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

Trial Summary

What is the purpose of this trial?

The proposed study is a multi-center, prospective randomized controlled trial comparing current standard of care treatment to the SEXTANT treatment protocol in patients with Type III open fractures of the tibia and IIIB fractures of the ankle and hindfoot.

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.

What data supports the effectiveness of the drug Tobramycin for treating fractures?

Tobramycin is an antibiotic that has shown effectiveness against certain bacteria like Pseudomonas aeruginosa, which can cause infections. It is particularly useful in treating infections resistant to other antibiotics, such as gentamicin. While its use in fractures isn't directly studied, its ability to combat bacterial infections could be beneficial in preventing or treating infections in fracture cases. ^{1 2 3 4 5}

Is tobramycin generally safe for use in humans?

Tobramycin has been evaluated in over 3,500 patients and is generally well tolerated, with drug-related side effects occurring in about 3.9% of patients, including effects on the nervous system (0.6%) and kidneys (1.5%). It is important to monitor serum drug levels during therapy to avoid potential toxicity, especially when used in combination with other forms of tobramycin. ^{1 6 7 8 9}

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

Tobramycin is unique in its use for fractures because it can be injected directly into the wound area to prevent infections, especially those caused by bacteria resistant to other antibiotics. This local application, combined with standard antibiotics, aims to reduce infection rates in open fractures, which is a novel approach compared to traditional systemic antibiotic treatments. ^{1 2 10 11 12}

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

Eligibility Criteria

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 am between 18 and 64 years old.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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 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]

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]

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]

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]

References

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

In vitro studies of tobramycin, an aminoglycoside antibiotic. [2021]

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

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

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

Tobramycin (nebramycin factor 6): in vitro activity against Pseudomonas aeruginosa. [2021]

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

Activity of newer aminoglycosides and carbenicillin, alone and in combination, against gentamicin-resistant Pseudomonas aeruginosa. [2021]

5. New Zealand 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. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis. [2013]

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

Technical report: precautions regarding the use of aerosolized antibiotics. Committee on Infectious Diseases and Committee on Drugs. [2019]

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

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

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

Tobramycin sulfate: a summary of worldwide experience from clinical trials. [2019]

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

Clinical experience with tobramycin in the treatment of infections due to gram-negative bacilli. [2019]

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

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

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

The use of tombramycin in the management of severe infections. Clinical and pharmacological data. [2019]