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WO2012174373A1 - Méthodes de traitement et d'inhibition d'agents pathogènes avec des mécanismes de résistance - Google Patents

Méthodes de traitement et d'inhibition d'agents pathogènes avec des mécanismes de résistance Download PDF

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Publication number
WO2012174373A1
WO2012174373A1 PCT/US2012/042659 US2012042659W WO2012174373A1 WO 2012174373 A1 WO2012174373 A1 WO 2012174373A1 US 2012042659 W US2012042659 W US 2012042659W WO 2012174373 A1 WO2012174373 A1 WO 2012174373A1
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WO
WIPO (PCT)
Prior art keywords
bacteria
resistant
wound
vancomycin
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/042659
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English (en)
Inventor
David LUCI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PLX Pharma Winddown Corp
Original Assignee
Dipexium Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dipexium Pharmaceuticals LLC filed Critical Dipexium Pharmaceuticals LLC
Publication of WO2012174373A1 publication Critical patent/WO2012174373A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to the field of bacteriology.
  • the present invention provides methods for inhibiting proliferation of an
  • Antibiotics which are also referred to in the art as antibacterial or antimicrobial agents, are natural substances of relatively small size in molecular terms, which are typically released by bacteria or fungi. These natural substances, as well as derivatives and/or modifications thereof, are used for many years as medications for treating infections caused by bacteria.
  • the present invention provides methods for inhibiting proliferation of an antimicrobial resistant bacteria in or on a wound harbored by a subject by exposing the resistant bacteria to pexiganan, where the proliferation is inhibited through the mechanism of action of pexiganan (i.e. causing cell lysis), and methods of topically treating a bacterial infection.
  • the present invention also provides a method for treating antimicrobial resistant bacterial strains comprising: providing an in vivo surface comprising resistant bacteria; and exposing the surface to a pharmaceutical composition comprising a therapeutically effective amount of pexiganan.
  • treating comprises killing resistant bacteria present within an existing infection.
  • the bacterial cells treated comprise antimicrobial resistant strains of staphylococcus, enterococcus, and/or enterobacteriaceae.
  • the surface treated comprises skin of a subject.
  • the present invention is not limited by the type of surface treated. Indeed, a variety of surfaces can be treated with a pharmaceutical composition of the present invention including, but not limited to, other types of organic surfaces (e.g., a mucosal surface, a wound surface, a food surface) as well as inorganic surfaces (e.g., medical devices, countertops, clothing, etc.).
  • the bacterial strains include Staphylococci, enterococci, and enterobacteriaceae.
  • the resistant strains include those resistant to beta lactamase antibiotics (e.g. methicillin, penicillin, oxacillin, etc.), vancomycin, and those that are known as extended-spectrum ⁇ -lactamase (ESBL) producing gram negative bacteria.
  • the resistant strains may include those strains that are sensitive to pexiganan, listed in Table 1.
  • the methods described herein are used to treat strains that are resistant to more than one class of antibiotics.
  • the methods described herein are used to treat strains that are resistant to at least three classes of antibiotics. In a further embodiment, the methods described herein are used to treat strains that are resistant to at least four different classes of antibiotics (see for example, the multidrug resistant strains of Acinetobacter baumanni listed in Table 1).
  • Staphylococci are gram positive bacterial pathogens that cause a wide variety of diseases ranging from superficial abscesses (e.g., boils, styes, furuncles and other localized abscesses) to deeper infections (e.g., osteomyelitis, pneumonia, endocarditis, urinary tract infections, septic arthritis, meningitis, post-operative wound infections, septicemia and food poisoning).
  • superficial abscesses e.g., boils, styes, furuncles and other localized abscesses
  • deeper infections e.g., osteomyelitis, pneumonia, endocarditis, urinary tract infections, septic arthritis, meningitis, post-operative wound infections, septicemia and food poisoning.
  • Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to -treat infections in humans. It may also be called multidrug-resistant Staphylococcus aureus or oxacillin-resistant Staphylococcus aureus (ORSA). MRSA is, according to the Merriam-Websters Medical Dictionary definition, any strain of Staphylococcus aureus that has developed resistance to beta-lactam antibiotics which include the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins. MRSA is especially troublesome in hospitals and nursing homes where patients with open wounds, invasive devices and weakened immune systems are at greater risk of infection than the general public.
  • Enterococcus is a genus of lactic acid bacteria of the phylum Firmicutes. Enterococci are Gram -positive cocci that often occur in pairs (diplococci) or short chains and are difficult to distinguish from Streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90-95%) and E. faecium (5-10%). There are rare clusters of infections with other species including E. casseliflavus, E. gallinarum, and E. raffinosus. Vancomycin-resistant enterococcus (VRE) spp. are becoming increasingly common in hospital settings.
  • VRE Vancomycin-resistant enterococcus
  • the Enterobacteriaceae are a large family of gram negative bacteria, including many of the more familiar pathogens, such as Salmonella and Escherichia coli. Genetic studies place them among the Proteobacteria, and they are given their own order (Enterobacteriales), though this is sometimes taken to include some related environmental samples.
  • ESBL Extended-spectrum 6-lactamase
  • ESBL bacteria are different from other superbugs, because "ESBL” does not refer to one specific kind of bacteria. Instead, it refers to an antibiotic-busting enzyme that many different kinds of bacteria can produce.
  • Magainins are naturally occurring cationic peptides found in animals and have broad-spectrum antimicrobial activity through their interaction with anionic phospholipids of microbial cells, which result in disruption of the cell membranes.
  • Pexiganan also known as MSI-78, is a 22-residue analog of the class of magainins. See U.S. Patent No. 5,912,231, the entire content of which is hereby incorporated by reference.
  • a therapeutically effective amount of a pharmaceutical composition comprising pexiganan is contacted with a wound on a subject to treat or ameliorate a bacterial infection.
  • the term "therapeutically effective amount” means the amount of polypeptide that is sufficient to show a meaningful benefit, e.g., healing of a wound, inhibition of proliferation, prevention or amelioration of bacterial contamination or infection, or an increase in rate of healing of a wound, inhibition of proliferation, prevention or amelioration of such contamination and infections.
  • the meaningful benefit is statistically significant as compared to a control.
  • Contacting a subject with the pexiganan polypeptides can be done with an amount and for a time sufficient to reduce bacterial infection or presence.
  • wound means any type of injury in which the skin is torn, cut, punctured, or damaged.
  • the wound can be acute or chronic.
  • Chronic wounds are those that are caused by a relatively slow process that leads to tissue damage.
  • Chronic wounds include, for example, pressure, venous, and diabetic ulcers.
  • Diabetic ulcers or “diabetic foot infections”, refers to non-healing wounds associated with people who have diabetes. The non-healing wounds of the diabetic foot are considered one of the most significant complications of diabetes, representing a major worldwide medical, social, and economic burden that greatly affects patient quality of life.
  • an insufficiency in the circulation or other systemic support of the tissue causes it to fail and disintegrate leading to a chronic wound.
  • non-healing wounds are associated with inadequate circulation, poorly functioning veins, poor constriction of the veins and capillaries of the outer extremities, and immobility, non-healing wounds occur most frequently in the elderly and in people with diabetes. Diabetics often suffer from nerve damage in their feet and legs, allowing small wounds or irritations to develop without awareness. Given the abnormalities of the microvasculature and other side effects of diabetes, these wounds take a long time to heal and require a specialized treatment approach for proper healing. In addition to the wound not healing, infection can then take hold of the site leading to a chronic abscess.
  • subject refers to a mammalian subject, preferably a human subject, more preferably a human subject having a chronic wound, e.g. a subject suffering from diabetes.
  • Bacterial infections may be caused by a wide variety of gram positive, gram negative, aerobic, and anaerobic bacteria.
  • the methods of the present invention are contemplated as useful as treatments against infections caused by bacteria which are resistant to other classes of antimicrobial compounds.
  • compositions comprising a therapeutically effective amount of pexiganan in combination with other components such as a pharmaceutically acceptable diluent, carrier, or excipient, are provided herein and can be used in the methods described herein.
  • pharmaceutically acceptable means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • compositions of the invention may be formulated for administration by any route, such as topical or parenteral.
  • the compositions may be in the form of powders, granules, creams or liquid preparations, such as sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, pastes, creams or lotions, foams, drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • the ointments, pastes, creams or lotions may contain, in addition to the active compound and/or compositions of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and/or zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound and/or a composition of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and/or polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound and/or a composition of the present invention to the body.
  • Such patches can be made by dissolving or dispersing the compound and/or the composition in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound and/or the composition across the skin. Either providing a rate controlling membrane or dispersing the compound and/or the composition in a polymer matrix or gel can control the rate of such flux.
  • the pharmaceutical compositions may be formulated and used as foams.
  • Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product.
  • Example 1 is provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
  • Example 1 is provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
  • Pseudomonas aeruginosa ATCC 27853 Pexiganan (dilution range 0.25 - 512 pg/ml, as appropriate for the indicated species; 250 milligrams of compound was supplied by the sponsor).
  • Comparator testing with levofloxacin was used to assure proper performance of testing reagents.
  • ESBL-producing strains (8; including TEM, SHV and CTX-M types)
  • Gram-positive cocci (20 total isolates) ureus (10 total)
  • CU unsupplemented low cation Mueller-Hinton broth (Ca++ at 5.3 mg/L; Mg++ at 3.8 mg/L)
  • CA CLSI recommended cation-adjusted Mueller-Hinton broth (Ca++ at 20-25 mg/L; Mg++ at 10-12.5)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le domaine de la bactériologie. Plus particulièrement, la présente invention porte sur des procédés d'inhibition de la prolifération d'une bactérie antimicrobienne résistante chez un sujet ou sur une lésion située sur ledit sujet, par exposition de ladite bactérie à une quantité thérapeutiquement efficace de pexiganan.
PCT/US2012/042659 2011-06-16 2012-06-15 Méthodes de traitement et d'inhibition d'agents pathogènes avec des mécanismes de résistance Ceased WO2012174373A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161497726P 2011-06-16 2011-06-16
US61/497,726 2011-06-16

Publications (1)

Publication Number Publication Date
WO2012174373A1 true WO2012174373A1 (fr) 2012-12-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015521599A (ja) * 2012-06-12 2015-07-30 ディペキシウム ファーマシューティカルズ インコーポレイテッド 安定なペキシガナン製剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009070564A2 (fr) * 2007-11-27 2009-06-04 Macrochem Corporation Compositions et procédés utilisables dans le cadre de la prévention d'infections associées à des implants transcutanés ostéointégrés
US20090297588A1 (en) * 2008-05-28 2009-12-03 Spin'tec Engineering Gmbh Antibiotic dressing for the treatment of infected wounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009070564A2 (fr) * 2007-11-27 2009-06-04 Macrochem Corporation Compositions et procédés utilisables dans le cadre de la prévention d'infections associées à des implants transcutanés ostéointégrés
US20090297588A1 (en) * 2008-05-28 2009-12-03 Spin'tec Engineering Gmbh Antibiotic dressing for the treatment of infected wounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GE ET AL.: "In Vitro Antibacterial Properties of Pexiganan, an Analog of Magainin", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, April 1999 (1999-04-01), pages 782 - 788 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015521599A (ja) * 2012-06-12 2015-07-30 ディペキシウム ファーマシューティカルズ インコーポレイテッド 安定なペキシガナン製剤

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