Therapeutic combination of daptomycin and protein synthesis inhibitor antibiotic, and methods of use

Abstract

A therapeutic combination comprises an antibacterially effective amount of daptomycin, and an amount of protein synthesis inhibitor antibiotic effective to prevent the development of daptomycin non-susceptibility in bacteria. Related combination therapies and methods are also included.

What is claimed is: 
     
         1 . A therapeutic combination comprising
 an antibacterially effective amount of daptomycin, and   an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, effective to prevent the development of daptomycin non-susceptible bacterial strains   
       
         
           
           
               
               
           
         
       
       wherein,
 Het is tetrazolyl or oxadiazolyl; 
 ring A is unsubstituted or has at least one fluorine substituent; 
 R 7  is H, PO(OH) 2  or PO(O) 2   −2 (M + ) 2 , wherein M +  is a metal cation; 
 R 3  is H or unsubstituted C 1-4  alkyl group. 
 
     
     
         2 . The therapeutic combination of  claim 1 , wherein the compound of Formula (I) is 
       
         
           
           
               
               
           
         
         wherein at least one of R 1  and R′  1  is fluorine; and 
         wherein the metal cation is Na + . 
       
     
     
         3 . The therapeutic combination of  claim 1 ,
 wherein the compound of Formula (I) is   
       
         
           
           
               
               
           
         
       
       wherein the metal cation is Na + . 
     
     
         4 . The therapeutic combination of  claim 1 , wherein the compound of Formula (I) is 
       
         
           
           
               
               
           
         
         wherein the metal cation is Na + . 
       
     
     
         5 . The therapeutic combination of  claim 1 ,
 wherein the combination of the daptomycin and the compound do not act synergistically to enhance antibacterial potency, wherein the FICI is >0.50.   
     
     
         6 . The therapeutic combination of  claim 1 ,
 wherein each component of the therapeutic combination is formulated for separate or sequential administration.   
     
     
         7 . The therapeutic combination of  claim 4 ,
 wherein each component of the therapeutic combination is formulated for separate or sequential administration.   
     
     
         8 . The therapeutic combination of  claim 1 ,
 wherein the therapeutic combination is formulated for simultaneous administration.   
     
     
         9 . The therapeutic combination of  claim 4 ,
 wherein the therapeutic combination is formulated for simultaneous administration.   
     
     
         10 . The therapeutic combination of  claim 1 , wherein the dosage of the compound of Formula (I) is no more than about 5 mg/kg. 
     
     
         11 . The therapeutic combination of  claim 4 , wherein the dosage of the compound of Formula (I) is no more than about 4 mg/kg. 
     
     
         12 . The therapeutic combination of  claim 4 , wherein the dosage of the compound of Formula (I) is no more than about 3 mg/kg. 
     
     
         13 . The therapeutic combination of  claim 4 , wherein the dosage of the compound of Formula (I) is no more than about 2 mg/kg. 
     
     
         14 . The therapeutic combination of  claim 4 , wherein the dosage of the compound of Formula (I) is no more than about 1 mg/kg. 
     
     
         15 . The therapeutic combination of  claim 4 , wherein the dosage of the compound of Formula (I) is no more than about 0.5 mg/kg. 
     
     
         16 . The therapeutic combination of  claim 1 , wherein the unit dose of the compound of Formula (I) is 200 mg. 
     
     
         17 . The therapeutic combination of  claim 4 , wherein the unit dose of the compound of Formula (I) is 200 mg. 
     
     
         18 . A method of treating a bacterial infection in a subject, comprising administering to the subject the therapeutic combination of  claim 1 . 
     
     
         19 . A method of treating a bacterial infection in a subject, comprising administering to the subject the therapeutic combination of  claim 4 . 
     
     
         20 . The method of  claim 18 , wherein the bacterially infected subject has a bacterial infection that requires treatment for greater than two weeks. 
     
     
         21 . The method of  claim 19 , wherein the bacterially infected subject has a bacterial infection that requires treatment for greater than two weeks. 
     
     
         22 . The method of  claim 18 , wherein the bacterial infection is a bacterial skin and skin structure infection or bacteremia. 
     
     
         23 . The method of  claim 19 , wherein the bacterial infection is a bacterial skin and skin structure infection or bacteremia. 
     
     
         24 . The method of  claim 18 , wherein the subject has endocarditis. 
     
     
         25 . The method of  claim 19 , wherein the subject has endocarditis. 
     
     
         26 . The method of  claim 21 , wherein the administering step further comprises administering the therapeutic combination for at least two weeks. 
     
     
         27 . The method of  claim 19 , wherein the administering step further comprises administering the same amount of daptomycin until the infection is resolved. 
     
     
         28 . The method of  claim 19 , wherein the bacterium is a gram-positive bacterium. 
     
     
         29 . The method of  claim 19 , wherein the bacterium is selected from the group consisting of  Staphylococcus, Streptococcus, Enterococcus, Clostridium, Corynebacterium,  and  Peptostreptococcus.    
     
     
         30 . The method of  claim 19 , wherein the bacterium is  Staphylococcus.