Evaluation of a New Strategy for Protocolized Antibiotic Care for Severe Open Fractures: SEXTANT 2

Evaluation of a New Strategy for Protocolized Antibiotic Care for Severe Open Fractures: SEXTANT 2 - A Continuation of the Multicenter Randomized Control Trial SEXTANT 1

The PRCT evaluates infection outcomes as well as fracture and antibiotic-related complications to include the emergence of resistant bacteria associated with two different antibiotic strategies in the treatment of Gustilo type IIIB tibia and hindfoot fractures (calcaneus and talus) and selected IIIA fractures of the tibia and trauma-related transtibial amputations that are performed in the "zone-of-injury". This study will be conducted in established METRC level 1 trauma centers.

The patients will be randomized as close to admission as possible to either 1) Standard of Care (SOC) prophylactic open fracture protocol, including the use of topical antibiotic as per the usual practice of the surgeon or 2) experimental protocol (SEXTANT). The SEXTANT protocol includes application of wound bioburden-targeted topical Vancomycin powder and Tobramycin powder antibiotic treatment at the time of final wound closure/coverage combined with 72 hours of systemic antibiotic coverage targeted to both gram-positive and gram-negative pathogens. The study will compare the results of the current SOC prophylactic coverage to the strategic wound bioburden treatment (SEXTANT) protocol.

Up until the time of definitive wound closure/coverage, all patients will be treated per the usual regimen of the surgeon / center and in accordance with current Trauma Quality Improvement Program (TQIP) and Surgical Quality Improvement Program (SQIP) recommendations for the care of open fractures.14,15,17 It includes the administration of systemic antibiotics as close to the time of injury as possible.

In the definitive wound closure/coverage procedure post-operative period, participants in the intervention arm will receive 72 hours of systemic antibiotic therapy targeted at the modern wound bioburden, and patients in the usual care arm will receive post-operative care per the usual practice of their surgeon. All other activities related to follow-up and related treatments will proceed per the usual practice of the surgeon.

Specific Aim 1: To determine if the SEXTANT treatment strategy designed to address the modern wound bioburden at the time of delayed wound closure/coverage is superior to the standard-of-care (SOC) antibiotic protocol. Our primary comparison will be the proportion of fracture-related infections (FRI) under the SEXTANT arm versus the FRI proportion for those under standard of care in the first 180 days following final wound closure/coverage. One-year rates of FRI will also be assessed.

Secondary Aims:

To compare rates of antibiotic-related complications (including aseptic nonunion) and serious adverse events (SAEs), including emergence of antibiotic-resistant pathogens, of the two treatment groups in the first 180 days following final wound closure/coverage. One-year rates will also be assessed.

To compare the terminal bioburden of the wounds at the time of delayed closure/coverage as sampled by standard tissue microbiology and assess the effectiveness of the antibiotic regimen.

(Exploratory) To employ emerging NextGen Sequencing rapid PCR platforms for wound pathogen identification in a sub-cohort of patients.

Inclusion Criteria:

1. Injury meeting at least one of the following criteria:

   a. Gustilo type III fractures of the tibia (OTA 41 plateau, OTA 42 shaft and OTA 43 pilon); ankle (OTA 44); calcaneus (OTA 82) and/or talus (OTA 81) with injury characteristics meeting at least one of the following criteria: i. All IIIB fractures ii. IIIA fractures that require a planned second debridement prior to definitive closure / coverage iii. IIIA fractures with extensive contamination or muscle damage precluding definitive internal fixation at the time of initial surgery iv. IIIA fractures with extensive degloving or wound greater than 10 cm after debridement (if indicated, primary wound closure is allowed. Primary wound closure refers to the definitive closure of the wound at the initial surgical event, without plans for re-entry for additional debridement and/or fracture fixation) v. IIIA fractures severe fracture comminution resulting from high energy trauma (if indicated, primary wound closure/coverage is allowed) vi. IIIA fractures with AO/OTA OFC contamination level of severe with material imbedded into bone or soft tissue or with a severe high risk environmental contamination from farm, fecal, dirty water inoculation or other equivalent (if indicated, primary wound closure/coverage is allowed) vii. IIIA Fractures where the skin could be closed after extensive muscle or bone removal (if indicated, primary wound closure/coverage is allowed) viii. IIIA fractures with bone loss resulting in a circumferential gap of 1 cm after debridement (if indicated, primary wound closure/coverage is allowed) ix. Fractures where fasciotomies were performed for impending or diagnosed compartment syndromes (regardless of the initial open or closed classification of the fracture x. Traumatic "zone-of-injury" trans-tibial amputations requiring DPC, and/or flap coverage

2. Ages 18 - 64 years inclusive

3. Patients may have risk factors for infection including diabetes, immunosuppression from steroids or other medications, HIV, or other infections.

4. Patients may have a traumatic brain injury.

5. Patients may have other fractures including spine, upper extremity fractures, contralateral lower extremity injuries, ipsilateral pelvis, hip, femur, or foot injuries.

6. Patients may be treated initially at an outside institution prior to transferring to the study institution, as long as the definitive wound closure/coverage was not performed prior to entrance into the study.

7. Patients with bilateral injuries that meet inclusion criteria may be included, but only the limb rated as "more severe" by the treating surgeon will be enrolled in the study.

8. Patients may have co-existing non-tibial or hindfoot infections, with or without antibiotic treatment.

9. Patients may be definitively stabilized using any method (nail, plate, ex fix, or cast).

10. Patients may have fasciotomy.

Exclusion Criteria:

1. Patient speaks neither English or Spanish

2. Patient in current therapy for a wound, implant or fracture site infection related to the study site.

3. Patient is pregnant, potentially pregnant, or lactating.

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

   1. Diagnosis of a severe psychiatric condition
   2. Intellectually challenged without adequate family support
   3. Resides outside of the hospital's catchment area, unless willing to follow-up by phone or telemedicine
   4. Planning to follow-up at another medical center, unless willing to follow-up by phone or telemedicine
   5. Being a prisoner
   6. Not having a means of contact (address, cell phone, home phone, e-mail)