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

NCT ID: NCT02620774

Last Updated: 2019-01-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-19
• Study Completion Date: 2017-04-30

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.

Conditions

Diabetes; Wound Infection; Healthy Volunteers

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ceftolozane/tazobactam

Intervention Type: DRUG

3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours

Microdialysis Catheter Insertion

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Ceftolozane/tazobactam

Intervention Type: DRUG

3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours

Microdialysis Catheter Insertion

Intervention Type: 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.

Interventions

Ceftolozane/tazobactam

3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours

Intervention Type: DRUG

Microdialysis Catheter Insertion

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.

Intervention Type: PROCEDURE

Other Intervention Names

Zerbaxa

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Hartford Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David P Nicolau, PharmD

Role: PRINCIPAL_INVESTIGATOR

Harford Hospital

Locations

Hartford Hospital

Hartford, Connecticut, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 28893779 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Nicolau-53433

Identifier Type: -

Identifier Source: org_study_id