Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses

Abstract

Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural surfaces that contain bacterial biofilm, including unexpected synergy or enhancing effects between bismuth-thiol (BT) compounds and certain antibiotics, to provide formulations including antiseptic formulations. 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 certain gram-positive bacterial infections, and distinct preferential efficacies of certain such compositions for treating certain gram-negative bacterial infections.

What is claimed is: 
     
         1 . A method for protecting a natural surface against one or more of a bacterial pathogen, a fungal pathogen and a viral pathogen, comprising: contacting the surface with an effective amount of a BT composition under conditions and for a time sufficient for one or more of: (i) prevention of infection of the surface by the bacterial, fungal or viral pathogen, (ii) inhibition of cell viability or cell growth of substantially all planktonic cells of the bacterial, fungal or viral pathogen, (iii) inhibition of biofilm formation by the bacterial, fungal or viral pathogen, and (iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the bacterial, fungal or viral pathogen, wherein the BT composition comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the BT composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound that has not been micronized, milled or subjected to super-critical fluid processing, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm, wherein the BT compound comprises bismuth or a bismuth salt and a thiol-containing compound and the BT composition comprises at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, doxycycline, clindamycin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and wherein the aminoglycoside antibiotic is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, and apramycin. 
     
     
         2 . The method of  claim 1  wherein the bacterial pathogen comprises at least one of: (i) one or more gram-negative bacteria; (ii) one or more gram-positive bacteria; (iii) one or more antibiotic-sensitive bacteria; (iv) one or more antibiotic-resistant bacteria; (v) a bacterial pathogen that is selected from the group consisting of  Staphylococcus aureus  ( S. aureus ), MRSA (methicillin-resistant  S. aureus ),  Staphylococcus epidermidis , MRSE (methicillin-resistant  S. epidermidis ),  Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa , drug-resistant  P. aeruginosa, Escherichia coli , enterotoxigenic  E. coli , enterohemorrhagic  E. coli, Klebsiella pneumoniae, Clostridium difficile, Heliobacter pylori, Legionella pneumophila, Enterococcus faecalis , methicillin-susceptible  Enterococcus faecalis, Enterobacter cloacae, Salmonella typhimurium, Proteus vulgaris, Yersinia enterocolitica, Vibrio cholera, Shigella flexneri , vancomycin-resistant  Enterococcus  (VRE),  Burkholderia cepacia  complex,  Francisella tularensis, Bacillus anthracis, Yersinia pestis, Pseudomonas aeruginosa, Streptococcus pneumonia , penicillin-resistant  Streptococcus pneumonia, Escherichia coli, Burkholderia cepacia, Bukholderia multivorans, Mycobacterium smegmatis  and  Acinetobacter baumannii.    
     
     
         3 . The method of  claim 1  in which at least one of: (a) the bacterial pathogen exhibits resistance to an antibiotic that is selected from the group consisting of methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline and tobramycin, (b) the surface comprises an epithelial tissue surface that is selected from the group consisting of epidermis, dermis, respiratory tract, gastrointestinal tract and glandular linings, (c) the step of contacting is performed one or a plurality of times, (d) at least one step of contacting comprises one of spraying, irrigating, dipping and painting the surface, (e) at least one step of contacting comprises one of inhaling, ingesting and orally irrigating, (f) at least one step of contacting comprises administering to a subject by a route that is selected from topically, intraperitoneally, orally, parenterally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, transbuccally, intranasally, via inhalation, intraoccularly, intraauricularly, intraventricularly, subcutaneously, intraadiposally, intraarticularly and intrathecally, and (g) the BT composition comprises one or more BT compounds selected from the group consisting of 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 . A method for protecting a natural surface against one or more of a bacterial pathogen, a fungal pathogen and a viral pathogen, comprising: contacting the surface with an effective amount of a BT composition under conditions and for a time sufficient for one or more of: (i) prevention of infection of the surface by the bacterial, fungal or viral pathogen, (ii) inhibition of cell viability or cell growth of substantially all planktonic cells of the bacterial, fungal or viral pathogen, (iii) inhibition of biofilm formation by the bacterial, fungal or viral pathogen, and (iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the bacterial, fungal or viral pathogen, wherein the BT composition comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the BT composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm, wherein at least one of: (a) the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing antibiotic comprises an antibiotic that is selected from the group consisting of an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a glycopeptide antibiotic, a lincosamide antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic, and (b) the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing 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, wherein at least one of: (a) the bacterial pathogen exhibits resistance to an antibiotic that is selected from the group consisting of methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline and tobramycin, (b) the surface comprises an epithelial tissue surface that is selected from the group consisting of epidermis, dermis, respiratory tract, gastrointestinal tract and glandular linings, (c) the step of contacting is performed one or a plurality of times, (d) at least one step of contacting comprises one of spraying, irrigating, dipping and painting the surface, (e) at least one step of contacting comprises one of inhaling, ingesting and orally irrigating, (f) at least one step of contacting comprises administering to a subject by a route that is selected from topically, intraperitoneally, orally, parenterally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, transbuccally, intranasally, via inhalation, intraoccularly, intraauricularly, intraventricularly, subcutaneously, intraadiposally, intraarticularly and intrathecally, and (g) the BT composition comprises one or more BT compounds selected from the group consisting of 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, and wherein the method further comprises contacting the surface with at least one of (i) a synergizing antibiotic and (ii) a cooperative antimicrobial efficacy enhancing antibiotic, simultaneously or sequentially and in any order with respect to the step of contacting the surface with the composition wherein at least one of: (A) the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing antibiotic comprises an antibiotic that is selected from the group consisting of an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a glycopeptide antibiotic, a lincosamide antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic, and (B) the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing 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. 
     
     
         5 . The method of  claim 4  which comprises overcoming antibiotic resistance where an antibiotic-resistant bacterial pathogen is present on the natural surface. 
     
     
         6 . The method of  claim 5  in which at least one of: (a) the bacterial pathogen is selected from the group consisting of  Staphylococcus aureus  ( S. aureus ), MRSA (methicillin-resistant  S. aureus ),  Staphylococcus epidermidis , MRSE (methicillin-resistant  S. epidermidis ),  Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa , drug-resistant  P. aeruginosa, Escherichia coli , enterotoxigenic  E. coli , enterohemorrhagic  E. coli, Klebsiella pneumoniae, Clostridium difficile, Heliobacter pylori, Legionella pneumophila, Enterococcus faecalis , methicillin-susceptible  Enterococcus faecalis, Enterobacter cloacae, Salmonella typhimurium, Proteus vulgaris, Yersinia enterocolitica, Vibrio cholera, Shigella flexneri , vancomycin-resistant  Enterococcus  (VRE),  Burkholderia cepacia  complex,  Francisella tularensis, Bacillus anthracis, Yersinia pestis, Pseudomonas aeruginosa, Streptococcus pneumonia , penicillin-resistant  Streptococcus pneumonia, Escherichia coli, Burkholderia cepacia, Bukholderia multivorans, Mycobacterium smegmatis  and  Acinetobacter baumannii , (b) the bacterial pathogen exhibits resistance to an antibiotic that is selected from the group consisting of methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline, tobramycin, clindamicin and gatifloxacin, (c) the surface comprises an epithelial surface of a tissue that is selected from the group consisting of epidermis, dermis, respiratory tract, gastrointestinal tract and glandular linings, (d) the step of contacting is performed one or a plurality of times, (e) at least one step of contacting comprises one of spraying, irrigating, dipping, coating and painting the surface, (f) at least one step of contacting comprises one of inhaling, ingesting and orally irrigating, (g) at least one step of contacting comprises administering to a subject by a route that is selected from topically, intraperitoneally, orally, parenterally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, transbuccally, intranasally, via inhalation, intraoccularly, intraauricularly, intraventricularly, subcutaneously, intraadiposally, intraarticularly and intrathecally, (h) the BT composition comprises one or more BT compounds selected from the group consisting of 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. 
     
     
         7 . An antiseptic composition for treating a natural surface that contains bacterial biofilm, comprising at least one of: (1) a composition that comprises (a) at least one BT composition that comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound which comprises bismuth or a bismuth salt and a thiol-containing compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm; and (b) at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, doxycycline, clindamycin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and (2) the composition of (1) wherein the aminoglycoside antibiotic is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, and apramycin. 
     
     
         8 . The composition of  claim 7  wherein the BT compound is selected from the group consisting of 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. 
     
     
         9 . A method for treating a natural surface that contains bacterial biofilm, comprising: (a) identifying a bacterial infection in or on the surface as comprising one of (i) gram positive bacteria, (ii) gram negative bacteria, and (iii) both (i) and (ii); and (b) administering to the surface a formulation that comprises one or more bismuth thiol (BT) compositions and at least one antibiotic compound that is capable of acting synergistically with, or enhancing, the BT compound, wherein the antibiotic compound comprises an antibiotic that is selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, clindamycin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and wherein the aminoglycoside antibiotic is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, and apramycin, wherein: (i) if the bacterial infection comprises gram positive bacteria, then the formulation comprises 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 formulation comprises effective amounts of at least one BT compound and amikacin, (iii) if the bacterial infection comprises both gram positive and gram negative bacteria, then the formulation comprises effective amounts of one or a plurality of BT compounds, rifamycin and amikacin, and thereby treating the surface, wherein the BT compound comprises bismuth or a bismuth salt and a thiol-containing compound. 
     
     
         10 . The method of  claim 9  wherein the bacterial infection comprises one or a plurality of antibiotic-resistant bacteria. 
     
     
         11 . The method of  claim 10  wherein treating comprises at least one of: (i) eradicating the bacterial biofilm, (ii) reducing the bacterial biofilm, and (iii) impairing growth of the bacterial biofilm. 
     
     
         12 . The method of  claim 9  wherein the BT composition comprises a plurality of solid microparticles that exhibit a unimodal size distribution when the composition is analyzed on a particle size analyzer and that comprise a bismuth-thiol (BT) compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μm to about 5 μm, wherein the BT compound comprises bismuth or a bismuth salt and a thiol-containing compound. 
     
     
         13 . The method of  claim 12  wherein the BT compound has not been micronized, milled or subjected to super-critical fluid processing.