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Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections

Primary Purpose

Diabetes, Wound Infection, Healthy Volunteers

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ceftolozane/tazobactam
Microdialysis Catheter Insertion
Sponsored by
Hartford Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Diabetes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Experimental: Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb
  • Active Comparator: Healthy Adult Volunteer

Exclusion Criteria:

All Participants:

  • Less than 18 years of age
  • History of hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or any β-lactam antibiotic
  • History of hypersensitivity to lidocaine or lidocaine derivatives
  • Females who are pregnant or breastfeeding
  • Concomitant receipt of any β-lactams antibiotic
  • Concomitant receipt of probenecid
  • Reduced kidney function defined as creatinine clearance of ≤ 50 mL/min
  • Any other reason felt by the investigator to potentially affect the outcomes of the study

Experimental Group Only:

  • No palpable pedal pulses present
  • Participants likely to require multiple surgical interventions during the study period, which therefore could affect placement of the microdialysis catheter

Active Comparator Group Only:

  • Positive urine drug screen (cocaine, tetrahydrocannabinol, opiates, benzodiazepines, and amphetamines)
  • History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening.
  • Use of tobacco- or nicotine-containing products in excess of the equivalence of 5 cigarettes per day.
  • Use of prescription or nonprescription drugs, vitamins, or dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, with the exception of acetaminophen at doses of ≤ 1 g/day. Herbal supplements, hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine devices (IUDs), postcoital contraceptive methods), and hormone replacement therapy must be discontinued at least 14 days prior to the first dose of study medication. Depo-Provera® must be discontinued at least 6 months prior to the first dose of study medication.

Sites / Locations

  • Hartford Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Diabetic Wound Infection

Healthy Volunteer

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
Number of Participants With Adverse Events
Number of reported or documented adverse events recorded during participation in the study.

Full Information

First Posted
December 1, 2015
Last Updated
July 31, 2018
Sponsor
Hartford Hospital
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02620774
Brief Title
Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
February 19, 2016 (Actual)
Primary Completion Date
April 2017 (Actual)
Study Completion Date
April 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hartford Hospital
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes, Wound Infection, Healthy Volunteers

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Diabetic Wound Infection
Arm Type
Experimental
Arm Description
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.
Arm Title
Healthy Volunteer
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ceftolozane/tazobactam
Other Intervention Name(s)
Zerbaxa
Intervention Description
3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours
Intervention Type
Procedure
Intervention Name(s)
Microdialysis Catheter Insertion
Intervention Description
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.
Primary Outcome Measure Information:
Title
Ceftolozane Tissue Penetration
Description
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.
Time Frame
16-24 hours
Title
Tazobactam Tissue Penetration
Description
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.
Time Frame
16-24 hours
Secondary Outcome Measure Information:
Title
Ceftolozane Area Under the Curve (AUC) in Tissue
Description
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.
Time Frame
16 to 24 hours post-dose
Title
Tazobactam AUC in Tissue
Description
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.
Time Frame
16 to 24 hours post-dose
Title
Ceftolozane Total Drug AUC in Plasma
Description
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.
Time Frame
16 to 24 hours post-dose
Title
Tazobactam Total Drug AUC in Plasma
Description
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.
Time Frame
16 to 24 hours post-dose
Title
Number of Participants With Adverse Events
Description
Number of reported or documented adverse events recorded during participation in the study.
Time Frame
Duration of study (34 hours)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Experimental: Type 1 or Type 2 diabetes and a mild to moderate (Grade 2 or 3) wound infection of the lower limb Active Comparator: Healthy Adult Volunteer Exclusion Criteria: All Participants: Less than 18 years of age History of hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or any β-lactam antibiotic History of hypersensitivity to lidocaine or lidocaine derivatives Females who are pregnant or breastfeeding Concomitant receipt of any β-lactams antibiotic Concomitant receipt of probenecid Reduced kidney function defined as creatinine clearance of ≤ 50 mL/min Any other reason felt by the investigator to potentially affect the outcomes of the study Experimental Group Only: No palpable pedal pulses present Participants likely to require multiple surgical interventions during the study period, which therefore could affect placement of the microdialysis catheter Active Comparator Group Only: Positive urine drug screen (cocaine, tetrahydrocannabinol, opiates, benzodiazepines, and amphetamines) History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening. Use of tobacco- or nicotine-containing products in excess of the equivalence of 5 cigarettes per day. Use of prescription or nonprescription drugs, vitamins, or dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, with the exception of acetaminophen at doses of ≤ 1 g/day. Herbal supplements, hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine devices (IUDs), postcoital contraceptive methods), and hormone replacement therapy must be discontinued at least 14 days prior to the first dose of study medication. Depo-Provera® must be discontinued at least 6 months prior to the first dose of study medication.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David P Nicolau, PharmD
Organizational Affiliation
Harford Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hartford Hospital
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06102
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28893779
Citation
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.
Results Reference
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Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections

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