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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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This study will determine the tissue penetration of ceftolozane/tazobactam (Zerbaxa, Merck & Co.), a novel β-lactam/β-lactamase combination antibiotic, into the extracellular, interstitial fluid of soft tissue in diabetic patients with lower limb wound infections. Penetration will be compared with a group of healthy volunteer control participants.
This study will enroll 10 patients with diabetes who are admitted with a lower limb wound infection and 6 healthy volunteer control participants. The study will take place in an inpatient unit at Hartford Hospital for all patients and in the Clinical Research Center at Hartford Hospital for all healthy volunteers. All participants will receive at least 3 doses of ceftolozane/tazobactam 1.5g every 8 hours. A microdialysis probe (Mdialysis Inc., N. Chelmsford MA) will be inserted into the subcutaneous soft tissue near the margin of the wound (patients) or in the thigh (healthy volunteers). The microdialysis probe is perfused with lactated Ringer's solution and samples are collected each hour for 8 hours after the final dose. A peripheral intravenous catheter will be inserted into an arm vein to collect blood samples simultaneously with microdialysis samples. Concentrations in tissue are compared with blood to determine percent penetration.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Diabetic Wound Infection | Experimental | 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 | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ceftolozane/tazobactam | Drug | 3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ceftolozane Tissue Penetration | 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. | 16-24 hours |
| Tazobactam Tissue Penetration | 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. | 16-24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Ceftolozane Area Under the Curve (AUC) in Tissue | 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. | 16 to 24 hours post-dose |
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Inclusion Criteria:
Exclusion Criteria:
All Participants:
Experimental Group Only:
Active Comparator Group Only:
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| Name | Affiliation | Role |
|---|---|---|
| David P Nicolau, PharmD | Harford Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hartford Hospital | Hartford | Connecticut | 06102 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28893779 | Derived | Monogue ML, Stainton SM, Baummer-Carr A, Shepard AK, Nugent JF, Kuti JL, Nicolau DP. Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers. Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01449-17. doi: 10.1128/AAC.01449-17. Print 2017 Dec. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Ceftolozane Tissue Penetration | 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. | Posted | Median | Full Range | ratio | 16-24 hours |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo | Nervous system disorders | Systematic Assessment |
No clinical or microbiological outcome data were collected; patient and volunteers were not matched based on demographic data; interference with the plasma assay was observed in two patients.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Nicolau | Center for Anti-infective Research and Development | 860-972-3941 | david.nicolau@hhchealth.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 27, 2016 | Oct 27, 2017 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D014946 | Wound Infection |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| C000594038 | ceftolozane, tazobactam drug combination |
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| Microdialysis Catheter Insertion | Procedure | A 20 kila-Dalton microdialysis probe (63 MD catheter; MDialysis Inc., N. Chelmsford, MA) will be inserted into the subcutaneous tissue at the margin of the wound (patient group) or in the thigh tissue (healthy volunteers). The probe will be left in place for the final dose and all tissue sampling procedures thereafter. This probe is perfused with a physiologic solution to collect interstitial fluid samples. The probe will then be removed after completion of sample collection. |
|
| Tazobactam AUC in Tissue | 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. | 16 to 24 hours post-dose |
| Ceftolozane Total Drug AUC in Plasma | 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. | 16 to 24 hours post-dose |
| Tazobactam Total Drug AUC in Plasma | 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. | 16 to 24 hours post-dose |
| Number of Participants With Adverse Events | Number of reported or documented adverse events recorded during participation in the study. | Duration of study (34 hours) |
| BG001 |
| 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Height | Median | Full Range | centimeters |
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| Weight | Median | Full Range | kilograms |
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| Body Mass Index | Median | Full Range | kg/m^2 |
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| Creatinine clearance | Median | Full Range | mL/min |
|
| OG001 | 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. |
|
|
| Primary | Tazobactam Tissue Penetration | 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. | 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. | Posted | Median | Full Range | ratio | 16-24 hours |
|
|
|
| Secondary | Ceftolozane Area Under the Curve (AUC) in Tissue | 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. | Posted | Median | Full Range | µg•h/mL | 16 to 24 hours post-dose |
|
|
|
| Secondary | Tazobactam AUC in Tissue | 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. | Posted | Median | Full Range | µg•h/mL | 16 to 24 hours post-dose |
|
|
|
| Secondary | Ceftolozane Total Drug AUC in Plasma | 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. | Posted | Median | Full Range | µg•h/mL | 16 to 24 hours post-dose |
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|
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| Secondary | Tazobactam Total Drug AUC in Plasma | 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. | 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. | Posted | Median | Full Range | µg•h/mL | 16 to 24 hours post-dose |
|
|
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| Secondary | Number of Participants With Adverse Events | Number of reported or documented adverse events recorded during participation in the study. | Posted | Count of Participants | Participants | Duration of study (34 hours) |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
| EG001 | 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. | 0 | 6 | 0 | 6 | 0 | 6 |
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| D007239 | Infections |