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 - 14 . (canceled) 
     
     
         15 . A bismuth-thiol composition, comprising a plurality of microparticles that comprise a bismuth-thiol (BT) compound, substantially all of said microparticles having a volumetric mean diameter of from 0.4 μm to 5 μm, wherein the BT compound comprises bismuth or a bismuth salt in association with 1,2-ethane dithiol. 
     
     
         16 . The bismuth-thiol composition of  claim 15 , wherein the BT compound comprises bismuth in association with 1,2-ethane dithiol. 
     
     
         17 . The bismuth-thiol composition of  claim 16 , wherein the BT compound comprises bismuth covalently associated with 1,2-ethane dithiol. 
     
     
         18 . The bismuth-thiol composition of  claim 15 , wherein the BT compound is BisEDT. 
     
     
         19 . The composition of  claim 18 , wherein at least 80% of the microparticles have a VMD of 0.4 μm to 5 μm. 
     
     
         20 . The composition of  claim 18 , wherein at least 80% of the microparticles have a VMD of 0.7 μm to 4 μm. 
     
     
         21 . The composition of  claim 18 , wherein at least 80% of the microparticles have a VMD of 1.0 μm to 3 μm. 
     
     
         22 . The composition of  claim 18 , wherein at least 90% of the microparticles have a VMD of 0.4 μm to 5 μm. 
     
     
         23 . The composition of  claim 18 , wherein at least 95% of the microparticles have a VMD of 0.4 μm to 5 μm. 
     
     
         24 . The composition of  claim 18 , wherein the microparticles have a peak VMD of about 1.3 microns. 
     
     
         25 . The composition of  claim 22 , wherein the size distribution of said microparticles is unimodal. 
     
     
         26 . The composition of  claim 18 , wherein the composition further comprises methylcellulose, sodium chloride and polysorbate. 
     
     
         27 . The composition of  claim 26 , wherein the composition is a liquid suspension. 
     
     
         28 . 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 the BT composition of  claim 15  under conditions and for a time sufficient for one or more of:   (i) treating an 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.   
     
     
         29 . A method for treating a bacterial infection resulting from an orthopedic procedure, comprising administering to a subject in need thereof with an effective amount of the BT composition of  claim 15 . 
     
     
         30 . The method of  claim 29 , wherein the bacterial infection comprises a biofilm. 
     
     
         31 . The method of  claim 29 , wherein the bacterial infection comprises one or more species of gram-negative bacteria. 
     
     
         32 . The method of  claim 29 , wherein the bacterial infection comprises one or more species of gram-positive bacteria. 
     
     
         33 . The method of  claim 29 , wherein the bacterial infection comprises one or more species of antibiotic-resistant bacteria. 
     
     
         34 . The method of  claim 33 , wherein the antibiotic is selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, doxycycline and tobramycin. 
     
     
         35 . The method of  claim 29 , wherein the bacterial infection comprises one or more of  Staphylococcus aureus , methicillin-resistant  S. aureus, Staphylococcus epidermidis , 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, 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  or  Acinetobacter baumannii.    
     
     
         36 . The method of  claim 29 , wherein treating the bacterial infection comprises inhibiting viability or growth of the bacteria. 
     
     
         37 . The method of  claim 29 , wherein the orthopedic procedure comprises orthopedic surgery, orthopedic therapy, arthroplasty or orthodontic therapy. 
     
     
         38 . The method of  claim 37 , wherein the orthopedic procedure is orthopedic surgery. 
     
     
         39 . The method of  claim 29 , wherein administering comprises local administration of the composition in on or the surgery site. 
     
     
         40 . The method of  claim 29 , wherein the bismuth-thiol compound is BisEDT. 
     
     
         41 . The method of  claim 29 , wherein the microparticles have not been micronized, milled, or subjected to supercritical fluid processing.