Clinical trial NCT02620774: Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes
Wound Infection
Healthy Volunteers
Lead sponsor: Hartford Hospital
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-12-03
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Primary outcomes:
measure: Ceftolozane Tissue Penetration
timeFrame: 16-24 hours
measure: Tazobactam Tissue Penetration
timeFrame: 16-24 hours
Secondary outcomes:
measure: Ceftolozane Area Under the Curve (AUC) in Tissue
timeFrame: 16 to 24 hours post-dose
measure: Tazobactam AUC in Tissue
timeFrame: 16 to 24 hours post-dose
measure: Ceftolozane Total Drug AUC in Plasma
timeFrame: 16 to 24 hours post-dose
measure: Tazobactam Total Drug AUC in Plasma
timeFrame: 16 to 24 hours post-dose
measure: Number of Participants With Adverse Events
timeFrame: Duration of study (34 hours)
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
Study officials:
affiliation: Harford Hospital
name: David P Nicolau, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
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.