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WO2017212239A1 - Traitement d'infections microbiennes resistant aux medicaments - Google Patents

Traitement d'infections microbiennes resistant aux medicaments Download PDF

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Publication number
WO2017212239A1
WO2017212239A1 PCT/GB2017/051625 GB2017051625W WO2017212239A1 WO 2017212239 A1 WO2017212239 A1 WO 2017212239A1 GB 2017051625 W GB2017051625 W GB 2017051625W WO 2017212239 A1 WO2017212239 A1 WO 2017212239A1
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WIPO (PCT)
Prior art keywords
antibiotic
agent
sulphur
containing compound
infection
Prior art date
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Ceased
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PCT/GB2017/051625
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English (en)
Inventor
Deborah DEBORAH O'NEIL
Douglas DOUGLAS FRASER-PITT
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NovaBiotics Ltd
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NovaBiotics Ltd
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Filing date
Publication date
Priority claimed from GBGB1609921.0A external-priority patent/GB201609921D0/en
Priority claimed from GBGB1621447.0A external-priority patent/GB201621447D0/en
Application filed by NovaBiotics Ltd filed Critical NovaBiotics Ltd
Publication of WO2017212239A1 publication Critical patent/WO2017212239A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • the invention relates to the use of a sulphur-containing compound in the rea men of a patient with a drug resistant microbial infection, in particular an antibiotic-resistant infection .
  • Drug-resistant infectious agents r namely those that are not efficiently killed or substantially growth-inhibited by antimicrobial compounds, are an increasingly important public health concern. Tuberculosis, gonorrhea, malaria and childhood ear infections are examples of diseases which have become more difficult to treat due to the emergence of drug- resistant pathogens. Antimicrobial resistance is becoming a factor in virtually all hospital-acquired (nosocomial) infections. It has been estimated that the annual cost of treating antibiotic resistant infections in the United States alone may be as high as $30 billion.
  • MDR-TB muitidrug-resistant tuberculosis
  • Colistin the most common polymyxin , is a last-resort treatment for: infections with bacteria such as E. coll and Klebsiella that resist all other available antibiotics.
  • bacteria such as E. coll and Klebsiella that resist all other available antibiotics.
  • researchers at South China Agricultural University in Guangzhou recently discovered a gene for resistance to colistin in infected livestock,, meat and humans (Yi-Yun Liu et al. , The Lancet, vol. 16, no. 2, px61 ⁇ 168, Feb 2016),
  • the flier-1 gene can pass easily between bacteria. This is particularly concerning in that gram-negative bacteria, which cause common gut, urinary and blood infections in humans, can now become “pan-resistant", with genes that defeat, ail antibiotics now available.
  • cysteamine has previously demonstrated the utility of cysteamine as an antimicrobial agent in cystic fibrosis.
  • the present inventors have now shown that cysteamine has broader potential in a wider range of bacterial infections.
  • the present inventors have now shown that cysteamine has an application in reversing drug resistance and thus improving therapeutic treatment of infections associated with resistant pathogens,
  • a sulphur-containing compound for use in the prophylaxis or treatment of an infection associated wit at least one microbe or microbial strain displaying at least some degree of drug resistance.
  • the infection is a drug-resistant .microbial infection.
  • the infection is a bacterial infection.
  • the bacterial infection is an antibiotic resistance bacterial infection.
  • the invention provides a prophylactic or curative treatment of an infection associated with at least one microbe or microbial strain displaying at least some degree of antimicrobial resistance comprising administering to a subject a sulphur-containing compound.
  • the patient is infected with a bacteria which has at least some or some degree of resistance to an antibacterial agent such as an antibiotic.
  • the infection may be an antibiotic-res stant infection .
  • the sulphur-contai ing compound restores a degree of sensitivity of the antibiotic-resista t infection (or causative bacterium of the infection) to the antibiotic.
  • a product comprising a sulphur-containing compound and a second agent being an antimicrobial agent .
  • the sulphur-containing agent and antimicrobial agent although both have antimicrobial properties, are not the same.
  • the antimic obial agent of the product of the present invention does not comprise peptides.
  • the product of the present invention does not comprise peptides.
  • the sulphur- containing compound and antimicrobial agent are not administered in a singular dosage unit but are each instead in separate dosage units.
  • the dosage units are preferably administered simultaneously but may be administered in a non-simultaneous fashion due to differential absorption at of the sulphur-containing agent and antimicrobial agent.
  • the product is for use in the prophylaxis or treatment of an infection associated with at least one microbe or microbial strain displaying at least some degree of drug resistance,
  • the invention provides a prophylactic or curative treatment of an infection associated with at least one microbe or microbial strain displaying at least some degree of antimicrobial resistance comprising administering to a subject a product comprising a sulphur- containing compound and a second agent being an antimicrobial agent.
  • the invention allows for the use of lower amounts of antimicrobials such as antibiotics when combined with a sulphur-contai ing compound.
  • a further aspect of the invention rovides a kit comp ising a first dosage unit comprising a sulphur-containing compound and a further dosage unit comprising an antibacterial agent.
  • the antibacterial agent may be an antibiotic.
  • '''sulphur-containing compound/'' is intended to cover cysteamir.e, cystamine or a derivative thereof.
  • the sulphur-co taining compound may be an aminothiol . Examples of aminothiols include cysteamine and derivatives thereof.
  • the term "derivative thereof” may encompass 2-methylthio ethylamine (cinnamate) , 2-methyl thio ethylurea, N- (2- methylthio ethyl) p-acetamido benzamide, 2-aminoethanethiol, N- ( 2-methylthio ethyl ⁇ p-acetamido benzenesulfonamide, N- ( 2- propylthioethyl) -p-methoxy benzamide, N- (butylthio ethyl) nicotinamide, N- ⁇ 2-dodecylthio ethyl) p-butoxybenzamide, N- (2-methylthio ethyl) p-toluenesulfonamide , K- (2- isopropylthio ethyl) propionamide, N- (2-octyithio ethyl) acetamide,
  • beta. -ureidoethylthio ethylamine hydrochloride 2- . beta , -acetamidoethylthio ethylamine tropate, 2,2' -thio diethylamine fumarate, 2,2'- t io diethy1urea, 3-.beta. -ami oethy11hio propylamine hydrochloride, S- . beta . -ureidoethyl thiocarbamate,
  • 2-ethoxycarbonylthio ethylamine hydrochloride 2TM dimethylamino carbonylthio ethylamine sulfate, 2- butoxycarbonyl methylthio ethylurea, 2- ethyioxycarbonylmethylthio ethylamine hydrochloride, 6- . beta . -aminoethylthio hexanoate of methyl hydrochloride, 5- . beta . -aminoethy11hio pentanoic acid,
  • the sulphur-containing compound may be an organic disulphide, such as cystamine.
  • the sulphur-containing compound of the invention may be administered in the form of pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanoi, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed.
  • the invention thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof for example the conventional non-toxic salts or the quaternary ammonium salts which a e formed, e.g., from inorganic or organic acids or bases .
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, blsulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate , dodecylsulfate, et anesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesu1fonate , 2-naphtha.lenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop.ionate, picrate, pivalate, propionate, succinate
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such aqents as lower alkyl halides, such as methyl, ethyl , propyl, and butyl chloride , bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain ha1ides such as decy.i , lauryl, myristyl and stearyi chlorides, bromides and iodides, aralkyl ha I ides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl , propyl, and butyl chloride , bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain ha1ides such as decy.i , la
  • antimicrobial resistance and “resistance” are used interchangeably to describe a situation where a pathogenic microbe has undergone some sort of change that reduces or eliminates the effectiveness of drugs, chemicals, or other agents to cure or prevent infections.
  • microbes is used in its common meaning, i.e. to co er pathogen!c organi sms so sma11 that a microscope is required to see them.
  • Microbes are also called microorganisms, and include bacteria, viruses, fungi, and parasites, out of which the former two, especially bacteria are the most relevant, for the purposes of the present invention .
  • antimicrobial agent is intended to cover drugs, chemicals, or other substances that either kill or slow the growth of microbes.
  • antimicrobial agents in use today are antibacterial drugs, antiviral agents, antifungal agents, and antiparasitic drugs.
  • the antimicrobial agent is an antibacterial agent, for example an antibiotic agent.
  • Antibiotic agents ma be bactericidal and/or bacteriostatic.
  • the antibiotic agent may contain a ⁇ -lactaxn ring.
  • the ⁇ - lactam ring is part of the core structure, of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactam . These antibiotic agent are called ⁇ -lactam. antibiotics.
  • the antibiotic agent is of the group consisting of aminoglycosides, ansamycins, carbacepheirt, ⁇ -lactams carbapenems, cephalosporins, (including first, second, third, fourth and fifth generation cephalosporins) , penicillin, monobactams) , glycylcyclines, lincosamides, iipopeptides, macrolides, nitrofurans, oxazolidinones, quinolones, sulfonamides, polypeptides and tetracyclins .
  • the antibiotic agent may be of the group consisting of aminoglycosides, ansamycins, carbacepbem, carbapenems, cephalosporins (including first, second, third, fourth and fifth generation cephalosporins), lincosamides, macrolides, monobactams, nitrofurans, quinoiones, penicillin, sulfonamides, polypeptides and tetracyclins.
  • the antibiotic agent may be effective against .mycobacteri .
  • the antibiotic agent may be an aminoglycoside such as Amikacin, Gentamicin, Kar.amyc.in, Neomycin, Netilmicin, Tobramycin or Paromomycin.
  • the antibiotic agent may be an such as Geldanamycin and Herbimycin
  • antibiotic agent may be a carbacepheirt such as Loracarbef.
  • the antibiotic agent is a carbapenem such as Ertapenem, Doripenem, Imipenem/Cilastatin or Meropenem.
  • the antibiotic agent may be a cephalosporins (first generation) such as Cefadroxil, Cefazolin, Cefalexin, Cefaiotin or Cefalcthin, or alternatively a Cephalosporins (second generation) such as Cefaclor, Cefamandole, Cefoxitin, Cefprozii or Cefuroxime .
  • first generation such as Cefadroxil, Cefazolin, Cefalexin, Cefaiotin or Cefalcthin
  • Cephalosporins second generation
  • the antibiotic agent may be a Cephalosporins (third generation) such as Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftibuten, Ceftizoxime and Ceftriaxone or a Cephalosporins (fourth generation) such as Cefepirtie and Ceftobiprole .
  • the antibiotic agent may be a lincosamides such as Clindamycin and Azithromycin, or a macrolide such as Azithromycin, Clarithromycin, Dirithromycin, Erythromycin , Roxithromycin, Troleandoraycin, Telithromycin and
  • the antibiotic agent may be a monobactams such as Aztreonam, or a nitrofuran such as Furazolidone or Nitrofurantoi .
  • the antibiotic agent may be a penicillin such as Amoxicillin, Ampicillin, Azlociliin, Carbenicillin, Cloxacillin, Dicioxacillin, Flucloxacil Lin, Mezlocillin, Nafcillin , Oxacillin, Penicillin G or V, Piperacillin, Temocillin and Ticarcillin.
  • the antibiotic agent may be an oxazolidinone such as iinezolid or tedizolid.
  • the antibiotic agent may be a sulfonamide such as Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazi e, Si1 er sulfadiazine, Sulfamethizole, Sulfamethoxazole,
  • a sulfonamide such as Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazi e, Si1 er sulfadiazine, Sulfamethizole, Sulfamethoxazole,
  • the antibiotic agent may be a quinolone such as Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trcvafloxacin, Grepafloxacin, Sparfloxacin and Teniafloxacin ,
  • the antibiotic agent may be a polypeptide, Examples of such polypeptides include Bacitracin, Colistin and Polymyxin B. In one embodiment, the antibiotic agent is not a polypeptide .
  • the antibiotic agent may be a lipopeptide .
  • lipopeptides include Daptomycin and Surfactin.
  • the antibiotic agent may be a tetracycline such as Demeclocycline, Doxycycline, Minocycline and Oxytetracycline
  • the antibiotic agent may be a glycylcycline .
  • examples of such giycyicyclines include ticjecycline .
  • the antibiotic agent may be effective against mycobacteria.
  • the antibiotic agent may be Clofazimine, Lamprene, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid,
  • the antibiotic agent is a macrolide and/or an aminoglycoside and/or suiphonamid.es.
  • the antibiotic agent is a macrolide and/or an aminoglycoside.
  • the antibiotic agent is a macrolide and/or sulphonamide . In one embodiment, the antibiotic agent is an aminoglycoside and./or sulphonamide .
  • the antibiotic is selected from tobramycin, azithromycin,, telithromycin, ciprofiaxin, ceftazidime ,
  • the antibiotic agent is not ciproflaxin. In another embodiment the antibiotic is not tobramycin.
  • the antibiotic agent may be active in the treatment or prophylaxis of infections caused by Enterobacteriaceae ⁇ e.g. E.coli or Klebsiella spp. , such as K, pneumoniae) or non- Enterobacteriaceae bacteria such as Burkhoideria spp.
  • Enterobacteriaceae e.g. E.coli or Klebsiella spp. , such as K, pneumoniae
  • non- Enterobacteriaceae bacteria such as Burkhoideria spp.
  • the antibiotic agent is active in the treatment or prophylaxis of infections caused by gram-negative or gram- positive bacteria, such as Pseudomonas spp., for example Pseudomonas aeruginosa, 3urk.hold.eria spp., Escherichia coli, Klebsiella spp., for example K. pneumoniae, Staphylococcus spp., for example S. aureus.
  • Pseudomonas spp. for example Pseudomonas aeruginosa
  • 3urk.hold.eria spp. Escherichia coli
  • Klebsiella spp. for example K. pneumoniae
  • Staphylococcus spp. for example S. aureus.
  • the antibiotic is not a ⁇ -iactam antibi ot ic..
  • the antibiotic is not a penicilli .
  • the antibiotic is not. a cephalosporin .
  • the antibiotic is not a carbapene .
  • the antibiotic is not a monobactam.
  • the normal dosing regime of the antibiotic can be reduced by up to 10%; such as by up to 20%; such, as by up to 30%; such as by up to 40%; such as by up to 50%; such as by up to 55%.
  • the dosing of an antibiotic in the present invention can be reduced, according to the dose provided by the MIC values exemplified in present invention.
  • the risk of developing antibiotic resistance can be dramatically reduced.
  • the effect of the antibiotic may be increased up to 10 times giving two alternative advantages; the micro-organisms are up to 10 times as susceptible increasing the efficiency of the therapy; alternatively the therapeutic dose can be reduced concurrently with 90% while maintaining the therapeutic effect .
  • the sulphur- containing compound and the additional antimicrobial agent may be administered simultaneously, sequentially or separately.
  • the sulphur-containing compound and the additional antimicrobial agent may be provided as a combination package.
  • the combination package may further instructions for simultaneo s, separate or sequential administration of each of the sulphur-containing compound and additional antimicrobial agent.
  • the sulphur-containing compound and the additional antimicrobial agent may be administered in any order. In one embodiment , the sulphur-containing compound is administered before the additional antimicrobial agent.
  • the present invention provides a product comprising a first active agent being sulphur-containing compound and a second agent being an antimicrobial agent.
  • the above mentioned active agents may be administered as free or fixed combinations.
  • Free combinations may be provided as combination packages containing all the active agents in free combinations.
  • Fixed combinations are often tablets or capsules.
  • the active agents may be administered simultaneously, sequentially or separately.
  • the active agents may be provided as a combination package.
  • the combination package may contain the product of the invention together with instructions for simultaneous, separate or sequential administration of each of the active agents.
  • the active agents can be administered in any order .
  • the active agents of the product of the invention may be provided as pharmaceutical compositions additionally containing one or more pharmaceutically acceptable, diluents, excipients and/or carriers, This applies to both fixed and free combinations.
  • the active agents of the present invention may be administered by any suitable route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and composition may, for example, be administered parenterally, orally, intranasal, intrabronchial, enterally, transdermally, sublinquaily, rectally, vaginally, ocularly, or topically.
  • parenteral refers to modes of administra ion which include intravenous, intramuscular, enteral, intraperi oneal, intrasternal, subcutaneous and intraarticular injection and infusion of which intravenous (including continuous intravenous administration) is most preferred) solutions in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic, with sufficient saline or glucose.
  • these aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • the sulphur-containing compound may be administered parenteraliy before parenteral administration of the additional antimicrobial agent.
  • the sulphur-containing compound may be administered parenter liy simultaneously with parenteral before administration of the additional antimicrobial agent.
  • the products of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser, nebuiiser, with or without the use of a suitable propel!ant ,
  • the products of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder.
  • the products of the invention may be dermally or transdermal ly administered, for example, by use of a skin patch, depot or subcutaneous injection. They may also be administered by pulmonary or rectal routes.
  • the pharmaceutical composition may be. in the form of; for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose; marmitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the products of the invention may also find application as /in an oral formulation wherein the product is formulated in a carrier, for example selected from, films, tapes, gels, microspheres, lozenges, chewing gum, dentrifices and mouthwash .
  • a carrier for example selected from, films, tapes, gels, microspheres, lozenges, chewing gum, dentrifices and mouthwash .
  • the amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the inhibitor to be administrated may need to be optimized for each individual.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 200 mg.
  • the daily dose can be administered in one to four doses per day.
  • the products of the invention may be administered to the respiratory tract.
  • the present invention also provides aerosol pharm.aceut.ical formulations comprising a product of the invention.
  • a nebuliser or inhaler containing a product of the invention.
  • the products of the invention may be suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active agents, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time.
  • Coatings, envelopes, and protective matrices may be made, for example, from polymeric, substances, such as polylactide-glycolates , liposomes , microemulsions , microparticles, nanoparticles, or waxes. These coatings, envelopes, and, protective matrices are useful to coat indwelling devices, e.g. stents, catheters, peritoneal dialysis tubing, draining devices and the like. Methods and Use
  • the invention provides the use of a sulphur-containing compound in the prophylaxis or treatment of an infection associated with at least one microbe or microbial strai displaying at least some degree of drug resistance.
  • the infection is a drug-resistant microbial infection.
  • the infection is a bacterial infection.
  • the bacterial infection is an antibiotic resistance bacterial infection.
  • the invention also provides a prophylactic, or curative treatment of an infection associated with at least one microbe or microbial strain displaying at least some degree of antimicrobial resistance comprising administering to a subject a sulphur-containing compound.
  • the bacterial infection may include an infection caused by mere than one microorganism, for example bacteria and any one of fungi, yeast, viruses and protozoa.
  • the bacterium may be a Gram-positive or a Gram-negative bacterium.
  • a bacterial pathogen may be derived from a bacterial species selected from the group consisting of:
  • Staphylococcus spp. e.g. Staphylococcus aureus such as
  • Enterococcus spp. e.g. Enterococcus faecalis; Streptococcus pyogenes; Listeria spp.; Pseudo onas spp,; Mycobacterium spp., e.g. Mycobacterium tuberculosis; Enterobacter spp.;
  • Helicobacter spp. e.g. Helicobacter pylori; Neisseria spp., e.g. Neisseria gonorrhea, Neisseria meningitidis; Borrelia burgdorferi; Shigella spp., e.g. Shigella flexneri;
  • the bacterium may include Pseudomonas spp., for example Pseudomonas aeruginosa; Staphylococcus spp., for example Staphylococcus aureus and Staphylococcus epidermidis Haemophilus spp., for example Haemophilus influenza; Burkholderia spp., for example Burkholderia cepacia; Streptococcus spp., Propionibacterium spp,, for example Propionibacteriurn acnes.
  • Pseudomonas spp. for example Pseudomonas aeruginosa
  • Staphylococcus spp. for example Staphylococcus aureus and Staphylococcus epidermidis
  • Haemophilus spp. for example Haemophilus influenza
  • Burkholderia spp. for example Burkholderia cepacia
  • the bacterium is selected from Pseudomonas spp., for example Pseudomonas aeruginosa and Staphylococcus spp,, for example Staphylococcus aureus and Staphylococcus epidermidis .
  • the bacterial infection is caused by Enterobacteriaceae (e.g. E.coli or Klebsiella spp., such as K. pneumoniae) or non-Enterohacteriaceae bacteria such as Burkholderia spp., for example B. cepacia or B .muitivorans .
  • Enterobacteriaceae e.g. E.coli or Klebsiella spp., such as K. pneumoniae
  • non-Enterohacteriaceae bacteria such as Burkholderia spp., for example B. cepacia or B .muitivorans .
  • the bacterial infection is caused by gram-negative or gram-positive bacteria, such as Pseudomonas spp., for example Pseudomonas aeruginosa, Burkholderia spp., Escherichia coli, Klebsiella spp., for example K. pneumoniae, staphylococcus spp., for example S. aureus, in particular ethicillin resistant S . aureus .
  • Pseudomonas spp. for example Pseudomonas aeruginosa
  • Burkholderia spp. Escherichia coli
  • Klebsiella spp. for example K. pneumoniae
  • staphylococcus spp. for example S. aureus, in particular ethicillin resistant S . aureus .
  • the bacterial infection is caused by a bacterium no including Burkholderia spp. In another embodiment of the invention, the bacterial infection is caused by a bacterium not including Pseudomonas spp. for example Pseudomonas aeruginosa.
  • the method of the invention may be used to minimise and prevent the formation of bacterial colonies, in particular bacterial biofilras in a variety of environments including, but not limited to, household, workplace, laboratory, industrial environment, aquatic environment (e. g. ipeline systems), medical devices including indwelling devices such as defined herein, dental devices or dental implants, animal body for example human body.
  • the method of the invention may be used to prevent or restrict, the formation of a bacterial colony.
  • the method of the present invention may be used to prevent or treat bacterial infections including topical infections, oral infections and systemic infections.
  • Topical infections may include wounds, ulcers and lesions for example, cutaneous wounds such cuts or burns, and conditions associated therewith .
  • Oral infections may include gingivitis, periodontitis and mucositis .
  • Systemic infections may include cystic fibrosis, COPD and other conditions associated with mucosal infections, for example, gastrointestinal, urogenital or other respiratory infectio s .
  • the product of the invention may be useful in the prevention of, delay of progression of, or treatment of a disease or condition selected from the group consisting of skin and wound infections, middle-ear infections, gastrointestinal tract infections, peritoneal membrane infections, urogenital tract infections, oral soft tissue infections, formation of dental plaque, eye infections (including contact iense contamination) , endocarditis, infections in cystic fibrosis, and infections of indwelling medical devices such as described herein.
  • a disease or condition selected from the group consisting of skin and wound infections, middle-ear infections, gastrointestinal tract infections, peritoneal membrane infections, urogenital tract infections, oral soft tissue infections, formation of dental plaque, eye infections (including contact iense contamination) , endocarditis, infections in cystic fibrosis, and infections of indwelling medical devices such as described herein.
  • Figure 1 is a graph showing that cysteamine chemopotentiates the activity of ciprofloxacin in the neutropenic mouse thigh model of infection with P. aeruginosa LES431.
  • Vehicle control 2. Colistin [5 mg./kg] (positive control), 3. Cysteamine only [1.25 mg/kg] , 4. Ciprofloxacin only [15 mg/kg] , and 5, Ciprofloxacin + Cysteamine.
  • MICioo values for Burkholderia strains are described as the concentration of antibiotic ⁇ in micrograms/ml) required, to inhibit the growth of all of the bacteria tested,, cultured over 48 hours at 37 °C in cation-adjusted Muller-Hinton broth.
  • the initial inoculum is prepared from a single colony recovered from frozen stocks (after confirmation of culture purity) which is transferred via sterile inoculation loop to 10 ml cation-adjusted Muller-Hinton broth in a 30 ml universal container. This is incubated aerobically and statically for 48 h at 37 °C prior to the experiment.
  • the inoculum. is standardised by comparison with 0,5 McFarland standard absorption at 625 nm. This is done by serially diluting 100 ⁇ of the liquid culture 2-fold in phosphate buffered saline on a 96-well microtitre plate and comparing with the mean value of triplicate 100 ⁇ volumes of 0.5 McFarland standards on the same plate. The closest dilution is then diluted a further 1:150 in sterile, twice- concentrated, cation-adjusted Muller-Hinton broth.
  • antibiotics of choice are serially diluted 2-fold in sterile distilled water to achieve 2x the relevant concentrations used in each experiment, by diluting 50 ⁇ of each antibiotic into 50 ⁇ volumes of distilled water.
  • Negative controls contain 50 ⁇ of sterile distilled water only. To these plates 50 ⁇ of 1:150 diluted inoculum is added to appropriate wells, Negative culture controls are also prepared by the addition of 50 ⁇ of sterile cation-adj usted Miiller-Hinton broth. This brings the final concentration of Miiller-Hinton broth to 1 x in 100 ⁇ volumes in each well each containing the required concentration of test antibiotic.
  • each 96-well plate will contain 3 experimental replicates for each Burkholderia strain at each concentration of antibiotic.
  • the plates are then read at 625nm using the Biotek plate reader to obtain a time 0 h baseline absorbance reading.
  • the plates are then incubated for 48 h at 37 °C.
  • the plates are read at 625 ran using the Biotek plate reader to determine growth of bacteria over time in relevant concentrations of test antibiotic.
  • Mean absorbance values are calculated using Microsoft Excel and base line optical density values taken at time 0 h are subtracted.
  • the concentration of antibiotic required for complete inhibition of bacterial growth is determined as the concentration with absorbance the same as or below those for the uninoculated controls.
  • Various volumes may be used to perform the serial dilutions depending upon the amount of antibiotic required for the challenge experiments if performing multiple experimental replicates, or preparing the same antibiotic to challenge a number of different strains of Bcc.
  • Antibiotic plates can be prepared in advance of the experiment, depending upon the. stability of the antibiotic used, by performing the dilutions and freezing the plates at -20°C prior to the day of the experiment..
  • Negat ive, uninoculated, controls are prepared by adding 50 ⁇ of cation-adjusted Miiller Hinton broth. Incolum are prepared as described above, using the referenced method (LSI. 2012a. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved Standard - Ninth Edition; M07-A9. Wayne, PA; Clinical and Laboratory Standards Institute).
  • a time 0 h reading is then taken at 625 ran using the Biotek plate reader to determine background absorbance.
  • the plates are then incubated, statically, for a further 48 h at 37°C prior to another reading at 625 nm to determine growth and the efficacy of antibiotic co-therapy.
  • Etest ® assessment of antibiotic MIC of Neisseria gonorrhoeae GC agar plates were prepared containing Vitox supplement (Oxoid- K Thermo Fisher Scientific, MA, USA) with and without a range, of concentrations of filter-sterilised cysteamine. This is done by autoclaving the required volume of GC agar in solution at 121 e C for 15 min. Following this the agar is allowed to cool to 60°C prior to the addition of vitox supplement (for the cultivation of fastidious N. gonorrhoeae) and cysteamine solutions as required to final concentration ranges of 0, 128, 256, and 512 mg/L in 100 ml volumes. The agar is then poured, evenly, under aseptic conditions and the plates are allowed to set and dry in a safety cabinet or lamina flow hood.
  • Vitox supplement Oxoid- K Thermo Fisher Scientific, MA, USA
  • N, gonorrhoeae is prepared by culturing overnight at 37°C in a 5% CO2 atmosphere on GC agar plus vitox plate.
  • a suspension of N. gonorrhoeae cells is made by asepticaily transferring loops of overnight growth from the surface of the GC agar plus vitox plate into sterile PBS under aseptic conditions. This is then serially diluted two-fold in PBS to reach the required optical density by comparison to 0.5 McFarland standard.
  • a sterile swab is then inoculated with the appropriate dilution of suspended cells in PBS and this is used to create a spread plate by streaking over the full surface of the appropriately labelled plate and allowed to absorb .
  • Etest ® strip containing a standardised gradient, of antibiotic is placed (using sterile forceps) onto the surface of inoculated plate. Plates are then incubated upside down at 37°C in a 5% CO 2 atmosphere for 24 hrs to allow growth of N. gonorrhoeae and the appearance of a zone of clearance on each plate (where this occurs) .
  • the MIC can be determined by the point at which along this gradient strip no further growth occurs leading to a zone of clearance on the surface of the agar. Experiments were conducted in triplicate on 3 separate occasions.
  • mice were rendered neut opoenic with cyclophosphamide prior to infection. They were separated into groups of 5 animals per treatment. Inoculation (confirmed by culture) was with 1.52 x 10" cfu/ml of P. aeruginosa strain LES4.31 and conducted 1 hour prior to treatment which was i. v. for saline vehicle controls, ciprofloxacin, and cysteamine treated mice, and SC for colistin (used as a positive control) . Animals were sacrificed 25 h post infection (24 h post-treatment) and thigh weights and cfu/g of tissue were calculated and recorded.
  • Serial plasma cysteamine concentrations were measured for 24 h after the first dose. Participants were reviewed every week, for 6 weeks, except at 4 weeks. Plasma cysteamine concentrations were measured 8 h after dosing when reviewed at 1, 2 and 3 weeks and 6 h after dosing when reviewed at 5 weeks. Sputum cysteamine concentration was also quantified at the 5-week assessment. Routine monitoring of clinical microbiology and reporting of speciation and resistance profile of major colonising microorganisms from patients continued as normal, prior to, during where necessary and after the trial by the hospital microbiology .labo atory.
  • Bcc isolates used in this study were either type strains purchased from the American Type Culture Collection (AT'CC) , the National Collection of Type Cultures (NCTC) , of Public Health England, or Deutsche Sammiung von Mikroorganismen und Zelikulturen (DSMZ) . Clinical strains were gifted from either Aberdeen Royal Infirmary, or the University of Glasgow Dental School .
  • CLSI & EUCAST interpretative criteria do not exist for Burkholderia or non- Enterobacteriaceae against AZM.
  • the criteria applied here are CLSI guidelines for Enterobacteriaceae: S - ⁇ 16 mg/L, R - >32 mg L
  • CLSI & EUCAST interpretative criteria do not exist for Pseudomonas or non- Enterobacteriaceae against AZM.
  • the criteria applied here are CLSI
  • EUCAST breakpoints for enterobacteraciae (£. coli and . pneumoniae), as there are no CLSI breakpoints for collstin and enterobacteraciae: S - ⁇ 2 mg/L, R - >2 mg/L.
  • CLSI breakpoints for Pseudomonas spp. were used as there are no CLSI or EUCAST breakpoints for colistin versus Burkholderia spp.
  • Tabie 14 Antimicrobial activity ⁇ MIC in g/l) of representative aminoglycoside antibiotics (A8X) against a range of dirsicatiy relevant antibiotic resistant intermediate) strains of bacteria. S/l/R denotes sensitivity, intermediate or resistant as efm& bv CLSi for each relevant bacteria! species. Fa Mycobacte abscessus the interpretive criteria for Nocardia sp» was used as recommended. ⁇ Reduction In E3 ⁇ 4
  • MIC in g/l Antimicrobial activity (MIC in g/l) of representative fluoroquinolone antibiotics (ABX) against a range of clinically relevant antibiotic resistant ( intermediate) strains of bacteria.
  • S/l/R denotes sensitivity, intermediate or resistant as defined by CLSI for each relevant bacterial species.
  • MIC in g/l Antimicrobial activity (MIC in g/l) of representative macrolide antibiotics (ABX) against a range of clinically relevant antibiotic resistant strains bacteria.
  • S l/ denotes sensitivity, intermediate or resistant as defined by CLSI for each relevant bacterial species.
  • ⁇ Reduction in MIC is shown as the fraction the MIC value for the clinical antibiotic found when used in combination with cysteamine, compared to the antibiotic used alone.
  • MIC in g/l Antimicrobial activity (MIC in g/l) of the polymyxin, colistin (ABX) against a range of clinically relevant antibiotic resistant (or intermediate) strains bacteria.
  • S/l/R denotes sensitivity, intermediate or resistant as defined by CLSI for each relevant bacterial species. Reduction in MIC is shown as the fraction the MIC value for the clinical antibiotic found when used in combination with cysteamine, compared to the antibiotic used alone.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • MSSA Methicillin-sensitive Staphylococcus aureus
  • PR pan-resistant
  • S sensitive
  • Cip ciprofloxacin-resistant
  • Cip 8 ciprofloxacin sensitive.
  • Cip R P. aeruginosa Cip s P. aeruginosa
  • Table 20 Accompanies Figure 1 below - The reduction of microbial burden in the neutropoenic mouse thigh model of infection (illustrated graphically in Figure shown as a Iog10 reduction of cfu g compared with vehicle control. Colistin (at 5 mg kg) was used a s a positive control.
  • Ciprofloxacin [15 mg/kg] 2.02

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Abstract

La présente invention concerne un composé contenant du soufre destiné à être utilisé dans la prophylaxie ou le traitement d'une infection associée à au moins un microbe ou une souche microbienne présentant au moins un certain degré de résistance aux médicaments. L'invention concerne également un produit comprenant un premier agent qui est un composé contenant du soufre et un second agent qui est un agent antimicrobien, en particulier un agent antibiotique.
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CN111351689A (zh) * 2020-03-16 2020-06-30 集美大学 一种细菌染色法的制片方法及其应用

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