Tobramycin Injection for Open Fractures

Recruiting in Lexington (>99 mi)

+2 other locations

Overseen By Adam N. Musick, BS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Massachusetts General Hospital

Must not be taking: Aminoglycosides

Disqualifiers: Under 18, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Perioperative period

600 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of the drug Tobramycin Injection for treating open fractures?

Research shows that using local tobramycin injections in combination with other antibiotics can significantly reduce infection rates in open fractures. Additionally, studies have found that local antibiotic therapy with tobramycin is beneficial in lowering infectious complications in severe open fractures. ^{1 2 3 4 5}

Is Tobramycin Injection generally safe for humans?

Tobramycin has been used in various forms to treat infections, but it can have side effects like kidney damage and hearing loss, especially when used in high doses or combined with other forms. Monitoring blood levels during treatment is important to avoid these toxic effects. ^{1 6 7 8 9}

How does the drug Tobramycin Injection differ from other treatments for open fractures?

Tobramycin Injection is unique for open fractures because it is administered locally into the wound cavity, which may enhance its effectiveness in preventing infections compared to standard systemic antibiotics alone. This local delivery method allows the drug to directly target the site of injury, potentially reducing the rate of fracture-related infections. ^{1 2 10 11 12}

Research Team

Arun Aneja, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults over the age of 18 with an open fracture to an arm or leg are eligible for this trial. It's not suitable for those under 18, pregnant individuals, or anyone allergic to tobramycin or aminoglycoside antibiotics.

Inclusion Criteria

I am over 18 years old.

I have an open fracture in my arm, leg, or both.

Exclusion Criteria

Pregnancy

I am allergic to tobramycin or similar antibiotics.

I was treated with a dissolvable antibiotic carrier before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a local aqueous tobramycin injection plus standard of care treatment or standard of care treatment alone

Perioperative period

Follow-up

Participants are monitored for fracture-related infection and healing outcomes

12 months

Treatment Details

Interventions

• Tobramycin Injection

Trial Overview The study is testing if injecting Tobramycin directly into the wound during surgery can prevent infections better than just using standard IV antibiotics in people with open fractures.

Participant Groups

Group I: Tobramycin Treatment Group Experimental Treatment 1 Intervention

Participants in this group receive a local aqueous tobramycin injection (2mg/mL) plus standard of care treatment.

Group II: Standard of Care Treatment Group Active Control 1 Intervention

Participants in this group receive standard of care treatment.

Tobramycin Injection is already approved in United States for the following indications:

Approved in United States as Tobramycin for:

• Bacteremia
• Bacterial Infection
• Bone infection
• Burns, External
• Cystic Fibrosis
• Endocarditis
• Febrile Neutropenia
• Intraabdominal Infection
• Kidney Infections
• Meningitis
• Peritonitis
• Pneumonia
• Rabbit Fever
• Sepsis
• Shunt Infection
• Skin or Soft Tissue Infection

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

David Landy

Lead Sponsor

Trials

1

Recruited

600+

Arun Aneja

Lead Sponsor

Trials

2

Recruited

670+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

This study will evaluate the effectiveness of local aqueous tobramycin injection combined with standard IV antibiotic prophylaxis in reducing fracture-related infections (FRI) after open fracture fixation, involving 600 participants across two trauma centers.

The trial aims to assess not only the rate of FRI but also fracture nonunion rates and bacterial speciation, providing comprehensive insights into the safety and efficacy of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does prophylactic local tobramycin injection lower open fracture infection rates? Aneja, A., Kavolus, MW., Teasdall, RJ., et al.[2022]

In a study of 119 type III B compound fractures treated over six years, the use of local tobramycin-PMMA-beads significantly reduced wound infections and osteomyelitis rates, demonstrating its efficacy in managing these serious injuries.

The overall amputation rate was 5%, with a higher rate of 9.7% for lower leg fractures, indicating that while the treatment was effective, severe cases still posed significant risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of type II B open fracture--therapeutic regimen and results]. Ostermann, PA., Ekkernkamp, A., Henry, SL., et al.[2013]

Both formulations of inhaled tobramycin (Tobi and Bramitob) significantly improve lung function and reduce Pseudomonas aeruginosa density in patients with cystic fibrosis, based on randomized controlled studies.

Inhaled tobramycin is well tolerated, with no evidence of serious side effects like renal or ototoxicity, and it may enhance patient compliance by reducing nebulisation time, which can improve overall quality of life and reduce healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin for inhalation in cystic fibrosis: Beyond respiratory improvements. Chuchalin, A., Amelina, E., Bianco, F.[2013]

In a study of 351 patients with open fractures, local injections of aminoglycosides (gentamicin and tobramycin) alongside systemic antibiotics significantly reduced the overall infection rate from 19.7% to 9.5%.

The use of local antibiotics was identified as an independent predictor of lower rates of both deep and superficial infections, without affecting the rate of fracture nonunion, indicating their potential safety and efficacy in infection prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local Injection of Aminoglycosides for Prophylaxis Against Infection in Open Fractures. Lawing, CR., Lin, FC., Dahners, LE.[2022]

Tobramycin is an aminoglycoside antibiotic that is more effective against Pseudomonas aeruginosa than gentamicin and may have a lower risk of causing hearing loss (ototoxicity), making it a promising option for treating certain infections in pediatric patients.

It is crucial to confirm in vitro susceptibility to tobramycin before use, as resistance can occur, and careful monitoring of serum concentrations is necessary to ensure safe and effective dosing, especially in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary: An appraisal of tobramycin usage in pediatrics. McCracken, GH., Nelson, JD.[2019]

Two patients experienced falsely elevated serum tobramycin concentrations while receiving both inhaled and intravenous tobramycin, highlighting a potential risk of toxicity.

These cases emphasize the need for clear guidelines on monitoring and administering concurrent inhaled and intravenous tobramycin therapy in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin. Elidemir, O., Maciejewski, SR., Oermann, CM.[2019]

High strength tobramycin solution (20% tobramycin sulfate) can be effectively nebulized using various nebulizer systems, with the NE-U22 Omron® and Aeroneb Go® showing the highest efficiency in delivering the medication.

Compared to the standard TOBI® solution, the high strength tobramycin solution resulted in over 73% more respirable inhaled dose, potentially improving treatment outcomes for cystic fibrosis patients with chronic Pseudomonas aeruginosa infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems. Mashat, M., Clark, BJ., Assi, KH., et al.[2018]

In a study involving 25 rabbits with osteomyelitis, tobramycin-loaded calcium phosphate beads significantly reduced bacterial growth of Staphylococcus aureus by 3.2 to 3.4 log10 CFU/g of bone tissue compared to control groups.

The use of tobramycin-loaded CPB resulted in no evidence of bacterial growth and prevented chronic osteomyelitis, suggesting it could be a highly effective local treatment option for bone infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo efficacy of tobramycin-loaded synthetic calcium phosphate beads in a rabbit model of staphylococcal osteomyelitis. Lulu, GA., Karunanidhi, A., Mohamad Yusof, L., et al.[2020]

The combination of tobramycin and carbenicillin showed a synergistic effect against clinical strains of Pseudomonas aeruginosa, effective in treating experimental sepsis, with a success rate of 67%.

While the combination was effective, it did not increase the nephrotoxic effects of tobramycin, indicating that the toxicity levels remained consistent with tobramycin used alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin]. Vinogradova, IV., Filippos'iants, ST., Shevniuk, LA.[2020]

Tobramycin effectively penetrates the aqueous humor of the eye after being given either intramuscularly or intravenously, achieving therapeutic levels in 36 cataract patients.

Subconjunctival administration of tobramycin can reach levels in the eye that exceed the minimum inhibitory concentration needed to combat common bacteria like Pseudomonas and Staphylococcus, with no reported adverse effects, making it a promising option for treating acute ocular infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin levels in human eyes. Furgiuele, FP., Smith, JP., Baron, JG.[2019]

Subconjunctival injection of tobramycin sulphate resulted in therapeutically effective concentrations in the aqueous humour (mean: 18.9 microgram/ml), indicating its potential effectiveness for treating ocular infections.

In contrast, intramuscular injections of tobramycin produced insignificant levels in the aqueous humour, suggesting that this route is not effective for ocular treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penetration of tobramycin sulphate into the human eye. Petounis, A., Papapanos, G., Karageorgiou-Makromihelaki, C.[2019]

Subconjunctival injections of Tobramycin resulted in significantly higher concentrations of the antibiotic in the aqueous humor compared to intramuscular injections, indicating a more effective delivery method for targeting eye infections.

The subconjunctival application of Tobramycin was well tolerated in animal experiments, suggesting it is a safe option for administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental investigations of the aqueous humor and blood serum of rabbits following injection of tobramycin]. Papapanos, G., Petunis, A., Karageorgiou, X.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Does prophylactic local tobramycin injection lower open fracture infection rates? [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

[Treatment of type II B open fracture--therapeutic regimen and results]. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Tobramycin for inhalation in cystic fibrosis: Beyond respiratory improvements. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Local Injection of Aminoglycosides for Prophylaxis Against Infection in Open Fractures. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Commentary: An appraisal of tobramycin usage in pediatrics. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin. [2019]

7. England pubmed.ncbi.nlm.nih.gov

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems. [2018]

8. England pubmed.ncbi.nlm.nih.gov

In vivo efficacy of tobramycin-loaded synthetic calcium phosphate beads in a rabbit model of staphylococcal osteomyelitis. [2020]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin]. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Tobramycin levels in human eyes. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Penetration of tobramycin sulphate into the human eye. [2019]

12. Germany pubmed.ncbi.nlm.nih.gov

[Experimental investigations of the aqueous humor and blood serum of rabbits following injection of tobramycin]. [2019]