WO2016004216A2 - Hydrogels for treating and ameliorating infections and methods of making and using them - Google Patents

Hydrogels for treating and ameliorating infections and methods of making and using them Download PDF

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Publication number
WO2016004216A2
WO2016004216A2 PCT/US2015/038852 US2015038852W WO2016004216A2 WO 2016004216 A2 WO2016004216 A2 WO 2016004216A2 US 2015038852 W US2015038852 W US 2015038852W WO 2016004216 A2 WO2016004216 A2 WO 2016004216A2
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Prior art keywords
antibiotic
optionally
hydrogel
infection
concentration
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PCT/US2015/038852
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French (fr)
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WO2016004216A3 (en
Inventor
John Maki
Newell Bascomb
Fredric Young
Eun Seok GILL
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Vicus Therapeutics, Llc
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Publication of WO2016004216A2 publication Critical patent/WO2016004216A2/en
Publication of WO2016004216A3 publication Critical patent/WO2016004216A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • compositions, formulations, kits and other products of manufacture, and methods for treating, ameliorating (e.g., reducing the severity of, slowing the progress of) or preventing infections, comprising local administration of drugs via a hydrogel component or material, wherein optionally amount or concentration of drugs in the hydrogel component or material is a "very high” or an "ultra-high” dose of drugs.
  • the products of manufacture, devices, kits, and compositions, and methods as provided herein are antimicrobial and target infections caused, e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus (MRSAs), or biofilms.
  • MDROs multiple drug resistance organisms
  • MRSAs methicillin-resistant Staphylococcus aureus
  • biofilms e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus
  • skin, skin structure or bone infections are treated, ameliorated or prevented by products of manufacture, devices, kits, and compositions, and methods as provided herein.
  • MRSA Methicillin-Resistant Staphylococcus aureus
  • beta-lactam antibiotics include the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins. Resistance makes MRSA infection more difficult to treat with standard types of antibiotics and thus more dangerous.
  • MRSA is especially troublesome in hospitals, prisons and nursing homes, where patients with open wounds, invasive devices, and weakened immune systems are at greater risk of infection than the general public. MRSA began as a hospital-acquired infection (nosocomial infection) but has developed limited endemic status and is now sometimes community-acquired.
  • Biofilms Bacteria that attach to a surface and grow as a bio film are protected from antibiotic killing. Reduced antibiotic susceptibility contributes to the persistence of bio film infections such as those associated with implanted devices or chronic wounds.
  • the protective mechanisms at work in bio films appear to be distinct from those that are responsible for conventional antibiotic resistance. In biofilms, poor antibiotic penetration, nutrient limitation, slow growth, adaptive stress responses, and formation of persister cells are hypothesized to constitute a multi-layered defense.
  • products of manufacture, devices or compositions comprising:
  • a sterile hydrogel comprising a hydrogel material, wherein the hydrogel is:
  • an antibiotic or a plurality of antibiotics wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
  • sterile hydrogel material or sterile hydrogel is mixed with the antibiotic or plurality of antibiotics
  • antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel:
  • the hydrogel is capable of self-assembling, gelling or setting when exposed to an environment comprising a salt concentrations > 1 mM (or gelation, self-assembly or setting is initiated by salt concentrations > 1 mM);
  • the hydrogel is capable of self-assembling, gelling or setting into a 3D hydrogel having a nanometer scale and/or a fibrous structure with an average pore size of between about 50 to 200 nm; or,
  • the hydrogel is at a concentration of about: 0.1% to 5%> (w/v), 0.5%> to 4% (w/v), 1% to 3% (w/v), 1% to 10% (w/v), 1% to 15% (w/v), 1% to 20% (w/v), 1% to 25% (w/v), 1% to 30% (w/v), 1% to 40% (w/v), or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%
  • the hydrogel or hydrogel material comprises a self-assembling peptide
  • the hydrogel or hydrogel material comprises a plurality of synthetic peptides characterized by stable B-sheet structure with ionic side-chain interactions after setting, gelling or self-assembling;
  • the hydrogel or hydrogel material comprises a 16-amino acid synthetic peptide (Ac-[RADA]4-CONH 2 ), or SEQ ID NO: l, and optionally the hydrogel comprises PURAMATRIXTM (PuraMatrixTM) (BD Biosciences, San Jose, CA), or PURADERMTM (PuraDermTM) (3DMatrix, Ltd, Tokyo, Japan);
  • the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu
  • the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile ( ⁇ ) 3 ⁇ (SEQ ID NO:3);
  • the hydrogel or hydrogel material comprises a cellulose, a chitin, a chitosan or a deacetylated chitin, a laminin, a collagen, an elastin, a fibrin, a gelatin, an alginic acid, a hyaluronic acid (HA), or a combination thereof,
  • the HA comprise a thiolated HA or a tyraminated HA
  • the collagen comprises a collagen IV or a collagen I,
  • the cellulose comprises a hemicellulose methyl cellulose (MC), a hydroxypropyl cellulose (HPC), a hydroxypropylmethyl cellulose (HPMC), a
  • CMC carboxymethyl cellulose
  • hydrogel a cellulose-inorganic hybrid hydrogel
  • the hydrogel or hydrogel material comprises a polyethylene glycol (PEG), a polyethelene glycol diacrylate (PEGDA), an ethylene glycol dimethacrylate (EGDMA); a cyclodextrin; a p-dioxanone; a hydroxyethyl methacrylate; a poly(methyl methacrylate); a methylene-bis-acrylamide; a poly(acrylic acid); a polyacrylonitrile; a poly(butylene oxide); a polycaprolactone; a poly(ethylene imine); a poly(ethylene oxide); a poly(ethyl methacrylate); a propylene fumarate; a poly(glucosylethyl methacrylate); a poly(hydroxy butyrate); a poly(hydroxyethyl methacrylate); a poly(hydroxypropyl methacrylamide); a poly(lactic acid); a poly(lactic-co-glycolic acid); PNIPAAm,
  • the hydrogel or hydrogel material comprises any combination of (a) to (g).
  • the sterile pure water or a sterile isotonic solution or buffer comprises a saline, a phosphate buffered saline (PBS), or an equivalent buffer;
  • the product of manufacture, device or composition of (a) wherein: (1) the saline is used at an undiluted concentration of about 0.25% to 2.5%, 0.25%> to 1.5%, 0.5%> to 1.0%, 0.54%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%, or at a concentration of about: 0.1% to 5%, 0.5% to 4%, 1% to 3%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 25%, 1% to 30%, 1% to 40%, or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more; or, (2) the PBS is
  • the antibiotic or plurality of antibiotics comprises:
  • an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) or prevent a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
  • MDRO multiple drug resistance organism
  • MRSA methicillin-resistant Staphylococcus aureus
  • glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
  • the lincosamide antibiotic is a clindamycin or a lincomycin
  • the macrolide antibiotic is a clarithromycin or an azithromycin
  • the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
  • oxazolidinone antibiotic is a linozoli or a posizolid antibiotic
  • dihydrofolate reductase inhibitor antibiotic is a
  • sulfonamide bacteriostatic antibiotic is a sulfamethoxazole
  • ansamycin antibiotic is a rifamycin antibiotic
  • the rifamycin antibiotic is a rifampin
  • polymyxin antibiotic is a colistin
  • a ⁇ -Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
  • gentamycin at a concentration of about 0.1%
  • vancomycin at a
  • a ciclopirox at a concentration of about 0.1%
  • a colistin at a concentration of about 0.1%
  • the antifungal is a ciclopirox olamine
  • product of manufacture, device or composition as provided herein further comprises:
  • deferoxamine also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal
  • the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
  • an antiseptic wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPTTM or SERASEPTTM,
  • the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • a hemostatic agent comprising a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
  • the product of manufacture, device or composition as provided herein is in an in situ milieu or environment.
  • methods for treating, preventing or ameliorating or preventing an infection comprising: applying or administering to an individual in need thereof; or, applying or administering to an infected tissue, a wound or surgical site; the product of manufacture, device or composition as provided herein.
  • the product of manufacture, device or composition as provided herein is applied therapeutically and/or prophylactically to: an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant
  • Staphylococcus aureus or a bio film
  • a surgical site infection or an MDRO- or MRSA- or bio film-infected surgical site an infected skin or skin structure or an MDRO- or MRSA- or bio film-infected skin or skin structure
  • MDRO- or MRSA- or bio film-infected skeletal or a bone a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10% total body surface area) burn, or an infected burn.
  • the infection treated by the methods and/or the product of manufacture, device or composition as provided herein is caused by: (a) a bacteria, a parasite, a fungus or a virus; (b) a gram negative bacteria or a gram positive bacteria; (c) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria; (d) a non-cultureable pathogen; or, (e) any combination of (a) to (d).
  • the applying or administering to the individual e.g., a human or an animal in need thereof of the product of manufacture, device or composition, or the applying or administering to the infected tissue, wound or surgical site of the product of manufacture, device or composition; is:
  • any combination of (a) to (c), and optionally the systemic infection treatment comprises a single intravenous (IV) dose, or daily IV dosages, of 1200 mg of oritavancin.
  • the infection treated, ameliorated or prevented is: (a) a local or a systemic multiple drug resistance organism (MDRO) caused infection; (b) a skin or skin structure, or skin wound, infection, wherein optionally the skin or skin structure, or skin wound infection is caused by a Streptococcus, a Group A Streptococcus, a Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptostreptococcus, an Aeromonas, or a Clostridium:, or, (c) a wound or a surgical site infection.
  • MDRO multiple drug resistance organism
  • the applying or administering of the product of manufacture, device or composition as provided herein, to the individual in need thereof; or, the applying or administering of the product of manufacture, device or composition as provided herein, to an infected tissue, a wound or surgical site is: (a) before debridement of the infected tissue, a wound or surgical site; (b) after debridement of the infected tissue, a wound or surgical site; or, (c) any combination of (a) and (b).
  • provided are methods for treating, preventing or disrupting a biofilm comprising applying to an individual, a tissue, an organ, or a tooth, in need thereof; or, applying to an infected tissue, a wound or surgical site; the product of manufacture, device or composition as provided herein.
  • provided are methods for treating, preventing or disrupting a biofilm comprising applying to a device, a medical device, an implant, a dental implant, a breast implant, a prosthesis, a stent, a catheter; the product of
  • a device comprising a product of manufacture, device or composition as provided herein.
  • kits, or an integrated point of care mixing kit comprising: (a) a sterile hydro gel material or sterile hydro gel as provided herein, or as used to practice a product of manufacture, device or composition as provided herein as provided herein, or, a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter as provided herein, wherein optionally the sterile hydrogel material or sterile hydrogel is: (i) in a substantially liquid form capable of setting, gelling or self-assembling; (ii) a partially assembled or gelled hydrogel; or, (iii) in a set, gelled or self-assembled state; or a substantially set, gelled or self-assembled state; (b) the kit of (a), further comprising instructions for practicing any method as provided herein.
  • therapeutic combinations comprising:
  • (A) (a) (i) a product of manufacture, device, or composition as provided herein, (ii) a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter as provided herein, or (iii) a kit, or an integrated point of care mixing kit, as provided herein; and, (b) an antibiotic or a plurality of antibiotics, an antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic
  • the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics, and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel; or
  • deferoxamine also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal
  • iron chelators is at a concentration of between about 0.05% to 0.5%
  • the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
  • an antiseptic wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPTTM or SERASEPTTM, and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • polihexanide also known as polyhexamethylene biguanide
  • LAVASEPTTM or SERASEPTTM LAVASEPTTM or SERASEPTTM
  • the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • a hemostatic agent comprising a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
  • the antibiotic or a plurality of antibiotics are used in (or against, or to treat, ameliorate or prevent) an infection of a local or a systemic:
  • MDRO multiple drug resistance organism
  • MRSA methicillin-resistant Staphylococcus aureus
  • an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
  • MDRO multiple drug resistance organism
  • MRSA methicillin-resistant Staphylococcus aureus
  • glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
  • an aminoglycoside, a macrolide or a lincosamide antibiotic wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
  • an oxazolidinone antibiotic wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic
  • a dihydrofolate reductase inhibitor antibiotic wherein optionally the dihydrofolate reductase inhibitor antibiotic is a trimethoprim
  • a sulfonamide bacteriostatic antibiotic wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
  • an ansamycin antibiotic wherein optionally the ansamycin antibiotic is a rifamycin antibiotic, and optionally the rifamycin antibiotic is a rifampin,
  • a ⁇ -Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
  • gentamycin at a concentration of about 0.1%
  • vancomycin at a
  • a ciclopirox at a concentration of about 0.1%
  • a colistin at a concentration of about 0.1%
  • antihelminthic wherein optionally the antifungal is a ciclopirox olamine;
  • the therapeutic combination is used in the treatment, amelioration, prevention or healing of: an infection; a systemic infection; an infected tissue; a wound or surgical site; an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA) or a biofilm; a surgical site infection or an MDRO- or MRSA- or bio film-infected surgical site; an infected skin or skin structure or an MDRO- or MRSA- or biofilm-infected skin or skin structure; a skeletal or a bone infection or an MDRO- or MRSA- or biofilm-infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10 cm ) chronic
  • the infection is caused by: (a) a bacteria, a parasite, a fungus or a virus; (b) a gram negative bacteria or a gram positive bacteria; (c) a
  • Staphylococcus an Enterobacter, an Enterococcus , a Acinetobacter, Pseudomonas, or a Klebsiella bacteria; (d) a non-cultureable pathogen; or, (e) any combination of (a) to (d).
  • the infection is an infection of a skin or skin structure, or skin wound infection caused by a Streptococcus, a Group A Streptococcus, a
  • Streptococcus pyogenes a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptostreptococcus, an Aeromonas, or a Clostridium.
  • an antibiotic or a plurality of antibiotics wherein optionally the antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
  • the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics, and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel,
  • MDRO multiple drug resistance organism
  • MRSA methicillin-resistant Staphyloc
  • Streptococcus pyogenes a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptos!reptococcus, an Aeromonas, or a Clostridium.
  • the antibiotic or a plurality of antibiotics comprise:
  • an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
  • MDRO multiple drug resistance organism
  • MRSA methicillin-resistant Staphylococcus aureus
  • glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation, Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
  • an aminoglycoside, a macrolide or a lincosamide antibiotic wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
  • a sulfonamide bacteriostatic antibiotic wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
  • an ansamycin antibiotic wherein optionally the ansamycin antibiotic is a rifamycin antibiotic, and optionally the rifamycin antibiotic is a rifampin,
  • a ⁇ -Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem, (j) a trimethoprim and a sulfamethoxazole;
  • gentamycin at a concentration of about 0.1%
  • vancomycin at a
  • a ciclopirox at a concentration of about 0.1%
  • a colistin at a concentration of about 0.1%
  • antihelminthic wherein optionally the antifungal is a ciclopirox olamine;
  • the product of manufacture, device or composition further comprises:
  • deferoxamine also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal
  • iron chelators is at a concentration of between about 0.05% to 0.5%
  • the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • an antiseptic wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPTTM or SERASEPTTM, and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • polihexanide also known as polyhexamethylene biguanide
  • LAVASEPTTM or SERASEPTTM LAVASEPTTM or SERASEPTTM
  • the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
  • a hemostatic agent comprising a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
  • novel products of manufacture, devices, kits, and compositions, and methods for treating, ameliorating (e.g., reducing the severity of, slowing the progress of) or preventing infections, comprising local administration of drugs via a hydrogel component as provided herein, including local administration of drugs incorporating a locally applied "very high", or "ultra-high” dose of drugs.
  • one, a set, or a combination of antibiotics are used, including antibiotics indicated for the systemic treatment of a microbial, e.g., a bacterial infection.
  • antibiotics are administered using a product of manufacture, a device or a composition as provided herein, or by a method as provided herein, at the same time, before and/or after systemic therapy, i.e., by combining systemic therapy with use of a product of manufacture, a device or a composition as provided herein, or by practicing a method as provided herein.
  • the antibiotics administered using a product of manufacture, a device or a composition as provided herein, or by practicing a method as provided herein, at the same time, before and/or after systemic therapy are locally administered, or locally applied, at "very high", or "ultrahigh" doses.
  • the products of manufacture, devices, kits, and compositions, and methods as provided herein are antimicrobial and target infections caused, e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus (MRSAs), including MDRO- or MRSA- or biofilm-caused infections.
  • MDROs multiple drug resistance organisms
  • MRSAs methicillin-resistant Staphylococcus aureus
  • skin, skin structure or bone infections are treated, ameliorated or prevented by products of manufacture, devices, kits, and compositions, and methods as provided herein.
  • the products of manufacture, devices, kits, and compositions, and methods as provided herein are used on combination with systemic therapies, including e.g., the same or different antibiotics, or other drugs or biologies (such as cytokines) used in the hydrogels used to practice the invention.
  • systemic therapies including e.g., the same or different antibiotics, or other drugs or biologies (such as cytokines) used in the hydrogels used to practice the invention.
  • hydrogels used to practice the invention can comprise a high, or an ultra-high, dose of a drug or drugs that are indicated for the systemic treatment of an infection, e.g., a bacterial, fungal, protozoal or viral infection.
  • an infection e.g., a bacterial, fungal, protozoal or viral infection.
  • a combination of antibiotics that are synergistic for the treatment of MRS A or MDRO or bio films includes vancomycin and gentamicin; thus, in alternative embodiments, hydrogels used to practice the invention can comprise vancomycin and/or gentamicin, and this hydrogel can be used in
  • gentamicin e.g., a high-dose gentamicin
  • a combination of antibiotics comprises a ciclopirox that is currently approved for fungal infections, but has activity against gram negative bacteria and synergistic with other drugs, e.g., via iron chelation and/or biofilm disruption.
  • a combination of antibiotics comprises a deferoxamine, which is synergistic with other drugs via iron chelation and/or biofilm disruption.
  • a combination of antibiotics comprises a polihexanide, an antiseptic, with unique membrane disrupting properties, which can be synergistic with other drugs.
  • a combination of antibiotics comprises a tranexamic acid, which is a product that can stop bleeding after debridement and pooling of blood.
  • products of manufacture, devices, kits, and compositions are used or combined with a physiologic saline and/or a phosphate buffered saline (PBS), or an equivalent buffer.
  • PBS phosphate buffered saline
  • hydrogel is re-applied upon every dressing change, e.g., once or twice daily, or every other day, and/or after each debridement, e.g., every 3 to 7 days, or every 2, 3, 4 ,5, 6, 7, 8, 9 or 10 days.
  • biofilm-based wound care because newly formed wound biofilms (or bioburdens) are more susceptible to antimicrobial treatment, products of manufacture, devices, kits, and compositions as provided herein, are applied in conjunction with the use of serial or repeated debridement to continually remove mature biofilm, followed by biofilm wound management strategies, including application of products of manufacture, devices, kits, and compositions as provided herein while the bioburden / biofilm is still immature.
  • practicing this invention comprises use of debridement, including serial or repeated debridement, e.g., debridement as needed, for both the removal of non- viable tissue and for removal or potential new or existing biofilm, followed by administration or application of products of manufacture, devices, kits, or compositions as provided herein.
  • debridement including serial or repeated debridement, e.g., debridement as needed, for both the removal of non- viable tissue and for removal or potential new or existing biofilm, followed by administration or application of products of manufacture, devices, kits, or compositions as provided herein.
  • debridement including serial or repeated debridement, e.g., debridement as needed
  • the hydrogel or hydrogel material comprises a self- assembling peptide.
  • the hydrogel or hydrogel material comprises a plurality of synthetic peptides characterized by stable B-sheet structure with ionic side-chain interactions after setting, gelling or self-assembling.
  • the hydrogel or hydrogel material comprises a self-assembling peptide comprising: the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile (IEIK) 3 I (SEQ ID NO:3); or, the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu- Asp-Leu (KLDL) 3 (SEQ ID NO:2); or, a 16-amino acid synthetic peptide (Ac-[RADA] 4 -CONH 2 ), or SEQ ID NO: l, which optionally can be or comprise a PURAMATRIXTM
  • PURAMATRIXTM (PuraMatrixTM) and PURASTATTM (PuraStatTM) comprise a laboratory-designed, 16-amino acid polypeptide with a repeating sequence of arginine, alanine, and aspartic acid, or RADARADARADARADA (termed RADA 4 or [RADA] 4 ) (SEQ ID NO: l).
  • RADARADARADARADA termed RADA 4 or [RADA] 4
  • the alternating positively and negatively charged amino acids (arginine and aspartic acid), along with the non-polar alanines in-between the charged amino acids, create two distinct structural surfaces, one hydrophilic and the other hydrophobic (Zhang and Airman, 1999[5]).
  • the RADA polypeptide monomer building blocks form ⁇ -sheet structures upon exposure to physiological concentrations of salt, i.e., tissue culture media orphysiological fluids such as blood, via complementary ionic bond formation at the hydrophilic surface of the molecules (Hauser, et al. 2010 [3]).
  • salt i.e., tissue culture media orphysiological fluids such as blood
  • the hydrophobic sides of the peptide form a double sheet inside of the fibers and the hydrophilic side forms the outside of the nano fibers that interact with water molecules, forming an extremely high water content hydrogel; for example, in one embodiment, a PURASTAT ® (PuraStat ® ) or equivalent hydrogel comprising 2.5% RADA peptide or equivalent and 97.5% water is used to practice the invention.
  • a PURASTAT ® PuraStat ®
  • equivalent hydrogel comprising 2.5% RADA peptide or equivalent and 97.5% water is used to practice the invention.
  • PURASTAT ® (PuraStat ® ), based on the self-assembling peptide platform technology of PURAMATRIXTM (PuraMatrixTM), is a CE (Conformite Europeenne, meaning "European Conformity") mark approved surgical hemostatic agent.
  • PuraStat ® is safe, synthetic, non-biogenic, biocompatible, resorbable peptide hydrogel with no risk of transmissible spongiform encephalopathy (TSE) transmission.
  • PURAMATRIXTM PuraMatrixTM
  • PURASTATTM PuraStatTM
  • PURAMATRIXTM and PURASTATTM PURASTATTM
  • PURAMATRIXTM PuraMatrixTM
  • PURASTATTM PURASTATTM
  • PURAMATRIXTM PuMatrixTM
  • PURASTATTM PuraStatTM
  • PURAMATRIXTM can be easily washed away during dressing changes and facilitate the removal of biomaterials and/or bacteria prior to reapplication of the gel. Also, because PURAMATRIXTM
  • PuraMatrixTM and PURASTATTM are easily washed off without injury, the skin and any residual material that may be left is biocompatible and resorbable; and once the infection is cleared, the wound can be closed and heal via 2nd intention (the wound is allowed to granulate), tertiary intention (e.g. delayed primary closure), or optionally can heal with a tissue graft.

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Abstract

In alternative embodiments, the invention provides pharmaceutical compositions, formulations, kits and other products of manufacture, and methods, for treating, ameliorating (e.g., reducing the severity of, slowing the progress of) or preventing infections, comprising local administration of drugs via a hydrogel component or material, wherein optionally amount or concentration of drugs in the hydrogel component or material is a "very high" or an "ultra-high" dose of drugs. In alternative embodiments, the products of manufacture, devices, kits, and compositions, and methods as provided herein are antimicrobial and target infections caused, e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus (MRSAs), or a biofilm. In alternative embodiments, skin, skin structure or bone infections are treated, ameliorated or prevented by products of manufacture, devices, kits, and compositions, and methods as provided herein.

Description

HYD OGELS FOR TREATING AND AMELIORATING INFECTIONS AND METHODS OF MAKING AND USING
THEM
RELATED APPLICATIONS
This Patent Convention Treaty (PCT) International Application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. (USSN) 62/019,812, filed July 01, 2014. The aforementioned application is expressly incorporated herein by reference in its entirety and for all purposes.
FIELD OF THE INVENTION
This invention relates generally to medicine, pharmaceutical formulations and medical devices. In alternative embodiments, provided are pharmaceutical compositions, formulations, kits and other products of manufacture, and methods, for treating, ameliorating (e.g., reducing the severity of, slowing the progress of) or preventing infections, comprising local administration of drugs via a hydrogel component or material, wherein optionally amount or concentration of drugs in the hydrogel component or material is a "very high" or an "ultra-high" dose of drugs. In alternative embodiments, the products of manufacture, devices, kits, and compositions, and methods as provided herein are antimicrobial and target infections caused, e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus (MRSAs), or biofilms. In alternative embodiments, skin, skin structure or bone infections are treated, ameliorated or prevented by products of manufacture, devices, kits, and compositions, and methods as provided herein.
BACKGROUND
Methicillin-Resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several difficult-to-treat infections in humans. MRSAs are resistant to beta-lactam antibiotics, which include the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins. Resistance makes MRSA infection more difficult to treat with standard types of antibiotics and thus more dangerous.
MRSA is especially troublesome in hospitals, prisons and nursing homes, where patients with open wounds, invasive devices, and weakened immune systems are at greater risk of infection than the general public. MRSA began as a hospital-acquired infection (nosocomial infection) but has developed limited endemic status and is now sometimes community-acquired.
Bacteria that attach to a surface and grow as a bio film are protected from antibiotic killing. Reduced antibiotic susceptibility contributes to the persistence of bio film infections such as those associated with implanted devices or chronic wounds. The protective mechanisms at work in bio films appear to be distinct from those that are responsible for conventional antibiotic resistance. In biofilms, poor antibiotic penetration, nutrient limitation, slow growth, adaptive stress responses, and formation of persister cells are hypothesized to constitute a multi-layered defense.
New approaches to treating MDROs and bio film infections are needed to address these challenges.
SUMMARY
In alternative embodiments, provided are products of manufacture, devices or compositions, comprising:
(a) a sterile hydrogel comprising a hydrogel material, wherein the hydrogel is:
(i) in a substantially liquid form capable of setting, gelling or self- assembling;
(ii) a partially assembled or gelled hydrogel, in a partially assembled or gelled form; or,
(iii) in a set, gelled or self-assembled state; or a substantially set, gelled or self-assembled state,
and optionally the set, gelled or self-assembled state is in situ; and
(b) an antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
wherein optionally the sterile hydrogel material or sterile hydrogel is mixed with the antibiotic or plurality of antibiotics,
and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel:
(i) while the hydrogel is still in a substantially liquid state, un-self-assembled state, or ungelled state;
(ii) before the hydrogel has self-assembled, set or gelled,
(iii) before the hydrogel has set or self-assembled into a 3D hydrogel,
(iv) after the set, gelled or self-assembled hydrogel, or the substantially set, or self-assembled hydrogel, has been disrupted or sheared; or
(v) at the same time the hydrogel has set, gelled or self-assembled hydrogel, the hydrogel has substantially set, gelled or self-assembled.
In alternative embodiments: (a) the hydrogel is capable of self-assembling, gelling or setting when exposed to an environment comprising a salt concentrations > 1 mM (or gelation, self-assembly or setting is initiated by salt concentrations > 1 mM); (b) the hydrogel is capable of self-assembling, gelling or setting into a 3D hydrogel having a nanometer scale and/or a fibrous structure with an average pore size of between about 50 to 200 nm; or, (c) the hydrogel is at a concentration of about: 0.1% to 5%> (w/v), 0.5%> to 4% (w/v), 1% to 3% (w/v), 1% to 10% (w/v), 1% to 15% (w/v), 1% to 20% (w/v), 1% to 25% (w/v), 1% to 30% (w/v), 1% to 40% (w/v), or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more (w/v).
In alternative embodiments:
(a) the hydrogel or hydrogel material comprises a self-assembling peptide;
(b) the hydrogel or hydrogel material comprises a plurality of synthetic peptides characterized by stable B-sheet structure with ionic side-chain interactions after setting, gelling or self-assembling;
(c) the hydrogel or hydrogel material comprises a 16-amino acid synthetic peptide (Ac-[RADA]4-CONH2), or SEQ ID NO: l, and optionally the hydrogel comprises PURAMATRIX™ (PuraMatrix™) (BD Biosciences, San Jose, CA), or PURADERM™ (PuraDerm™) (3DMatrix, Ltd, Tokyo, Japan);
(d) the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu
(KLDL)3 (SEQ ID NO:2); (e) the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile (ΙΕΙΚ)3Ι (SEQ ID NO:3);
(f) the hydrogel or hydrogel material comprises a cellulose, a chitin, a chitosan or a deacetylated chitin, a laminin, a collagen, an elastin, a fibrin, a gelatin, an alginic acid, a hyaluronic acid (HA), or a combination thereof,
wherein optionally the HA comprise a thiolated HA or a tyraminated HA;
or optionally the collagen comprises a collagen IV or a collagen I,
or optionally the cellulose comprises a hemicellulose methyl cellulose (MC), a hydroxypropyl cellulose (HPC), a hydroxypropylmethyl cellulose (HPMC), a
carboxymethyl cellulose (CMC) or a cellulose-inorganic hybrid hydrogel;
(g) the hydrogel or hydrogel material comprises a polyethylene glycol (PEG), a polyethelene glycol diacrylate (PEGDA), an ethylene glycol dimethacrylate (EGDMA); a cyclodextrin; a p-dioxanone; a hydroxyethyl methacrylate; a poly(methyl methacrylate); a methylene-bis-acrylamide; a poly(acrylic acid); a polyacrylonitrile; a poly(butylene oxide); a polycaprolactone; a poly(ethylene imine); a poly(ethylene oxide); a poly(ethyl methacrylate); a propylene fumarate; a poly(glucosylethyl methacrylate); a poly(hydroxy butyrate); a poly(hydroxyethyl methacrylate); a poly(hydroxypropyl methacrylamide); a poly(lactic acid); a poly(lactic-co-glycolic acid); PNIPAAm, poly(N-isopropyl acrylamide); a poly(N-vinyl pyrrolidone); a poly(propylene oxide); a poly( vinyl alcohol); a poly(vinyl acetate); a poly(vinyl amine), or any combination thereof; or
(h) the hydrogel or hydrogel material comprises any combination of (a) to (g).
In alternative embodiments: (a) the sterile pure water or a sterile isotonic solution or buffer comprises a saline, a phosphate buffered saline (PBS), or an equivalent buffer; (b) the product of manufacture, device or composition of (a), wherein: (1) the saline is used at an undiluted concentration of about 0.25% to 2.5%, 0.25%> to 1.5%, 0.5%> to 1.0%, 0.54%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%, or at a concentration of about: 0.1% to 5%, 0.5% to 4%, 1% to 3%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 25%, 1% to 30%, 1% to 40%, or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more; or, (2) the PBS is at a concentration of about 0.25% to 2.5%, 0.25% to 1.5%, 0.5% to 1.0%, 0.54%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%, or at a concentration of about: 0.1% to 5%, 0.5% to 4%, 1% to 3%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 25%, 1% to 30%, 1% to 40%, or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more.
In alternative embodiments, the antibiotic or plurality of antibiotics, comprises:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) or prevent a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic,
wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic,
wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic,
wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic,
(e) a dihydrofolate reductase inhibitor antibiotic,
wherein optionally the dihydrofolate reductase inhibitor antibiotic is a
trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic,
wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
(g) an ansamycin antibiotic,
wherein optionally the ansamycin antibiotic is a rifamycin antibiotic,
and optionally the rifamycin antibiotic is a rifampin,
(h) a polymyxin antibiotic,
wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
(j) a trimethoprim and a sulfamethoxazole; (k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(j) a gentamicin, a vancomycin and a colistin;
(o) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic,
wherein optionally the antifungal is a ciclopirox olamine;
(p) any combination of (a) through (o).
In alternative embodiments the product of manufacture, device or composition as provided herein further comprises:
(a) an iron chelator, wherein optionally the iron chelator comprises a
deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal),
and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
(b) an antiseptic, wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™,
and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent, wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
(d) any combination of (a) to (c).
In alternative embodiments the product of manufacture, device or composition as provided herein is in an in situ milieu or environment.
In alternative embodiments provided are methods for treating, preventing or ameliorating or preventing an infection, comprising: applying or administering to an individual in need thereof; or, applying or administering to an infected tissue, a wound or surgical site; the product of manufacture, device or composition as provided herein.
In alternative embodiments, the product of manufacture, device or composition as provided herein is applied therapeutically and/or prophylactically to: an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant
Staphylococcus aureus (MRSA) or a bio film; a surgical site infection or an MDRO- or MRSA- or bio film-infected surgical site; an infected skin or skin structure or an MDRO- or MRSA- or bio film-infected skin or skin structure; a skeletal or a bone infection or an
MDRO- or MRSA- or bio film-infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10% total body surface area) burn, or an infected burn.
In alternative embodiments, the infection treated by the methods and/or the product of manufacture, device or composition as provided herein, is caused by: (a) a bacteria, a parasite, a fungus or a virus; (b) a gram negative bacteria or a gram positive bacteria; (c) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria; (d) a non-cultureable pathogen; or, (e) any combination of (a) to (d).
In alternative embodiments, the applying or administering to the individual (e.g., a human or an animal) in need thereof of the product of manufacture, device or composition, or the applying or administering to the infected tissue, wound or surgical site of the product of manufacture, device or composition; is:
(a) in conjunction or simultaneously with: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy;
(b) before: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy;
(c) after: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy; or
(d) any combination of (a) to (c), and optionally the systemic infection treatment comprises a single intravenous (IV) dose, or daily IV dosages, of 1200 mg of oritavancin.
In alternative embodiments, the infection treated, ameliorated or prevented is: (a) a local or a systemic multiple drug resistance organism (MDRO) caused infection; (b) a skin or skin structure, or skin wound, infection, wherein optionally the skin or skin structure, or skin wound infection is caused by a Streptococcus, a Group A Streptococcus, a Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptostreptococcus, an Aeromonas, or a Clostridium:, or, (c) a wound or a surgical site infection.
In alternative embodiments, the applying or administering of the product of manufacture, device or composition as provided herein, to the individual in need thereof; or, the applying or administering of the product of manufacture, device or composition as provided herein, to an infected tissue, a wound or surgical site, is: (a) before debridement of the infected tissue, a wound or surgical site; (b) after debridement of the infected tissue, a wound or surgical site; or, (c) any combination of (a) and (b).
In alternative embodiments, provided are methods for treating, preventing or disrupting a biofilm, comprising applying to an individual, a tissue, an organ, or a tooth, in need thereof; or, applying to an infected tissue, a wound or surgical site; the product of manufacture, device or composition as provided herein.
In alternative embodiments, provided are methods for treating, preventing or disrupting a biofilm, comprising applying to a device, a medical device, an implant, a dental implant, a breast implant, a prosthesis, a stent, a catheter; the product of
manufacture, device or composition as provided herein.
In alternative embodiments, provided are a device, a medical device, an implant, a dental implant, a breast implant, a prosthesis, a stent, a catheter, comprising a product of manufacture, device or composition as provided herein.
In alternative embodiments, provided are kits, or an integrated point of care mixing kit, comprising: (a) a sterile hydro gel material or sterile hydro gel as provided herein, or as used to practice a product of manufacture, device or composition as provided herein as provided herein, or, a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter as provided herein, wherein optionally the sterile hydrogel material or sterile hydrogel is: (i) in a substantially liquid form capable of setting, gelling or self-assembling; (ii) a partially assembled or gelled hydrogel; or, (iii) in a set, gelled or self-assembled state; or a substantially set, gelled or self-assembled state; (b) the kit of (a), further comprising instructions for practicing any method as provided herein.
In alternative embodiments, provided are therapeutic combinations comprising:
(A) (a) (i) a product of manufacture, device, or composition as provided herein, (ii) a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter as provided herein, or (iii) a kit, or an integrated point of care mixing kit, as provided herein; and, (b) an antibiotic or a plurality of antibiotics, an antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
wherein optionally the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics, and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel; or
(B) the therapeutic combination of (A), further comprising:
(a) an iron chelator, wherein optionally the iron chelator comprises a
deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal), and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
(b) an antiseptic, wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™, and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent, wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
(d) any combination of (a) to (c).
In alternative embodiments the antibiotic or a plurality of antibiotics are used in (or against, or to treat, ameliorate or prevent) an infection of a local or a systemic:
multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy.
In alternative embodiments the antibiotic or plurality of antibiotics comprise:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic,
wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic, wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic, wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic, (e) a dihydrofolate reductase inhibitor antibiotic, wherein optionally the dihydrofolate reductase inhibitor antibiotic is a trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic, wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
(g) an ansamycin antibiotic, wherein optionally the ansamycin antibiotic is a rifamycin antibiotic, and optionally the rifamycin antibiotic is a rifampin,
(h) a polymyxin antibiotic, wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
(j) a trimethoprim and a sulfamethoxazole; (k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(j) a gentamicin, a vancomycin and a colistin;
(o) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic, wherein optionally the antifungal is a ciclopirox olamine;
(p) any combination of (a) through (o).
In alternative embodiments, the therapeutic combination is used in the treatment, amelioration, prevention or healing of: an infection; a systemic infection; an infected tissue; a wound or surgical site; an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA) or a biofilm; a surgical site infection or an MDRO- or MRSA- or bio film-infected surgical site; an infected skin or skin structure or an MDRO- or MRSA- or biofilm-infected skin or skin structure; a skeletal or a bone infection or an MDRO- or MRSA- or biofilm-infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10% total body surface area) burn, or an infected burn.
In alternative embodiments, the infection is caused by: (a) a bacteria, a parasite, a fungus or a virus; (b) a gram negative bacteria or a gram positive bacteria; (c) a
Staphylococcus, an Enterobacter, an Enterococcus , a Acinetobacter, Pseudomonas, or a Klebsiella bacteria; (d) a non-cultureable pathogen; or, (e) any combination of (a) to (d).
In alternative embodiments, the infection is an infection of a skin or skin structure, or skin wound infection caused by a Streptococcus, a Group A Streptococcus, a
Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptostreptococcus, an Aeromonas, or a Clostridium.
In alternative embodiments provided are uses of:
(a) (i) a product of manufacture, device, or composition as provided herein, (ii) a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter as provided herein, or (iii) a kit, or an integrated point of care mixing kit, as provided herein; and
(b) an antibiotic or a plurality of antibiotics, wherein optionally the antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
wherein optionally the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics, and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer, and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel,
for:
(a) treating, ameliorating or preventing a local or a systemic infection, or an infection caused by a multiple drug resistance organism (MDRO), or a methicillin- resistant Staphylococcus aureus (MRSA);
(b) treating, ameliorating or preventing an infection; a systemic infection; an infected tissue; a wound or surgical site; an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA); a surgical site infection or an MDRO or MRSA infected surgical site; an infected skin or skin structure or an MDRO or MRSA infected skin or skin structure; a skeletal or a bone infection or an MDRO or MRSA infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10% total body surface area) burn, or an infected burn;
(c) treating, ameliorating or preventing an infection caused by:
(i) a bacteria, a parasite, a fungus or a virus;
(ii) a gram negative bacteria or a gram positive bacteria; or
(iii) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria; (iv) a non-cultureable pathogen; or
(v) any combination of (i) to (iv); or
(d) treating, ameliorating or preventing an infection of a skin or skin structure, or skin wound infection caused by a Streptococcus, a Group A Streptococcus, a
Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptos!reptococcus, an Aeromonas, or a Clostridium.
n alternative embodiments of the uses, the antibiotic or a plurality of antibiotics comprise:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic, wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation, Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic, wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic, wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic,
(e) a dihydrofolate reductase inhibitor antibiotic, wherein optionally the dihydrofolate reductase inhibitor antibiotic is a trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic, wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
(g) an ansamycin antibiotic, wherein optionally the ansamycin antibiotic is a rifamycin antibiotic, and optionally the rifamycin antibiotic is a rifampin,
(h) a polymyxin antibiotic, wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem, (j) a trimethoprim and a sulfamethoxazole;
(k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(j) a gentamicin, a vancomycin and a colistin;
(o) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic, wherein optionally the antifungal is a ciclopirox olamine;
(p) any combination of (a) through (o).
In alternative embodiments of the uses, the product of manufacture, device or composition further comprises:
(a) an iron chelator, wherein optionally the iron chelator comprises a
deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal), and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(b) an antiseptic, wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™, and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent, wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
(d) any combination of (a) to (c).
The details of one or more aspects of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes.
DETAILED DESCRIPTION
In alternative embodiments, provided are novel products of manufacture, devices, kits, and compositions, and methods, for treating, ameliorating (e.g., reducing the severity of, slowing the progress of) or preventing infections, comprising local administration of drugs via a hydrogel component as provided herein, including local administration of drugs incorporating a locally applied "very high", or "ultra-high" dose of drugs. In alternative embodiments, one, a set, or a combination of antibiotics are used, including antibiotics indicated for the systemic treatment of a microbial, e.g., a bacterial infection. In alternative embodiments, antibiotics are administered using a product of manufacture, a device or a composition as provided herein, or by a method as provided herein, at the same time, before and/or after systemic therapy, i.e., by combining systemic therapy with use of a product of manufacture, a device or a composition as provided herein, or by practicing a method as provided herein. In alternative embodiments, the antibiotics administered using a product of manufacture, a device or a composition as provided herein, or by practicing a method as provided herein, at the same time, before and/or after systemic therapy, are locally administered, or locally applied, at "very high", or "ultrahigh" doses.
In alternative embodiments, the products of manufacture, devices, kits, and compositions, and methods as provided herein are antimicrobial and target infections caused, e.g., by multiple drug resistance organisms (MDROs), or a methicillin-resistant Staphylococcus aureus (MRSAs), including MDRO- or MRSA- or biofilm-caused infections. In alternative embodiments, skin, skin structure or bone infections are treated, ameliorated or prevented by products of manufacture, devices, kits, and compositions, and methods as provided herein.
In alternative embodiments, the products of manufacture, devices, kits, and compositions, and methods as provided herein are used on combination with systemic therapies, including e.g., the same or different antibiotics, or other drugs or biologies (such as cytokines) used in the hydrogels used to practice the invention.
In alternative embodiments, hydrogels used to practice the invention can comprise a high, or an ultra-high, dose of a drug or drugs that are indicated for the systemic treatment of an infection, e.g., a bacterial, fungal, protozoal or viral infection. For example, in one exemplary embodiment, a combination of antibiotics that are synergistic for the treatment of MRS A or MDRO or bio films includes vancomycin and gentamicin; thus, in alternative embodiments, hydrogels used to practice the invention can comprise vancomycin and/or gentamicin, and this hydrogel can be used in
conjunction with systemic therapy comprising administration of a vancomycin and/or a gentamicin, e.g., a high-dose gentamicin.
In alternative embodiments, provided are uses of combinations of antibiotics that make the treatment a super broad spectrum by targeting different types of bacteria. This can be especially important for the treatment of mature biofilm that have multiple types of bacteria, e.g., gram negative and gram positive bacteria, living symbiotically, and optionally also for the treatment of non-cultureable bacteria, which must be treated empirically, hence this "broadest acting" embodiment is best way to go.
For example, in one exemplary embodiment, a combination of antibiotics comprises a ciclopirox that is currently approved for fungal infections, but has activity against gram negative bacteria and synergistic with other drugs, e.g., via iron chelation and/or biofilm disruption.
In another exemplary embodiment, a combination of antibiotics comprises a deferoxamine, which is synergistic with other drugs via iron chelation and/or biofilm disruption. In another exemplary embodiment, a combination of antibiotics comprises a polihexanide, an antiseptic, with unique membrane disrupting properties, which can be synergistic with other drugs. In another exemplary embodiment, a combination of antibiotics comprises a tranexamic acid, which is a product that can stop bleeding after debridement and pooling of blood.
In another exemplary embodiment, products of manufacture, devices, kits, and compositions are used or combined with a physiologic saline and/or a phosphate buffered saline (PBS), or an equivalent buffer.
In alternative embodiments of products of manufacture, devices, kits, and compositions as provided herein, or when practicing methods as provided herein, hydrogel is re-applied upon every dressing change, e.g., once or twice daily, or every other day, and/or after each debridement, e.g., every 3 to 7 days, or every 2, 3, 4 ,5, 6, 7, 8, 9 or 10 days.
In alternative embodiments, for biofilm-based wound care, because newly formed wound biofilms (or bioburdens) are more susceptible to antimicrobial treatment, products of manufacture, devices, kits, and compositions as provided herein, are applied in conjunction with the use of serial or repeated debridement to continually remove mature biofilm, followed by biofilm wound management strategies, including application of products of manufacture, devices, kits, and compositions as provided herein while the bioburden / biofilm is still immature. Thus, in alternative embodiments, practicing this invention comprises use of debridement, including serial or repeated debridement, e.g., debridement as needed, for both the removal of non- viable tissue and for removal or potential new or existing biofilm, followed by administration or application of products of manufacture, devices, kits, or compositions as provided herein. Hydro gel and Hydro gel materials
In alternative embodiments, the hydrogel or hydrogel material comprises a self- assembling peptide. In alternative embodiments, the hydrogel or hydrogel material comprises a plurality of synthetic peptides characterized by stable B-sheet structure with ionic side-chain interactions after setting, gelling or self-assembling. In alternative embodiments, the hydrogel or hydrogel material comprises a self-assembling peptide comprising: the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile (IEIK)3I (SEQ ID NO:3); or, the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu- Asp-Leu (KLDL)3 (SEQ ID NO:2); or, a 16-amino acid synthetic peptide (Ac-[RADA]4-CONH2), or SEQ ID NO: l, which optionally can be or comprise a PURAMATRIX™
(PuraMatrix™) (BD Biosciences, San Jose, CA), a PURASTAT™ (PuraStat™) (BD
Biosciences, San Jose, CA), or a PURADERM™ (PuraDerm™) (3DMatrix, Ltd, Tokyo, Japan), or equivalents.
PURAMATRIX™ (PuraMatrix™) and PURASTAT™ (PuraStat™) comprise a laboratory-designed, 16-amino acid polypeptide with a repeating sequence of arginine, alanine, and aspartic acid, or RADARADARADARADA (termed RADA4 or [RADA]4) (SEQ ID NO: l). The alternating positively and negatively charged amino acids (arginine and aspartic acid), along with the non-polar alanines in-between the charged amino acids, create two distinct structural surfaces, one hydrophilic and the other hydrophobic (Zhang and Airman, 1999[5]). The RADA polypeptide monomer building blocks form β-sheet structures upon exposure to physiological concentrations of salt, i.e., tissue culture media orphysiological fluids such as blood, via complementary ionic bond formation at the hydrophilic surface of the molecules (Hauser, et al. 2010 [3]).
With regard to fibril formation, the hydrophobic sides of the peptide form a double sheet inside of the fibers and the hydrophilic side forms the outside of the nano fibers that interact with water molecules, forming an extremely high water content hydrogel; for example, in one embodiment, a PURASTAT® (PuraStat®) or equivalent hydrogel comprising 2.5% RADA peptide or equivalent and 97.5% water is used to practice the invention.
PURASTAT® (PuraStat®), based on the self-assembling peptide platform technology of PURAMATRIX™ (PuraMatrix™), is a CE (Conformite Europeenne, meaning "European Conformity") mark approved surgical hemostatic agent. PuraStat® is safe, synthetic, non-biogenic, biocompatible, resorbable peptide hydrogel with no risk of transmissible spongiform encephalopathy (TSE) transmission. PURASTAT®
(PuraStat®), a fully transparent slightly viscous aqueous peptide (2.5%) solution, is sold in a pre-filled syringe and is currently available in lmL, 3mL and 5mL unit doses indicated for hemostasis in several surgical circumstances.
PURAMATRIX™ (PuraMatrix™) and PURASTAT™ (PuraStat™) are biocompatible, and do not induce a foreign body reaction which can disrupt immune function and promote infection. PURAMATRIX™ (PuraMatrix™) and PURASTAT™ (PuraStat™) do not form a matrix that permits bacteria adherence and promote bacterial infection.
Also, PURAMATRIX™ (PuraMatrix™) and PURASTAT™ (PuraStat™) can be easily washed away during dressing changes and facilitate the removal of biomaterials and/or bacteria prior to reapplication of the gel. Also, because PURAMATRIX™
(PuraMatrix™) and PURASTAT™ (PuraStat™) are easily washed off without injury, the skin and any residual material that may be left is biocompatible and resorbable; and once the infection is cleared, the wound can be closed and heal via 2nd intention (the wound is allowed to granulate), tertiary intention (e.g. delayed primary closure), or optionally can heal with a tissue graft.
A number of aspects of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other aspects are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A product of manufacture, a device, or a composition, comprising:
(a) a sterile hydrogel comprising a hydrogel material, wherein the hydrogel is:
(i) in a substantially liquid form capable of setting, gelling or self- assembling;
(ii) a partially assembled or gelled hydrogel, in a partially assembled or gelled form; or,
(iii) in a set, gelled or self-assembled state; or a substantially set, gelled or self-assembled state,
and optionally the set, gelled or self-assembled state is in situ; and
(b) an antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about O.OOIX, 0.005X, 0.01X, 0.02X, 0.05X, O.IX, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about O.OOIX and 10X, or between about O.IX and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
wherein optionally the sterile hydrogel material or sterile hydrogel is mixed with the antibiotic or plurality of antibiotics,
and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer,
and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel:
(i) while the hydrogel is still in a substantially liquid state, un-self-assembled state, or ungelled state;
(ii) before the hydrogel has self-assembled, set or gelled,
(iii) before the hydrogel has set or self-assembled into a 3D hydrogel,
(iv) after the set, gelled or self-assembled hydrogel, or the substantially set, gelled or self-assembled hydrogel, has been disrupted or sheared; or
(v) at the same time the set, gelled or self-assembled hydrogel, or the substantially set, gelled or self-assembled hydrogel, is being disrupted or sheared into a disrupted, unassembled, disassembled, or ungelled, or substantially disrupted, unassembled, disassembled, or ungelled, state, wherein optionally before mixing the antibiotic or plurality of antibiotics of (b) with the sterile hydrogel of (a), the partially assembled or gelled hydrogel of (a) is substantially unassembled, disassembled, or ungelled,
and optionally the unassembling, disassembling, or ungelling is accomplished by a sheer force.
2. The product of manufacture, device, or composition of claim 1, wherein:
(a) the hydrogel is capable of self-assembling, gelling or setting when exposed to an environment comprising a salt concentrations > 1 mM (or gelation, self-assembly or setting is initiated by salt concentrations > 1 mM);
(b) the hydrogel is capable of self-assembling, gelling or setting into a 3D hydrogel having a nanometer scale and/or a fibrous structure with an average pore size of between about 50 to 200 nm; or
(c) the hydrogel is at a concentration of about: 0.1% to 5%> (w/v), 0.5%> to 4%> (w/v), 1% to 3% (w/v), 1% to 10% (w/v), 1% to 15% (w/v), 1% to 20% (w/v), 1% to
25% (w/v), 1% to 30% (w/v), 1% to 40% (w/v), or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%) or more (w/v).
3. The product of manufacture, device, or composition of any of claims 1 to 2, wherein:
(a) the hydrogel or hydrogel material comprises a self-assembling peptide;
(b) the hydrogel or hydrogel material comprises a plurality of synthetic peptides characterized by stable B-sheet structure with ionic side-chain interactions after setting, gelling or self-assembling;
(c) the hydrogel or hydrogel material comprises a 16-amino acid synthetic peptide (Ac-[RADA]4-CONH2), or SEQ ID NO: l, and optionally the hydrogel comprises
PURAMATRIX™ (PuraMatrix™) (BD Biosciences, San Jose, CA), or PURADERM™ (PuraDerm™) (3DMatrix, Ltd, Tokyo, Japan);
(d) the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu
(KLDL)3 (SEQ ID NO:2); (e) the hydrogel or hydrogel material comprises a self-assembling peptide comprising the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile (ΙΕΙΚ)3Ι (SEQ ID NO:3);
(f) the hydrogel or hydrogel material comprises a cellulose, a chitin, a chitosan or a deacetylated chitin, a laminin, a collagen, an elastin, a fibrin, a gelatin, an alginic acid, a hyaluronic acid (HA), or a combination thereof,
wherein optionally the HA comprise a thiolated HA or a tyraminated HA;
or optionally the collagen comprises a collagen IV or a collagen I,
or optionally the cellulose comprises a hemicellulose methyl cellulose (MC), a hydroxypropyl cellulose (HPC), a hydroxypropylmethyl cellulose (HPMC), a
carboxymethyl cellulose (CMC) or a cellulose-inorganic hybrid hydrogel;
(g) the hydrogel or hydrogel material comprises a polyethylene glycol (PEG), a polyethelene glycol diacrylate (PEGDA), an ethylene glycol dimethacrylate (EGDMA); a cyclodextrin; a p-dioxanone; a hydroxyethyl methacrylate; a poly(methyl methacrylate); a methylene-bis-acrylamide; a poly(acrylic acid); a polyacrylonitrile; a poly(butylene oxide); a polycaprolactone; a poly(ethylene imine); a poly(ethylene oxide); a poly(ethyl methacrylate); a propylene fumarate; a poly(glucosylethyl methacrylate); a poly(hydroxy butyrate); a poly(hydroxyethyl methacrylate); a poly(hydroxypropyl methacrylamide); a poly(lactic acid); a poly(lactic-co-glycolic acid); PNIPAAm, poly(N-isopropyl acrylamide); a poly(N-vinyl pyrrolidone); a poly(propylene oxide); a poly( vinyl alcohol); a poly(vinyl acetate); a poly(vinyl amine), or any combination thereof; or
(h) the hydrogel or hydrogel material comprises any combination of (a) to (g).
4. The product of manufacture, device or composition of any of claims 1 to 3, wherein
(a) the sterile pure water or a sterile isotonic solution or buffer comprises a saline, a phosphate buffered saline (PBS), or an equivalent buffer;
(b) the product of manufacture, device or composition of (a), wherein:
(1) the saline is used at an undiluted concentration of about 0.25% to 2.5%, 0.25% to 1.5%, 0.5% to 1.0%, 0.54%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%, or at a concentration of about: 0.1% to 5%, 0.5% to 4%, 1% to 3%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 25%, 1% to 30%, 1% to 40%, or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more; or (2) the PBS is at a concentration of about 0.25% to 2.5%, 0.25% to 1.5%, 0.5% to 1.0%, 0.54%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%, or at a concentration of about: 0.1% to 5%, 0.5% to 4%, 1% to 3%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 25%, 1% to 30%, 1% to 40%, or about 0.1%, , 0.25%, , 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or more.
5. The product of manufacture, device or composition of any of claims 1 to 4, wherein the antibiotic or plurality of antibiotics, comprises:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic,
wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic,
wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic,
wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic,
(e) a dihydrofolate reductase inhibitor antibiotic,
wherein optionally the dihydrofolate reductase inhibitor antibiotic is a
trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic,
wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole, (g) an ansamycin antibiotic,
wherein optionally the ansamycin antibiotic is a rifamycin antibiotic,
and optionally the rifamycin antibiotic is a rifampin, (h) a polymyxin antibiotic,
wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
j) a trimethoprim and a sulfamethoxazole;
(k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(o) a gentamicin, a vancomycin and a colistin;
(p) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic,
wherein optionally the antifungal is a ciclopirox olamine; or
(q) any combination of (a) through (p).
6. The product of manufacture, device or composition of any of claims 1 to 5, further comprising:
(a) an iron chelator,
wherein optionally the iron chelator comprises a deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal),
and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
(b) an antiseptic,
wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™,
and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent, wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
(d) any combination of (a) to (c).
7. The product of manufacture, device or composition of any of claims 1 to 6, wherein the product of manufacture, device or composition is in situ.
8. A method for treating, preventing or ameliorating an infection, comprising: applying or administering to an individual in need thereof; or, applying or administering to an infected tissue, a wound or surgical site; the product of manufacture, device or composition as set forth in any of claims 1 to 6.
9. The method of claim 8, wherein the product of manufacture, device or composition is applied therapeutically and/or prophylactically to: an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA) or a biofilm; a surgical site infection or an MDRO-, MRSA- or biofilm- infected surgical site; an infected skin or skin structure or an MDRO-, MRSA- or biofilm- infected skin or skin structure; a skeletal or a bone infection or an MDRO-, MRSA- or biofilm- infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10%> total body surface area) burn, or an infected burn.
10. The method of any of claims 8 or 9, wherein the infection is caused by:
(a) a bacteria, a parasite, a fungus or a virus;
(b) a gram negative bacteria or a gram positive bacteria; or
(c) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria;
(d) a non-cultureable pathogen; or
(e) any combination of (a) to (d).
11. The method of any of claims 9 to 11, wherein the applying or administering to the individual in need thereof of the product of manufacture, device or composition, or the applying or administering to the infected tissue, wound or surgical site of the product of manufacture, device or composition; is:
(a) in conjunction or simultaneously with: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy;
(b) before: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy;
(c) after: a systemic infection treatment or a treatment to prevent or ameliorate an infection, or a prophylactic or a preventive treatment, or an antimicrobial, antibacterial, antifungal or an antiviral therapy; or
(d) any combination of (a) to (c),
and optionally the systemic infection treatment comprises a single intravenous (IV) dose, or daily IV dosages, of 1200 mg of oritavancin.
12. The method of any of claims 8 to 11, wherein the infection treated,
ameliorated or prevented is:
(a) a local or a systemic multiple drug resistance organism (MDRO), or a biofilm caused infection;
(b) a skin or skin structure, or skin wound, infection, or biofilm infection, wherein optionally the skin or skin structure, or skin wound infection, or biofilm infection, is caused by a Streptococcus, a Group A Streptococcus, a Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Baeteroides, a Peptostreptococcus, an
Aeromonas. or a Clostridium; or
(c) a wound or a surgical site infection.
13. The method of any of claims 8 to 12, wherein the applying or administering of the product of manufacture, device or composition as set forth in any of claims 1 to 6, to the individual in need thereof; or, the applying or administering of the product of manufacture, device or composition as set forth in any of claims 1 to 6, to an infected tissue, a wound or surgical site, is: (a) before debridement of the infected tissue, a wound or surgical site;
(b) after debridement of the infected tissue, a wound or surgical site; or
(c) any combination of (a) and (b).
14. A method for treating, preventing or disrupting a bio film, comprising applying to an individual, a tissue, an organ, or a tooth, in need thereof; or, applying to an infected tissue, a wound or surgical site; the product of manufacture, device or composition, as set forth in any of claims 1 to 6.
15. A method for treating, preventing or disrupting a bio film, comprising applying to a device, a medical device, an implant, a dental implant, a breast implant, a prosthesis, a stent, a catheter; the product of manufacture, device or composition, as set forth in any of claims 1 to 6.
16. A device, a medical device, an implant, a dental implant, a breast implant, a prosthesis, a stent, a catheter, comprising a product of manufacture, device or
composition, as set forth in any of claims 1 to 6.
17. A kit, or an integrated point of care mixing kit, comprising
(a) a sterile hydrogel material or sterile hydrogel of any of claims 1 to 6, or as used in any of claims 1 to 6, or, a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter of claim 16,
wherein optionally the sterile hydrogel material or sterile hydrogel is: (i) in a substantially liquid form capable of setting, gelling or self-assembling; (ii) a partially assembled or gelled hydrogel; or, (iii) in a set, gelled or self-assembled state; or a substantially set, gelled or self-assembled state;
(b) the kit of (a), further comprising instructions for practicing any of the methods of claims 8 to 13.
18. A therapeutic combination comprising:
(A) (a)
(i) a product of manufacture, device, or composition of any of claims 1 to 6,
(ii) a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter of claim 16, or (iii) a kit, or an integrated point of care mixing kit, of claim 18; and
(b) an antibiotic or a plurality of antibiotics,
an antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about 0.001X, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about 0.00 IX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics,
wherein optionally the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics,
and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer,
and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel; or
(B) the therapeutic combination of (A), further comprising:
(a) an iron chelator,
wherein optionally the iron chelator comprises a deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal),
and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
(b) an antiseptic,
wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™,
and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent,
wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin; (d) any combination of (a) to (c).
19. The therapeutic combination of claim 18, wherein:
(i) the antibiotic or a plurality of antibiotics are used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), or biofilm, antibiotic therapy; or
(ii) the antibiotic or a plurality of antibiotics comprise:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), or biofilm, antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic,
wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic,
wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic,
wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic,
(e) a dihydrofolate reductase inhibitor antibiotic,
wherein optionally the dihydrofolate reductase inhibitor antibiotic is a
trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic,
wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
(g) an ansamycin antibiotic,
wherein optionally the ansamycin antibiotic is a rifamycin antibiotic,
and optionally the rifamycin antibiotic is a rifampin,
(h) a polymyxin antibiotic, wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
j) a trimethoprim and a sulfamethoxazole;
(k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(o) a gentamicin, a vancomycin and a colistin;
(p) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic,
wherein optionally the antifungal is a ciclopirox olamine; or
(q) any combination of (a) through (p).
20. The therapeutic combination of claim 18 or claim 19, wherein the therapeutic combination is used in the treatment, amelioration, prevention or healing of: an infection; a systemic infection; an infected tissue; a wound or surgical site; an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA), or a biofilm; a surgical site infection or an MDRO-, a MRSA- or a biofilm-infected surgical site; an infected skin or skin structure or an MDRO-, a MRSA- or a biofilm-infected skin or skin structure; a skeletal or a bone infection or an MDRO-, a MRSA- or a biofilm-infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10%> total body surface area) burn, or an infected burn.
21. The therapeutic combination of any of claims 18 to 20, wherein the infection is caused by:
(a) a bacteria, a parasite, a fungus or a virus; (b) a gram negative bacteria or a gram positive bacteria; or
(c) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria;
(d) a non-cultureable pathogen; or
(e) any combination of (a) to (d).
22. The therapeutic combination of claim 21, wherein the infection is an infection of a skin or skin structure, or skin wound infection caused by a Streptococcus, a Group A Streptococcus, a Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptostreptococcus, m Aeromonas, or a Clostridium.
23. Use of:
(a)
(i) a product of manufacture, device, or composition of any of claims 1 to 6, (ii) a device, medical device, implant, dental implant, breast implant, prosthesis, stent, or catheter of claim 16, or
(iii) a kit, or an integrated point of care mixing kit, of claim 18; and (b) an antibiotic or a plurality of antibiotics,
wherein optionally the antibiotic or a plurality of antibiotics, wherein the antibiotic or plurality of antibiotics is in an amount equivalent to: about
O.OOIX, 0.005X, 0.01X, 0.02X, 0.05X, 0.1X, 0.2.X, 0.50X, IX, 2X, 5X, 10X, 15X, 20X, 25X, 30X, 40X, 50X, 60X, 70X, 80X, 90X or 100X or more times, or between about O.OOIX and 10X, or between about 0.1X and 100X, a single unit dosage of the antibiotic or plurality of antibiotics, or a total daily dosage of the antibiotic or plurality of antibiotics
wherein optionally the sterile hydrogel material or sterile hydrogel of (a) is mixed with the antibiotic or plurality of antibiotics,
and optionally the antibiotic or plurality of antibiotics are first mixed in a sterile pure water or a sterile isotonic solution or buffer,
and optionally the antibiotic or plurality of antibiotics are mixed with the sterile hydrogel material or sterile hydrogel,
for: (a) treating, ameliorating or preventing a local or a systemic infection, or an infection caused by a multiple drug resistance organism (MDRO), or a methicillin- resistant Staphylococcus aureus (MRSA), or a biofilm;
(b) treating, ameliorating or preventing an infection; a systemic infection; an infected tissue; a wound or surgical site; an infection caused by a multiple drug resistance organism (MDRO) or a methicillin-resistant Staphylococcus aureus (MRSA), or a biofilm; a surgical site infection or an MDRO-, a MRSA- or a biofilm-infected surgical site; an infected skin or skin structure or an MDRO-, a MRSA- or a biofilm-infected skin or skin structure; a skeletal or a bone infection or an MDRO-, a MRSA- or a biofilm-infected skeletal or a bone; a refractory large (>10 cm ) chronic wound, or an infected chronic wound; a diabetic foot ulcer or an infected ulcer; a venous leg ulcer or an infected venous leg ulcer; a pressure ulcer or an infected pressure ulcer; or, a burn, a third degree burn, a large (>10% total body surface area) burn, or an infected burn;
(c) treating, ameliorating or preventing an infection caused by:
(i) a bacteria, a parasite, a fungus or a virus;
(ii) a gram negative bacteria or a gram positive bacteria; or
(iii) a Staphylococcus, an Enterobacter, an Enterococcus, a Acinetobacter, Pseudomonas, or a Klebsiella bacteria;
(iv) a non-cultureable pathogen; or
(v) any combination of (i) to (iv); or
(d) treating, ameliorating or preventing an infection of a skin or skin structure, or skin wound infection caused by a Streptococcus, a Group A Streptococcus, a
Streptococcus pyogenes, a Staphylococcus, a Staphylococcus aureus, a Bacteroides, a Peptoslreplococcus, an Aeromonas, or a Clostridium.
24. The use of claim 23, wherein the antibiotic or a plurality of antibiotics comprise:
(a) an antibiotic or a plurality of antibiotics used in (or against, or to treat, ameliorate or prevent an infection of) a local or a systemic: multiple drug resistance organism (MDRO), or a methicillin-resistant Staphylococcus aureus (MRSA), or a biofilm, antibiotic therapy;
(b) a glycopeptide, a lipopeptide or a lipoglycopeptide antibiotic, wherein optionally the glycopeptide, lipopeptide or lipoglycopeptide antibiotic is: a vancomycin, a daptomycin, an oritavancin (Targanta Therapeutics Corporation,
Cambridge, MA), a teicoplanin, a telavancin, a bleomycin, a ramoplanin or a decaplanin;
(c) an aminoglycoside, a macrolide or a lincosamide antibiotic,
wherein optionally the lincosamide antibiotic is a clindamycin or a lincomycin, and optionally the macrolide antibiotic is a clarithromycin or an azithromycin, and optionally the aminoglycoside antibiotic is a neomycin, a gentamicin, a verdamicin, a sisomicin, a netilmicin, a mutamicin, a retymicin or a hygromycin B, or any combination thereof;
(d) an oxazolidinone antibiotic,
wherein optionally the oxazolidinone antibiotic is a linozoli or a posizolid antibiotic,
(e) a dihydrofolate reductase inhibitor antibiotic,
wherein optionally the dihydrofolate reductase inhibitor antibiotic is a
trimethoprim,
(f) a sulfonamide bacteriostatic antibiotic,
wherein optionally the sulfonamide bacteriostatic antibiotic is a sulfamethoxazole,
(g) an ansamycin antibiotic,
wherein optionally the ansamycin antibiotic is a rifamycin antibiotic,
and optionally the rifamycin antibiotic is a rifampin,
(h) a polymyxin antibiotic,
wherein optionally the polymyxin antibiotic is a colistin,
(i) a β-Lactam antibiotic (beta-lactam antibiotic), which optionally can be a penicillin, a penicillin derivative (a penam), a cephalosporin (a cephem), a monobactam, a carbapenem,
j) a trimethoprim and a sulfamethoxazole;
(k) a trimethoprim, a sulfamethoxazole and a rifampin;
(1) a gentamycin at a concentration of about 0.1%; a vancomycin at a
concentration of about 0.1%, a ciclopirox at a concentration of about 0.1%; a colistin at a concentration of about 0.1%;
(m) a gentamicin and a vancomycin;
(n) a gentamicin, a vancomycin and a cilopirox;
(o) a gentamicin, a vancomycin and a colistin; (p) an antifungal, an anti-parasitic, an antiviral, an anthelmintic or an
antihelminthic,
wherein optionally the antifungal is a ciclopirox olamine; or
(q) any combination of (a) through (p).
25. The use of claim 23 or claim 24, wherein the product of manufacture, device or composition further comprises:
(a) an iron chelator,
wherein optionally the iron chelator comprises a deferoxamine (also known as desferoxamine B, desferoxamine B, DFO, DFO-B, DFOA, DFB or desferal),
and optionally the iron chelators is at a concentration of between about 0.05% to 0.5%, and optionally the deferoxamine is at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin ;
(b) an antiseptic,
wherein optionally the antiseptic comprises a polihexanide (also known as polyhexamethylene biguanide), or a LAVASEPT™ or SERASEPT™,
and optionally the antiseptic is at a concentration of between about 0.05% to 0.5%; or at a concentration of about 0.1%, optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin or a colistin;
(c) a hemostatic agent,
wherein optionally the hemostatic agent comprises a tranexamic acid, or a synthetic analog of the amino acid lysine, or a synthetic analog of the amino acid lysine, or a tranexamic acid, optionally at a concentration of about 0.005% to 0.5%, or at a concentration of about 0.1% optionally in combination with a gentamycin, a vancomycin, a cilopirox, a ortavancin and a colistin;
(d) any combination of (a) to (c).
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WO2022035779A1 (en) * 2020-08-10 2022-02-17 Gel4Med, Inc. Self-assembling amphiphilic peptide hydrogels
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EP4049671A1 (en) * 2004-07-06 2022-08-31 3D Matrix, Inc. Purified amphiphilic peptide compositions and uses thereof
US8299052B2 (en) * 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
ES2709125T3 (en) * 2006-09-26 2019-04-15 Massachusetts Inst Technology Modified self-assembling peptides
JP5497451B2 (en) * 2007-12-05 2014-05-21 株式会社スリー・ディー・マトリックス Wound healing / reconstruction material

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CN114341157A (en) * 2019-07-22 2022-04-12 新加坡科技研究局 A series of injectable hydrogels self-assembled from short peptides for various biomedical applications
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