Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses
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Publication Number
US-9028878-B2
Publication Date
2015-05-12
Expiration Date
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.
Core Innovation
The invention relates to protecting a natural surface against one or more of a bacterial pathogen, a fungal pathogen and a viral pathogen by contacting the surface with an effective amount of a BT composition. The BT composition includes a plurality of solid microparticles that exhibit a unimodal size distribution, with substantially all microparticles having a volumetric mean diameter from about 0.4 µm to about 5 µm. The BT composition comprises a bismuth-thiol (BT) compound having bismuth or a bismuth salt and a thiol-containing compound, and the BT compound is not micronized, milled or subjected to super-critical fluid processing.
The BT composition comprises at least one antibiotic compound capable of acting synergistically with, or enhancing, the BT compound. The antibiotic compound includes an antibiotic selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, doxycycline, clindamycin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, and the aminoglycoside antibiotic is selected from amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, and apramycin. A related aspect provides an antiseptic composition and treatment method for natural surfaces containing bacterial biofilm, using the same unimodal, specified-diameter BT microparticles and synergistic antibiotic combinations.
The invention also includes conditions directed to inhibiting cell viability or cell growth of substantially all planktonic cells, inhibiting biofilm formation, and inhibiting biofilm viability or biofilm growth of substantially all biofilm-form cells. The treatment method further includes identifying whether a bacterial infection comprises gram positive bacteria, gram negative bacteria, or both, and administering formulations comprising BT compounds with antibiotic combinations that include rifamycin and/or amikacin depending on the gram status.
Claims Coverage
The independent claims cover methods and compositions for protection of natural surfaces from pathogens and treatment of bacterial biofilm using BT compositions defined by unimodal solid microparticle size distributions plus bismuth-thiol chemistry, combined with synergistic antibiotic compounds. Across the independent claims, inventive features include pathogen- and biofilm-targeted outcomes, specific microparticle size/distribution constraints, exclusion of certain BT processing methods, and defined antibiotic synergy or enhancement pairings with gram-status-guided selection.
Unimodally sized solid BT microparticles with defined diameter range
BT composition comprises a plurality of solid microparticles exhibiting a unimodal size distribution on a particle size analyzer, with substantially all microparticles having a volumetric mean diameter from about 0.4 µm to about 5 µm.
Bismuth-thiol compound not processed by micronization, milling, or super-critical fluid processing
BT composition comprises a bismuth-thiol (BT) compound comprising bismuth or a bismuth salt and a thiol-containing compound, where the BT compound has not been micronized, milled or subjected to super-critical fluid processing.
Synergistic or enhancement antibiotic included with BT composition
BT composition comprises at least one antibiotic compound capable of acting synergistically with, or enhancing, the BT compound, where the antibiotic compound is selected from methicillin, vancomycin, nafcillin, gentamicin, ampicillin, chloramphenicol, doxycycline, clindamycin, gatifloxacin, cefazolin and an aminoglycoside antibiotic, with the aminoglycoside selected from the listed group including amikacin and gentamicin.
Protecting a natural surface to prevent infection and inhibit planktonic and biofilm growth/viability
Method contacting the natural surface with an effective amount of the BT composition under conditions and for a time sufficient for one or more of preventing infection by bacterial, fungal and/or viral pathogens; inhibiting cell viability or cell growth of substantially all planktonic cells; inhibiting biofilm formation; and inhibiting biofilm viability or biofilm growth of substantially all biofilm-form cells.
Antiseptic composition for treating natural surfaces containing bacterial biofilm
Antiseptic composition for treating a natural surface containing bacterial biofilm comprising at least one BT composition with unimodal solid microparticles in the specified diameter range together with at least one antibiotic compound capable of acting synergistically with, or enhancing, the BT compound.
Gram-status guided administration with rifamycin and/or amikacin
Method treating a natural surface containing bacterial biofilm that includes identifying whether the bacterial infection comprises gram positive bacteria, gram negative bacteria, or both, and administering a formulation comprising effective amounts of at least one BT compound and antibiotics including rifamycin and/or amikacin depending on the gram status.
Across the independent claims, the inventive focus is the use of a BT composition defined by unimodally sized solid microparticles within a specified volumetric mean diameter range, containing a bismuth-thiol compound with bismuth or a bismuth salt and a thiol-containing compound that is not micronized, milled, or super-critically processed. The BT microparticles are combined with antibiotics capable of synergy or enhancement, and the methods target prevention of infection and inhibition of planktonic and biofilm formation, viability, or growth, including antiseptic compositions for bacterial biofilm and gram-status guided formulations with rifamycin and/or amikacin.
Stated Advantages
Prevention of infection of the surface by bacterial, fungal or viral pathogens.
Inhibition of cell viability or cell growth of substantially all planktonic cells of the bacterial, fungal or viral pathogen.
Inhibition of biofilm formation by the bacterial, fungal or viral pathogen.
Inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the bacterial, fungal or viral pathogen.
Treating a natural surface containing bacterial biofilm using an antiseptic composition comprising BT microparticles and a synergistic or enhancing antibiotic.
Enhances cefazolin activity to reduce S. aureus infection in injured bone/hardware when BT is combined with systemic cefazolin.
Documented Applications
Protecting a natural surface against bacterial, fungal and viral pathogens by contacting the surface with the BT composition under conditions sufficient for infection prevention and inhibition of planktonic and biofilm outcomes.
Treating a natural surface that contains bacterial biofilm by administering a formulation comprising BT compositions and synergistic or enhancing antibiotics, including formulations guided by gram positive/gram negative status.
Treating a natural surface containing bacterial biofilm using an antiseptic composition comprising a BT composition with unimodal solid microparticles and an antibiotic capable of acting synergistically with, or enhancing, the BT compound.
In vivo use in a rat femur critical defect model for an open fracture infection, where BT combined with systemic cefazolin enhances cefazolin activity and reduces S. aureus infection in injured bone/hardware.
In vitro and in vivo evaluation of antimicrobial efficacy and synergy/enhancement of microparticulate BT BisEDT/BT analogs with antibiotics against multiple bacteria using checkerboard/FICI analysis.
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