Intraosseous Versus Intravenous Vancomycin in Below-Knee Amputation for Ischemic Diabetic Foot

Does Intraosseous Compared With Intravenous Vancomycin Alter Local Exposure, Systemic Safety, and Early Outcomes in Patients With Ischemic Diabetic Foot Undergoing Below-knee Amputation? A Randomized Trial

This randomized clinical trial compared two routes of vancomycin administration in patients undergoing below-knee amputation for ischemic diabetic foot infection. Patients with diabetic foot infection and impaired lower-extremity circulation may have reduced delivery of intravenously administered antibiotics to the amputation stump. Intraosseous administration may increase local antibiotic exposure at the surgical site while reducing systemic exposure.

Participants were randomly assigned to receive either intraosseous vancomycin or intravenous vancomycin before skin incision. The study evaluated vancomycin concentrations in amputation stump subcutaneous tissue, simultaneous serum vancomycin concentrations, tissue-to-serum concentration ratios, inflammatory marker trajectories, early wound outcomes, pain scores, drain output, reintervention, mortality, renal safety, and systemic adverse events through postoperative follow-up.

Study Overview

• Status: Completed
• Conditions: Diabetic Foot Infection; Diabetic Amputation Foot Wound; Diabetic Foot Disease
• Intervention / Treatment: Drug: Intraosseous Vancomycin; Drug: Intravenous Vancomycin

Detailed Description

Patients with diabetic foot infection and distal ischemia scheduled for below-knee amputation were evaluated by a multidisciplinary diabetic foot council. Eligible patients were randomized in a 1:1 ratio to receive either intraosseous or intravenous vancomycin before skin incision.

In the intraosseous group, 500 mg of vancomycin diluted in 100 mL of normal saline was administered into the proximal tibial metaphysis using a sterile intraosseous vascular access system immediately before skin incision. In the intravenous group, 500 mg of vancomycin was administered intravenously at the same preincision time point. No tourniquet was used.

During surgery, a subcutaneous soft-tissue sample was obtained from the planned amputation stump region, and a simultaneous venous serum sample was collected. Vancomycin concentrations were measured in both samples. The primary pharmacokinetic outcomes were stump subcutaneous soft-tissue vancomycin concentration, serum vancomycin concentration, tissue-to-serum concentration ratio, and attainment of an exploratory local concentration benchmark of at least 16 µg/g.

Secondary outcomes included postoperative trajectories of white blood cell count, C-reactive protein, procalcitonin, and interleukin-6; early postoperative pain scores; total drain output during the first 24 hours; early wound-healing outcomes assessed using ASEPSIS scores; surgical reintervention; mortality; renal safety outcomes based on serum creatinine; and systemic adverse events including vancomycin infusion reaction, allergic reaction, symptomatic deep vein thrombosis, and pulmonary embolism.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Istanbul
    • Istanbul, Istanbul, Turkey (Türkiye), 34010
      • Basaksehir Cam ve Sakura City Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or older
• Diagnosis of diabetes mellitus
• Diabetic foot infection with distal ischemia
• Scheduled to undergo below-knee amputation
• Absence of a feasible further revascularization option, as determined by the cardiovascular surgery and interventional radiology teams
• Adequate circulation at and proximal to the planned below-knee amputation level for stump healing
• Ability to provide written informed consent

Exclusion Criteria:

• Documented allergy or hypersensitivity to vancomycin or cephalosporins
• Dialysis dependence
• Systemic vancomycin use within 48 hours before surgery
• Previous Syme amputation or more proximal amputation
• Planned amputation at a level other than below the knee
• Incomplete perioperative pharmacokinetic sampling

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intraosseous Vancomycin; Participants received 500 mg of vancomycin diluted in 100 mL of 0.9% normal saline via intraosseous administration into the proximal tibial metaphysis immediately before skin incision.	Drug: Intraosseous Vancomycin; Participants received a single dose of 500 mg vancomycin diluted in 100 mL of 0.9% normal saline into the proximal tibial metaphysis using a sterile intraosseous vascular access system immediately before skin incision.
Active Comparator: Intravenous Vancomycin; Participants received 500 mg of vancomycin intravenously at the same preincision time point before below-knee amputation.	Drug: Intravenous Vancomycin; Participants received a single dose of 500 mg vancomycin intravenously at the same preincision time point before below-knee amputation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subcutaneous Soft-Tissue Vancomycin Concentration (mcg/g)	Vancomycin concentration in intraoperative stump subcutaneous tissue, measured by institutional laboratory assay.	Perioperatively, during below-knee amputation
Serum Vancomycin Concentration (mcg/mL)	Vancomycin concentration in simultaneous venous serum, measured by institutional laboratory assay.	Perioperatively, during below-knee amputation
Tissue-to-Serum Vancomycin Concentration Ratio	Ratio calculated by dividing stump subcutaneous tissue vancomycin concentration by simultaneous serum vancomycin concentration.	Perioperatively, during below-knee amputation
Participants With Stump Tissue Vancomycin Concentration ≥16 mcg/g	Number of participants with intraoperative stump subcutaneous tissue vancomycin concentration ≥16 mcg/g.	Perioperatively, during below-knee amputation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
White Blood Cell Count (10^3/uL)	Description: White blood cell count measured by laboratory blood test.	Preoperative, postoperative 12 hours, postoperative day 1, day 3, day 7, and day 30
C-Reactive Protein Concentration (mg/L)	C-reactive protein concentration measured by laboratory blood test.	Preoperative, postoperative 12 hours, postoperative day 1, day 3, day 7, and day 30
Procalcitonin Concentration (ng/mL)	Procalcitonin concentration measured by laboratory blood test.	Preoperative, postoperative day 1, day 3, day 7, and day 30
Interleukin-6 Concentration (pg/mL)	Interleukin-6 concentration measured by laboratory blood test.	Preoperative, postoperative day 1, day 3, day 7, and day 30
Total Drain Output (mL)	Total postoperative drain output measured in milliliters.	From postoperative day 0 to postoperative day 1
Participants With ASEPSIS Score >20	Number of participants with clinically relevant wound-healing impairment, defined as ASEPSIS score >20.	Through postoperative day 7
Visual Analog Scale Pain Score	Pain intensity was assessed using the Visual Analog Scale for pain, a 0-to-10 scale in which 0 indicates no pain and 10 indicates the worst imaginable pain. Higher scores indicate worse pain.	Postoperative 6 hours, 24 hours, and day 3
Peak ASEPSIS Wound Score	Peak wound score was assessed using the Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of deep tissues, Isolation of bacteria, and Stay as inpatient (ASEPSIS) wound scoring method. The minimum score is 0, and higher scores indicate worse wound healing or more severe surgical site infection. Scores greater than 20 indicate wound infection or clinically relevant wound-healing impairment, and scores greater than 40 indicate severe wound infection or poor wound-healing outcome.	Through postoperative day 7

Collaborators and Investigators

• Sponsor: Başakşehir Çam & Sakura City Hospital

Publications and helpful links

General Publications

• Wininger AE, Gurusamy P, Sullivan TC, Serpelloni S, Taraballi F, Park KJ, Brown TS. Intraosseous Versus Intravenous Vancomycin in Tourniquetless Primary Total Knee Arthroplasty: A Randomized Trial. J Arthroplasty. 2024 Sep;39(9 Suppl 2):S224-S228. doi: 10.1016/j.arth.2024.02.083. Epub 2024 Mar 8.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2025
• Primary Completion (Actual): June 15, 2026
• Study Completion (Actual): June 21, 2026

Study Registration Dates

• First Submitted: January 4, 2026
• First Submitted That Met QC Criteria: January 4, 2026
• First Posted (Actual): January 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 27, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Vancomycin; diabetic foot; below-knee amputation; intraosseoz
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Angiopathies; Diabetes Complications; Skin Diseases; Skin Ulcer; Leg Ulcer; Diabetic Neuropathies; Foot Ulcer; Skin and Connective Tissue Diseases; Diabetic Foot; Peptides; Amino Acids, Peptides, and Proteins; Carbohydrates; Glycoconjugates; Glycopeptides; Vancomycin
• Other Study ID Numbers: E-96317027-514.10-285164594

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the final article, after de-identification, will be made available to researchers whose proposed use of the data has been approved by a methodologically sound proposal.
• IPD Sharing Time Frame: Data will be available beginning 2 months and ending 12 months after article publication.
• IPD Sharing Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding author at lezginmert@gmail.com
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No