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.

1 - 9 . (canceled) 
     
     
         10 . 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 a formulation that comprises one or more bismuth thiol (BT) compositions to the surface, 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.   
     
     
         11 . The method of  claim 10  wherein the bacterial infection comprises one or a plurality of antibiotic-resistant bacteria. 
     
     
         12 . The method of  claim 11  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. 
     
     
         13 . The method of  claim 10  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. 
     
     
         14 . The method of  claim 13  wherein the BT compound has not been micronized, milled or subjected to super-critical fluid processing. 
     
     
         15 . A bismuth thiol (BT) composition comprising a synergizing or enhancing combination of:
 (a) one or more bismuth thiol (BT) compounds; and   (b) (1) at least one antibiotic that exhibits an anti-bacterial effect that is enhanced by said one or more BT compounds, or
 (2) at least one antibiotic with which said one or more BT compounds synergizes to produce an anti-bacterial effect, 
   wherein the anti-bacterial effect is selected from (i) prevention of infection by a bacterial pathogen, (ii) inhibition of cell viability or cell growth of substantially all planktonic cells of a bacterial pathogen, (iii) inhibition of biofilm formation by a bacterial pathogen, and (iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of a bacterial pathogen, and   wherein the BT composition does not comprise bismuth-ethanedithiol (BisEDT) and tobramycin as the synergizing or enhancing combination.   
     
     
         16 . The BT composition of  claim 15  in which at least one of:
 (a) bismuth-1,2-ethane dithiol (BisEDT) is the BT compound and the at least one antibiotic is selected from amikacin, aztreonam, cefotaxime, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa,    
 (b) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin, cefazolin, cefepime, imipenem, ampicillin/sulbactam, levofloxacin, rifampicin, paromomycin, and sodium pyrithione, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (c) BisEDT is the BT compound and the at least one antibiotic is selected from clindamycin, gatifloxacin, gentamicin, minocycline, vancomycin, cefazolin, nafcillin, rifampin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus epidermidis , or 
 (d) BisEDT is the BT compound and the at least one antibiotic is chloramphenicol, wherein the BT composition is capable of enhanced or synergizing activity against chloramphenicol-resistant  Esherichia coli.    
 
     
     
         17 . The BT composition of  claim 15  in which at least one of:
 (a) BisEDT is the BT compound and the at least one antibiotic is selected from nafcillin and gentamycin, wherein the BT composition is capable of enhanced or synergizing activity against nafcillin-resistant  Staphylococcus aureus,    
 (b) BisEDT is the BT compound and the at least one antibiotic is selected from ampicillin and chloramphenicol, wherein the BT composition is capable of enhanced or synergizing activity against ampicillin-resistant  Esherichia coli,    
 (c) BisEDT is the BT compound and the at least one antibiotic is doxycycline, wherein the BT composition is capable of enhanced or synergizing activity against tetracycline-resistant  Esherichia coli,    
 (d) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin, cefazolin, cefepime, gatifloxacin, and vancomycin, wherein the BT composition is capable of enhanced or synergizing activity against methicillin-resistant  Staphylococcus aureus  (MRSA), 
 (e) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin and nafcillin, wherein the BT composition is capable of enhanced or synergizing activity against methicillin-resistant  Staphylococcus aureus  (MRSA), or 
 (f) BisEDT is the BT compound and the at least one antibiotic is cefepime, wherein the BT composition is capable of enhanced or synergizing activity against cefepime-resistant methicillin-resistant  Staphylococcus aureus  (MRSA). 
 
     
     
         18 . The BT composition of  claim 15  in which:
 BisEDT is the BT compound and the at least one antibiotic is selected from oxacillin, piperacillin, cefuroxime, cefotaxime, cefepime, imipenem, aztreonam, streptomycin, tobramycin, tetracycline, minocycline, ciprofloxacin, levofloxacin, erythromycin, linezolid, phosphomycin, capreomycin, and isoniazid, 
 wherein the BT composition is capable of enhanced or synergizing activity against one or more of  Staphylococcus aureus , methicillin-resistant  Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae , penicillin-resistant  Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia cepacia, Bukholderia multivorans, Acinetobacter baumanii , and  Mycobacterium smegmatis.    
 
     
     
         19 . The BT composition of  claim 15  in which at least one of:
 (a) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and rifampicin is the at least one antibiotic, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (b) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (c) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and cefotaxime is the at least one antibiotic, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.    
 
     
     
         20 . The BT composition of  claim 15  in which at least one of:
 (a) bismuth-pyrithione/2,3-butanedithiol (BisPyr/BDT) is the BT compound and the at least one antibiotic is selected from rifampicin and cefazolin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus , or 
 (b) bismuth-pyrithione/2,3-butanedithiol (BisPyr/BDT) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa.    
 
     
     
         21 . The BT composition of  claim 15  in which at least one of:
 (a) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is selected from rifampicin and cefazolin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (b) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (c) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is cefotzxime, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.    
 
     
     
         22 . The BT composition of  claim 15  in which at least one of:
 (a) bismuth-1,2-ethane dithiol/2-hydroxy-1-propanethiol is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, cefotaxime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (b) bismuth-1,2-ethane dithiol/2-hydroxy-1-propanethiol is the BT compound and the at least one antibiotic is cefotaxime, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.    
 
     
     
         23 . A method for treating or preventing a bacterial infection, comprising contacting bacteria at a site of bacterial infection with a bismuth thiol (BT) composition that comprises a synergizing or enhancing combination of:
 (a) one or more bismuth thiol (BT) compounds; and   (b) (1) at least one antibiotic that exhibits an anti-bacterial effect that is enhanced by said one or more BT compounds, or
 (2) at least one antibiotic with which said one or more BT compounds synergizes to produce an anti-bacterial effect, 
   wherein the anti-bacterial effect is selected from (i) prevention of infection by a bacterial pathogen, (ii) inhibition of cell viability or cell growth of substantially all planktonic cells of a bacterial pathogen, (iii) inhibition of biofilm formation by a bacterial pathogen, and (iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of a bacterial pathogen, and wherein the BT composition does not comprise bismuth-ethanedithiol (BisEDT) and tobramycin as the synergizing or enhancing combination.   
     
     
         24 . The method of  claim 23  wherein in the BT composition at least one of:
 (a) bismuth-1,2-ethane dithiol (BisEDT) is the BT compound and the at least one antibiotic is selected from amikacin, aztreonam, cefotaxime, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa,    
 (b) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin, cefazolin, cefepime, imipenem, ampicillin/sulbactam, levofloxacin, rifampicin, paromomycin, and sodium pyrithione, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (c) BisEDT is the BT compound and the at least one antibiotic is selected from clindamycin, gatifloxacin, gentamicin, minocycline, vancomycin, cefazolin, nafcillin, rifampin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus epidermidis,    
 (d) BisEDT is the BT compound and the at least one antibiotic is chloramphenicol, wherein the BT composition is capable of enhanced or synergizing activity against chloramphenicol-resistant  Esherichia coli,    
 (e) BisEDT is the BT compound and the at least one antibiotic is selected from nafcillin and gentamycin, wherein the BT composition is capable of enhanced or synergizing activity against nafcillin-resistant  Staphylococcus aureus,    
 (f) BisEDT is the BT compound and the at least one antibiotic is selected from ampicillin and chloramphenicol, wherein the BT composition is capable of enhanced or synergizing activity against ampicillin-resistant  Esherichia coli,    
 (g) BisEDT is the BT compound and the at least one antibiotic is doxycycline, wherein the BT composition is capable of enhanced or synergizing activity against tetracycline-resistant  Esherichia coli,    
 (h) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin, cefazolin, cefepime, gatifloxacin, and vancomycin, wherein the BT composition is capable of enhanced or synergizing activity against methicillin-resistant  Staphylococcus aureus  (MRSA), 
 (i) BisEDT is the BT compound and the at least one antibiotic is selected from gentamicin and nafcillin, wherein the BT composition is capable of enhanced or synergizing activity against methicillin-resistant  Staphylococcus aureus  (MRSA), 
 (j) BisEDT is the BT compound and the at least one antibiotic is cefepime, wherein the BT composition is capable of enhanced or synergizing activity against cefepime-resistant methicillin-resistant  Staphylococcus aureus  (MRSA), or 
 (k) BisEDT is the BT compound and the at least one antibiotic is selected from oxacillin, piperacillin, cefuroxime, cefotaxime, cefepime, imipenem, aztreonam, streptomycin, tobramycin, tetracycline, minocycline, ciprofloxacin, levofloxacin, erythromycin, linezolid, phosphomycin, capreomycin, and isoniazid, wherein the BT composition is capable of enhanced or synergizing activity against one or more of  Staphylococcus aureus , methicillin-resistant  Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae , penicillin-resistant  Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia cepacia, Bukholderia multivorans, Acinetobacter baumanii , and  Mycobacterium smegmatis.    
 
     
     
         25 . The method of  claim 23  wherein in the BT composition at least one of:
 (a) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and rifampicin is the at least one antibiotic, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (b) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (c) bismuth-2,3-dimercaptopropanol (BisBAL) is the BT compound and cefotaxime is the at least one antibiotic, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.    
 
     
     
         26 . The method of  claim 23  wherein in the BT composition at least one of:
 (a) bismuth-pyrithione/2,3-butanedithiol (BisPyr/BDT) is the BT compound and the at least one antibiotic is selected from rifampicin and cefazolin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus , or 
 (b) bismuth-pyrithione/2,3-butanedithiol (BisPyr/BDT) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa.    
 
     
     
         27 . The method of  claim 23  wherein in the BT composition at least one of:
 (a) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is selected from rifampicin and cefazolin, wherein the BT composition is capable of enhanced or synergizing activity against  Staphylococcus aureus,    
 (b) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (c) bismuth-pyrithione/1,2-ethane dithiol (BisPyr/EDT) is the BT compound and the at least one antibiotic is cefotzxime, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.    
 
     
     
         28 . The method of  claim 23  wherein in the BT composition at least one of:
 (a) bismuth-1,2-ethane dithiol/2-hydroxy-1-propanethiol is the BT compound and the at least one antibiotic is selected from aztreonam, cefepime, cefotaxime, and piperacillin, wherein the BT composition is capable of enhanced or synergizing activity against  Pseudomonas aeruginosa , or 
 (b) bismuth-1,2-ethane dithiol/2-hydroxy-1-propanethiol is the BT compound and the at least one antibiotic is cefotaxime, wherein the BT composition is capable of enhanced or synergizing activity against  Klebsiella pneumoniae.