Antibiotic Care for Fractures

Recruiting at 32 trial locations

Overseen By Suna Chung, MPH

Age: 18 - 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Major Extremity Trauma Research Consortium

Disqualifiers: Severe psychiatric condition, 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: 1-2 weeks

1200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to prevent infections in individuals with severe leg and ankle fractures. Researchers compare the standard treatment to a new approach using the antibiotics Tobramycin and Vancomycin. The trial targets individuals with serious fractures in the tibia, ankle, or hindfoot, particularly those who have undergone multiple procedures to repair these injuries. Eligible participants have these specific fractures and face infection risks, possibly due to conditions like diabetes or a weakened immune system. The goal is to determine if the new antibiotic method can more effectively prevent infections after surgery. As a Phase 3 trial, this study represents the final step before FDA approval, allowing participants to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients can have risk factors for infection and may be on medications like steroids, so it seems you might be able to continue some medications. It's best to discuss this with the trial coordinators.

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

Research shows that using the antibiotics vancomycin and tobramycin together on wounds is generally safe for people. Previous studies have demonstrated this combination's effectiveness in reducing infection risk after surgeries, particularly in severe open fractures. For example, one study found a significant decrease in infection rates when these antibiotics were applied directly to the wound. Another study reported a 12% reduction in infection risk for patients treated with these local antibiotics compared to those who received standard care.

These findings suggest that vancomycin and tobramycin are usually well-tolerated and can help prevent infections in high-risk situations. While all treatments can have side effects, the evidence so far supports the safe use of these antibiotics in the situations described. Participants should consult their doctor if they have questions or concerns about joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the use of Vancomycin and Tobramycin for treating fracture-related infections because this treatment method offers a unique approach. Unlike traditional treatments, which typically involve oral or systemic antibiotics, this method applies antibiotics directly to the wound surface, fracture site, and any exposed hardware. This targeted delivery could potentially improve effectiveness by concentrating the antibiotics exactly where they're needed most, right at the site of potential infection. Additionally, this approach is combined with systemic antibiotic therapy, which may enhance the overall infection-fighting power. This dual method aims to reduce recovery time and improve outcomes for patients with fractures.

What evidence suggests that this trial's treatments could be effective for open fractures?

In this trial, participants in the experimental treatment arm will receive a combination of vancomycin and tobramycin applied directly to the wound surface, fracture site, and exposed hardware, followed by systemic antibiotic therapy. Studies have shown that using vancomycin and tobramycin together can lower the risk of infections in open fractures. Specifically, one study found that this antibiotic combination reduced the rate of deep surgical site infections (SSIs) during fracture treatments. Another analysis demonstrated that using both whole-body and directly applied antibiotics significantly decreased the SSI rate compared to using just one type. Research also indicates that vancomycin powder helps reduce infection risk after fixing high-risk tibia fractures. Overall, these antibiotics show promise for preventing infections in open fractures. ^{1 3 4 6 7}

Who Is on the Research Team?

Micahel J Bosse, MD

Principal Investigator

Carolinas Medical Center

Rachel Seymour, PhD

Principal Investigator

Atrium Health Musculoskeletal Institute Research

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 18-64 with severe open fractures of the tibia, ankle, or hindfoot that require further surgery after initial stabilization. Suitable for those with additional injuries or risk factors like diabetes and immunosuppression. Not for intellectually challenged individuals without support, those unlikely to follow up due to location or lack of contact means, prisoners, or patients already receiving infection treatment at the study site.

Inclusion Criteria

You have had a head injury.

I have a severe ankle fracture.

I may have other fractures besides the one being studied.

Exclusion Criteria

I am currently being treated for an infection at the site related to the study.

You have a cognitive disability and lack sufficient family support.

Patient likely to have difficulty maintaining follow-up, including:

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard care or the SEXTANT protocol, including administration of Vancomycin and Tobramycin, followed by at least 72 hours of systemic antibiotic therapy

1-2 weeks

Follow-up

Participants are monitored for surgical site infections, fracture revision rates, and antibiotic-related adverse events

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tobramycin
• Vancomycin

Trial Overview The SEXTANT trial is comparing standard care against a new protocol involving Vancomycin and Tobramycin in treating Type III open fractures. It's a multi-center study where participants are randomly chosen to receive either the current standard treatment or the experimental antibiotic regimen.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 1 Intervention

The patients in the SEXTANT cohort will have 1000 mg of Vancomycin and 1200 mg of Tobramycin administered to the wound surface, fracture site and exposed hardware (if any) just prior to suture closure of the wound or flap. The SEXTANT cohort will then receive at least 72 hours of systemic antibiotic therapy targeted to the modern wound bioburden.

Group II: Control Active Control 1 Intervention

Participants in the control group will receive standard of care treatment for their injury, to include all institution specific standard treatment (prophylactic and otherwise) for preventing and treating infection.

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

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 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]

Tobramycin is a potent aminoglycoside antibiotic effective against Pseudomonas aeruginosa, with 83 out of 96 strains showing a minimum inhibitory concentration (MIC) of 3.12 µg/ml or lower, indicating strong antibacterial activity.

The combination of tobramycin with carbenicillin demonstrated additive or synergistic effects against 79 strains of P. aeruginosa, suggesting that this combination could enhance treatment efficacy and is achievable at clinically relevant blood levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin (nebramycin factor 6): in vitro activity against Pseudomonas aeruginosa. Meyer, RD., Young, LS., Armstrong, D.[2021]

Tobramycin sulfate is an effective antibiotic for treating various infections caused by susceptible gram-negative bacteria and staphylococci, with a satisfactory response rate of over 86% in a study of 3,506 patients.

The drug is well tolerated, with only 3.9% of patients experiencing drug-related adverse effects, primarily affecting the nervous system (0.6%) and kidneys (1.5%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin sulfate: a summary of worldwide experience from clinical trials. Bendush, CL., Weber, R.[2019]

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 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]

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]

Tobramycin inhalation powder (TIP) is an effective treatment for cystic fibrosis patients with Pseudomonas aeruginosa infection, showing non-inferior efficacy compared to nebulized tobramycin inhalation solution (TIS) in clinical trials.

TIP offers advantages in convenience and administration time, being delivered in one-third the time of TIS, and patients reported higher satisfaction with TIP despite a slightly higher incidence of cough.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin inhalation powder: a review of its use in the treatment of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis. McKeage, K.[2021]

Tobramycin was effective in treating severe infections, particularly in broncho-pulmonary infections and septicemia without lung involvement, but showed poor results in septicemia originating from lung infections.

The study highlighted tobramycin's effectiveness against staphylococcal infections and its potential advantage over gentamicin for certain Pseudomonas strains, suggesting it should be considered for initial treatment in serious infections due to the risk of gentamicin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of tombramycin in the management of severe infections. Clinical and pharmacological data. Baron, D., Drugeon, H., Nicolas, F., et al.[2019]

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]

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 10 children aged 2-16 years receiving 300mg of nebulised tobramycin via the eFlow nebuliser, serum tobramycin levels exceeded 1mg/L in 3 children, indicating potential systemic absorption.

Raised urinary NAG levels in 5 children suggest early signs of renal toxicity associated with tobramycin use, highlighting the need for monitoring kidney function in pediatric patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis. Guy, EL., Bosomworth, M., Denton, M., et al.[2013]

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. 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 ...

3. 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, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05849090

Vancomycin and Tobramycin Powder Use in Acute Open ... A recent randomized control trial found a 4% decrease risk of infection following powdered vancomycin placement at the time of hardware fixation. However, a ...

5. 2minutemedicine.com 2minutemedicine.com/vancomycin-tobramycin-local-antibiotic-powder-may-reduce-the-incidence-of-orthopedic-surgical-site-infections/

Vancomycin/tobramycin local antibiotic powder may ... Vancomycin/tobramycin local antibiotic powder may reduce the incidence of orthopedic surgical site infections · World Health Organization warns ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11956753/

Orthopaedic infections: novel treatment strategies and ... The results of the VANCO trial suggested that intrawound vancomycin powder significantly reduced the gram-positive infections in patients with ...

7. aaos.org aaos.org/SSITraumaCPG

Prevention of Surgical Site Infections After Major Extremity ... The probability of deep infection was lower in the vancomycin powder than the control group with the effect of vancomycin powder attributed to ...