Diabetes, Wound Infection, Healthy Volunteers
Conditions
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.
Interventions
3 or more doses of ceftolozane/tazobactam intravenously administered over 60 minutes every 8 hours
PROCEDUREMicrodialysis 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.
Sponsors
Merck Sharp & Dohme LLC
Hartford Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Number of Participants With Adverse Events | Duration of study (34 hours) | Number of reported or documented adverse events recorded during participation in the study. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| 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. | 6 |
| Total | 16 |
Baseline characteristics
| Characteristic | Diabetic Wound Infection | Healthy Volunteer | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 5 Participants | 15 Participants |
| Age, Continuous | 53 years | 28 years | 44 years |
| Body Mass Index | 33.4 kg/m^2 | 24.0 kg/m^2 | 29.9 kg/m^2 |
| Creatinine clearance | 108.4 mL/min | 121.5 mL/min | 113.3 mL/min |
| Height | 182.9 centimeters | 170.2 centimeters | 178.1 centimeters |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 10 participants | 6 participants | 16 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
| Weight | 114.8 kilograms | 69.1 kilograms | 97.7 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 1 / 10 | 0 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 |
Outcome results
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.
Time frame: 16-24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Ceftolozane Tissue Penetration | 0.75 ratio |
| Healthy Volunteer | Ceftolozane Tissue Penetration | 0.87 ratio |
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.
Time frame: 16-24 hours
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Tazobactam Tissue Penetration | 1.18 ratio |
| Healthy Volunteer | Tazobactam Tissue Penetration | 0.85 ratio |
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.
Time frame: 16 to 24 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Ceftolozane Area Under the Curve (AUC) in Tissue | 121.5 µg•h/mL |
| Healthy Volunteer | Ceftolozane Area Under the Curve (AUC) in Tissue | 130.6 µg•h/mL |
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.
Time frame: 16 to 24 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Ceftolozane Total Drug AUC in Plasma | 191.6 µg•h/mL |
| Healthy Volunteer | Ceftolozane Total Drug AUC in Plasma | 191.3 µg•h/mL |
Secondary
Number of Participants With Adverse Events
Number of reported or documented adverse events recorded during participation in the study.
Time frame: Duration of study (34 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Diabetic Wound Infection | Number of Participants With Adverse Events | 1 Participants |
| Healthy Volunteer | Number of Participants With Adverse Events | 0 Participants |
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.
Time frame: 16 to 24 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Tazobactam AUC in Tissue | 15.8 µg•h/mL |
| Healthy Volunteer | Tazobactam AUC in Tissue | 13.8 µg•h/mL |
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.
Time frame: 16 to 24 hours post-dose
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetic Wound Infection | Tazobactam Total Drug AUC in Plasma | 27.1 µg•h/mL |
| Healthy Volunteer | Tazobactam Total Drug AUC in Plasma | 22.2 µg•h/mL |