TREATING INFECTIONS WITH CEFTOLOZANE/TAZOBACTAM IN SUBJECTS HAVING IMPAIRED RENAL FUNCTION
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.
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.