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WO2009081117A1 - Polythérapie antibactérienne pour le traitement d'infections bactériennes - Google Patents

Polythérapie antibactérienne pour le traitement d'infections bactériennes Download PDF

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Publication number
WO2009081117A1
WO2009081117A1 PCT/GB2008/004192 GB2008004192W WO2009081117A1 WO 2009081117 A1 WO2009081117 A1 WO 2009081117A1 GB 2008004192 W GB2008004192 W GB 2008004192W WO 2009081117 A1 WO2009081117 A1 WO 2009081117A1
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Prior art keywords
group
imidazole
composition according
phenyl
gram
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PCT/GB2008/004192
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English (en)
Inventor
Malcolm Philip Young
Olosola Clement Idowu
Catherine Mary Thomas
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E-Therapeutics Plc
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Publication of WO2009081117A1 publication Critical patent/WO2009081117A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 provides a product comprising a synergistic combination of gemfibrozil (5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid), or derivative, or structural analog, or metabolite thereof, and a therapeutically active imidazole, as a combined preparation for the treatment of infections caused or contributed to by gram-positive bacteria.
  • Gram-positive bacteria such as Staphylococci, Streptococci, and Enterococci and Clostridia are extremely important pathogens in both human and veterinary medicine. In the United States, between 1995 and 1998, 60% of hospital bloodstream infections involved gram-positive bacteria. This percentage is continuing to increase. Clostridium difficile is one of the most common causes of hospital-acquired diarrhea. Mortality from C. difficile-associated disease ranges from 6-30% when pseudomembranous colitis (inflammation and bleeding of the colon) is present.
  • Antibiotic resistance in bacteria has been selected through the prolific use of these drugs both in human medicine and animal husbandry, indiscriminate prescribing practices, and patient non-compliance with treatment regimes. Therapeutic options for the treatment of such drug-resistant microorganisms, especially gram-positive bacteria, are becoming increasingly limited.
  • the problem of antibiotic resistance is exacerbated by the spread of drug-resistant organisms, and the dissemination of resistance genes between bacteria.
  • the threat to the successful management of bacterial infections posed by the development and spread of antibiotic resistance is one of the most significant problems within healthcare and veterinary medicine.
  • Staphylococci are major causes of serious healthcare associated infection (HAI).
  • HAI healthcare associated infection
  • strains of Staphylococcus that have developed or obtained varying levels of resistance to antibiotics such as methicillin (meticillin).
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRSA methicillin-resistant S. aureus
  • bacterial biof ⁇ lms structured communities of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface (Costerton et al, 1999)
  • bacterial biofilms can develop on poultry processing instrumentation (Arnold & Silvers, 2000) and may cause treatment failure of mastitis in cows infected with S. aureus (Melchior et al., 2006).
  • biofilms of bacteria have been shown to colonise many medical devices, including orthopaedic implants (Brua et al., 2007). In the UK, 35% of hip prostheses' infection is attributable to S.
  • MRSA septic loosening, fracture non-union and osteomyelitis
  • the association of MRSA with the use of orthopaedic devices is extremely problematic due to the increased spectrum of resistance of this organism, in addition to the protection from the immune system given by the biof ⁇ lm growth phase, often necessitating the removal of a contaminated device, causing further trauma to the patient and increasing medical costs.
  • Colonisation with MRSA is the general precursor to the development of an MRSA infection, so interventions that reduce levels of human colonisation or the colonisation of surfaces such as medical devices will reduce the spread of infections in healthcare facilities.
  • Methicillin resistance in Staphylcocci develops by the alteration of the target of the drug, ⁇ -lactam antibiotics, such as methicillin, act on sensitive strains by binding to and inhibiting proteins called "Penicillin Binding Proteins". Resistance to methicillin in Staphylococci occurs by the alteration one of these proteins, PBP2', so that ⁇ - lactams bind poorly to it. This results in the bacterium becoming resistant to all currently available ⁇ -lactam drugs. MRSA and MRSE infections can be treated with glycopeptide drugs, such as vancomycin.
  • VISA vancomycin intermediately sensitive Staphylococcus aureus
  • VRSA vancomycin resistant Staphylococcus aureus
  • Clostridium difficile-associated diarrhoea Clostridium difficile-associated diarrhoea
  • Clostridium difficile is extremely hardy; by forming spores, it can survive extremes of temperature, ethanol and antibiotics, and as such is very difficult to treat.
  • the presence of a large number of mobile genetic elements within the genome of C. difficile are thought to be responsible for the multiple-drug resistance observed in this species.
  • the use of these broad-spectrum agents reduces bacterial colonisation in the intestine, permitting the overgrowth of C. difficile.
  • oral vancomycin was used in the treatment of CDAD 3 but because of the risk of promotion and selection of vancomycin resistant gut flora (such as Enterococci), vancomycin is recommended only for cases that do not respond to the primary treatment (metronidazole).
  • Recently, resistance to vancomycin and metronidazole in C. difficile isolates has been reported, and the use of these agents has been shown to increase the density of vancomycin-resistant Enterococcus
  • VRE vancomycin-resistant Enterococci
  • MRSA, MRSE, VISA, VRSA and VRE are genotypically and phenotypically distinct from other, sensitive Staphylococci and Enterococci, tending to form discrete clonal lineages.
  • MRSA- 15 and EMRSA- 16 are regarded as endemic in the majority of UK hospitals.
  • SCCmec gene cassette contains the genes for methicillin resistance as well as genes important for enabling the cassette to move between strains; it commonly contains many other genes encoding resistance to other antibiotic classes.
  • a genetic comparison between an EMRSA-16 strain and a sensitive Staphylococcal strain revealed that the MRSA strain contained an extra 106 genes, many of which were important for the virulence and drug resistance of the strain.
  • VRE outbreaks are commonly clonal, with the vanA gene cassette (coding for cell-wall precursors that do not bind to vancomycin) being the most prevalent genetic resistance mechanism.
  • Drug resistance can be specific, i.e. particular to a certain drug or class of drugs, or non-specific in that the resistance applies to a range of drugs, not necessarily related.
  • VISA an increase in cell wall thickness is a major contributor to the observed drug resistance.
  • VISA and VRSA may be defined as any staphylococcal strain with a vancomycin MIC of 4-8mg/L (VISA) or greater or equal to 8mg/L (VRSA). These levels of resistance can be due to an increase in cell wall thickness, by the production of cell- wall precursors incapable of binding vancomycin, or via another mechanism.
  • VISA gram-positive organisms
  • VRSA vancomycin resistant gram-positive organisms
  • D-ala-D-lac precursors for example, D-ala-D-lac precursors.
  • the presence of vancomycin resistance in staphylococcal and enterococcal strains may be identified by the measurement of the MIC to vancomycin by broth or agar dilution, or by Etest®, or by the identification of vanA, vanB, vanC, vanD, vanE, vanG genes, or similar, by polymerase chain reaction (PCR).
  • the current invention also encompasses the subclass of VISA strains that are heterogeneous VISA (hVISA); these are vancomycin susceptible methicillin-resistant Staphylococcus aureus by conventional testing but have a sub-population of intermediately resistant cells. hVISA strains are thought to be the precursors of VISA.
  • hVISA heterogeneous VISA
  • the management of human infections caused by MRSA, MRSE, VISA, VRSA and VRE reflect the genotypic and phenotypic differences outlined above, and require greater investment in hospital infrastructure, facilities for patient isolation, and infection control measures than for other strains of Staphylococci and Enterococci.
  • the ease at which Clostridium difficile can spread within the hospital environment, and the ability of the bacterium to form heat-stable antibiotic-resistant spores, means that C. difficile infections also require more extensive infection control measures than those required for most other gram-positive infections; recent cost estimates attributable to CDAD in the UK and USA exceed US$4000 per case.
  • the treatment options for infections contributed to or caused by VISA, VRSA and VRE are now severely limited.
  • Staphylococci and Enterococci is not predictable from membership of this chemical class; some imidazoles demonstrate antibacterial activity against these difficult to treat organisms, whilst others show none.
  • Gemfibrozil is known to act synergistically with isoniazid and fluoroquinolones against intracellular bacteria, such as listeria monocytogenes.
  • the reason for this synergy is that gemfibrozil blocks an anionic transporter on the human macrophage cells, thus allowing a higher concentration of fluoroquinolone or isoniazid to accumulate.
  • This property of gemfibrozil has no bearing on bacteria that are not intracellular pathogens, such as Enterococci and Clostridia.
  • the synergistic effect of gemfibrozil with certain imidazoles was demonstrated for bacteria growing without the presence of human cells. Due to the substantial differences between human and bacterial cells, the effect of gemfibrozil on bacterial cells is unpredictable.
  • Gemfibrozil is known to inhibit the activity of certain membrane transporters by binding to the P-glycoprotein component of the transporter.
  • Bacteria have many different membrane transporters, which differ between species and within a species; proteins coding for over 200 membrane transporters have been identified in one sequenced MRSA strain. The substrates for many of these transporters are unknown.
  • P-glycoprotein inhibitor gemfibrozil
  • the present invention discloses the knowledge that the combination of certain imidazoles with gemfibrozil is capable of inhibiting the growth of MRSA, MRSE, VISA, VRSA VRE and Clostridia strains at dramatically lower concentrations than either agent used singly, or their additive effect.
  • An objective of the present invention is to provide a new and effective treatment for infections contributed to or caused by difficult to treat gram-positive bacteria, such as, MRSA, MRSE, VISA, VRSA VRE and Clostridia.
  • the present invention provides a composition comprising a therapeutically active imidazole, and/or a derivative thereof, and gemfibrozil, or derivative, or structural analog, or metabolite thereof.
  • the present invention provides a composition as hereinbefore described for treating an infection contributed to or caused by gram-positive bacteria.
  • the present invention provides a composition as hereinbefore described for treating an infection contributed to or caused by a difficult to treat gram-positive bacterium.
  • Difficult to treat bacteria include, but shall not be limited to Clostridium difficile and multi-drug resistant organisms.
  • Such multi-drug resistant bacteria include, but shall not be limited to, MRSA, MRSE, VISA, VRSA, VRE and/or Clostridium.
  • the present invention provides a method of treating a subject suffering from an infection contributed to or caused by multi-drug resistant gram-positive bacteria, said method comprising the step of administering an effective amount of a therapeutically active imidazole, and/or a derivative thereof, with gemfibrozil, or derivative, or structural analog, or metabolite thereof, separately, simultaneously or sequentially.
  • the method of the invention particularly provides a method of treating a subject suffering from an infection contributed to or caused by one or more of MRSA, MRSE, VISA 5 VRSA VRE and/or Clostridium.
  • the present invention concerns the use of a compound comprising imidazole and/or derivatives thereof, in combination with gemfibrozil, or derivative, or structural analog, or metabolite thereof, for the preparation of medicaments or for use in methods effective in treating infections contributed to or caused by MRSA, MRSE, VISA 5 VRSA VRE and/or Clostridium.
  • R 1 and R 2 are independently selected from hydrogen lower alkyl, phenyl or substituted phenyl, wherein said substituted phenyl contains at least one phenyl substituent selected from the group consisting of halo, lower alkyl and lower alkoxy;
  • R is independently selected from hydrogen, lower alkyl, phenyl or substituted phenyl wherein said substituted phenyl contains at least one phenyl substituent selected from the group consisting of halo, lower alkyl and lower alkoxy; ⁇ ⁇ is zero or 1; n 2 is zero or 1; n 3 is zero, 1 or 2 X' is S, Oxy or not present
  • Ar is independently selected from the group consisting of phenyl, substituted phenyl, thienyl and halothienyl, said substituted phenyl containing at least one phenyl substituent selected from the group consisting of halo, lower alkyl and lower alkoxy;ri 4 is zero or 1
  • Ar' is a member selected from the group consisting of phenyl, substituted phenyl and ⁇ -tetralyl, said substituted phenyl containing at least one phenyl substituent selected from the group consisting of phenyl, thienyl, phenyl thio, halo, lower alkyl, lower alkoxy, cyano, nitro and amino;
  • R' is a member selected from the group consisting of hydrogen, methyl and ethyl; and R" is a member selected from the group consisting of hydrogen and methyl; provided that: (i) when X is NH, then said R is hydrogen;
  • lower alkyl and lower alkoxy encompass straight or branch chained hydrocarbons having from about 1 to about 6 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc.
  • halo refers to halogens of atomic weight less than 127, i.e., fluoro, iodo, bromo and chloro.
  • Preferred substituted phenyls with respect to the symbol Ar are mono-, di- and trihalo-phenyl, thiol-dihalo-phenyl, lower alkylphenyl and lower alkoxy phenyl; and mono-, di- and tri-halophenyl, di-phenyl, thiol-phenyl, lower alkoxyphenyl, cyanophenyl, mono-, di-nitrophenyl and amino phenyl with regard to the symbol Ar'.
  • the therapeutically active imidazoles selected from the group consisting of clotrimazole, econazole, miconazole, butoconazole, fenticonazole, oxiconazole nitrate, sertaconazole, sulconazole, and tioconazole and derivatives thereof.
  • the therapeutically active imidazoles selected from the group l-[(2-Chlorophenyl)di ⁇ henylmethyl]-lH-imidazole (C 22 H 17 ClN 2 ), l-[2- [(4-Cholo ⁇ henyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-lH-imidazole (C 18 H 15 Cl 3 N 2 O) and l-[2-(2,4-Dichlorophenyl)-2-[(2,4-dichlorophenyl) methoxy]ethyl]-lH-imidazole (C 18 H 14 Cl 4 N 2 O), otherwise known as clotrimazole, econazole and miconazole, respectively.
  • the formulae for each of these compounds are as follows.
  • Other compounds of interest may include ( ⁇ )-l-[4-(4-Chlorophenyl)-2[(2,6- dichlorophenyl)thio]butyl]-lH-imidazole (C 19 H 17 Cl 3 N 2 S: Butoconazole), l-[2-(2,4- Dichlorophenyl)-2-[[4-phenylthio)phenyl]methoxy]ethyl]-lH-imidazole (C 24 H 20 Cl 2 N 2 OS: Fenticonazole), (Z)4-(2,4-DicMorophenyl)-2-(lH-imidazol-l- yl)ethanone O-[2,4-dichlorophenyl)-methyl]oxime mononitrate (CI 8 HHCI 4 N 4 O 4 : Oxiconazole Nitrate), l-[2-[(7-chlorobenzothiophen-3-yl)methoxy]-2-(2,4- dichlor
  • the present invention also encompasses uses of various salts and therapeutically active addition salts of compounds corresponding to formula (I) and derived from the abovementioned compounds comprising imidazole; in particular, for example, miconazole nitrate (C 18 H 14 Cl 4 N 2 O • HNO 3 ), and econazole nitrate (C 18 H 15 Cl 3 N 2 O • HNO 3 ).
  • Derivatives of gemfibrozil as hereinbefore described shall include, but shall not be limited to, metabolites of gemfibrozil.
  • compounds comprising gemfibrozil and/or its metabolites or derivatives for use in combination with the above imidazoles in connection with the present invention are provided by the following formula:
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
  • the present invention provides a composition comprising one or more of clotrimazole, clotrimazole nitrate, econazole, econazole nitrate, miconazole, miconazole nitrate in combination with gemfibrozil in the manufacture of a medicament for the treatment of an infection contributed to or caused by MRSA, MRSE, VISA, VRSA, VRE and/or Clostridium.
  • a therapeutically imidazole in the manufacture of a combination medicament for treating an infection, e.g. an infection contributed to or caused by MRSA thereby reducing the emergence of VISA or VRSA.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof may be administered orally, topically to the site of an infection, transmucosally, transdermally or intravenously.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof may be formulated as polymeric nanoparticles such as alginate or polylactide-co-glycolide nanoparticles, or as sterile pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient.
  • Such carriers or excipients are well known to one of skill in the art and may include, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, lactic acid, water salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cyclodextrins, such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, sulfobutylether 7 - ⁇ cyclodextrin and hydroxypropyl- ⁇ -
  • Synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof may be administered in combination with another treatment.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof may be administered in combination with a chemotherapeutic agent, a detergent to facilitate permeation, an immunostimulatory compound or drug, an oligonucleotide, a cytokine, hormone or the like.
  • transdermal delivery devices may include, for example, a patch, dressing, bandage or plaster adapted to release a compound or substance through the skin of a patient.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof, may be combined with some form of matrix or substrate, such as a non-aqueous polymeric carrier, to render it suitable for use in a transdermal delivery system.
  • matrix or substrate such as a non-aqueous polymeric carrier
  • This mixture may be further strengthened by the use of a woven or knit, non- woven, relatively open mesh fabric, to produce a patch, bandage, plaster or the like which may be temporarily attached to a particular region of a patient's body. In this way, while in contact with a patient's skin, the transdermal delivery device releases the compound or substance directly to the site of infection or through the skin as required.
  • the compounds provided herein may also be used as sterilising or cleaning aids for use, for example, on surfaces to reduce and/or eliminate contamination by MRSA, MRSE 5 VISA, VRSA or VRE.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof such as, for example miconazole or miconazole nitrate with disulfiram, may be prepared for application to any surface suspected of being contaminated by MRSA, MRSE, VISA, VRSA or VRE.
  • compounds of the present invention may be added to or diluted in an appropriate excipient or solution prior to use as a sterilising or cleaning agent. Exemplary excipients are described above.
  • Such sterilising or cleaning solutions may be used to decontaminate, for example, furniture, floors, equipment including for example specialised hospital equipment and/or surgical equipment.
  • synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof, may be administered to a medical or veterinary surface to inhibit the growth of MRSA, MRSE, VISA, VRSA VRE and/or Clostridium, and reduce the likelihood of the emergence and spread of vancomycin resistance in that environment.
  • surface refers to any surface whether medical or industrial, that provides an interface between a fluid and a solid. The interface between fluid and solid may be intermittent, and may be caused by flowing or stagnant fluid, aerosols, or other means for air-borne fluid exposure.
  • the surface described herein refers more specifically to a plane whose mechanical structure is compatible with the adherence of bacteria such as S. aureus and Enterococcus species.
  • the terminology "medical or veterinary surface” encompasses the inner and outer aspects of various instruments and devices, both disposable and non-disposable. Examples include the entire spectrum of medical devices
  • the terminology "surfaces found in medical environments” includes the inner and outer aspects of various instruments and devices, whether disposable or intended for repeated uses. Examples include the entire spectrum of articles adapted for medical use, including scalpels, needles, scissors and other devices used in invasive surgical, therapeutic or diagnostic procedures; implantable medical devices, including artificial blood vessels, catheters and other devices for the removal or delivery of fluids to patients, artificial hearts, artificial kidneys, orthopaedic pins, plates and implants; catheters and other tubes (including urological and biliary tubes, endotracheal tubes, peripherally insertable central venous catheters, dialysis catheters, long term tunnelled central venous catheters, peripheral venous catheters, short term central venous catheters, arterial catheters, pulmonary catheters, Swan-Ganz catheters, urinary catheters, peritoneal catheters), urinary devices (including long term urinary devices, tissue bonding urinary devices, artificial urinary sphincters, urinary dilators), shunts (including ventricular or ar
  • Surfaces found in the medical environment also include the inner and outer aspects of pieces of medical equipment, medical gear worn or carried by personnel in the health care setting. Such surfaces can include counter tops and fixtures in areas used for medical procedures or for preparing medical apparatus, tubes and canisters used in respiratory treatments, including the administration of oxygen, of solubilised drugs in nebulisers and of aesthetic agents. Also included are those surfaces intended as biological barriers to infectious organisms in medical settings, such as gloves, aprons and face-shields. Commonly used materials for biological barriers may be latex-based or non-latex based, such as vinyl. Other such surfaces can include handles and cables for medical or dental equipment not intended to be sterile.
  • such surfaces can include those non-sterile external surfaces of tubes and other apparatus found in areas where blood or body fluids or other hazardous biomaterials are commonly encountered.
  • the compounds described herein may be used to eliminate and/or reduce contamination by MRSA, MRSE, VISA, VRSA VRE and/or Clostridium, on parts of the body, particularly for example, the hands.
  • Synergistic combinations comprising imidazole or derivatives thereof with gemfibrozil and/or derivatives or metabolites thereof, may be diluted as an aqueous or non-aqueous solution (dissolved in aqueous, non aqueous or organic solvent) and which may be applied to a body part, for example the hands.
  • Such a solution may find particular application in, for example hospitals, care homes and or nurseries where the prevalence and transmission rates of MRSA, MRSE, VISA, VRSA VRE and/or Clostridium are often high.
  • the methods and medicaments described herein may be used prophylactically as a means to prevent the development of an infection caused or contributed to by MRSA, MRSE, VISA, VRSA VRE and/or Clostridium, or to reduce the likelihood of the development of VISA or VRSA from an MRSA infection.
  • Medicaments and/or methods for prophylactic use may be administered or applied to any person at risk of developing an infection caused or contributed to by MRSA, MRSE, VISA 5 VRSA VRE and/or Clostridium. For example, people working in care homes, nursing homes, sports centres, community centres, shops, restaurants, cafes, nurseries and/or schools may require prophylactic treatments.
  • the medicaments and/or methods described herein may have particular application in institutions housing, sheltering, caring or otherwise holding people or patients vulnerable to or "at risk" of developing or contracting MRSA, MRSE, VISA, VRSA VRE and/or Clostridium.
  • the medicaments and methods may be particularly useful in hospitals, nursing homes, nurseries and/or schools. More generally, an elderly, young or immunocompromised person or patient may particularly benefit from the medicaments and methods described herein.
  • the methods and medicaments of the present invention may be particularly useful to those undergoing a prolonged stay in hospital, for example in an intensive care facility.
  • the medicaments and methods described herein may be useful in community centres, sports facilities, shops, restaurants, cafes or other places where transmission of bacteria, particularly MRSA, MRSE, VISA, VRSA VRE and/or Clostridium, is likely.
  • MICs Minimum inhibitory concentrations of a range of clinical and control bacterial organisms were measured according to BSAC (British Society for Antimicrobial Chemotherapy) guidelines (Andrews 2001), for single agents and imidazole with 5l2mg/L gemfibrozil, described briefly as follows. MICs were measured by broth dilution. PREPARATION OF BROTHS.
  • Stock solutions were prepared at concentrations of lOOOmg/L and 100mg/L. The appropriate amounts of each stock solution were added to the wells of a 96well microtitre plate to give a range of final concentrations (after the addition of overnight culture of bacteria) from 1 to 32 mg/L. MICs of imidazole were measured with and without the presence of 512mg/L gemfibrozil.
  • test organisms were grown overnight in 5mL 1ST broth. Each well of a microtitre plate was inoculated with diluted overnight culture to give a final inoculum of 5 x 10 5 cfu/mL.
  • Microtitre plates were incubated at 37°C in air for 18-20 hours. INTERPRETATION OF RESULTS
  • the MIC is the minimum amount of an antibiotic at which there is no visible growth of bacteria. Synergy was reported if the inhibitory effect of the drugs in combination were greater than the sum of the inhibitory effects of each drug singly.
  • Table one shows that the combination of gemfibrozil (dissolved in ethanol and water) with miconazole gives substantially lower MICs than the comparative MICs for miconazole used singly, against a range of multi-resistant Staphylococcal strains. A growth control demonstrated that the ethanol solute did not affect the measurement of the MICs.
  • VRE Enterocoocus faecium
  • VRE Enterococcus faecalis
  • VRE Enterococcus faecium

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Abstract

La présente invention concerne une composition contenant un imidazole thérapeutiquement actif, ou un dérivé correspondant, et du gemfibrozil, ou un dérivé correspondant. L'invention concerne également une méthode permettant de traiter un sujet souffrant d'une infection à l'aide d'une telle composition.
PCT/GB2008/004192 2007-12-21 2008-12-19 Polythérapie antibactérienne pour le traitement d'infections bactériennes WO2009081117A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2011022798A1 (fr) * 2009-08-28 2011-03-03 Biolab Sanus Farmacêutica Ltda. Composés éthers aralkyl benzyliques, procédé de préparation de ceux-ci, composés intermédiaires, utilisation desdits composés, méthode de traitement et/ou de prévention, composition pharmaceutique et médicament les contenant
US20110257078A1 (en) * 2008-07-18 2011-10-20 E-Therapeutics Plc Antibacterial combination therapy for the treatment of gram positive bacterial infections
CN113614092A (zh) * 2019-02-22 2021-11-05 阿尼弗拉有限公司 提供抗革兰氏阳性细菌增强的抗菌活性的组合物及其用途

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US20110257078A1 (en) * 2008-07-18 2011-10-20 E-Therapeutics Plc Antibacterial combination therapy for the treatment of gram positive bacterial infections
US8614179B2 (en) * 2008-07-18 2013-12-24 E-Therapeutics Plc Antibacterial combination therapy for the treatment of gram positive bacterial infections
WO2011022798A1 (fr) * 2009-08-28 2011-03-03 Biolab Sanus Farmacêutica Ltda. Composés éthers aralkyl benzyliques, procédé de préparation de ceux-ci, composés intermédiaires, utilisation desdits composés, méthode de traitement et/ou de prévention, composition pharmaceutique et médicament les contenant
CN102625800A (zh) * 2009-08-28 2012-08-01 生物实验萨纽斯药物有限公司 芳烷基苄基醚化合物、其制备方法、中间体化合物、此类化合物的用途、治疗和/或预防的方法、包含这些化合物的药物组合物和药物
JP2013503111A (ja) * 2009-08-28 2013-01-31 バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー． アラルキルベンジルエーテル化合物、その製造方法、中間体化合物、そのような化合物の使用、治療および／または予防の方法、それを含む薬学的組成物および医薬
US8975289B2 (en) 2009-08-28 2015-03-10 Biolab Sanus Farmaceutical Ltda. Benzyl aralkyl ether compounds, method for preparing same, intermediate compounds, use of said compounds, method for treatment and/or prevention, pharmaceutical composition and medicament containing same
CN113614092A (zh) * 2019-02-22 2021-11-05 阿尼弗拉有限公司 提供抗革兰氏阳性细菌增强的抗菌活性的组合物及其用途

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