Critically Ill, Pneumonia
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics and lung penetration of intravenous Ceftolozane/tazobactam in critically ill participants.
Detailed description
This is a Phase 1, prospective, multicenter, non-comparative, open-label study to characterize the plasma pharmacokinetics and intrapulmonary penetration of ceftolozane/tazobactam in two groups of participants. Group 1: approximately 25 ventilated participants with suspected or proven pneumonia receiving concurrent standard antibiotic therapy. Within Group 1, efforts will be made to enroll approximately 5 participants with a CLCR ≥ 150 mL/min (as calculated by the Cockcroft-Gault equation). Group 2: 8-10 critically ill participants with CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation).
Interventions
DRUGCeftolozane/Tazobactam - Multiple Doses
4-6 doses of ceftolozane/tazobactam every 8 hours as a 60-minute intravenous infusion as follows: * Participants with CLCR \> 50 mL/min will receive 4-6 doses of 3 g ceftolozane/tazobactam every 8 hours * Participants with CLCR 30 - 50 mL/min will receive 4-6 doses of 1.5 g ceftolozane/tazobactam every 8 hours * Participants with CLCR 15 - 29 mL/min will receive 6 doses of 750 mg ceftolozane/tazobactam every 8 hours
DRUGCeftolozane/Tazobactam - Single Dose
Single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent prior to any study-related procedure not part of normal medical care. 2. If female,must not be pregnant or nursing, and is either: 1. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or 2. Of childbearing potential and: * Is practicing an effective method of contraception (e.g., oral/parenteral contraceptives or a barrier method) and for at least 1 month prior to baseline assessments, or * Has a vasectomized partner, or * Is currently abstinent from sexual intercourse. Participants must be willing to practice the chosen contraceptive method or remain abstinent during the conduct of the study and for at least 30 days after last dose of study medication. 3. Non-vasectomized males are required to practice effective birth control methods (e.g., abstinence, use of a condom or use of other barrier device) during the conduct of the study and for at least 30 days after last dose of study medication; 4. Participants in Group 1 must meet the following criteria: 1. Males or females age 18 years or older; 2. Intubated and on mechanical ventilation for at least 24 hours prior to time of enrollment (includes participants with tracheostomy who are mechanically ventilated); 3. Proven or suspected bacterial pneumonia, as confirmed by the presence of at least one of the prescribed clinical signs and symptoms. 4. Receiving antibiotic therapy for proven or suspected bacterial pneumonia at the time of enrollment and expected to continue on antibiotic therapy while in the study 5. Participants in Group 2 must meet the following criteria: 1. Males or females aged 18 - 54 years; 2. Acute Physiology and Chronic Health Evaluation II (APACHE II) score between 12 and 35, inclusive; 3. CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) within 24 hours of dosing; 4. Documented infection or presumed infection.
Exclusion criteria
1. Has a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibacterial (a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment); 2. Hemoglobin \< 7 g/dL at baseline; 3. Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam, probenecid or ceftolozane/tazobactam (non-study use); 4. Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the Investigator); 5. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the participant or the quality of study data; 6. Planned or prior participation in any interventional drug study within the last 30 days; 7. Participants in Group 1 must not meet any of the following criteria: 1. Receipt of effective systemic antibiotic therapy for the treatment of proven or suspected bacterial pneumonia for more than 72 hours prior to start of the first dose of study drug 2. Any of the following diagnoses or conditions that may interfere with the PK assessment/interpretation: * Cystic fibrosis, acute exacerbation of chronic bronchitis or obstructive airway disease, chronic severe respiratory disease , or active pulmonary tuberculosis, * Full thickness burns (greater than 15% of total body surface area), * Lung transplant recipient or donor, * Any condition or situation where bronchoscopy is not advisable; 8. End-stage renal disease defined as a CLCR \< 15 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight), OR requirement for continuous renal replacement therapy or hemodialysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL, plasma clearance, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for creatinine clearance (CLCR), every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax, maximum plasma concentration, of ceftolozane or tazobactam. Pharmacokinetic (PK) data analysis was performed by non-compartmental analysis (NCA) method using Phoenix WinNonlin version 6.3 or later. |
| Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | Up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the last infusion. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples and epithelial lining fluid (ELF) were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the epithelial lining fluid, ELF to plasma ratio of ceftolozane and tazobactam. |
| Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax, time of maximum plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast, last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast, time of last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last, AUC from the first to time of the last dose, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. |
| AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞, AUC from the time of the dose to infinity, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the t1/2, terminal elimination half-life, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss, volume of distribution at steady state, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Up to 5 days | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
| Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Clast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Tlast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| AUC0-last of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| AUC0-∞ of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞ of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| T1/2 of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the T1/2 of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| Vss of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
| CL of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. |
Participant flow
Recruitment details
Adult males or non-pregnant or non-nursing females that were mechanically ventilated or critically ill were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Mechanically Ventilated Participants with proven or suspected pneumonia, undergoing mechanical ventilation will receive 4-6 doses of ceftolozane/tazobactam every 8 hours as a 60-minute intravenous infusion as follows:
* Those with Creatinine clearance (CLCR) \> 50 mL/min will receive 4-6 doses of 3 g ceftolozane/tazobactam every 8 hours
* Those with CLCR 30 - 50 mL/min will receive 4-6 doses of 1.5 g ceftolozane/tazobactam every 8 hours
* Those with CLCR 15 - 29 mL/min will receive 6 doses of 750 mg ceftolozane/tazobactam every 8 hours | 26 |
| Critically Ill Critically ill participants with CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation) will receive a single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion. | 10 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not Treated | 1 | 0 |
Baseline characteristics
| Characteristic | Critically Ill | Total | Mechanically Ventilated |
|---|---|---|---|
| Age, Continuous | 36.2 Years STANDARD_DEVIATION 9.65 | 55.9 Years STANDARD_DEVIATION 18.9 | 63.5 Years STANDARD_DEVIATION 15.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 33 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 8 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 28 Participants | 19 Participants |
| Sex: Female, Male Female | 6 Participants | 16 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 20 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 4 | 0 / 1 | 0 / 10 |
| other Total, other adverse events | 14 / 21 | 1 / 4 | 1 / 1 | 6 / 10 |
| serious Total, serious adverse events | 0 / 21 | 0 / 4 | 0 / 1 | 0 / 10 |
Outcome results
Primary
Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last, AUC from the first to time of the last dose, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 242 h*ug/mL |
| Mechanically Ventilated- Ceftolozane | Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 390 h*ug/mL |
| Mechanically Ventilated -Tazobactam | Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 50.7 h*ug/mL |
| Mechanically Ventilated -Tazobactam | Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 63.0 h*ug/mL |
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.44, 1.81]
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.11, 1.39]
Primary
AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞, AUC from the time of the dose to infinity, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 353 h*ug/mL |
| Mechanically Ventilated- Ceftolozane | AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 605 h*ug/mL |
| Mechanically Ventilated -Tazobactam | AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 58.1 h*ug/mL |
| Mechanically Ventilated -Tazobactam | AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 69.8 h*ug/mL |
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.51, 1.95]
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.09, 1.33]
Primary
Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples and epithelial lining fluid (ELF) were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the epithelial lining fluid, ELF to plasma ratio of ceftolozane and tazobactam.
Time frame: Up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the last infusion.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma and ELF drug concentrations were both determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 2 Hr Post-dose | 0.360 Ratio | Standard Deviation 0.212 |
| Mechanically Ventilated- Ceftolozane | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 6 Hr Post-dose | 1.02 Ratio | Standard Deviation 0.773 |
| Mechanically Ventilated- Ceftolozane | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 4 Hr Post-dose | 1.76 Ratio | Standard Deviation 3.24 |
| Mechanically Ventilated- Ceftolozane | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 8 Hr Post-dose | 0.786 Ratio | Standard Deviation 0.248 |
| Mechanically Ventilated- Ceftolozane | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 1 Hr Post-dose | 0.213 Ratio | Standard Deviation 0.13 |
| Mechanically Ventilated -Tazobactam | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 8 Hr Post-dose | 1.06 Ratio | Standard Deviation 0.543 |
| Mechanically Ventilated -Tazobactam | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 1 Hr Post-dose | 0.234 Ratio | Standard Deviation 0.14 |
| Mechanically Ventilated -Tazobactam | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 2 Hr Post-dose | 0.471 Ratio | Standard Deviation 0.241 |
| Mechanically Ventilated -Tazobactam | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 4 Hr Post-dose | 2.34 Ratio | Standard Deviation 4.25 |
| Mechanically Ventilated -Tazobactam | Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants. | 6 Hr Post-dose | 2.59 Ratio | Standard Deviation 2.36 |
Primary
Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast, last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 14.0 ug/mL |
| Mechanically Ventilated- Ceftolozane | Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 24.0 ug/mL |
| Mechanically Ventilated -Tazobactam | Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 1.52 ug/mL |
| Mechanically Ventilated -Tazobactam | Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 1.14 ug/mL |
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.5, 1.96]
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.14, 1.55]
Primary
Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for creatinine clearance (CLCR), every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax, maximum plasma concentration, of ceftolozane or tazobactam. Pharmacokinetic (PK) data analysis was performed by non-compartmental analysis (NCA) method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 73.0 ug/mL |
| Mechanically Ventilated- Ceftolozane | Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 100 ug/mL |
| Mechanically Ventilated -Tazobactam | Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 22.6 ug/mL |
| Mechanically Ventilated -Tazobactam | Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 26.1 ug/mL |
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.21, 1.56]
Comparison: Accumulation Ratio of Last Dose/First Dose90% CI: [1.03, 1.29]
Primary
Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL, plasma clearance, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 4.90 L/h | Geometric Coefficient of Variation 64.1 |
| Mechanically Ventilated- Ceftolozane | Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 4.52 L/h | Geometric Coefficient of Variation 67.7 |
| Mechanically Ventilated -Tazobactam | Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 15.0 L/h | Geometric Coefficient of Variation 68.5 |
| Mechanically Ventilated -Tazobactam | Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 14.1 L/h | Geometric Coefficient of Variation 75.6 |
Primary
Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the t1/2, terminal elimination half-life, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 4.15 Hours | Geometric Coefficient of Variation 56.1 |
| Mechanically Ventilated- Ceftolozane | Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 4.86 Hours | Geometric Coefficient of Variation 61.5 |
| Mechanically Ventilated -Tazobactam | Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 2.15 Hours | Geometric Coefficient of Variation 56.4 |
| Mechanically Ventilated -Tazobactam | Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 2.33 Hours | Geometric Coefficient of Variation 49.7 |
Primary
Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast, time of last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 7.95 Hours |
| Mechanically Ventilated- Ceftolozane | Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 7.98 Hours |
| Mechanically Ventilated -Tazobactam | Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 7.95 Hours |
| Mechanically Ventilated -Tazobactam | Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 7.98 Hours |
Primary
Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax, time of maximum plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 1.00 Hours |
| Mechanically Ventilated- Ceftolozane | Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 1.00 Hours |
| Mechanically Ventilated -Tazobactam | Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 1.00 Hours |
| Mechanically Ventilated -Tazobactam | Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 1.00 Hours |
Primary
Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss, volume of distribution at steady state, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.
Population: All mechanically ventilated participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Critically ill participants were not analyzed in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 27.5 Liter | Geometric Coefficient of Variation 29.9 |
| Mechanically Ventilated- Ceftolozane | Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 29.4 Liter | Geometric Coefficient of Variation 45.5 |
| Mechanically Ventilated -Tazobactam | Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | First Dose | 39.9 Liter | Geometric Coefficient of Variation 28.9 |
| Mechanically Ventilated -Tazobactam | Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Last Dose | 40.4 Liter | Geometric Coefficient of Variation 38.8 |
Secondary
AUC0-last of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | AUC0-last of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 188 h*ug/mL |
| Mechanically Ventilated -Tazobactam | AUC0-last of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 31.0 h*ug/mL |
Secondary
AUC0-∞ of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞ of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | AUC0-∞ of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 233 h*ug/mL |
| Mechanically Ventilated -Tazobactam | AUC0-∞ of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 34.8 h*ug/mL |
Secondary
Clast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | Clast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 5.82 ug/mL |
| Mechanically Ventilated -Tazobactam | Clast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 0.357 ug/mL |
Secondary
CL of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | CL of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 8.98 L/h | Geometric Coefficient of Variation 57.6 |
| Mechanically Ventilated -Tazobactam | CL of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 28.7 L/h | Geometric Coefficient of Variation 67.9 |
Secondary
Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 68.9 ug/mL |
| Mechanically Ventilated -Tazobactam | Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 17.4 ug/mL |
Secondary
Number of Participants With Adverse Events (AEs)
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time frame: Up to 5 days
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | Number of Participants With Adverse Events (AEs) | 16 Participants |
| Mechanically Ventilated -Tazobactam | Number of Participants With Adverse Events (AEs) | 6 Participants |
Secondary
T1/2 of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the T1/2 of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | T1/2 of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 2.59 Hours | Geometric Coefficient of Variation 51.1 |
| Mechanically Ventilated -Tazobactam | T1/2 of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 1.47 Hours | Geometric Coefficient of Variation 43.5 |
Secondary
Tlast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | Tlast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 7.95 Hours |
| Mechanically Ventilated -Tazobactam | Tlast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 7.85 Hours |
Secondary
Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mechanically Ventilated- Ceftolozane | Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 1.02 Hours |
| Mechanically Ventilated -Tazobactam | Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 1.02 Hours |
Secondary
Vss of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later.
Time frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Population: All critically ill participants who received at least 1 dose of study drug at the correctly assigned dose level, and whose plasma drug concentration was determined. Mechanically ventilated participants were not analyzed in this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mechanically Ventilated- Ceftolozane | Vss of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 30.2 Liter | Geometric Coefficient of Variation 41.1 |
| Mechanically Ventilated -Tazobactam | Vss of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | 51.6 Liter | Geometric Coefficient of Variation 41.1 |