Diabetes, Wound Infection, Healthy Volunteers
Conditions
Brief summary
This study will determine the tissue penetration of tedizolid (Sivextro, Merck & Co.), a novel oxazolidinone 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 3 to 6 doses of oral tedizolid 200mg once daily. 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 for the 24 hours following the final dose (i.e., 48-72 hours). 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
DRUGTedizolid
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 tedizolid or linezolid * History of hypersensitivity to lidocaine or lidocaine derivatives * Pregnant or breastfeeding * Presence of anemia, thrombocytopenia, or leukopenia as defined by hematocrit, platelet, or white blood cell count \< 75% of the lower limit of normal * Concomitant receipt of linezolid * 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 |
|---|---|---|
| Tedizolid Tissue Penetration | 48-72 hours | The ratio of tedizolid tissue concentrations to blood concentrations following the final tedizolid dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tedizolid Area Under the Curve (AUC) in Tissue | 48-72 hours | The area under the drug concentration-time curve (AUC) in tissue reflects the actual tissue exposure to drug after administration of a dose of the drug and is expressed in mg\*h/L. Venous blood was obtained via peripheral intravenous catheter at 48 hours from the start of the first dose (i.e., immediately before administration of the 3rd dose), and at 49, 50, 50.5, 51, 51.5, 52, 54, 56, 60, 64 and 72 hours. Dialysate samples of 120μL were collected in 200µL microvials simultaneously with plasma at 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 64, 68 and 72 hours following administration of the first dose. |
| Tedizolid AUC in Plasma | 48-72 hours | The area under the plasma drug concentration-time curve (AUC) reflects the actual plasma exposure to drug after administration of a dose of the drug and is expressed in mg\*h/L |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Diabetic Wound Infection Participants with a documented medical 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 3 to 6 doses of oral tedizolid 200mg once daily, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 24 hours.
Tedizolid
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. | 10 |
| Healthy Volunteers Participants will be male or female healthy adult volunteers with no significant medical or medication history. Participants will receive 3 to 6 doses of oral tedizolid 200mg once daily, followed by sampling of interstitial tissue fluid at the margin of the wound by a microdialysis probe over 24 hours.
Tedizolid
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. | 6 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Eligibility Criteria Not Met | 1 | 0 |
Baseline characteristics
| Characteristic | Diabetic Wound Infection | Total | Healthy Volunteers |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 17 | 44 years STANDARD_DEVIATION 17 | 33 years STANDARD_DEVIATION 9 |
| Albumin | 3.1 g/dL STANDARD_DEVIATION 0.4 | 3.6 g/dL STANDARD_DEVIATION 0.8 | 4.6 g/dL STANDARD_DEVIATION 0.3 |
| Body Mass Index | 31.5 kg/m^2 STANDARD_DEVIATION 6.3 | 30.4 kg/m^2 STANDARD_DEVIATION 6 | 28.5 kg/m^2 STANDARD_DEVIATION 5.4 |
| Creatinine clearance | 90.4 mg/ml STANDARD_DEVIATION 31.9 | 94.6 mg/ml STANDARD_DEVIATION 29.6 | 101.5 mg/ml STANDARD_DEVIATION 26.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 8 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 66.6 inches STANDARD_DEVIATION 5 | 66.3 inches STANDARD_DEVIATION 4.7 | 65.7 inches STANDARD_DEVIATION 4.5 |
| PEDIS Grade Grade 2 | 1 Participants | 1 Participants | — |
| PEDIS Grade Grade 3 | 9 Participants | 9 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 15 Participants | 5 Participants |
| Region of Enrollment United States | 10 Participants | 16 Participants | 6 Participants |
| Serum creatinine | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 0.9 mg/dL STANDARD_DEVIATION 0.1 |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 3 Participants |
| Weight | 89.4 kg STANDARD_DEVIATION 21 | 85.7 kg STANDARD_DEVIATION 19.9 | 79.5 kg STANDARD_DEVIATION 17.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 6 |
| other Total, other adverse events | 2 / 11 | 3 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 6 |
Outcome results
Primary
Tedizolid Tissue Penetration
The ratio of tedizolid tissue concentrations to blood concentrations following the final tedizolid dose
Time frame: 48-72 hours
Population: One volunteer and one patient participant were excluded due to low concentrations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetic Wound Infection | Tedizolid Tissue Penetration | 0.98 ratio | Standard Deviation 0.43 |
| Healthy Volunteers | Tedizolid Tissue Penetration | 0.82 ratio | Standard Deviation 0.08 |
Secondary
Tedizolid Area Under the Curve (AUC) in Tissue
The area under the drug concentration-time curve (AUC) in tissue reflects the actual tissue exposure to drug after administration of a dose of the drug and is expressed in mg\*h/L. Venous blood was obtained via peripheral intravenous catheter at 48 hours from the start of the first dose (i.e., immediately before administration of the 3rd dose), and at 49, 50, 50.5, 51, 51.5, 52, 54, 56, 60, 64 and 72 hours. Dialysate samples of 120μL were collected in 200µL microvials simultaneously with plasma at 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 64, 68 and 72 hours following administration of the first dose.
Time frame: 48-72 hours
Population: One volunteer and one patient participant were excluded due to low concentrations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetic Wound Infection | Tedizolid Area Under the Curve (AUC) in Tissue | 3.44 mg*h/L | Standard Deviation 1.5 |
| Healthy Volunteers | Tedizolid Area Under the Curve (AUC) in Tissue | 5.20 mg*h/L | Standard Deviation 1.61 |
Secondary
Tedizolid AUC in Plasma
The area under the plasma drug concentration-time curve (AUC) reflects the actual plasma exposure to drug after administration of a dose of the drug and is expressed in mg\*h/L
Time frame: 48-72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetic Wound Infection | Tedizolid AUC in Plasma | 18.47 mg*h/L | Standard Deviation 9.7 |
| Healthy Volunteers | Tedizolid AUC in Plasma | 28.71 mg*h/L | Standard Deviation 9.58 |