Treating infections with ceftolozane/tazobactam in subjects having impaired renal function

Abstract

Disclosed are methods of administering cephalosporin/tazobactam to human patients with end stage renal disease undergoing hemodialysis and suffering from a complicated intra-abdominal infection or a complicated urinary tract infection.

What is claimed is: 
     
         1 . A method of treating an infection in a patient having an estimated creatinine clearance of up to about 50 mL/min, comprising administering to the patient in need thereof a dose of ceftolozane and tazobactam in a 2:1 weight ratio between ceftolozane active and tazobactam active, on two or more successive days of treatment, in amounts and at a dosing interval effective to provide at least an unbound concentration of ceftolozane of at least 8 micrograms/mL for at least 30% of the time between successive treatment days and unbound tazobactam of about 1 microgram/mL for at least 20% of the time and about 0.5 microgram/mL for about or higher than 50% of the time. 
     
     
         2 . The method of  claim 1 , wherein the patient has an estimated CrCL of 15 to 29 mL/min and a total of 375 mg of the ceftolozane and tazobactam are administered every 8 hours. 
     
     
         3 . The method of  claim 1 , wherein a total of 250 mg ceftolozane active and 125 mg tazobactam active is intravenously administered every 8 hours to the patient having a creatinine clearance of 15-29 ml/min for treating an infection selected from the group consisting of a complicated intra-abdominal infection (cIAI) and a complicated urinary tract infection (cUTI). 
     
     
         4 . The method of  claim 1 , wherein the dose is selected from the table below based on the estimated creatinine clearance (CrCL) of the patient 
       
         
           
                 
                 
               
                     
                 
                   Estimated CrCL 
                     
                 
                   (mL/min) 
                   Recommended Dosage Regimen for CXA-201 
                 
                     
                 
                   30 to 50 
                   750 mg IV every 8 hours 
                 
                   15 to 29 
                   375 mg IV every 8 hours 
                 
                   End stage 
                   A single loading dose of 750 mg followed by a 150 mg 
                 
                   Renal Disease 
                   maintenance dose administered IV every 8 hours for 
                 
                   (ESRD) on 
                   the remainder of the treatment period (on 
                 
                   hemodialysis 
                   hemodialysis days, the dose should be 
                 
                   (HD) 
                   administered at the earliest possible time following 
                 
                     
                   completion of dialysis) 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . The method of  claim 4 , wherein the infection is selected from the group consisting of a complicated intra-abdominal infection (cIAI) and a complicated urinary tract infection (cUTI). 
     
     
         6 . The method of  claim 5 , wherein each dose of ceftolozane and tazobactam is administered at the same or different durations of 1-4 hours each. 
     
     
         7 . The method of  claim 5 , wherein each dose is administered in a 1-hour intravenous infusion. 
     
     
         8 . The method of  claim 4 , further comprising doubling the dose administered after the patient receives each hemodialysis. 
     
     
         9 . The method of  claim 5 , wherein the infection is a complicated intra-abdominal infection, and the method further comprises administering to the patient a therapeutically effective amount of metronidazole. 
     
     
         10 . The method of  claim 9 , wherein the complicated intra-abdominal infection is caused by a microorganism selected from the group consisting of:  Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Escherichia coli  CTX-M-14 extended spectrum beta-lactamase producing strains,  Escherichia coli  CTX-M-15 extended spectrum beta-lactamase producing strains,  Klebsiella oxytoca, Klebsiella pneumonia, Klebsiella pneumoniae  CTX-M-15 extended spectrum beta-lactamase producing strains,  Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Streptococcus anginosus, Streptococcus constellatus , and  Streptococcus salivarius.    
     
     
         11 . The method of  claim 5 , wherein the complicated urinary tract infection is caused by one of the following Gram-negative microorganisms:  Escherichia coli, Escherichia coli  levofloxacin resistant strains,  Escherichia coli  CTX-M-14 extended spectrum beta-lactamase producing strains,  Escherichia coli  CTX-M-15 extended spectrum beta-lactamase producing strains,  Klebsiella pneumoniae, Klebsiella pneumonia  levofloxacin resistant strains,  Klebsiella pneumonia  CTX-M-15 extended spectrum beta-lactamase producing strains,  Proteus mirabilis  or  Pseudomonas aeruginosa.    
     
     
         12 . The method of  claim 5 , wherein the ceftolozane active is provided as ceftolozane sulfate and the tazobactam active is provided as tazobactam sodium. 
     
     
         13 . The method of  claim 5 , wherein the pharmaceutical composition is obtained by reconstituting a mixture comprising a total of 1000 mg ceftolozane active and 500 mg tazobactam active with sterile water for injection or 0.9% Sodium Chloride for injection, USP to form a reconstituted solution and withdrawing a portion of the reconstituted solution and adding it to an infusion bag containing 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP. 
     
     
         14 . The method of  claim 1 , wherein the doses are selected from the group consisting of:
 a) a loading dose of 600 mg ceftolozane active and 300 mg tazobactam active, and a maintenance dose of 300 mg ceftolozane active and 150 mg tazobactam active;   b) a loading dose of 500 mg ceftolozane active and 250 mg tazobactam active, and a maintenance dose of 300 mg ceftolozane active and 150 mg tazobactam active;   c) a loading dose of 500 mg ceftolozane active and 250 mg tazobactam active, and a maintenance dose of 100 mg ceftolozane active and 50 mg tazobactam active;   d) a loading dose of 400 mg ceftolozane active and 200 mg tazobactam active, and a maintenance dose of 100 mg ceftolozane active and 50 mg tazobactam active;   e) 300 mg Ceftolozane active and 150 mg tazobactam active;   f) 100 mg ceftolozane active and 50 mg tazobactam active.   
     
     
         15 . The method of  claim 14 , where each dose is administered in a 1-hour intravenous infusion. 
     
     
         16 . The method of  claim 1 , wherein the doses are selected from the group consisting of:
 a) a loading dose of 600 mg ceftolozane active and 300 mg tazobactam active, and a maintenance dose of 300 mg ceftolozane active and 150 mg tazobactam active, all 1-hour intravenous infusion;   b) a loading dose of 500 mg ceftolozane active and 250 mg tazobactam active, and a maintenance dose of 300 mg ceftolozane active and 150 mg tazobactam active, all 1-hour intravenous infusion;   c) a loading dose of 500 mg ceftolozane active and 250 mg tazobactam active, and a maintenance dose of 100 mg ceftolozane active and 50 mg tazobactam active, all 1-hour intravenous infusion;   d) a loading dose of 400 mg ceftolozane active and 200 mg tazobactam active, and a maintenance dose of 100 mg ceftolozane active and 50 mg tazobactam active;   e) 300 mg Ceftolozane active and 150 mg tazobactam active, 1-hour intravenous infusion;   f) 100 mg ceftolozane active and 50 mg tazobactam active, 1-hour intravenous infusion; and   g) 300 mg ceftolozane active and 150 mg tazobactam active, 4-hour intravenous infusion.   
     
     
         17 . A method of treating an overdose in a patient by reducing the concentration of ceftolozane in the blood of a subject comprising subjecting the blood of the patient to hemodialysis for a period of 3-4 hours to reduce the exposure of ceftolozane in the blood of the subject by 66%. 
     
     
         18 . A method of treating an infection in a patient having an estimated creatinine clearance of about 15-29 mL/min, comprising intravenously administering to the patient in need thereof a dose of 375 mg of ceftolozane and tazobactam in a 2:1 weight ratio between ceftolozane active and tazobactam active, every 8 hours. 
     
     
         19 . The method of  claim 18 , wherein the infection is selected from the group consisting of a complicated intra-abdominal infection (cIAI) and a complicated urinary tract infection (cUTI). 
     
     
         20 . The method of  claim 19 , wherein the infection is a complicated intra-abdominal infection, and the method further comprises administering to the patient a therapeutically effective amount of metronidazole.