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WO2017060489A1 - Méthodes pour inhiber ou réduire des biolfilms bactériens - Google Patents

Méthodes pour inhiber ou réduire des biolfilms bactériens Download PDF

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Publication number
WO2017060489A1
WO2017060489A1 PCT/EP2016/074096 EP2016074096W WO2017060489A1 WO 2017060489 A1 WO2017060489 A1 WO 2017060489A1 EP 2016074096 W EP2016074096 W EP 2016074096W WO 2017060489 A1 WO2017060489 A1 WO 2017060489A1
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Prior art keywords
biofilm
tissue
plk
ett
bacteria
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PCT/EP2016/074096
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English (en)
Inventor
Virginie Herve
Antoine GUILLON
Mustapha SI-TAHAR
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université De Tours François Rabelais,
Centre Hospitalier Régional Universitaire De Tours
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Publication of WO2017060489A1 publication Critical patent/WO2017060489A1/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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—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
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • 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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/04—Tracheal tubes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0205—Materials having antiseptic or antimicrobial properties, e.g. silver compounds, rubber with sterilising agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0238—General characteristics of the apparatus characterised by a particular materials the material being a coating or protective layer

Definitions

  • the present invention relates to methods for inhibiting or reducing Pseudomonas biofilm formation, in particular Pseudomonas aeruginosa biofilm. More specifically, the present invention relates to cationic polymers and their use in treating Pseudomonas aeruginosa bio films present in endotracheal tube (ETT) of mechanically ventilated patients.
  • ETT endotracheal tube
  • Pseudomonas aeruginosa has been shown to form biofilms on a number of surfaces, including the tissues of the cystic fibrosis lung (Govanand Deretic, 1996) and on abiotic surfaces such as contact lenses and catheter lines (Nickel et al., 1985; 1989; Millerand Ahearn, 1987; Fletcher et al., 1993). This ubiquitous organism is also the cause of nosocomial infections in immunocompromised patients and individuals with severe burns (Bodeyei al., 1983).
  • VAP Ventilator-associated pneumonia
  • Ventilator-associated tracheobronchitis is also common in critically ill patients. This infection represents an intermediate process between colonization of lower respiratory tract and VAP. VAT is characterized by increased purulent sputum production and lower respiratory tract inflammation resulting in difficult weaning and prolonged duration of mechanical ventilation (4).
  • Bacterial biofilm is universally present within the endotracheal tube (ETT) of mechanically ventilated patients, representing a potential source of infection (5).
  • ETT endotracheal tube
  • Biofilm on the ETT is a complex structure made of pathogens enclosed within a self-produced polymeric matrix, and respiratory secretions. The accumulation of biofilm and secretions within the ETT progressively obstructs its lumen, particularly in patients on long-term mechanical ventilation.
  • Biofilm plays a role in the development of VAP or in the relapse of VAP after treatment. Indeed, biofilm is an adaptive survival advantage for bacteria as it increases bacterial resistance to antimicrobials (9). Of note is that the effects of systemic antibiotic treatment on ETT biofilm treatment or prevention are very limited. Antibiotics do not eradicate ETT biofilm (10, 11), and only dedicated prototypes have shown removal of biofilm and secretions from within the ETT (12). However, those prototypes required disconnection of the ventilator for a period of time longer than standard suctioning.
  • VAP or VAT may relapse from bacterial disseminated from the ETT biofilm towards the lower respiratory tract, giving rise to infection.
  • the present invention relates to a method of inhibiting or reducing Pseudomonas biofilm formation on a surface comprising the step of applying to the surface an amount of a cationic polymer.
  • cationic polymers that can be used in the present invention have the following formula (I):
  • ⁇ R is NH2 or NH linked to a histidine residue or other molecules including charged amino acids, a gluconoyl residue, a glycosyl residue or a PEG moiety, • i is the degree of polymerization comprised between 10 and 75, preferably between 10 and 50, and more preferably between 20 and 50, for example between 20 and 40 or between 30 and 50.
  • cationic polymers such as poly-aL-lysine have the following properties: i/ they "condensate" the biofilm present in a medical device as endotracheal tube of mechanically ventilated patients, ii/ they act as aeruginosa biofilm agents.
  • the inventors demonstrated that cationic polymers efficiently and rapidly eliminate bacteria from biofilms.
  • a first aspect of the invention relates to a method of inhibiting or reducing Pseudomonas biofilm formation on a surface comprising the step of applying to the surface an amount of a cationic polymer according to the invention.
  • the cationic polymers that can be used in the present invention have the following formula (I):
  • R is NH2 or NH linked to a histidine residue or other molecules including charged amino acids, a gluconoyl residue, a glycosyl residue or a PEG moiety,
  • • i is the degree of polymerization comprised between 10 and 75, preferably between 10 and 50, and more preferably between 20 and 50, for example between 20 and 40 or between 30 and 50.
  • said cationic polymers for use according to the invention comprise a sufficient amount of lysine residues (whether histidinylated or not) condensate the Pseudomonas aeruginosa biofilm present in a surface and/or to act as anti-Pseudomonas aeruginosa biofilm agents.
  • amount or “sufficient amount” "or dosage level” is intended to be an amount of cationic polymers of the invention, that, when applied brings about a positive response with respect to condensate the Pseudomonas aeruginosa biofilm present in a surface and/or to act as anti-Pseudomonas aeruginosa biofilm agents.
  • Actual dosage levels of the cationic polymer of the present invention may be varied so as to obtain an amount of the cationic polymer which is effective to achieve the desired anti-biofilm response for a particular surface, mode of application (solution or by aerosolization).
  • the dosage when cationic polymers of the invitation are applied in solution is between 1 to 10 mL, preferably between 3 to 7mL more preferably 5mL.
  • the dosage when cationic polymers of the invitation are applied by aerosolization is between 10 to 1 ⁇ , preferably between 100 to 300 ⁇ more preferably 200 ⁇ .
  • the effect of antibiofilm activity can be measured by monitoring condensation and reduction of the bacterial biofilm present in a surface prior to and after application with the compositions according to the invention, using in vitro assays (Susceptibility assay) adapted from different assays (George A. 0'Toole,Microtiter Dish Biofilm Formation Assay, J Vis Exp. 2011; (47): 2437).
  • the cationic polymers of formula (I) have a ratio of grafting of at least 10%, 20%, 30%, 40%, 50%, or 60%, preferably comprised between 10% and 60%, or between 10%> and 55%, or between 10%> and 40%>, more preferably between 10%> and 35%.
  • the cationic polymers of the present invention have a ratio of grafting of between at least 10% and 60%, and a degree of polymerization i between 20 and 50 or between 20 and 40.
  • the cationic polymers of the present invention may have a ratio of grafting of between at least 10%> and 60%>, or between 10%> and 55%, or between 10% and 40%, and a degree of polymerization i between 30 and 40.
  • cationic polymers of formula (I) will be named hereafter as pLK(XX)His(YY), wherein XX refers to the average degree of polymerisation of the cationic polymers and YY refers to the average number of histidine grafted to lysine residues.
  • the cationic polymers of the present invention are pLK36-
  • Lysyl (non-histidinylated) residues of the cationic polymers of the present invention may optionally be further at least partially replaced by other known positively charged amino acids, including without limitation histidine, arginine or ornithine.
  • positively charged refers to the side chain of the amino acids which has a net positive charge at a pH of 7.0.
  • a cationic polymer according to the invention typically may include at least 50% (per monomeric unit), 60% or at least 70%> of positively charged amino acid residues, preferably at least 50%>, 60%>, 70%> (per monomeric unit) of lysine residues, for example between 50%> and 90%) (per monomeric unit) of lysine residues.
  • Parameters such as the number of monomers (e.g. number of amino acids), the type of monomeric units (e.g. type of amino acids) and the percentage of positively charged monomeric units (e.g percentage of positively charged amino acids in a polyaminoacid) may be optimized by measuring the efficacy of the final structure in an in vitro assay for assessing condensatethe bacterial biofilm present in a surface and/or to act as anti-Pseudomonas aeruginosa biofilm agents, as disclosed in the Examples below (Susceptibility assay of Pseudomonas aeruginosa biofilm).
  • cationic polymers for use according to the present invention include poly- L-lysine, without derivatized or substituted with histidine or neutral residue.
  • Equivalent amino acids may also be used in the cationic polymers of the invention, including amino acids having side chain modifications or substitutions, the final polymer retaining its advantageous property of acting as anti-Pseudomonas aeruginosa biofilm agents.
  • amino acids may be used, or chemically modified amino acids, including amino acid analogs such as penicillamine (3-mercapto-D-valine), naturally occurring non-proteogenic amino acids and chemically synthesized compounds that have properties known in the art to be characteristic of an amino acid.
  • amino acid analogs such as penicillamine (3-mercapto-D-valine), naturally occurring non-proteogenic amino acids and chemically synthesized compounds that have properties known in the art to be characteristic of an amino acid.
  • Cationic polymers useful for this invention can be produced using technique well known in the Art, including either chemical synthesis or recombinant DNA techniques.
  • Cationic polypeptides can be synthesized using Solid Phase Peptide Synthesis techniques with tBoc or Fmoc protected alpha-amino acids (Scholz, C.et ah, J Control Release, 2011).
  • polycationic polypeptides can be produced using recombinant DNA techniques (See Coliganei al, Current Protocols in Immunology, Wiley Intersciences, 1991, Unit 9; US Pat. No. 5,593,866).
  • the cationic polymers may be PEGylated.
  • PEGylation is the process of covalent attachment of polyethylene glycol polymer chains to another molecule.
  • Polyethylene glycol (PEG) molecules may be added onto cationic polymers in order to limit DNA complexes aggregation, adsorption of proteins and to lower aggregate as well as polymer cytotoxicity (Ogris, M.et al, P. Gene Ther, 1999; Toncheva, V. et al, Biochim Biophys Acta, 1998 ; Choi, Y. et al., 1999).
  • the covalent attachment of PEG to cationic polymers may facilitate and does not compromise administration of said cationic polymers into the airways in the form of an aerosol (Dailey, L. A., et al, J Control Release, 2004).
  • the covalent attachment of PEG moiety onto cationic polymer can be performed by two ways leading either to a PEG-grafted-polymer or a block copolymer.
  • PEG-grafted polylysine (PEG-g-pLK) is prepared by reaction of the N- hydroxysuccinimide derivative of the methoxypolyethylene glycol (mPEG)propionic acid (for instance of 5000 Da)with the ⁇ -amino group of the lysyl residues of pLK (Mockey, M., et al, Cancer Gene Ther,2007).
  • PEG-pLK(XX)His(YY) block copolymer can be prepared either by :
  • the cationic polymers in accordance with the present invention are glycosylated.
  • derivatization of lysyl residues of poly-L-lysine with mannose, galactose or lactose is described in (Erbacher, P. et al (Bioconjug Chem,1995); Erbacher, P., et al. (Hum Gene Ther, 1996).
  • Mannosyl-PEG, galactosyl-PEG or lactosyl-PEG may be grafted on poly-L-lysine as described in (Sagara, K. et al. (J Control Release,2002).
  • the cationic polymers in accordance with the present invention are gluconoylated in order to decrease the number of positive charges and the cytotoxicity.
  • derivatization of lysyl residues of poly-L-lysine with ⁇ - gluconolactone is described in (Erbacher, P. et al(Biochim Biophys Acta, 1997).
  • bacterial biofilm has its general meaning in the art and refers to structured communities or aggregates of bacterial cells in which cells adhere to each other and/or to a living or inert (non-living) surface. These adherent cells are frequently embedded within a self- produced matrix of extracellular polymeric substance.
  • Biofilms represent a prevalent mode of microbial life in natural, industrial and hospital settings. Biofilms can contain many different types of microorganism, e.g. bacteria, archaea, protozoa, fungi and algae. According the method of the invention, the biofilm is produced by Pseudomonas bacteria.
  • Pseudomonas bacteria has its general meaning in the art and refers to bacteria that occur normally or pathogenically in lung of humans and other animals.
  • the term “Pseudomonas bacteria” refers to but it is not limited to gram-negative bacteria Pseudomonas, e.g; a bacterium of the Pseudomonas aeruginosa group such as P. aeruginosa group P. aeruginosa, P. alcaligenes, P. anguilliseptica, P. argentinensis, P. borbori, P. citronellolis, P. flavescens, P. mendocina, P. nitroreducens, P. oleovorans, P. pseudoalcaligenes, P. resinovorans, P. straminea, .
  • the Pseudomonas biofilm according to the invention is Pseudomonas aeruginosa biofilm.
  • Pseudomonas aeruginosa is a common Gram-negative bacteria that can cause disease in animals, including humans. It is citrate, catalase, and oxidase positive. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many natural and artificial environments. It uses a wide range of organic material for food; in animals, its versatility enables the organism to infect damaged tissues or those with reduced immunity. The symptoms of such infections are generalized inflammation and sepsis.
  • surface refers to any surface where bacteria (e.g. Pseudomonas bacteria) are liable to grow on.
  • the surface is an artificial surface or is a biological surface.
  • artificial surfaces include but are not limited to surfaces that can be used for medical, sanitary, veterinary, food preparation (e.g. food industry), agribusiness or agronomic purposes.
  • the material is made of plastic, metal, glass or polymers.
  • the surface is any surface that constitutes an environment wherein development of enteric bacteria is not desirable (e.g. hospitals, intensive care units, dental offices).
  • the surface is a surface of hospital furniture, non implantable and implantable devices or medical tools that are liable to be in contact with patients.
  • the cationic polymer of the present invention is applied to a surface of a material.
  • the term "material” denotes any material for any purposes, including but not limiting to, research purposes, diagnostic purposes, and therapeutic purposes.
  • the material is a natural material or is an artificial material (i.e. a man-made material).
  • the material can be less or more solid, less or more flexible, can have less or ability to swell...
  • the material is an artificial material.
  • the material is selected form the group consisting of membranes, scaffold materials, films, sheets, tapes, patches, meshes or medical devices.
  • the material is biocompatible material.
  • biocompatible generally refers having the property or characteristic of not generating injury, toxicity or immunological reaction to living tissues. Accordingly, the material does not substantively provoke injury, toxicity or an immunological reaction, such as a foreign body reaction or inflammatory response (in particular excessive inflammatory response), upon for example implantation of the material in a subject.
  • the material is biodegradable.
  • biodegradable as used herein is defined to include both bioabsorbable and bioresorbable materials.
  • biodegradable it is meant that the materials decompose, or lose structural integrity under body conditions (e.g., enzymatic degradation or hydrolysis) or are broken down (physically or chemically) under physiologic conditions in the body such that the degradation products are excretable or absorbable by the body.
  • the material may be made from any biocompatible polymer.
  • the biocompatible polymer may be synthetic or natural.
  • the biocompatible polymer may be biodegradable, non-biodegradable or a combination of biodegradable and non-biodegradable.
  • Representative natural biodegradable polymers which may be used include but are not limited to polysaccharides, such as alginate, dextran, chitin, hyaluronic acid, cellulose, collagen, gelatin, fucans, glycosamino-glycans, and chemical derivatives thereof (substitutions and/or additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art); and proteins, such as albumin, casein, zein, silk, and copolymers and blends thereof, alone or in combination with synthetic polymers.
  • polysaccharides such as alginate, dextran, chitin, hyaluronic acid, cellulose, collagen, gelatin, fucans, glycosamino-glycans, and chemical derivatives thereof (substitutions and/or additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made
  • Synthetically modified natural polymers which may be used include but are not limited to cellulose derivatives, such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, and chitosan.
  • suitable cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, and cellulose sulfate sodium salt. These are collectively referred to herein as "celluloses.”
  • Representative synthetic degradable polymers suitable for use include but are not limited to polyhydroxy acids prepared from lactone monomers, such as glycolide, lactide, caprolactone, ⁇ - caprolactone, valerolactone, and ⁇ -valerolactone, as well as pluronics, carbonates (e.g., trimethylene carbonate, tetramethylene carbonate, and the like); dioxanones (e.g., 1,4- dioxanone and p-dioxanone), 1 ,dioxepanones (e.g., l,4-dioxepan-2-one and 1,5- dioxepan-2- one), and combinations thereof.
  • lactone monomers such as glycolide, lactide, caprolactone, ⁇ - caprolactone, valerolactone, and ⁇ -valerolactone
  • pluronics e.g., trimethylene carbonate, tetramethylene carbonate, and the like
  • carbonates
  • Polymers formed therefrom include: polylactides; poly(lactic acid); polyglycolides; poly(glycolic acid); poly(trimethylene carbonate); poly(dioxanone); poly(hydroxybutyric acid); poly(hydroxyvaleric acid); poly(lactide-co-(s- caprolactone-)); poly(glycolide-co-(8-caprolactone)); polycarbonates; poly(pseudo amino acids); poly(amino acids); poly(hydroxyalkanoate)s; polyalkylene oxalates; polyoxaesters; polyanhydrides; polyortho esters; and copolymers, block copolymers, homopolymers, blends, and combinations thereof.
  • suitable non-bioabsorbable materials include but are not limited to polyolefms, such as polyethylene and polypropylene including atactic, isotactic, syndiotactic, and blends thereof; polyethylene glycols; polyethylene oxides; ultra high molecular weight polyethylene; copolymers of polyethylene and polypropylene; polyisobutylene and ethylene-alpha olefin copolymers; fluorinated polyolefms, such as fluoroethylenes, fluoropropylenes, fluoroPEGSs, and polytetrafluoroethylene; polyamides, such as nylon and polycaprolactam; polyamines; polyimines; polyesters, such as polyethylene terephthalate and polybutylene terephthalate; aliphatic polyesters; polyethers; polyether-esters, such as polybutester; polytetramethylene ether glycol; 1 ,4-butanediol; polyurethan
  • the material is a mesh, in particular a surgical mesh.
  • mesh is intended to include any element having an openwork fabric or structure, and may include but is not limited to, an interconnected network of wire- like segments, a sheet of material having numerous apertures and/or portions of material removed, or the like.
  • surgical mesh is used to a mesh suitable for use in surgical procedures, such as, for example, meshes that do not require suturing to the abdominal wall. Surgical meshes, which are used to reinforce weakened areas of abdominal, pelvic, or thoracic tissues, or to replace a portion of internal structural soft tissue that has neither been damaged nor removed surgically, can also be made to have anti-adhesion properties.
  • Surgical mesh drug eluting delivery devices can include one or more therapeutic agents provided with a drug eluting mesh wrap implant placed adjacent to medical devices and internal tissue as described therein.
  • the meshes are available in various single layer, multi-layer, and 3 -dimensional configurations made without bioabsorbable adhesion coatings and films.
  • the meshes are most often constructed of synthetic non-absorbable polymer materials, such as polyethylene, polytetrafluoroethylene, and polypropylene, and can include a carrier having a therapeutic agent attached thereto, incorporated within, or coated thereon.
  • PP polystyrene
  • ePTFE ePTFE
  • Polyester POL
  • PP is a hydrophobic polymer of carbon atoms with alternating methyl moieties. This material is flexible, strong, easily cut, readily integrated by surrounding tissues and resists infection. The monofilament nature provides large pores facilitating fibrovascular ingrowth, infection resistance and improved compliance. PP remains the most popular material in mesh hernia repair.
  • PTFE is a chemically inert synthetic fluoropolymer which has a high negative charge, therefore water and oils do not adhere to it. This material does not incorporate into human tissue and becomes encapsulated. Poor tissue incorporation increases hernia recurrence and an infected PTFE mesh must be explanted. PTFE is micro porous, which allows bacteria passage but prevents macrophage passage; therefore the body cannot clear the infection.8 and 9 PTFE was expanded to be improved, and it became a uniform, fibrous and micro porous structure with improved strength called ePTFE. Although it is not incorporated into tissue and has a high incidence of seroma formation, ePTFE remains inert and produces little inflammatory effects, which allows it to be placed directly on viscera.
  • POL is a carbon polymer of terepthalic acid and can be fashioned into strong fibers suitable to be woven into a prosthetic mesh. It is a hydrophilic material and is degraded by hydrolysis.
  • the mesh structure for this surgical application serves as a drug eluting delivery apparatus for local therapeutic delivery within the body. Affixing the carrier and or coating directly onto the surgical mesh makes it easier to handle the device without the drawbacks of film, namely tearing, folding, and rapid dissolving when contacting body fluids, and the lack of fixation or anchoring means.
  • Non-absorbable mesh structures generally provide more handling strength and directional placement control during installation than bio-absorbable or bio-dissolvable polymer films.
  • the material is an implant.
  • implants Regular improvements have been made to facilitate the use of implants. These include: preformed or precut implants adapted to different techniques (4D Dome®; Ultrapro Plug®, Perfix plug®) for the plug techniques; different pre-cut prostheses to allow the passage of the spermatic cord (Lichtenstein technique); meshes that assume the anatomical contours of the inguinal region for the pre -peritoneal technique (ex. Swing Mesh 4A®, 3D Max®).
  • the implant is designed to facilitate its implantation.
  • the material is a bioprosthesis.
  • the bioprostheses used in abdominal wall surgery derive from animal (xenogenic prostheses from porcine (dermis or intestinal mucosa) or bovine (pericardium) origin, reticulated or not) or human (allogenic) tissues. They are constituted by type I, III or IV collagen matrixes as well as sterile acellular elastin produced by decellularization, sterilization and viral inactivation, in order to enhance integration and cellular colonization of the prosthesis by the host tissues.
  • Comercial examples include but are not limited to Tutopatch®, SIS®, Tissue Science® process, Surgiguard®, Strattice®, CollaMend®, Permacol® , Surgisis®, XenMatrix®, Veritas® (non-reticulated bovine pericardial bioprosthesis), Protexa (porcine dermis), Alloderm®, Flex HD® Acellular Hydrated Dermis and AlloMaxTM (formerly NeoformTM) (acellular collagen matrix derived from human dermis.
  • the material is an orthopaedic implant.
  • orthopaedic implant include but are not limited to prosthetic knees, hips, shoulders, fingers, elbows, wrists, ankles, fingers and spinal elements.
  • the material is a medical device.
  • the medical device can be implanted at a variety of locations in the body including many different subcutaneous and sub- muscular locations.
  • the medical devices include those used to sense and/or affect bodily function upon implantation and/or for carrying out various other functions in the body. These can be but are not limited to pacing devices, defibrillators, implantable access systems, monitors, stimulators including neurostimulators, ventricular assist devices, pain pumps, infusion pumps and other implantable objects or systems or components thereof, for example, those used to deliver energy and/or substances to the body and/or to help monitor bodily function.
  • cardiovascular devices e.g., implantable venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pacemaker leads
  • neurologic/neurosurgical devices e.g., ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions
  • gastrointestinal devices e.g., chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesion
  • genitourinary devices e.g., uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible steriliz
  • the medical device is a tracheal tube, more particularly endotracheal tube.
  • a tracheal tube is a catheter (or a probe) that is inserted into the trachea for the primary purpose of establishing and maintaining a patent airway.
  • the two main objectives of the tracheal tube insertion are: (i) to ensure the adequate exchange of oxygen and carbon dioxide, (ii) to protect the airways from inhalation of the oropharynx or gastric contents.
  • An endotracheal tube is a specific type of tracheal tube that is nearly always inserted through the mouth (orotracheal) or nose (nasotracheal).
  • a tracheostomy tube is another type of tracheal tube that is inserted into a tracheostomy stoma (following a tracheotomy) to maintain a patent lumen.
  • a tracheal button is a rigid plastic cannula that can be placed into the tracheostomy after removal of a tracheostomy tube to maintain patency of the lumen.
  • Endotracheal and tracheostomy tubes have a wide range of internal and external diameters and lengths according to the clinical context: premature baby, newborn, infant, adult.
  • Endotracheal and tracheostomy tubes may have (or not): a cuff at the distal extremity, a subglottic suction line, a preformed shape, a spiral wire embedded in the wall of the tube (to reinforced the tube).
  • Tracheostomy tubes may have extra fenestrations to improve weaning and phonation.
  • biological surfaces include but are not limited to plant or animal surface. In some embodiments, the surface is a tissue surface.
  • the cationic polymer of the present invention is applied to at least one tissue surface selected from the group consisting of skin tissue, hair tissue, nail tissue, corneal tissue, tongue tissue, oral cavity tissue, esophageal tissue, anal tissue, urethral tissue, vaginal tissue, urinary epithelial tissue, salivary gland tissue, mammary gland tissue, lacrimal gland tissue, sweat gland tissue, prostate gland tissue, bulbourethral gland tissue, Bartholin's gland tissue, uterine tissue, respiratory and gastrointestinal tract goblet cell tissue, gastric mucosal tissue, gastric gland tissue, pancreatic tissue, spleen tissue, pulmonary tissue, pituitary gland tissue, thyroid gland tissue, parathyroid gland tissue, testicular tissue, ovarian tissue, respiratory gland tissue, gastrointestinal gland tissue, adrenal gland tissue, renal tissue, liver tissue, adipose tissue, duct cell tissue, gall bladder tissue, epidydimal tissue, vas deferens tissue, blood vessel tissue, lymph gland tissue, lymphatic tissue, a
  • R is NH2
  • • i is the degree of polymerization comprised between 10 and 75, preferably between 10 and 50, and more preferably between 20 and 50, for example between 20 and 40, or between 30 and 40.
  • the method of the present invention further comprises the step of applying at least one antimicrobial agent.
  • antimicrobial agent has its general meaning in the art and refers to antibacterial agent, antiprotozoal agent or antifungal agent such as described in US2013/0029981.
  • the antimicrobial agent may be a biocide, an antibiotic agent or another specific therapeutic entity.
  • Suitable antibiotic agents include, without limitation, penicillin, quinoline, vancomycin, sulfonamides, ampicillin, ciprofloxacin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, and sulfisoxazole.
  • antimicrobial agents include but are not limited to antibacterial agent, antiprotozoal agent or antifungal agent, a biocide, an antibiotic agent or another specific therapeutic agent.
  • Suitable antibiotic agents include, without limitation, penicillin, quinoline, vancomycin, sulfonamides, ampicillin, ciprofloxacin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, and sulfisoxazole.
  • the cationic polymer of the invention is applied to the surface using conventional techniques. Coating, dipping, spraying, spreading and solvent casting are possible approaches. More particularly, said applying is manual applying, applicator applying, instrument applying, manual spray applying, aerosol spray applying, syringe applying, airless tip applying, gas-assist tip applying, percutaneous applying, surface applying, topical applying, internal applying, enteral applying, parenteral applying, protective applying, catheter applying, endoscopic applying, arthroscopic applying, encapsulation scaffold applying, stent applying, wound dressing applying, vascular patch applying, vascular graft applying, image-guided applying, radiologic applying, brush applying, wrap applying, or drip applying.
  • the cationic polymer of the present invention is applied in solution to a surface.
  • the cationic polymer of the present invention is applied to a surface using aerosol spray applying (or aerosolization).
  • aerosolization is the process or act of converting some physical substance into the form of particles small and light enough to be carried on the air i.e. into an aerosol.
  • the method of the invention is particular suitable for preventing the development of Pseudomonas bacteria growth on the surface and thus for preventing any contamination or infection that can be driven by said bacteria.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Anti-bio film activity of pLK against PAK-LUX strain of P. aeruginosa.
  • PAK-Lux biofilm was treated with PBS, pLK 10 ⁇ or pLK 100 ⁇ .
  • A Visualization of P. aeruginosa (PAK-Lux) bio films formed in vitro in 96-wells plate (by bioluminescence measurement) after treatment.
  • B Visualization of PAK-Lux biofilms formed in vitro in sterile EET (by bioluminescence measurement) after treatment.
  • Figure 2 Action of pLK against PAK-LUX biofilm. Scanning electron micrographs of PAK-LUX biofilms formed in vitro in sterile EET after treatment with either PBS, pLK 10 ⁇ or pLK 100 ⁇ (Magnification x 5,000 and x 20,000).
  • Figure 3 Action of pLK against patient EET biofilm. Scanning electron micrographs of patient EET biofilms (collected during hospitalization) after treatment with either PBS, pLK 10 ⁇ or pLK 100 ⁇ (Magnification x 5,000 and x 20,000).
  • a first count corresponding to live bacteria in the biofilm outer layer was determined after vortex/sonication /vortex (step 1) (A) and a second count corresponding to live bacteria in the biofilm inner layer was evaluated on the remaining ETT biofilm (step 2) (B).
  • Poly-L-Lysine was purchased from Sigma (St. Quentin Fallavier, France) unless otherwise stated. pLK was diluted in IX phosphate buffered saline (PBS, pH 7.4) (Gibco, Invitrogen, Life Technologies, Saint-Aubin, France) and a fresh stock was made for each experiment. pLK was used at 10 and 100 ⁇ .
  • ETT Endotracheal tube
  • ETT were purchased from Covidien (MallinckrodtTM TaperGuard Tracheal Tube, Mansfield, USA). We collected ETTs from mechanically-ventilated patients with current or former P. aeruginosa respiratory infection, and extubated due to clinical improvement, change in the ETT for technical reasons, or patient death. This study was approved by the French bioethics authorities (L'Espace de Reflexion Ethique Region Centre) and was conducted in accordance with the ethical standards of the Helsinki Declaration. All patients (or their relatives) included in this study were personally informed by a written document about the collection of used-ETT, as well as their right to object to the study and obtain access to the data, according to articles L.l 121-1 and Rl 121-2 of the French Public Health Code.
  • strains of P. aeruginosa were grown to exponential phase in LB medium with aeration, at 37°C.
  • Biofilms were allowed to form as described above with PAK-Lux. After incubation, the 96-well microplates were rinsed with sterile PBS (pH 7.2) and placed in contact with various concentrations of pLK diluted in LB medium (0, 10 and 100 ⁇ ), during 24 h, at 37°C. Then, each well was washed with sterile PBS and luminescence was measured. The data presented were derived from a single experiment which was performed in triplicate.
  • step 1 ETT section was placed in a Falcon tube containing 5 mL PBS, vortexed during 30 seconds, sonicated during 5 minutes and vortexed again during 30 seconds. Solution was removed and enumerated. Results obtained after 'step reflect live bacteria in the biofilm outer layer. Then, a second enumeration was determined after the following step (step 2): remaining ETT biofilm was removed with a 10 ⁇ - ⁇ and diluted in PBS. Obtained solution was enumerated.
  • Results obtained after 'step 2' reflect live bacteria in the biofilm inner layer. For enumeration, 100 ⁇ ⁇ of each dilution were spread on Cetrimide plates which were further incubated for 18 h at 37°C for isolation of colonies. All results were expressed on percentage (mean ⁇ SEM) of CFU/100 ⁇ ,.
  • EET were treated with 200 of sprayed LB, pLK 10 ⁇ or pLK 100 ⁇ during 2 minutes, at room temperature. Spray was done via an Aerosolizer Micro Sprayer® Model IA-1C (Penn Century). Following steps were identical to those described before.
  • pigs were euthanized with an intravenous injection of sodium pentobarbital at 200 mg/kg (Dolethal, Vetoquinol, S.A., Lure, France).
  • bronchoalveolar lavage fluid BAL
  • BALs were centrifuged (2,000 rpm, 10 min, 4°C) and the supernatant was stored at -80°C for subsequent analysis.
  • BAL cytokine levels interleukin-6 (IL-6) and IL-8 were assessed using commercially available immunoenzymatic assay (ELISA) kits containing pig-specific monoclonal antibodies, according to the manufacturers' instructions (R&D Systems, Minneapolis, MN, USA). The obtained concentrations were transformed into pg/ml values using a nonlinear regression curve. Histological studies were performed on eight samples were collected per pig: trachea, bronchial ramification, bronchus (right and left), different areas of the right lung (cranial and medial lobes) and the left lung (cranial and medial lobes). The samples were fixed in a 4% formaldehyde solution for subsequent histologic analysis.
  • ELISA immunoenzymatic assay
  • tissue samples were embedded in paraffin, and 5 ⁇ histological sections were stained with hematoxylin and eosin.
  • Pathologist who was blinded to the study groups performed the histological analyses. Examinations included testing for the presence of edema, intra-alveolar and interstitial hemorrhages and polymorphonuclear and mononuclear cell infiltration. Each assessed histological characteristic was attributed a score from 0 to 5 according to the level observed in the tissue.
  • pLK eliminate Pseudomonas aeruginosa (PAK-Lux) biofilm in 96-well microplate.
  • Biofilms were formed with a luminescent P. aeruginosa strain (PAK-Lux) in 96-well microplates and visualized by imager after treatment with either LB medium, or pLK at 10 or 100 ⁇ . In absence of pLK, a dense and homogeneous luminescence was recorded, corresponding to the control condition. After a treatment with pLK 10 ⁇ , we observed a decrease of luminescence, indicating a degradation of P. aeruginosa biofilm. Moreover, a total absence of luminescence was recorded corresponding to an elimination of the biofilm when treated with pLK 100 ⁇ ( Figure 1A).
  • P. aeruginosa strain PAK-Lux
  • pLK activity against P. aeruginosa biofilm was also evaluated by numeration of live bacteria after treatment.
  • a first bacterial enumeration reflecting live bacteria in the biofilm outer layer was determined by ETT wash with PBS following by vortex/sonication/vortex step (step 1).
  • a second bacterial enumeration, reflecting live bacteria in the biofilm inner layer was determined from the remaining ETT biofilm (step 2).
  • Bacterial enumeration obtained without pLK treatment corresponded to 100 % of survival. After treatment, bacteria enumeration showed an almost complete killing with less than 1% of live bacteria with 10 ⁇ and 100 ⁇ pLK solution (Table 1, line 1). Altogether, these results suggested an antibiofilm effect of pLK characterized by a degradation of biofilm structure and an alteration of bacteria membrane.
  • PAK-Lux strain bio films were formed with different P. aeruginosa clinical strains in ETT. Without pLK treatment, images observed with SEM, were identical to those obtained with PAK-Lux biofilm, showing interconnected bacteria by fiber- like structures. After pLK treatment, a reduction of the fiber-like structures was noticed with presence of micro- vesicles at bacteria surface. Less than 0.5 % of live bacteria were enumerated when EET was treated with 10 ⁇ and 100 ⁇ pLK solution (Table 1, line 2).
  • pLK condensates the biofilm structure and unmasks bacteria of patient EET biofilm ETT were collected from mechanically ventilated patients, colonized by P. aeruginosa (Table 2). Sections of EET containing biofilm were treated either with LB, pLK 10 ⁇ or pLK 100 ⁇ . Without pLK treatment, an abundant biofilm was observed with complex matrices in the inner surface of the ETT and no bacteria were observed on this matrix surface. As expected, this biofilm was totally different from the artificial ones ( Figures 2 and 3). This difference is most probably due to the presence of patient respiratory secretion which plays an important role in the biofilm formation. Another change was the P.
  • mean concentration of IL- 6 was of 146 ⁇ 26 pg/mL for the control group and of 155 ⁇ 155 pg/mL for the treated group; and mean concentration of IL-8 was of 271 ⁇ 11 pg/mL for the control group and of 85 ⁇ 85 pg/mL for the treated group.
  • IL-6 and IL-8 concentrations were not detected with ELISA, explaining the calculated SEM. No tracheal or lung lesion and no local inflammation were observed by histological studies, in treated pigs compared to controls, showing that ETT repeated instillations with pLK 10 ⁇ solution were well tolerated.
  • SAPS II mean ⁇ SEM 44 ⁇ 7
  • SAPS Simplified Acute Physiologic Score
  • SEM Standard Error of the Mean
  • ICU Intensive Care Unit Table 3.

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Abstract

La présente invention concerne des méthodes pour inhiber ou réduire la formation de biofilms dePseudomonas, en particulier de film de Pseudomonas aeruginosabio. Plus spécifiquement, la présente invention concerne des polymères cationiques et leur utilisation dans le traitement de biofilm de Pseudomonas aeruginosa présent dans le tube endotrachéal (TET) de patients ventilés mécaniquement.
PCT/EP2016/074096 2015-10-09 2016-10-07 Méthodes pour inhiber ou réduire des biolfilms bactériens WO2017060489A1 (fr)

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WO2021130269A1 (fr) 2019-12-23 2021-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Combinaison d'une alpha-pll avec un bêta-lactame destinée au traitement d'une résistance bactérienne à des antibiotiques

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021130269A1 (fr) 2019-12-23 2021-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Combinaison d'une alpha-pll avec un bêta-lactame destinée au traitement d'une résistance bactérienne à des antibiotiques

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