Tobramycin Injection to Prevent Infection in Open Fractures

Does Prophylactic Local Tobramycin Injection Lower Open Fracture Infection Rates?

The goal of open extremity fracture (OEF) treatment is to promote fracture healing and restore function while preventing the development of infection. This is achieved through systematic and timely wound debridement and irrigation, fracture stabilization, tetanus prophylaxis, systemic and local antimicrobial therapy, and judicious timing of wound closure based on cleanliness. Early prophylactic systemic antibiotics lower infection rates in open fractures but have limitations of achieving adequate concentration at the hypoperfused wound area. OEF wounds are frequently poor in vasculature secondary to the soft tissue injury, hence adequate concentration of antibiotic cannot permeate to the tissue at risk. If systemic antibiotic concentrations are increased to achieve minimum inhibitory concentration (MIC) for pathogens at the wound, there is heightened concern for systemic drug toxicity. In sharp contrast, locally administered antibiotics achieve high drug concentration directly within the wound cavity with minimal systemic side effects. Local antibiotic therapy has shown to reduce rates of open fracture wound infection. With the serious implications of postoperative infections in OEF, it is imperative that all measures including further use of prophylactic local antibiotics be considered to prevent fracture-related infection (FRI). The overarching hypothesis for this project is that a novel synergistic combination of local aqueous tobramycin plus perioperative weight-based IV cephalosporin antibiotic prophylaxis will reduce the rate of FRI one year after OEF surgery. This in turn will improve OEF patient outcomes, decreasing morbidity and return to the operating room (OR) without any adverse effect on fracture healing. Regardless of the treatment group, bacterial speciation will be determined for patients that do develop FRI to help guide future treatment. The goal is to improve the clinical outcome and recovery of the population that sustains an OEF by decreasing the rate of FRI and fracture nonunions while concurrently educating on bacterial speciation and resistance.

Study Overview

• Status: Recruiting
• Conditions: Surgical Site Infection; Wound Infection; Fractures, Open
• Intervention / Treatment: Drug: Tobramycin Injection

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Arun Aneja, MD, PhD; Phone Number: 617-726-6546; Email: aaneja@mgh.harvard.edu
• Study Contact Backup: Name: Austin Foster, MD; Phone Number: 617-643-1231; Email: jfoster14@mgh.harvard.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Active, not recruiting
      • University of Kentucky
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: William Obremskey, MD; Email: william.obremskey@vumc.org
      • Contact: Karen M Trochez; Email: karen.m.trochez@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Open fracture to arm, leg, or both
• Over the age of 18

Exclusion Criteria:

• Under the age of 18
• Allergy to tobramycin or any other antibiotic in the aminoglycoside family
• Previously treated with a resorbable antibiotic carrier
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tobramycin Treatment Group; Participants in this group receive a local aqueous tobramycin injection (2mg/mL) plus standard of care treatment.	Drug: Tobramycin Injection; 80 milligrams of tobramycin diluted in 40 milliliters of normal saline
No Intervention: Standard of Care Treatment Group; Participants in this group receive standard of care treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of infection	Rate of infection one year after open fracture fixation surgery.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tobramycin effects on non-union	Modified radiographic union score for tibial fracture (mRUST) scores combined with clinical observation of functional weight bearing at 3 months will be assessed. If union status remains unclear, nonunion will be further defined as a need for secondary bone grafting or surgical intervention.	3 months after surgery
Tobramycin effects on non-union	Modified radiographic union score for tibial fracture (mRUST) scores combined with clinical observation of functional weight bearing at 6 months will be assessed. If union status remains unclear, nonunion will be further defined as a need for secondary bone grafting or surgical intervention.	6 months after surgery
Tobramycin effects on non-union	Modified radiographic union score for tibial fracture (mRUST) scores combined with clinical observation of functional weight bearing at 12 months will be assessed. If union status remains unclear, nonunion will be further defined as a need for secondary bone grafting or surgical intervention.	12 months after surgery
Difference in bacterial specification between treatment and standard of care group.	Upon identification of a fracture-related infection within the first 12 months following surgical fixation, sterile intraoperative cultures will be obtained and grown over 21 days to determine bacterial speciation.	12 months
Difference in antibiotic resistance between treatment and standard of care group.	Upon identification of a fracture-related infection within the first 12 months following surgical fixation, sterile intraoperative cultures will be obtained and grown over 21 days to determine antimicrobial resistance.	12 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Arun Aneja, MD, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: July 6, 2021
• First Submitted That Met QC Criteria: July 6, 2021
• First Posted (Actual): July 16, 2021

Study Record Updates

• Last Update Posted (Estimated): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Non-union; Tobramycin; Aminoglycoside; Local antibiotic; Open extremity fracture; fracture related infection
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Wounds and Injuries; Disease Attributes; Infections; Communicable Diseases; Fractures, Bone; Surgical Wound Infection; Wound Infection; Fractures, Open; Anti-Infective Agents; Anti-Bacterial Agents; Tobramycin
• Other Study ID Numbers: 2023P003263; GRANT13200494 (Other Grant/Funding Number: DOD, Department of Defense)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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