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

Phase 1

Completed

Conditions: Diabetes
Wound Infection
Healthy Volunteers

Interventions: Drug: Ceftolozane/tazobactam
Procedure: Microdialysis Catheter Insertion

Registration Number: NCT02620774

Lead Sponsor: Hartford Hospital

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Diabetic Wound Infection	Ceftolozane/tazobactam	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.
Diabetic Wound Infection	Microdialysis Catheter Insertion	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	Microdialysis Catheter Insertion	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.
Healthy Volunteer	Ceftolozane/tazobactam	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 Outcome Measures

Name	Time	Method
Ceftolozane Tissue Penetration	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.
Tazobactam Tissue Penetration	16-24 hours	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

Name	Time	Method
Ceftolozane Area Under the Curve (AUC) in Tissue	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.
Tazobactam AUC in Tissue	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.
Ceftolozane Total Drug AUC in Plasma	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.
Tazobactam Total Drug AUC in Plasma	16 to 24 hours post-dose	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	Duration of study (34 hours)	Number of reported or documented adverse events recorded during participation in the study.