Antibacterial Use of Halogenated Salicylanilides

Abstract

The invention relates to a halogenated salicylanilide selected from closantel, rafoxanide, oxyclozanide and niclosamide and derivatives thereof including salts, hydrates, esters and the like for use in the topical treatment or prevention of infections caused by Gram-positive bacteria such as Staphylococcus , in particular Staphylococcus aureus , and Streptococcus , in particular Streptococcus pyogenes . Gram positive bacteria treated with the halogenated salicylanilides exhibit a very low frequency of appearance of resistant mutants compared to commonly used topical antibiotics.

1 - 35 . (canceled) 
     
     
         36 . A method of treating a disease or infection caused by Gram positive bacteria in a subject, the method comprising topically administering to the subject an effective amount of a halogenated salicylanilide selected from niclosamide or a salt or hydrate thereof;
 wherein the Gram positive bacteria is not a propionibacteria.   
     
     
         37 . The method according to  claim 36 , wherein the Gram-positive bacteria develops spontaneous mutations which confer resistance to the halogenated salicylanilide at a frequency of less than 10 −6  at the MIC of the halogenated salicylanilide to the Gram positive bacteria. 
     
     
         38 . The method according to  claim 37 , wherein the Gram-positive bacteria develops spontaneous mutations which confer resistance to the halogenated salicylanilide at a frequency of less than 4×10 −9  at the MIC of the halogenated salicylanilide to the Gram positive bacteria. 
     
     
         39 . The method according to  claim 36 , wherein the Gram-positive bacteria wherein the Gram positive bacteria is selected from  Staphylococcus  spp or  Streptococcus  spp. 
     
     
         40 . The method according to  claim 36 , wherein the infection or disease is selected from the group consisting of impetigo, infected eczema, rosacea, bacterial conjunctivitis, atopic dermatitis and related infections, sycosis barbae, superficial folliculitis, paronychia erythrasma, secondary infected dermatoses, carbuncles, furonculosis, ecthyma, cellulitis, erysipelas, necrotising fasciitis, secondary skin infections of wounds, dermatitis, scabies and diabetic ulcers. 
     
     
         41 . The method according to  claim 36 , wherein the infection or disease is selected from the group consisting of impetigo, infected eczema, rosacea, bacterial conjunctivitis and atopic dermatitis. 
     
     
         42 . The method according to  claim 36 , wherein the topical administration is for 2 weeks or less. 
     
     
         43 . The method according to  claim 36 , wherein the halogenated salicylanilide is comprised in a formulation the components of which are selected such that the formulation provides a local pH of less than 6 at the site of infection. 
     
     
         44 . The method according to  claim 36 , wherein the subject is a human. 
     
     
         45 . A method of treating or preventing a disease or infection caused by Gram positive bacteria in a subject, the method comprising topically administering to the subject an effective amount of a halogenated salicylanilide selected from the group consisting of closantel, rafoxanide, oxyclozanide and niclosamide or a salt or hydrate or ester thereof; wherein the Gram-positive bacteria is resistant to a drug selected from fusidic acid, mupirocin and retapamulin. 
     
     
         46 . The method according to  claim 45 , wherein the Gram positive bacteria is not a propionibacteria. 
     
     
         47 . The method according to  claim 45 , wherein the Gram-positive bacteria develops spontaneous mutations which confer resistance to the halogenated salicylanilide at a frequency of less than 10 −6  at the MIC of the halogenated salicylanilide to the Gram positive bacteria. 
     
     
         48 . The method according to  claim 45 , wherein the Gram-positive bacteria develops spontaneous mutations which confer resistance to the halogenated salicylanilide at a frequency of less than 10 −9  at the MIC of the halogenated salicylanilide to the Gram positive bacteria. 
     
     
         49 . The method according to  claim 45 , wherein the Gram-positive bacteria wherein the Gram positive bacteria is selected from  Staphylococcus  spp or  Streptococcus  spp. 
     
     
         50 . The method according to  claim 45 , wherein the infection or disease is selected from the group consisting of impetigo, infected eczema, rosacea, bacterial conjunctivitis, atopic dermatitis and related infections, sycosis barbae, superficial folliculitis, paronychia erythrasma, secondary infected dermatoses, carbuncles, furonculosis, ecthyma, cellulitis, erysipelas, necrotising fasciitis, secondary skin infections of wounds, dermatitis, scabies and diabetic ulcers. 
     
     
         51 . The method according to  claim 45 , wherein the infection or disease is selected from the group consisting of impetigo, infected eczema, rosacea, bacterial conjunctivitis and atopic dermatitis. 
     
     
         52 . The method according to  claim 45 , wherein the topical administration is for 2 weeks or less. 
     
     
         53 . The method according to  claim 45 , wherein the halogenated salicylanilide is comprised in a formulation the components of which are selected such that it provides a local pH of less than 6 at the site of infection. 
     
     
         54 . The method according to  claim 45 , wherein the salicylanilide is niclosamide or a salt or hydrate thereof. 
     
     
         55 . (canceled) 
     
     
         56 . A method of treating or preventing or eliminating bacterial colonization by Gram positive bacteria in a subject, the method comprising topically administering to the subject an effective amount a halogenated salicylanilide selected from the group consisting of closantel, rafoxanide, oxyclozanide and niclosamide, or a salt or hydrate or ester thereof. 
     
     
         57 . The method of  claim 56  wherein the halogenated salicylanilide is topically administered to the subject prior to performing a surgical procedure on the subject. 
     
     
         58 . The method of  claim 56 , wherein the halogenated salicylanilide is administered to the nose of the subject, either intranasally or to the external skin of the nose. 
     
     
         59 . The method of  claim 56 , wherein the halogenated salicylanilide is topically administered to the nose of the subject prior to performing a surgical procedure on the nose or face of the subject. 
     
     
         60 . The method of  claim 36 , wherein the subject is an animal. 
     
     
         61 . The method of  claim 45 , wherein the subject is a human. 
     
     
         62 . The method of  claim 45 , wherein the subject is an animal. 
     
     
         63 . The method of  claim 56 , wherein the subject is a human. 
     
     
         64 . A topical pharmaceutical formulation comprising a halogenated salicylanilide selected from the group consisting of closantel, rafoxanide, oxyclozanide and niclosamide and derivatives thereof including salts, hydrates and esters, wherein the components of the formulation are selected such that it provides a local pH of less than 6 at when topically applied to a site of infection in a subject.