Trial Outcomes & Findings for Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections (NCT NCT02620774)

Results Overview

The ratio of ceftolozane tissue concentration area under the curve (AUC) to plasma concentrations AUC following the final (i.e., 3rd) ceftolozane/tazobactam dose. Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Plasma and dialysate concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of ceftolozane AUC in blood and tissue.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

16 participants

Primary outcome timeframe

16-24 hours

Results posted on

2019-01-15

Participant Flow

Participant milestones

Participant milestones
Measure	Diabetic Wound Infection Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Overall Study STARTED	10	6
Overall Study COMPLETED	10	6
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=10 Participants	1 Participants n=6 Participants	1 Participants n=16 Participants
Age, Categorical Between 18 and 65 years	10 Participants n=10 Participants	5 Participants n=6 Participants	15 Participants n=16 Participants
Age, Categorical >=65 years	0 Participants n=10 Participants	0 Participants n=6 Participants	0 Participants n=16 Participants
Age, Continuous	53 years n=10 Participants	28 years n=6 Participants	44 years n=16 Participants
Sex: Female, Male Female	1 Participants n=10 Participants	2 Participants n=6 Participants	3 Participants n=16 Participants
Sex: Female, Male Male	9 Participants n=10 Participants	4 Participants n=6 Participants	13 Participants n=16 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United States	10 participants n=10 Participants	6 participants n=6 Participants	16 participants n=16 Participants
Height	182.9 centimeters n=10 Participants	170.2 centimeters n=6 Participants	178.1 centimeters n=16 Participants
Weight	114.8 kilograms n=10 Participants	69.1 kilograms n=6 Participants	97.7 kilograms n=16 Participants
Body Mass Index	33.4 kg/m^2 n=10 Participants	24.0 kg/m^2 n=6 Participants	29.9 kg/m^2 n=16 Participants
Creatinine clearance	108.4 mL/min n=10 Participants	121.5 mL/min n=6 Participants	113.3 mL/min n=16 Participants

PRIMARY outcome

Timeframe: 16-24 hours

The ratio of ceftolozane tissue concentration area under the curve (AUC) to plasma concentrations AUC following the final (i.e., 3rd) ceftolozane/tazobactam dose. Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Plasma and dialysate concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of ceftolozane AUC in blood and tissue.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Ceftolozane Tissue Penetration	0.75 ratio Interval 0.35 to 1.0	0.87 ratio Interval 0.54 to 2.2

PRIMARY outcome

Timeframe: 16-24 hours

Population: Seven of the 10 enrolled participants in the Diabetic Wound Infection cohort provided data for tazobactam in plasma. Assay interference was observed in samples for two participants, and one participant had concentrations below the lower limit of the detection for the assay. This explains the difference with participant flow numbers.

The ratio of tazobactam tissue concentration area under the curve (AUC) to plasma concentration AUC following the final (3rd) ceftolozane/tazobactam dose. Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Plasma and dialysate concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of tazobactam AUC in blood and tissue.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=7 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Tazobactam Tissue Penetration	1.18 ratio Interval 0.54 to 1.44	0.85 ratio Interval 0.63 to 2.1

SECONDARY outcome

Timeframe: 16 to 24 hours post-dose

The ceftolozane AUC in tissue from 16 to 24 hours. Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Dialysate concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of ceftolozane AUC.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Ceftolozane Area Under the Curve (AUC) in Tissue	121.5 µg•h/mL Interval 72.7 to 191.7	130.6 µg•h/mL Interval 95.4 to 189.4

SECONDARY outcome

Timeframe: 16 to 24 hours post-dose

The tazobactam AUC in tissue over 16 to 24 hours Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Dialysate concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of tazobactam AUC.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Tazobactam AUC in Tissue	15.8 µg•h/mL Interval 8.6 to 32.9	13.8 µg•h/mL Interval 7.7 to 18.7

SECONDARY outcome

Timeframe: 16 to 24 hours post-dose

The ceftolozane total drug AUC in plasma over 16 to 24 hours Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Plasma concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of ceftolozane AUC.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Ceftolozane Total Drug AUC in Plasma	191.6 µg•h/mL Interval 147.1 to 286.6	191.3 µg•h/mL Interval 118.1 to 274.3

SECONDARY outcome

Timeframe: 16 to 24 hours post-dose

Population: Seven of the 10 enrolled participants in the Diabetic Wound Infection cohort provided data for tazobactam in plasma. Assay interference was observed in samples for two participants, and one participant had concentrations below the lower limit of the detection for the assay. This explains the difference with participant flow numbers.

The tazobactam total drug AUC in plasma over 16 to 24 hours Note. Ceftolozane/tazobactam doses were administered at 0, 8, and 16 hours. Plasma concentrations were determined at hours 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours after the first dose for determination of tazobactam AUC.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=7 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Tazobactam Total Drug AUC in Plasma	27.1 µg•h/mL Interval 15.0 to 70.0	22.2 µg•h/mL Interval 19.2 to 36.4

SECONDARY outcome

Timeframe: Duration of study (34 hours)

Number of reported or documented adverse events recorded during participation in the study.

Outcome measures

Outcome measures
Measure	Diabetic Wound Infection n=10 Participants Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 Participants Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Number of Participants With Adverse Events	1 Participants	0 Participants

Adverse Events

Diabetic Wound Infection

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Healthy Volunteer

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Diabetic Wound Infection n=10 participants at risk Participants with a documented history of Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 8 hours.	Healthy Volunteer n=6 participants at risk Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive at least 3 doses of intravenous ceftolozane/tazobactam 1.5g every 8 hours, followed by sampling of interstitial tissue fluid in the thigh by a microdialysis probe over 8 hours.
Nervous system disorders Vertigo	10.0% 1/10 • Number of events 1 • Adverse events were collected until study completion (approximately 34 hours). All abnormal laboratory determinations were followed until resolution unless follow-up is determined to be unnecessary by the study physician. For the control group, participants were discharged from the study after a 4 hour monitoring period from removal of microdialysis catheters. Adverse event: any pathologic or unintended change in the structure, function, or chemistry associated with the use of the study drug, whether or not considered drug related: MILD - present, but easily tolerated MODERATE - discomfort that interferes with usual activities SEVERE - incapacitating, inability to do usual activities A serious adverse event will be defined as any which results in death or is immediately life-threatening, requires in-participant hospitalization.	0.00% 0/6 • Adverse events were collected until study completion (approximately 34 hours). All abnormal laboratory determinations were followed until resolution unless follow-up is determined to be unnecessary by the study physician. For the control group, participants were discharged from the study after a 4 hour monitoring period from removal of microdialysis catheters. Adverse event: any pathologic or unintended change in the structure, function, or chemistry associated with the use of the study drug, whether or not considered drug related: MILD - present, but easily tolerated MODERATE - discomfort that interferes with usual activities SEVERE - incapacitating, inability to do usual activities A serious adverse event will be defined as any which results in death or is immediately life-threatening, requires in-participant hospitalization.

Additional Information

David Nicolau

Center for Anti-infective Research and Development

Phone: 860-972-3941

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place