METHODS FOR TREATING INTRAPULMONARY INFECTIONS
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 a patient in need thereof, the method comprising intravenously administering to the patient a pharmaceutical composition in a dose of about 1 gram of ceftolozane active and 0.5 gram of tazobactam active repeatedly administered every 8 hours, with each dose administration providing a mean plasma Area Under Curve (AUC,0-t) of about 158.5 micrograms hour/ml of ceftolozane and a mean plasma Area Under Curve (AUC,0-t) of about 19.3 micrograms hour/ml of tazobactam to treat the infection in said patient, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval.
2 . The method of claim 1 , wherein the ceftolozane is administered in an amount effective to provide a concentration of at least 8 micrograms/mL in the blood of the patient for at least 60% of the interval between doses.
3 . The method of claim 1 , wherein the pharmaceutical composition is repeatedly administered as a combined ceftolozane/tazobactam preparation.
4 . The method of claim 1 , wherein the ceftolozane and the tazobactam are each separately administered to the patient.
5 . The method of claim 1 , wherein the pharmaceutical composition is repeatedly administered as a 60-minute infusion every 8 hours.
6 . The method of claim 5 , wherein the pharmaceutical composition is repeatedly administered as a combined ceftolozane/tazobactam preparation.
7 . The method of claim 6 , wherein the ELF penetration ratio of the pharmaceutical composition is about 0.48 for ceftolozane and about 0.44 for tazobactam.
8 . The method of claim 1 , wherein the ceftolozane and tazobactam are administered for a 10 day course of treatment.
9 . The method of claim 1 , wherein the infection comprises Pseudomonas aeruginosa.
10 . The method of claim 1 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt.
11 . The method of claim 1 , wherein the ceftolozane is (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein the infection is a complicated intra-abdominal infection.
13 . The method of claim 1 , wherein the infection is a complicated urinary tract infection.
14 . The method of claim 1 , wherein the tazobactam and the ceftolozane are the only antibiotics administered to treat said infection.
15 . A method of treating an infection in a patient in need thereof, the method comprising intravenously administering to the patient a pharmaceutical composition in a single dose of about 1 gram of ceftolozane active and 0.5 gram of tazobactam active repeatedly administered every 8 hours, wherein the pharmaceutical composition is administered in an amount effective to provide a ceftolozane concentration of at least 8 micrograms/mL in the blood of the patient for at least 60% of the interval between doses.
16 . The method of claim 15 , wherein the pharmaceutical composition is administered to the patient every 8 hours as a 60-minute infusion to produce in said patient an epithelial lining fluid (ELF) Area Under Curve (AUC,0-t) of about 75.1 micrograms hour/ml of ceftolozane and a mean ELF Area Under Curve (AUC,0-t) of about 8.5 micrograms hour/ml of tazobactam to treat the infection in said patient, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval.
17 . The method of claim 15 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt.
18 . The method of claim 15 , wherein the ceftolozane is ((6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.
19 . The method of claim 15 , wherein the pharmaceutical composition dose is repeatedly administered as a combined ceftolozane/tazobactam preparation.
20 . The method of claim 15 , wherein the pharmaceutical composition is repeatedly administered as a 60-minute infusion every 8 hours.
21 . The method of claim 15 , wherein the infection is a complicated intra-abdominal infection.
22 . The method of claim 15 , wherein the infection is a complicated urinary tract infection.
23 . A method of treating an infection in a subject comprising the step of intravenously administering ceftolozane and tazobactam in about a 2:1 weight ratio every 8 hours as a 1 hour infusion to a subject in need thereof.
24 . The method of claim 23 , comprising administering to a subject a dose with a total of 0.5 grams of tazobactam active and a total of 1 gram of ceftolozane active.
25 . The method of claim 23 , comprising administering a total of 3 g of ceftolozane per day and 1.5 g of tazobactam per day to the subject, and the tazobactam and the ceftolozane are the only antibiotics administered to treat said infection.
26 . A solution comprising 0.5 grams of tazobactam active and 1 gram of ceftolozane active, wherein parenteral administration of said solution to a selected human treatment group every 8-hours as a 60-minute infusion produces in said selected human treatment group a mean plasma Area Under Curve (AUC,0-t) of about 158.5 micrograms hour/ml of ceftolozane and a mean plasma Area Under Curve (AUC,0-t) of about 19.3 micrograms hour/ml of tazobactam to treat the infection in said human treatment group, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval.
27 . The solution of claim 26 , wherein said solution administered to the human treatment group every 8 hours as a 60-minute infusion produces in said selected human treatment group a mean epithelial lining fluid (ELF) Area Under Curve (AUC,0-t) of about 75.1 micrograms hour/ml of ceftolozane and a mean ELF Area Under Curve (AUC,0-t) of about 8.5 micrograms hour/ml of tazobactam to treat the infection in said human treatment group, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval.
28 . The solution of claim 26 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt.
29 . The solution of claim 26 , wherein the ceftolozane is ((6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.
30 . The solution of claim 26 , wherein the selected human treatment group has a treatment-emergent adverse events in Table 4 during treatment with the solution:
Subjects with at least 1 TEAE
5 (20.0)
6 (23.1)
Diarrhea
1 (4.0)
3 (11.5)
Viral Upper Respiratory Infection
1 (4.0)
0 (0)
Musculoskeletal Chest Pain
1 (4.0)
0 (0)
Somnolence
1 (4.0)
0 (0)
Hematuria
1 (4.0)
0 (0)
Cough
1 (4.0)
0 (0)
Type I Hypersensitivity
0 (0)
1 (3.8)
Alanine Aminotransferase Increased
0 (0)
1 (3.8)
Aspartate Aminotransferase Increased
0 (0)
1 (3.8)
Blood Creatine Phosphokinase Increased
0 (0)
1 (3.8)
Hyperkalemia
0 (0)
1 (3.8)