Methods for treating intrapulmonary infections

Abstract

This disclosure relates to the treatment of intrapulmonary bacterial infections, including treatment of nosocomial pneumonia lung infections with pharmaceutical compositions containing the cephalosporin ceftolozane.

1 . A method of treating an infection in the lung, the method comprising repeatedly intravenously administering a pharmaceutical composition comprising a total of about 2.0 g of ceftolozane to a subject in need thereof every 8 hours. 
     
     
         2 . The method of  claim 1 , wherein the pharmaceutical composition further comprises tazobactam. 
     
     
         3 . The method of  claim 1 , wherein the infection is pneumonia. 
     
     
         4 . The method of  claim 1 , wherein the infection is nosocomial pneumonia. 
     
     
         5 . The method of  claim 1 , wherein the infection is ventilator acquired pneumonia. 
     
     
         6 . The method of  claim 1 , wherein the infection is hospital acquired pneumonia. 
     
     
         7 . The method of  claim 1 , wherein the infection comprises one or more pathogens selected from the group consisting of:  Pseudomonas aeruginosa, E. coli  and  K. pneumonia.    
     
     
         8 . The method of  claim 1 , wherein the infection comprises a pathogen with a minimum inhibitory concentration for CXA-201 of less than or equal to 8 micrograms/mL. 
     
     
         9 . The method of  claim 1 , wherein the method comprises administering the ceftolozane as a 60-minute infusion. 
     
     
         10 . The method of  claim 1 , wherein the ceftolozane is a hydrogen sulfate salt. 
     
     
         11 . The method of  claim 1 , wherein the ceftolozane is (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid. 
     
     
         12 . The method of  claim 2 , wherein the method further comprises one or more of the following:
 a. the infection comprises a pathogen with a minimum inhibitory concentration for CXA-201 of less than or equal to 8 micrograms/mL;   b. the infection comprises one or more pathogens selected from the group consisting of:  Pseudomonas aeruginosa, E. coli  and  K. pneumonia;      c. the infection is selected from the group consisting of: nosocomial pneumonia, ventilator acquired pneumonia and hospital acquired pneumonia;   d. the ceftolozane is administered every 8 hours with 1.0 g tazobactam;   e. the ceftolozane and tazobactam are administered as a 60 minute infusion; and   f. the ceftolozane is selected from the group consisting of: (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-ethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid and a hydrogen sulfate salt.   
     
     
         13 . A method of treating an infection selected from the group consisting of: nosocomial pneumonia, ventilator acquired pneumonia and hospital acquired pneumonia, the method comprising repeatedly intravenously administering 2.0 g of ceftolozane and 1.0 g of tazobactam to a subject in need thereof every 8 hours. 
     
     
         14 . The method of  claim 13 , wherein the infection comprises a pathogen with a minimum inhibitory concentration for CXA-201 of less than or equal to 8 micrograms/mL. 
     
     
         15 . The method of  claim 13 , wherein the method comprises administering the ceftolozane as a 60-minute infusion. 
     
     
         16 . The method of  claim 13 , wherein the ceftolozane is a hydrogen sulfate salt. 
     
     
         17 . The method of  claim 13 , wherein the ceftolozane is administered in the pharmaceutical composition as (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid. 
     
     
         18 . The method of  claim 13 , wherein the method further comprises one or more of the following:
 a. the infection comprises a pathogen with a minimum inhibitory concentration for CXA-201 of less than or equal to 8 micrograms/mL;   b. the infection comprises one or more pathogens selected from the group consisting of:  Pseudomonas aeruginosa, E. coli  and  K. pneumonia;      c. the ceftolozane is administered every 8 hours with 1.0 g tazobactam;   d. the ceftolozane and tazobactam are administered as a 60 minute infusion; and   e. the ceftolozane is selected from the group consisting of: (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-ethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid and a hydrogen sulfate salt.   
     
     
         19 . A method of treating an infection in the lung, the method comprising repeatedly intravenously administering a compound of formula (I): 
       
         
           
           
               
               
           
         
         to the subject every 8 hours in a dose amount effective to provide a concentration of ceftolozane in the epithelial lining fluid (ELF) of at least 8 micrograms/mL for about 60% of the dosing interval between doses. 
       
     
     
         20 . The method of  claim 19 , wherein the method further comprises administering tazobactam with the compound formula (I). 
     
     
         21 . The method of  claim 20 , comprising administering the compound of formula (I) in a dose amount providing 2.0 g of the ceftolozane compound (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid. 
     
     
         22 . The method of  claim 21 , wherein the compound of the ceftolozane compound and the tazobactam are administered together in a 2:1 weight ratio. 
     
     
         23 . The method of  claim 22 , wherein the ceftolozane and tazobactam are administered as a 60-minute infusion. 
     
     
         24 . The method of  claim 22 , wherein the infection comprises one or more pathogens selected from the group consisting of:  Pseudomonas aeruginosa, E. coli  and  K. pneumonia.    
     
     
         25 . A method of treating an infection selected from the group consisting of: nosocomial pneumonia, ventilator acquired pneumonia and hospital acquired pneumonia, the method comprising repeatedly intravenously administering a pharmaceutical composition comprising 2.0 g of (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureidol-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-RZ)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid to a subject in need thereof every 8 hours. 
     
     
         26 . The method of  claim 25 , wherein the pharmaceutical composition further comprises tazobactam. 
     
     
         27 . The method of  claim 26 , wherein the method comprises administering about 1.0 g of the tazobactam in the pharmaceutical composition. 
     
     
         28 . The method of  claim 27 , wherein the infection comprises one or more pathogens selected from the group consisting of:  Pseudomonas aeruginosa, E. coli  and  K. pneumonia.    
     
     
         29 . The method of  claim 27 , wherein the pharmaceutical composition is administered in a 60-minute infusion. 
     
     
         30 . The method of  claim 25 , wherein the infection comprises  Pseudomonas aeruginosa.