pharmaceutical compositions of a mixture of minocycline and EDTA were useful in maintaining the patency of a catheter port. Recently, Raad, I. and R. Sheretz in US Patent No.
  • one aspect of the invention provides a composition comprising: (a) a small amount of at least one iron-sequestering glycoprotein; and (b) a sparing amount. of at least one cationic polypeptide, wherein the amount of each components (a) and (b) is sufficient to form, in combination, a synergistic, antimicrobial composition, hi yet another alternative embodiment, a composition of the invention comprises: (a) a small amount of at least one iron-sequestering glycoprotein and (b) a sparing amount of at least one chelating agent, wherein the amount of each of components (a) and (b) is sufficient to form, in combination, a synergistic antimicrobial composition, hi yet another alternative embodiment, a composition of the invention comprises: (a) a small amount of at least one iron-sequestering glycoprotein, (b) a sparing amount of at least one cationic polypeptide and (c) a sparing amount of at least one chelating agent, wherein the amount of each of
  • the invention provides a composition for inhibiting bacterial biofilm on devices comprising: an iron-sequestering glycoprotein; a cationic polypeptide; and a chelating agent.
  • the composition is effective against biofilms produced by bacterial species selected from the group consisting of Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus epidermidis.
  • the composition is effective against biofilms produced by gram-negative bacterial species selected from the group consisting of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and Pseudomonas aeruginosa.
  • the composition is effective against biofilms produced by gram-positive bacterial species selected from the group consisting of Enterococcus faecalis and Staphylococcus epidermidis.
  • the invention also provides a composition for inhibiting bacterial biofilm on devices comprising an iron-sequestering glycoprotein; and a cationic polypeptide.
  • the composition is effective against biofilms produced by bacterial species selected from the group consisting of Staphylococcus epidermidis, Enterococcus faecalis, E.
  • composition is particularly effective against biofilms produced by bacterial species selected from the group consisting of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae Pseudomonas aeruginosa and Staphylococcus epidermidis.
  • the invention further teaches a composition for inhibiting bacterial biofilm on devices comprising: an iron-sequestering glycoprotein; and a chelating agent.
  • the composition is effective against biofilms produced by bacterial species selected from the group consisting of Staphylococcus epidermidis, Enterococcus faecalis, E.
  • the composition is particularly effective against biofilms produced by Staphylococcus epidermidis.
  • the iron-sequestering glycoprotein is between about 125 mg/L and about 2000 mg/L of the composition.
  • the cationic polypeptide is between about 12.5 mg/L and about 200 mg/L of the composition.
  • the chelating agent is between about 12.5 mg/L and about 200 mg/L of the composition.
  • the iron-sequestering glycoprotein may be selected from the group consisting of ovotransferrin, lactoferrin and serotransferrin.
  • the cationic polypeptide may be selected from the group consisting of protamine sulfate, polylysine, defensin, lactoperoxidase and lysozyme.
  • the chelating agent may be selected from the group consisting of Ethylenediaminetetraacetate (EDTA), Ethyleneglycolbis(aminoethlyl)tetraacetate (EGTA), Diethylenetriaminepentaacetic acid (DTPA), Ethylenediaminedi(o-hydroxyphenylacetic) acid (EDDHA), Iminodiacetic acid (IDA), Cyclohexanediaminotetraacetic acid (CDTA), Hydroxyethylethylenediaminetetraacetic acid (HEDTA), Hydroxyethylnitrilodiacetic acid (HEIDA) and Nitrilotetraacetate (NTA).
  • EDTA Ethylenediaminetetraacetate
  • EGTA Ethyleneglycolbis(aminoethlyl)tetraacetate
  • DTPA Diethylenetriaminepentaacetic acid
  • ETDHA Ethylenediaminedi(o-hydroxyphenylacetic) acid
  • the iron-sequestering agent is ovotransferrin
  • the cationic polypeptide is protamine sulfate
  • the chelating agent is EDTA.
  • the ovotransferrin may be present at about 2 mg/ml
  • the protamine sulfate may be present at about 0.2 mg/ml
  • the EDTA may be present at about 0.2 mg/ml.
  • the composition may further comprise one or more ingredients selected from the group consisting of: water, a binding or bonding or coupling agent, a surfactant, a quaternary ammonium compound, an antibiotic and a pH adjuster.
  • the invention also teaches methods of preparing a device comprising treating at least a surface of the device with the composition of the invention.
  • the invention also teaches methods of preparing a device comprising coating a device with the composition of the invention.
  • the method may further comprise treating the device with quaternary ammonium compound before coating the device with the composition.
  • the quaternary ammonium compound may be selected from the group consisting of tridodecylmethyl ammonium chloride and benzalkonium chloride.
  • the composition may further comprise hydrogel.
  • the hydrogel may be selected from the group consisting of polyvinylpyrrolidone-hydrogel, polyvinyl alcohol-hydrogel and polyethylene glycol-hydrogel.
  • the treated device may be a medical device.
  • the device may be a catheter.
  • the catheter may be an indwelling catheter.
  • the indwelling catheter may be selected from a group consisting of a central venous catheter, a peripheral intravenous catheter, an arterial catheter, a haemodialysis catheter, an umbilical catheter, precutaneous nontunneled silicone catheter, a cuffed tunneled central venous catheter and a subcutaneous central venous port.
  • the catheter may be selected from a group consisting of urinary catheter and a peritoneal catheter.
  • the device may be selected from the group consisting of catheters, pacemakers, prosthetic heart valves, prosthetic joints, voice prostheses, contact lenses, and intrauterine devices.
  • the device may be selected from the group consisting of pipes, heat exchangers and computer chips.
  • the invention also teaches methods of preparing a device comprising incorporating the composition of the invention into polymers which are used to form the device, and methods of preparing a device comprising impregnating the composition of the invention into the device.
  • Figure 1 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by E. coli.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 2 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by Enterococcus faecalis.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 3 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by Klebsiella pneumoniae.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 4 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by Pseudomonas aeruginosa.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 5 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by Proteus mirabilis.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 6 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA (ethylenediaminetetraacetate) alone and in combinations (OT+PS, OT+EDTA & PS+EDTA) on biofilm formation by Staphylococcus epidermidis.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA ethylenediaminetetraacetate
  • Figure 7 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by E. coli.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA EDTA alone and in combination
  • Figure 8 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by Enterococcus faecalis.
  • Figure 9 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by Pseudomonas aeruginosa.
  • Figure 10 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by Klebsiella pneumoniae.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA EDTA alone and in combination
  • Figure 11 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by Proteus mirabilis.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA EDTA alone and in combination
  • Figure 12 is a bar graph showing the effects of ovotransferrin (OT), protamine sulfate (PS) and EDTA alone and in combination (OT+PS+EDTA) on biofilm formation by Staphylococcus epidermidis.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA EDTA alone and in combination
  • Figure 13 shows the effects of synergistic composition on biofilm formation by Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus epidermidis in a catheter.
  • the present inventor has found that an unexpectedly high level of synergy occurs in antimicrobial compositions that contain at least one iron-sequestering glycoprotein, one cationic polypeptide and one chelating agent.
  • the synergy is evidenced by the small quantities of each of these compounds that need to be used to produce an effective antimicrobial composition. The necessary overall amount of the compounds is less than that which would be required if any of the compounds were to be used on their own.
  • Synergy was found with antimicrobial compositions that contain at least one iron-sequestering glycoprotein with at least one cationic polypeptide or at least one chelating agent.
  • the present invention teaches synergistic antimicrobial compositions offering superior anti- biofilm activity, containing combinations of iron-sequestering glycoproteins with other antimicrobial agents, such as, for example, cationic polypeptides and/or chelating agents with quaternary ammonium compounds or surfactants.
  • the invention also teaches the use of synergistic antimicrobial composition in immersing or flushing or coating devices, such as catheters to inhibit biofilm formation.
  • the compositions can also be incorporated into polymers which are -used to form the devices such as catheters by impregnating or by drug- polymer conjugation.
  • the synergistic antimicrobial compositions require remarkably small amounts of active ingredients (compared to that which has been used in the fast) to be effective. Because such small amounts of active ingredients need to be used for these inventive synergistic antimicrobial compositions, the compositions are medically safe and environmentally friendly. These compositions have properties that include those of the separate compounds but go beyond them in efficacy and scope of application. The extremely low levels, and hence increased efficacy, of the active compounds or ingredients make this invention very desirable.
  • Novel compositions that combine iron-sequestering glycoprotein together with cationic polypeptides and/or chelating agents such that lesser quantities of iron-sequestering glycoprotein, cationic polypeptides and /or chelating agents than would normally be necessary for an antimicrobial composition are used to achieve significant biofilm inhibition. Higher concentrations of these compounds can be used if it is desired for certain applications.
  • the amount of iron-sequestering glycoprotein to be used in the synergistic antimicrobial composition of this invention can be between 125 to 2000 mg/L. The higher end of this stated range might be used to prepare a concentrated product that would be diluted prior to use.
  • the amount of iron-sequestering glycoprotein to be used in this invention is preferably between about 125 to 1000 mg/L.
  • the amount of cationic polypeptide to be used should be between about 12.5 to 200 mg/L. The higher end of this range might apply if the compositions were formulated as a concentrate.
  • the amount of cationic polypeptide to be used in this invention is preferably between about 12.5-100 mg/L.
  • the amount of chelating agent to be used should be between about 12.5 to 200 mg/L. The higher end of this range might apply if the compositions were formulated as a concentrate.
  • the amount of chelating agent to be used in this invention is preferably between about 12.5-100 mg/L.
  • a three-component composition containing a chelating agent, a cationic polypeptide and an iron-sequestering glycoprotein
  • these compounds can be combined in the following manner.
  • a chelating agent can be dissolved in water.
  • a cationic polypeptide can be added thereafter, followed by an iron-sequestering glycoprotein. It should be noted, however, that the addition order is not critical.
  • chelating agent and cationic polypeptide such as, EDTA (ethylenediaminetetraacetate) and protamine sulfate, respectively are not readily soluble in water, they are preferably added to the composition in small amounts and stirred well. It may be necessary to adjust the pH preferably to 7.4 in order to make EDTA readily soluble.
  • a composition of the invention comprises: (a) a small amount of at least one iron-sequestering glycoprotein; and (b) a sparing amount of at least one compound from the group consisting of a quaternary ammonium compounds and /or a surfactant, wherein, the amount of each of components (a) and (b) is sufficient to form, in combination, a synergistic antimicrobial composition.
  • the present invention includes adding an effective amount of composition to the surface of an object. This coating prevents the formation of biofilm on the surface, while showing moderate effect on the viability of microbes.
  • the moderate effect on the viability of microbes can be attributed to biologically acceptable non-lethal compounds in the composition, which include iron-sequestering ovotransferrin and protamine sulfate.
  • Lethal compounds such as silver or antibiotics often create selective pressure to increase the likelihood of amplifying silver-resistant or antibiotic resistant strains, thus rendering the antibiofilm agents useless. This is an important consideration when the object to be coated is a medical device that will be implanted in the body, where resident bacteria exist.
  • the apparatus and method of the present invention uses composition to prevent biofilm formation. The effect of composition on biofilm formation by catheter-associated bacterial strains on microtiter plates and on vinyl urethral catheters was investigated.
  • bacteria that produce biofilms include bacteria such as Staphylococcus epidermidis, Enterococcus faecalis, E. coli, Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus viridans . These bacteria are commonly found associated with medical devices including catheters.
  • Other bacteria producing biofilms which may be inhibited by the compositions of the present invention include Klebsiella oxytoca, Staphylococcus saprophyticus, Providentia stuartii and Serratia marcescens.
  • Examples of devices that can be protected using the compositions of the invention include tubings and other medical devices, such as catheters, pacemakers, prosthetic heart valves, prosthetic joints, voice prostheses, contact lenses, intrauterine devices.
  • Medical devices include disposable or permanent catheters, (e.g., central venous catheters, dialysis catheters, long-term tunneled central venous catheters, short-term central venous catheters, peripherally inserted central catheters, peripheral venous catheters, pulmonary artery Swan-Ganz catheters, urinary catheters, and peritoneal catheters), long-term urinary devices, tissue bonding urinary devices, vascular grafts, vascular catheter ports, wound drain tubes, ventricular catheters, hydrocephalus shunts heart valves, heart assist devices (e.g., left ventricular assist devices), pacemaker capsules, incontinence devices, penile implants, small or temporary joint replacements, urinary dilator, cannulas, elastomers, hydrogels, surgical
  • Medical devices also include any device which may be inserted or implanted into a human being or other animal, or placed at the insertion or implantation site such as the skin near the insertion or implantation site, and which include at least one surface which is susceptible to colonization by biofilm embedded microorganisms.
  • the composition of the invention is integrated into an adhesive, such as tape, thereby providing an adhesive which may prevent growth or proliferation of biofilm embedded microorganisms on at least one surface of the adhesive.
  • Medical devices for the present invention include surfaces of equipment in operating rooms, emergency rooms, hospital rooms, clinics, and bathrooms.
  • Implantable medical devices include orthopedic implants which may be inspected for contamination or infection by biofilm embedded microorganisms using endoscopy.
  • Insertable medical devices include catheters and shunts which can be inspected without invasive techniques such as endoscopy.
  • the medical devices may be formed of any suitable metallic materials or non-metallic materials known to persons skilled in the art. Examples of metallic materials include, but are not limited to, tivanium, titanium, and stainless steel, and derivatives or combinations thereof.
  • non-metallic materials include, but are not limited to, thermoplastic or polymeric materials such as rubber, plastic, polyesters, polyethylene, polyurethane, silicone, GortexTM (polytetrafluoroethylene), DacronTM (polyethylene tetraphthalate), TeflonTM (polytetrafluoroethylene), latex, elastomers and DacronTM sealed with gelatin, collagen or albumin, and derivatives or combinations thereof.
  • the medical devices include at least one surface for applying the composition of the invention. Preferably, the composition of the invention is applied to the entire medical device.
  • composition of the invention may include any number of active components and base materials known to persons skilled in the art. While the active components discussed herein may be 100% of the composition of the invention, preferably, the composition contains from at least about 0.01% to about 60% of the active components by weight based upon the total weight of the composition of the invention being employed, the preferred embodiment, the composition includes from at least about 0.5% to about 30% (by weight) active components.
  • compositions include, but are not limited to, buffer solutions, phosphate buffered saline, saline, water, polyvinyl, polyethylene, polyurethane, polypropylene, silicone (e.g., silicone elastomers and silicone adhesives), polycarboxylic acids, (e.g., polyacrylic acid, polymethacrylic acid, polymaleic acid, poly-(maleic acid monoester), polyaspartic acid, polyglutamic acid, aginic acid or pectimic acid), polycarboxylic acid anhydrides (e.g., polymaleic anhydride, polymethacrylic anhydride or polyacrylic acid anhydride), polyamines, polyamine ions (e.g., polyethylene imine, polyvinylarnine, polylysine, poly-(dialkylamineoethyl methacrylate), poly- (dialkylaminomethyl styrene) or poly-(vinylpyridine)), polyammonium
  • buffer solutions
  • the term "effective" is herein defined as a sufficient amount of the active components to substantially prevent the growth or proliferation of biofilm embedded microorganisms on the at least one surface of the medical device in the case of the composition of the invention being a coating; and as a sufficient amount of the active components to substantially penetrate, or break-up, the biofilm on the at least one surface of the medical device, thereby facilitating access of the active components, antimicrobial agents, and/or antifungal agents to the microorganisms embedded in the biofilm, and thus, removal of substantially all of the microorganisms from at least one surface of the medical device in the case of the composition of the invention being a solution.
  • the amount will vary for each of the active components and upon known factors such as pharmaceutical characteristics; the type of medical device; the degree of biofilm embedded microorganism contamination; and the use and length of use.
  • the invention is directed to a method for coating a medical device.
  • the method for coating a medical device includes the steps of providing a medical device, providing, or forming, a composition coating, and applying the composition coating to at least one surface of the medical device in an amount sufficient to substantially prevent the growth or proliferation of biofilm embedded microorganisms on at least one surface of the medical device.
  • the method for coating a medical device includes the steps of forming a composition of the invention of an effective concentration for activating the active components, and thus substantially preventing the growth or proliferation of microorganisms on at least one surface of the medical device, wherein the composition of the invention is formed by combining a active components and a base material. At least one surface of the medical device is then contacted with the composition of the invention under conditions wherein the composition of the invention covers at least one surface of the medical device.
  • Contacting includes, but is not limited to, impregnating, compounding, mixing, integrating, coating, spraying and dipping.
  • the invention in another aspect relates to a method for inhibiting biofilm embedded microorganisms from at least one surface of the medical device.
  • the method of inhibiting biofilm from at least one surface of the medical device includes the steps of providing a medical device having at least one surface, the at least one surface having biofilm attached thereto, and contacting the medical device with a composition as described in greater detail above. "Contacting” further includes, but is not limited to, soaking, rinsing, flushing, submerging, and wasliing.
  • the medical device should be contacted with the composition for a period of time sufficient to remove substantially all of the biofilm from the at least one surface of the medical device.
  • the medical device is submerged in the composition for at least 5 minutes.
  • the medical device may be flushed with the composition, hi the case of the medical device being a tubing, such as dental drain tubing, the composition may be poured into the dental drain tubing and both ends of the tubing clamped such that the composition is retained within the lumen of the tubing. The tubing is then allowed to remain filled with the composition for a period of time sufficient to remove substantially all of the microorganisms from at least one surface of the medical device, generally, for at least about 1 minute to about 48 hours. Alternatively, the tubing may be flushed by pouring the composition into the lumen of the tubing for an amount of time sufficient to prevent substantially all biofilm growth.
  • the concentration of active components in the compositions may vary as desired or necessary to decrease the amount of time the composition of the invention is in contact with the medical device. These variations in active components concentration are easily determined by persons skilled in the art.
  • the step of forming a composition of the invention may also include any one or all of the steps of adding an organic solvent, a medical device material penetrating agent, or adding an alkalinizing agent to the composition, to enhance the reactivity of the surface of the medical device with the composition.
  • the organic solvent, medical device material penetrating agent, and/or alkalinizing agent preferably facilitate adhesion of the composition to at least one surface of the medical device.
  • the composition coating is preferably fo ⁇ ned by combining a active components and a base material at room temperature and mixing the composition for a time sufficient to evenly disperse the active agents in the composition prior to applying the composition to a surface of the device.
  • the medical device may be contacted with the composition for a period of time sufficient for the composition to adhere to at least one surface of the device. After the composition is applied to a surface of the device, it is allowed to dry.
  • the device is preferably placed in contact with the composition by dipping the medical device in the composition for a period of time ranging from about 5 seconds to about 120 minutes at a temperature ranging from about 25°C to about 80°C.
  • the device is placed in contact with the composition by dipping the medical device in the composition for about 60 minutes at a temperature of about 45°C.
  • the device is then removed from the composition and the composition is allowed to dry.
  • the medical device may be placed in an oven, or other heated environment for a period of time sufficient for the composition to dry.
  • the composition is believed to provide the desired composition coating
  • multiple layers are preferred.
  • the multiple layers of the composition are preferably applied to the at least one surface of the medical device by repeating the steps discussed above.
  • the medical device is contacted with the composition three times, allowing the composition to dry on at least one surface of the medical device prior to contacting the medical device with the composition for each subsequent layer.
  • the medical device preferably includes three coats, or layers, of the composition on at least one surface of the medical device.
  • the method for coating medical devices with a composition coating includes the steps of forming a composition coating of an effective concentration to substantially prevent the growth or proliferation of biofilm on at least one surface of the medical device by dissolving the active components in an organic solvent, combining a medical device material penetrating agent to the active components and organic solvent, and combining an alkalinizing agent to improve the reactivity of the material of the medical device.
  • the composition is then heated to a temperature ranging from about 30°C to about 70°C to enhance the adherence of the composition coating to at least one surface of the device.
  • the composition coating is applied to at least one surface of the medical device, preferably by contacting the composition coating to the at least one surface of the medical device for a sufficient period of time for the composition coating to adhere to at least one surface of the medical device.
  • the medical device is removed from the composition coating and allowed to dry for at least 8 hours, and preferably, overnight, at room temperature.
  • the medical device may then be rinsed with a liquid, such as water and allowed to dry for at least 2 hours, and preferably 4 hours, before being sterilized.
  • the medical device may be placed into a heated environment such as an oven.
  • the method for coating the medical devices with a composition includes the steps of fo ⁇ ning the composition and incorporating the composition into the material forming the medical device during the formation of the medical device.
  • the composition may be combined with the material forming the medical device, e.g., silicone, polyurethane, polyethylene, GortexTM (polytetrafluoroethylene), DacronTM (polyethylene tetraphthalate), TeflonTM (polytetrafluoroethylene), and/or polypropylene, and extruded with the material forming the medical device, thereby incorporating the composition into material forming the medical device.
  • the composition may be incorporated in a septum or adhesive which is placed at the medical device insertion or implantation site.
  • An example of a coated medical device having a composition incorporated into the material forming the medical device in accordance with this embodiment is the catheter insertion seal having an adliesive layer described below in greater detail.
  • the invention is directed to coated medical- devices.
  • the coated medical devices include a composition coating applied to at least one surface of the medical device. Suitable medical devices and compositions are described above in greater detail.
  • the composition may be applied to at least one surface of the medical devices in any suitable manner.
  • the composition may be applied to the medical devices following any of the methods described above in greater detail.
  • OT ovotransferrin
  • PS protamine sulfate
  • EDTA EDTA
  • E. coli PI 8 Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis
  • Biofilm assays for catheter-associated bacteria were standardized following the procedure described by Jackson, et al. (J. Bacteriol. 184: 290-301). Bacteria were routinely cultured at 37°C in Luria- Bertani (LB) or Tryptic Soy Broth (TSB). Biofilm assays were generally carried out in colony-forming antigen (CFA) medium at 26°C. However, biofilm assays for Enterococcus faecalis and Staphylococcus epidermidis were carried out in TSB at 37°C.
  • CFA colony-forming antigen
  • Figures 1-12 show biofilm formation by the above catheter- associated bacterial strains in the wells of microtiter plate in the presence and absence of ovotransferrin, protamine sulfate and EDTA alone and in combinations at different concentrations. Values represent the Mean + Standard Deviation of three experiments with four replicates for each concentration. The composition consisting of all three compounds showed synergistic inhibitory effects on biofilm formation in Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus epidermidis ( Figures 7-12).
  • E. coli PI 8 Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis
  • the stained biofilms were rinsed several times with distilled water, and allowed to dry at room temperature for 15 min before examination.
  • the dye was solubilized with 33% acetic acid, and absorbance at 630 nm was determined using a spectrophotometer.
  • the effect of composition on biofilm formation by catheter-associated bacterial strains such as Staphylococcus epidermidis, Proteus mirabilis and Pseudomonas aeruginosa was tested by growth of the organisms in urethral catheters as described above.
  • Staphylococcus epidermidis and Proteus mirabilis formed biofilms mainly at the air liquid interface, while the biofilm formed by Pseudomonas aeruginosa was dispersed all along the catheter.
  • the composition inhibited biofilm formation in all organisms (Fig. 13, Table 2).
  • E. coli PI 8 Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis
  • Viable cell counts of catheter-associated bacterial strains were determined following a standard serial dilution plating method.
  • the number of dilutions depended on the initial density of the cell suspension. Plated out 100 ⁇ l of each dilution on LB agar or Tryptic Soy agar plates in duplicates.
  • synergistic composition had dramatic effect on the viable cell counts of E. coli and Staphylococcus epidermidis, it hardly showed any effect on that of other test organisms. Interestingly, when planktonic growth was measured in terms of turbidity on microtiter-plate the synergistic composition appeared to have minimal effect on the growth as compared to its effect on biofilm formation in all test organisms (see Example 1).
  • Staphylococcus epidermidis 1.0x10 s 1.6xl0 9 99.93

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Abstract

L'invention concerne une composition antimicrobienne synergique destinée à inhiber la formation de biofilms, qui comprend une glycoprotéine séquestrant le fer, un polypeptide cationique et un agent de chélation, ou une glycoprotéine séquestrant le fer et un polypeptide cationique. En outre, on peut avantageusement combiner dans une composition antimicrobienne des tensioactifs et des composés d'ammonium quaternaires aux glycoprotéines séquestrant le fer. L'invention concerne enfin des procédés d'utilisation d'une composition synergique destinée à inhiber la formation de biofilms de dispositifs médicaux.
PCT/CA2004/001477 2003-08-25 2004-08-06 Compositions antimicrobiennes synergiques et procedes d'inhibition de la formation de biofilms WO2005018701A1 (fr)

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US10/781,464 US7314857B2 (en) 2003-08-25 2004-02-17 Synergistic antimicrobial compositions and methods of inhibiting biofilm formation
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WO2007003028A1 (fr) * 2005-07-01 2007-01-11 Kane Biotech Inc. Compositions antimicrobinennes et utilisations associees
WO2007061942A2 (fr) 2005-11-18 2007-05-31 Glanbia Nutritionals (Ireland) Ltd. Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies
WO2008142102A2 (fr) * 2007-05-21 2008-11-27 Kedrion S.P.A. Utilisation de la transferrine pour préparer des compositions pharmaceutiques utiles pour traiter des infections bactériennes en tant que co-adjuvants dans une thérapie par antibiotique
WO2009064879A2 (fr) * 2007-11-13 2009-05-22 Medtronic Minimed, Inc. Revêtements antimicrobiens pour dispositifs médicaux et leurs procédés de préparation et d'utilisation
EP2124575A2 (fr) * 2006-12-26 2009-12-02 Sterilex Technologies, LLC Compositions antimicrobiennes
WO2010083589A1 (fr) * 2009-01-23 2010-07-29 Kane Biotech Inc. Compositions antimicrobiennes éliminant les biopellicules et leurs applications
JP2012072266A (ja) * 2010-09-28 2012-04-12 Kobayashi Pharmaceutical Co Ltd バイオフィルム除去剤、および、バイオフィルム除去用組成物
GB2484507A (en) * 2010-10-13 2012-04-18 Cev Biotecnologia Das Plantas S A Antimicrobial agent and chelating agent for inhibiting a plant pathogen
US8343536B2 (en) 2007-01-25 2013-01-01 Cook Biotech Incorporated Biofilm-inhibiting medical products
WO2014078900A1 (fr) 2012-11-23 2014-05-30 Hexima Limited Procédés anti-pathogènes
WO2014134731A1 (fr) * 2013-03-07 2014-09-12 Kane Biotech Inc. Compositions antimicrobiennes-antibiofilm et leurs procédés d'utilisation
EP2827841A4 (fr) * 2012-03-23 2015-10-21 Amicrobe Inc Compositions et utilisations de matériaux antimicrobiens ayant des propriétés compatibles avec un tissu
US9205179B2 (en) 2011-09-29 2015-12-08 Ethicon, Inc. Broad-spectrum antimicrobial compositions based on combinations of taurolidine and protamine and medical devices containing such compositions
US9622481B2 (en) 2009-01-23 2017-04-18 Kane Biotech Inc. Biofilm-removing antimicrobial compositions and uses thereof
EP3655020A4 (fr) * 2017-07-17 2021-04-07 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Méthodes antibactériennes et trousses associés
US11285189B2 (en) 2017-04-06 2022-03-29 Amicrobe, Inc. Compositions and uses of locally-applied antimicrobial synthetic cationic polypeptide(s) with enhanced performance and safety
USRE49129E1 (en) 2014-07-11 2022-07-12 Grifols Worldwide Operations Limited Method of treatment of hypoxia inducible factor (HIF)-related conditions

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US6149908A (en) * 1996-01-23 2000-11-21 Semper Ab Use of lactoperoxidase, a peroxide donor and thiocyanate for the manufacture of a medicament for treating Helicobacter pylori infection
US6267979B1 (en) * 1997-08-26 2001-07-31 Wake Forest University Chelators in combination with biocides: treatment of microbially induced biofilm and corrosion
CA2284364A1 (fr) * 1998-10-02 2000-04-02 Johnson & Johnson Vision Products, Inc. Dispositifs biomedicaux avec revetements antimicrobiens
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CN101212906B (zh) * 2005-07-01 2011-09-28 凯恩生物科技有限公司 用于在医疗装置上抑制微生物薄膜的生长和增殖的抗微生物组合物
AU2006265707B2 (en) * 2005-07-01 2012-06-14 Kane Biotech Inc. Antimicrobial compositions for inhibiting growth and proliferation of a microbial biofilm on medical devices
WO2007003028A1 (fr) * 2005-07-01 2007-01-11 Kane Biotech Inc. Compositions antimicrobinennes et utilisations associees
US8906364B2 (en) 2005-07-01 2014-12-09 Kane Biotech Inc. Antimicrobial compositions and uses thereof
WO2007061942A3 (fr) * 2005-11-18 2009-04-30 Glanbia Nutritionals Ireland L Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies
EP2815754A1 (fr) * 2005-11-18 2014-12-24 Glanbia Nutritionals (Ireland) Limited Compositions pour la reconstitution de l'interruption et l'inhibition de film biologique de plaies
WO2007061942A2 (fr) 2005-11-18 2007-05-31 Glanbia Nutritionals (Ireland) Ltd. Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies
EP2124575A2 (fr) * 2006-12-26 2009-12-02 Sterilex Technologies, LLC Compositions antimicrobiennes
EP2124575A4 (fr) * 2006-12-26 2013-01-09 Sterilex Technologies Llc Compositions antimicrobiennes
US8343536B2 (en) 2007-01-25 2013-01-01 Cook Biotech Incorporated Biofilm-inhibiting medical products
WO2008142102A3 (fr) * 2007-05-21 2009-03-12 Kedrion Spa Utilisation de la transferrine pour préparer des compositions pharmaceutiques utiles pour traiter des infections bactériennes en tant que co-adjuvants dans une thérapie par antibiotique
WO2008142102A2 (fr) * 2007-05-21 2008-11-27 Kedrion S.P.A. Utilisation de la transferrine pour préparer des compositions pharmaceutiques utiles pour traiter des infections bactériennes en tant que co-adjuvants dans une thérapie par antibiotique
WO2009064879A2 (fr) * 2007-11-13 2009-05-22 Medtronic Minimed, Inc. Revêtements antimicrobiens pour dispositifs médicaux et leurs procédés de préparation et d'utilisation
WO2009064879A3 (fr) * 2007-11-13 2010-04-15 Medtronic Minimed, Inc. Revêtements antimicrobiens pour dispositifs médicaux et leurs procédés de préparation et d'utilisation
CN101909666A (zh) * 2007-11-13 2010-12-08 美敦力迷你迈德公司 用于医疗设备的抗菌涂层以及该抗菌涂层的制备方法和使用方法
US8512731B2 (en) 2007-11-13 2013-08-20 Medtronic Minimed, Inc. Antimicrobial coatings for medical devices and methods for making and using them
US9622481B2 (en) 2009-01-23 2017-04-18 Kane Biotech Inc. Biofilm-removing antimicrobial compositions and uses thereof
US8753692B2 (en) 2009-01-23 2014-06-17 Kane Biotech Inc. Biofilm-removing antimicrobial compositions and uses thereof
US20110311647A1 (en) * 2009-01-23 2011-12-22 Kane Biotech Inc. Biofilm-removing antimicrobial compositions and uses thereof
WO2010083589A1 (fr) * 2009-01-23 2010-07-29 Kane Biotech Inc. Compositions antimicrobiennes éliminant les biopellicules et leurs applications
JP2012072266A (ja) * 2010-09-28 2012-04-12 Kobayashi Pharmaceutical Co Ltd バイオフィルム除去剤、および、バイオフィルム除去用組成物
GB2484507A (en) * 2010-10-13 2012-04-18 Cev Biotecnologia Das Plantas S A Antimicrobial agent and chelating agent for inhibiting a plant pathogen
US9205179B2 (en) 2011-09-29 2015-12-08 Ethicon, Inc. Broad-spectrum antimicrobial compositions based on combinations of taurolidine and protamine and medical devices containing such compositions
US9220814B2 (en) 2011-09-29 2015-12-29 Ethicon, Inc. Broad-spectrum antimicrobial compositions based on combinations of taurolidine and protamine and medical devices containing such compositions
US9446090B2 (en) 2012-03-23 2016-09-20 Amicrobe, Inc. Compositions and uses of antimicrobial materials with tissue-compatible properties
EP2827841A4 (fr) * 2012-03-23 2015-10-21 Amicrobe Inc Compositions et utilisations de matériaux antimicrobiens ayant des propriétés compatibles avec un tissu
RU2680959C2 (ru) * 2012-03-23 2019-03-01 Амикроб, Инк. Композиции и применение противомикробных материалов со свойствами биологической совместимости
US11298401B2 (en) 2012-03-23 2022-04-12 Amicrobe, Inc. Compositions and uses of antimicrobial materials with tissue-compatible properties
US12016898B2 (en) 2012-03-23 2024-06-25 Amicrobe, Inc. Compositions and uses of antimicrobial materials with tissue-compatible properties
EP2922398A4 (fr) * 2012-11-23 2016-05-04 Hexima Ltd Procédés anti-pathogènes
WO2014078900A1 (fr) 2012-11-23 2014-05-30 Hexima Limited Procédés anti-pathogènes
US9943564B2 (en) 2012-11-23 2018-04-17 Hexima Limited Anti-pathogenic methods
US10357536B2 (en) 2012-11-23 2019-07-23 Hexima Limited Anti-pathogenic methods
WO2014134731A1 (fr) * 2013-03-07 2014-09-12 Kane Biotech Inc. Compositions antimicrobiennes-antibiofilm et leurs procédés d'utilisation
USRE49129E1 (en) 2014-07-11 2022-07-12 Grifols Worldwide Operations Limited Method of treatment of hypoxia inducible factor (HIF)-related conditions
US11285189B2 (en) 2017-04-06 2022-03-29 Amicrobe, Inc. Compositions and uses of locally-applied antimicrobial synthetic cationic polypeptide(s) with enhanced performance and safety
EP3655020A4 (fr) * 2017-07-17 2021-04-07 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Méthodes antibactériennes et trousses associés

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