Topical Antibiotics for Surgical Site Infection

(TOBRA Trial)

Not currently recruiting at 46 trial locations

Overseen By Suna Chung, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Major Extremity Trauma Research Consortium

Must not be taking: Vancomycin, Aminoglycosides

Disqualifiers: Infection, Myonecrosis, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Immediate post-surgery

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two antibiotics, Vancomycin and Tobramycin, can better prevent infections after certain leg surgeries compared to using only Vancomycin. The focus is on surgeries for specific fractures in the lower leg (tibial plateau and tibial pilon), which have a higher risk of infection. Participants should have had these fractures fixed with plates and screws and meet conditions such as requiring an initial temporary fix or having an open fracture. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in infection prevention.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using vancomycin and tobramycin together as a cream or ointment can reduce infections at surgical sites in open fractures. One study found that applying these antibiotics before closing a wound lowered infection rates from 5.7% to 2%. This finding suggests that this antibiotic combination can effectively prevent infections.

Regarding safety, the combination is generally well-tolerated. Studies on using vancomycin directly on wounds have shown it reduces infections without major safety concerns. Although specific data on using vancomycin and tobramycin together is limited, existing research suggests they do not cause significant harm when used this way.

In summary, using vancomycin and tobramycin as a topical treatment is generally considered safe and can help lower infection rates in surgeries involving open fractures. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the use of topical antibiotics like Vancomycin and Tobramycin for preventing surgical site infections because this combination has the potential to offer enhanced protection compared to the standard practice. Unlike traditional systemic antibiotics that circulate throughout the entire body, these antibiotics are applied directly to the wound site, which could lead to more effective localized infection control and reduce the risk of antibiotic resistance. Additionally, the use of both Vancomycin and Tobramycin together could provide a broader spectrum of bacterial coverage, potentially lowering the chance of infection even further. This targeted approach might not only improve healing outcomes but also streamline recovery times for patients undergoing surgery.

What evidence suggests that this trial's treatments could be effective for reducing post-fixation infections in tibial fractures?

In this trial, participants in the treatment group will receive both vancomycin and tobramycin powders. Research has shown that this combination can reduce the risk of deep surgical site infections (SSIs) after fracture surgeries. Using both antibiotics results in fewer infections compared to vancomycin alone, which the control group receives. Vancomycin targets specific bacteria that commonly cause surgical infections, while tobramycin offers additional protection by targeting a broader range of bacteria. Overall, using these antibiotics together can significantly lower infection rates in surgeries for high-risk fractures. ^{1 4 5 6 7}

Who Is on the Research Team?

Robert O'Toole, MD

Principal Investigator

University of Maryland, Department of Orthopaedic Trauma

Renan C Castillo, PhD

Principal Investigator

Johns Hopkins Bloomberg School of Public Health

Anthony R Carlini, MS

Principal Investigator

Johns Hopkins Bloomberg School of Public Health

Are You a Good Fit for This Trial?

Adults aged 18-80 with high-risk tibial fractures initially treated with external fixation, who are now receiving plate and screw fixation. Ideal candidates have no severe allergies to Vancomycin or Tobramycin, are not pregnant, and can commit to follow-up appointments.

Inclusion Criteria

I have an open fracture type I, II, or IIIA.

I was first treated with a brace or cast and had definitive treatment after 3 days once swelling went down.

My leg fracture was treated with surgery using plates and screws, and it's at a high risk of infection.

Exclusion Criteria

Study injury is already infected at time of study enrollment.

Patients with allergies, drug administration reactions, or other sensitivities to Vancomycin (such as a history of Redman's Syndrome).

Currently pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Vancomycin powder or a combination of Vancomycin and Tobramycin powders in their wound bed immediately before wound closure

Immediate post-surgery

Follow-up

Participants are monitored for deep surgical site infections and antibiotic resistance

26 weeks

Extended Follow-up

Participants are monitored for additional sensitivity analyses and antibiotic resistance

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tobramycin
• Vancomycin

Trial Overview The TOBRA study is testing if a combination of Vancomycin and Tobramycin powders reduces infection rates post-surgery better than just Vancomycin powder in patients with certain high-risk leg fractures.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 1 Intervention

Standard of Care + Local Vancomycin + Local Tobramycin: Participants in the treatment group will receive a dose of 1000mg of Vancomycin powder AND a dose of 1200mg of Tobramycin powder in their wound bed, which is placed right before wound closure at the final stafe of definitive fracture fixation.

Group II: Control Active Control 1 Intervention

Standard of Care + Local Vancomycin: Participants in the control group will receive a dose of 1000mg of Vancomycin powder in their wound bed, which is placed right before wound closure at the final stage of definitive fracture fixation.

Tobramycin is already approved in United States, European Union for the following indications:

Approved in United States as Tobramycin for:

• Cystic fibrosis-associated bacterial infections
• Lower respiratory tract infections
• Urinary tract infections
• Eye infections
• Skin infections
• Bone infections
• Skin structure infections

Approved in European Union as Tobramycin for:

• Cystic fibrosis-associated bacterial infections
• Lower respiratory tract infections
• Urinary tract infections
• Eye infections
• Skin infections
• Bone infections
• Skin structure infections

Who Is Running the Clinical Trial?

Major Extremity Trauma Research Consortium

Lead Sponsor

Trials

32

Recruited

27,400+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

In a study of 116 septic surgical patients, tobramycin was found to be as effective as gentamicin in treating infections, with a higher likelihood of susceptibility to gram-negative bacteria.

While there were some cases of nephrotoxicity and ototoxicity, these were mostly linked to other factors like prior renal damage rather than tobramycin itself, indicating a relatively safe profile for this new antibiotic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of surgical infections with tobramcin. Stone, HH., Kolb, LD., Geheber, CE., et al.[2019]

Tobramycin was administered to 28 patients with gram-negative infections, showing effective serum levels and resulting in 18 cures, indicating its efficacy against bacteria like Pseudomonas aeruginosa and Klebsiella pneumoniae.

The treatment demonstrated minimal hepatic and renal toxicity, suggesting that tobramycin is a safe option for patients, even those with renal insufficiency when dosages were adjusted accordingly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with tobramycin in the treatment of infections due to gram-negative bacilli. Carmalt, ED., Cortez, LM., Rosenblatt, JE.[2019]

Tobramycin is highly effective against certain strains of Pseudomonas and Staphylococcus aureus, but many strains of Serratia and Streptococcus pneumoniae show resistance to it at achievable concentrations in humans.

The effectiveness of tobramycin can be influenced by the growth medium and the presence of calcium and magnesium ions, which inhibit its bactericidal action, while it works synergistically with carbenicillin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro studies of tobramycin, an aminoglycoside antibiotic. Dienstag, J., Neu, HC.[2021]

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]

In a study of 511 patients with bacterial eye infections, tobramycin was found to be significantly more effective than gentamicin sulfate in resolving symptoms and signs of infection.

Tobramycin also demonstrated greater antibacterial efficacy against common pathogens like Staphylococcus aureus and had a lower frequency of adverse reactions compared to gentamicin, likely due to differences in preservatives used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical tobramycin and gentamicin sulfate in the treatment of ocular infections: multicenter study. Cagle, G., Davis, S., Rosenthal, A., et al.[2014]

In a study of 26 gentamicin-resistant Pseudomonas aeruginosa isolates from hospitalized children, tobramycin showed the highest effectiveness, with 23% of isolates inhibited by achievable concentrations, while gentamicin and netilmicin were ineffective against all isolates.

Combining carbenicillin with tobramycin, sisomicin, or amikacin was found to be synergistic for 92% of the strains, suggesting that this combination could be a safe and effective initial treatment for infections caused by gentamicin-resistant Pseudomonas pending further susceptibility testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of newer aminoglycosides and carbenicillin, alone and in combination, against gentamicin-resistant Pseudomonas aeruginosa. Marks, MI., Hammerberg, S., Greenstone, G., et al.[2021]

Tobramycin solution for inhalation (TOBI) is the only FDA-approved inhaled antibiotic for maintenance therapy in cystic fibrosis patients aged 6 and older who are colonized with Pseudomonas aeruginosa, specifically for those with moderate lung function (25%-75% FEV1).

The approval of TOBI does not extend to treating acute pulmonary exacerbations in cystic fibrosis or for use in patients without cystic fibrosis, highlighting its specific therapeutic role and the lack of other inhaled antibiotics approved for similar use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Technical report: precautions regarding the use of aerosolized antibiotics. Committee on Infectious Diseases and Committee on Drugs. Prober, CG., Walson, PD., Jones, J.[2019]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38176854/

The Effect of Vancomycin and Tobramycin Local Antibiotic ... Conclusions: The use of vancomycin and tobramycin LAP lowered the rate of deep SSIs after open treatment of fractures on propensity-matched ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S002013832100749X

Intra-wound vancomycin and tobramycin powder for ... Recent literature demonstrates that vancomycin powder significantly reduces risk of Gram positive infections following fixation of high-risk tibia fractures, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12522455/

Use of Topical Antibiotics in Open Fractures - PubMed Central The pooled analysis demonstrated a significantly lower SSI rate in patients receiving both systemic and topical antibiotics compared with ...

4. thejns.org thejns.org/spine/view/journals/j-neurosurg-spine/43/4/article-p509.xml

Intraoperative vancomycin for preventing infection after open ... Several RCTs have been published regarding the efficacy of intraoperative vancomycin in preventing surgical infections in open spine surgery.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2590139724001285

A Multi-National AO spine survey with systematic review of ... The addition of topical vancomycin powder before wound closure has been shown to reduce the incidence of SSI from 5.7 % to 2 %. Further, the combined use of ...

6. eor.bioscientifica.com eor.bioscientifica.com/view/journals/eor/9/10/EOR-23-0023.xml

Efficacy and safety of vancomycin for local application in the ... Our study demonstrates that topical application of VP effectively reduces the occurrence of SSI, both superficial and periprosthetic joint ...

7. cureus.com cureus.com/articles/407869-use-of-topical-antibiotics-in-open-fractures-a-systematic-review-and-meta-analysis

Use of Topical Antibiotics in Open Fractures: A Systematic ... Adjunctive topical antibiotic administration was associated with a statistically significant reduction in SSI rates following open fractures.