Bismuth-thiols as antiseptics for epithelial tissues, acute and chronic wounds, bacterial biofilms and other indications

Abstract

Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating acute wounds, chronic wounds and/or a wound or epithelial tissue surface that contains bacterial biofilm, including unexpected synergy between bismuth-thiol (BT) compounds and certain antibiotics, to provide topical formulations including antiseptic formulations, for management and promotion of wound healing and in particular infected wounds. Previously unpredicted antibacterial properties and anti-biofilm properties of disclosed BT compounds and BT compound-plus-antibiotic combinations are also described, including preferential efficacies of certain such compositions for treating gram-positive bacterial infections, and distinct preferential efficacies of certain such compositions for treating gram-negative bacterial infections.

What is claimed is: 
     
         1 . A method of treating an acute wound, a chronic wound or a wound or epithelial tissue surface that contains bacterial biofilm in a subject, comprising:
 administering, to a wound site or to a wound or epithelial tissue surface that contains bacterial biofilm in the subject, a therapeutically effective amount of a topical formulation that comprises (a) a bismuth-thiol (BT) composition that comprises at least one BT compound, and (b) a pharmaceutically acceptable excipient or carrier for topical use.   
     
     
         2 . The method of  claim 1  wherein the topical formulation further comprises at least one antibiotic compound that is capable of acting synergistically with the BT compound. 
     
     
         3 . The method of either  claim 1  or  claim 2  wherein the BT compound is selected from BisBAL, BisEDT, Bis-dimercaprol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-mercapto-2-propanol, and Bis-EDT/2-hydroxy-1-propanethiol. 
     
     
         4 . The method of either  claim 1  or  claim 2  wherein the BT composition comprises a plurality of solid microparticles that comprise the at least one bismuth-thiol (BT) compound and that exhibit a unimodal size distribution when the BT composition is analyzed on a particle size analyzer, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm. 
     
     
         5 . The method of  claim 2  wherein the BT compound is selected from the group consisting of BisEDT and BisBAL. 
     
     
         6 . The method of either  claim 1  or  claim 2  wherein the wound site comprises an acute wound or a chronic wound that contains a bacterial infection. 
     
     
         7 . The method of  claim 6  wherein the bacterial infection comprises one or more of gram-positive bacteria and gram-negative bacteria. 
     
     
         8 . The method of  claim 6  wherein the bacterial infection comprises at least one bacterial population that is selected from a bacterial biofilm and planktonic bacteria. 
     
     
         9 . The method of  claim 2  wherein the antibiotic compound comprises an antibiotic that is selected from the group consisting of an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic. 
     
     
         10 . The method of  claim 9  wherein the antibiotic is an aminoglycoside antibiotic that is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin. 
     
     
         11 . The method of  claim 9  wherein the aminoglycoside antibiotic is amikacin. 
     
     
         12 . An antiseptic composition for treating an acute wound, a chronic wound or a wound or epithelial tissue surface that contains bacterial biofilm, comprising:
 (a) a bismuth-thiol (BT) composition that comprises at least one BT compound; (b) at least one antibiotic compound that is capable of acting synergistically with the BT compound; and (c) a pharmaceutically acceptable excipient or carrier for topical use.   
     
     
         13 . The antiseptic composition of  claim 12  wherein the BT compound is selected from BisBAL, BisEDT, Bis-dimercaprol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-mercapto-2-propanol, and Bis-EDT/2-hydroxy-1-propanethiol. 
     
     
         14 . The antiseptic composition of  claim 13  in which the BT composition comprises a plurality of solid microparticles that comprise the bismuth-thiol (BT) compound and that exhibit a unimodal size distribution when the microparticles are analyzed on a particle size analyzer, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm. 
     
     
         15 . The antiseptic composition of  claim 12  wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline, tobramycin, clindamicin, gatifloxacin and an aminoglycoside antibiotic. 
     
     
         16 . The composition of  claim 15  wherein the aminoglycoside antibiotic is selected from amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin. 
     
     
         17 . The composition of  claim 15  wherein the aminoglycoside antibiotic is amikacin. 
     
     
         18 . A method for treating an acute wound, a chronic wound or a wound or epithelial tissue surface that contains bacterial biofilm, comprising:
 (a) identifying a bacterial infection in a wound or epithelial tissue surface in a subject as comprising one of (i) gram positive bacteria, (ii) gram negative bacteria, and (iii) both (i) and (ii); and   (b) treating the wound or epithelial tissue surface by administering a topical formulation that comprises a BT composition which comprises one or more bismuth thiol (BT) compounds to the wound, wherein:
 (i) if the bacterial infection comprises gram positive bacteria, then the topical formulation comprises therapeutically effective amounts of at least one BT compound and at least one antibiotic that is rifamycin, 
 (ii) if the bacterial infection comprises gram negative bacteria, then the topical formulation comprises therapeutically effective amounts of at least one BT compound and amikacin, and 
 (iii) if the bacterial infection comprises both gram positive and gram negative bacteria, then the topical formulation comprises therapeutically effective amounts of one or a plurality of BT compounds, rifamycin and amikacin. 
   
     
     
         19 . The method of  claim 18  in which one or more of:
 (a) treating the wound prevents neuropathy resulting from chronic wound progression, 
 (b) the bacterial infection comprises one or a plurality of antibiotic-resistant bacteria, 
 (c) the wound is selected from a venous ulcer, a pressure ulcer, a diabetic ulcer, a decubitis ulcer, a gunshot wound, a puncture wound, a shrapnel wound, an ischemic wound, a surgical wound, a traumatic wound, acute arterial insufficiency, necrotizing fasciitis, osteomyelitis, a wound resulting from radiation poisoning, osteoradionecrosis, soft tissue radionecrosis, pyoderma gangrenosum, a gangrenous wound, a burn, a dermal infection and a malignancy, and 
 (d) the wound is an acute wound or a chronic wound that comprises a bacterial biofilm. 
 
     
     
         20 . The method of  claim 18  wherein treating the wound comprises at least one of: (i) eradicating the bacterial biofilm, (ii) reducing the bacterial biofilm, and (iii) impairing growth of the bacterial biofilm. 
     
     
         21 . The method of  claim 18  wherein the BT composition comprises a plurality of solid microparticles that comprise the one or more bismuth-thiol (BT) compound and that exhibit a unimodal size distribution when the BT composition is analyzed on a particle size analyzer, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm.