Noninferiority Comparison of Prophylactic Open Fracture Antimicrobial Regimens

NCT ID: NCT03560232

Last Updated: 2020-09-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-09
• Study Completion Date: 2020-02-19

Brief Summary

To demonstrate noninferiority of three different empiric antimicrobial regimens compared to the traditional antimicrobial regimen for the management of grade III open fractures as well as evaluate outcomes among these groups.

Detailed Description

Per the EAST practice management guidelines, an open fracture is defined as one in which the fracture fragments communicate with the environment through a break in the skin. The presence of an open fracture, either isolated or as part of a multiple injury complex, increases the risk of infection and soft tissue complications. Open fractures are further classified into Grade I - Grade III fractures per the Gustilo Classification. Grade III fractures are those with the highest likelihood of contamination and infection with infection rates ranging from 10% to 42%.

EAST guidelines currently recommend systemic gram positive coverage for all open fractures with the addition of gram negative coverage for all Grade III fractures. Antibiotics should be initiated as soon as possible following the injury and should be continued for 72 hours after the injury or not greater than 24 hours after soft tissue coverage was obtained. Traditionally, patients received the combination of Cefazolin and Gentamicin as the preferred prophylactic antibiotic regimen, despite the need for multiple antibiotics and the risk of nephrotoxicity associated with aminoglycosides. Whether there is clinically a more ideal prophylactic antibiotic available remains to be seen. This proposed research initiative is intended to evaluate several antibiotic regimens with similar spectrums of activity to see if there is an equally effective single agent with minimal nephrotoxicity associated with its use. In selecting the study antibiotics to be utilized in the protocol, available information was obtained regarding timing of antibiotics, organisms identified by culture results, and any studies available on specific antibiotic regimens. In regards to timing, there is evidence to support that time to antibiotics and time to the operating room may be more important than the particular antibiotic itself. Additionally, a recent study from 2015 looked at the organisms identified from culture results for Grade I through Grade III fractures in Germany. The vast majority of cultures obtained were gram positive organisms, even in the Grade III fractures, and included Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus capitis, various Streptococcus species, Enterococcus faecium and Corynebacterium. Interestingly, the only gram negative organism identified in the study was Escherichia coli. Lastly, when trying to identify antibiotic specific studies, a recent study was identified looking at Ceftriaxone as the agent of choice, while limiting the use of vancomycin and aminoglycosides. The conclusion of the study showed a significant decrease in vancomycin and aminoglycosides administered with no increase in infection rates.

Here at St. Elizabeth Youngstown Hospital, the investigator's current trauma and orthopedics practice management guideline has been reviewed and changed multiple times in the past several years. For the vast majority of time, the recommendation has been to use the traditional cefazolin/gentamicin combination. However, several cases of nephrotoxicity led to some hesitation in utilizing this regimen. Therefore, for a short time period, piperacillin/tazobactam was being used for all Grade III fractures instead. At present however, due to conflicting concerns regarding antimicrobial stewardship with utilizing broad spectrum piperacillin/tazobactam with the nephrotoxicity concerns of gentamicin, the approved guideline utilizes cefazolin/gentamicin for patients under 65 years of age and piperacillin/tazobactam for all patients greater than or equal to 65 years of age. This study aims to evaluate non-inferiority of ampicillin/sulbactam, ceftriaxone, and piperacillin/tazobactam when compared to the traditional regimen of cefazolin/gentamicin for grade III open fractures.

Conditions

Open Fracture; Post-Op Wound Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Cefazolin + Gentamicin

[Cefazolin]

Initial dose:

• Cefazolin 2g IV x1 dose (patient weight < 120kg)
• Cefazolin 3g IV x1 dose (patient weight >/= 120kg)

Subsequent dose:

• Cefazolin 2g IV every 8 hrs (CrCl >/= 40 mL/min)
• Cefazolin 2g IV every 12 hrs (CrCl 20-39 mL/min)
• Cefazolin 2g IV every 24 hrs (CrCl < 20 mL/min)

Duration:

• 24 hrs post-op after soft tissue coverage or total of 72 hrs, whichever comes first

[Gentamicin]

Initial dose:

• If Patient age </= 80 years old: 5 mg/kg adjusted body weight x1 dose (Max dose 500 mg)
• If Patient age >80 years old: 3 mg/kg adjusted body weight x1 dose (Max dose 300 mg)

Subsequent dose:

• Pharmacy Consult to dose gentamicin

Duration:

• 24 hrs post-op after soft tissue coverage or total of 72 hrs, whichever comes first

Group Type: ACTIVE_COMPARATOR

Cefazolin + Gentamicin

Intervention Type: DRUG

See arm description

Ceftriaxone

Initial dose:

• Ceftriaxone 2g IV x1 dose

Subsequent dose:

• Ceftriaxone 2g IV every 24 hours

Duration:

• One dose post-op after soft tissue coverage or total of 72 hours, whichever comes first

Group Type: ACTIVE_COMPARATOR

Ceftriaxone

Intervention Type: DRUG

See arm description

Ampicillin/Sulbactam

Initial dose:

• Ampicillin/Sulbactam 3g IV x1 dose

Subsequent dose:

• Ampicillin/Sulbactam 3g IV every 6 hours (CrCl >/= 30 mL/min)
• Ampicillin/Sulbactam 3g IV every 12 hours (CrCl 15-29 mL/min)
• Ampicillin/Sulbactam 3g IV every 24 hours (CrCl <15 mL/min)

Duration:

• 24 hours post-op after soft tissue coverage or total of 72 hours, whichever comes first

Group Type: ACTIVE_COMPARATOR

Ampicillin/sulbactam

Intervention Type: DRUG

See arm description

Piperacillin/Tazobactam

Initial dose:

• Piperacillin/Tazobactam 4.5g IV x1 dose over 30 minutes

Subsequent dose:

• Piperacillin/Tazobactam 3.375g IV every 8 hours over 4 hours (CrCl >/= 20 mL/min)
• Piperacillin/Tazobactam 3.375g IV every 12 hours over 4 hours (CrCl < 20 mL/min)

Duration:

• 24 hours post-op after soft tissue coverage or total of 72 hours, whichever comes first

Group Type: ACTIVE_COMPARATOR

Piperacillin/tazobactam

Intervention Type: DRUG

See arm description

Clindamycin + Gentamicin

Patients with known Penicillin allergy will receive:

[Clindamycin]

Initial dose:

• Clindamycin 900mg IV x1 dose

Subsequent dose:

• Clindamycin 600mg IV every 8 hours

Duration:

• 24 hours post-op after soft tissue coverage or total of 72 hours, whichever comes first

[Gentamicin]

Initial dose:

• If Patient age </= 80 years old: 5 mg/kg adjusted body weight x1 dose (Max dose 500 mg)
• If Patient age >80 years old: 3 mg/kg adjusted body weight x1 dose (Max dose 300 mg)

Subsequent dose:

• Pharmacy Consult to dose gentamicin

Duration:

• 24 hours post-op after soft tissue coverage or total of 72 hours, whichever comes first

Group Type: OTHER

Clindamycin + Gentamicin

Intervention Type: DRUG

See arm description

Interventions

Ceftriaxone

See arm description

Intervention Type: DRUG

Ampicillin/sulbactam

See arm description

Intervention Type: DRUG

Piperacillin/tazobactam

See arm description

Intervention Type: DRUG

Cefazolin + Gentamicin

See arm description

Intervention Type: DRUG

Clindamycin + Gentamicin

See arm description

Intervention Type: DRUG

Other Intervention Names

Rocephin; Unasyn; Zosyn; Ancef + Garamycin; Cleocin + Garamycin

Eligibility Criteria

Inclusion Criteria

• Age great than/equal to 18 years
• Diagnosis of Grade III open fracture

Exclusion Criteria

• Water-borne injury
• Farm-related injury

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mercy Health Ohio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Natalie I Rine, PharmD

Role: STUDY_CHAIR

MercyHealth Youngstown

Paul T Miller, PharmD

Role: STUDY_CHAIR

MercyHealth Youngstown

Tyson T Schrickel, MD

Role: STUDY_CHAIR

MercyHealth Youngstown

Stuart Drew, DO

Role: STUDY_CHAIR

MercyHealth Youngstown

David J Gemmel, PhD

Role: STUDY_CHAIR

MercyHealth Youngstown

Chad W Donley, MD

Role: PRINCIPAL_INVESTIGATOR

MercyHealth Youngstown

Allison R Lauver, PharmD

Role: STUDY_CHAIR

MercyHealth Youngstown

Locations

St. Joseph Warren Hospital

Warren, Ohio, United States

St. Elizabeth Youngstown Hospital

Youngstown, Ohio, United States

Countries

United States

References

Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma. 1984 Aug;24(8):742-6. doi: 10.1097/00005373-198408000-00009.

Reference Type: BACKGROUND

PMID: 6471139 (View on PubMed)

Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: update to practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma. 2011 Mar;70(3):751-4. doi: 10.1097/TA.0b013e31820930e5. No abstract available.

Reference Type: BACKGROUND

PMID: 21610369 (View on PubMed)

Lack WD, Karunakar MA, Angerame MR, Seymour RB, Sims S, Kellam JF, Bosse MJ. Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection. J Orthop Trauma. 2015 Jan;29(1):1-6. doi: 10.1097/BOT.0000000000000262.

Reference Type: BACKGROUND

PMID: 25526095 (View on PubMed)

Otchwemah R, Grams V, Tjardes T, Shafizadeh S, Bathis H, Maegele M, Messler S, Bouillon B, Probst C. Bacterial contamination of open fractures - pathogens, antibiotic resistances and therapeutic regimes in four hospitals of the trauma network Cologne, Germany. Injury. 2015 Oct;46 Suppl 4:S104-8. doi: 10.1016/S0020-1383(15)30027-9.

Reference Type: BACKGROUND

PMID: 26542854 (View on PubMed)

Rodriguez L, Jung HS, Goulet JA, Cicalo A, Machado-Aranda DA, Napolitano LM. Evidence-based protocol for prophylactic antibiotics in open fractures: improved antibiotic stewardship with no increase in infection rates. J Trauma Acute Care Surg. 2014 Sep;77(3):400-7; discussion 407-8; quiz 524. doi: 10.1097/TA.0000000000000398.

Reference Type: BACKGROUND

PMID: 25159242 (View on PubMed)

Lenarz CJ, Watson JT, Moed BR, Israel H, Mullen JD, Macdonald JB. Timing of wound closure in open fractures based on cultures obtained after debridement. J Bone Joint Surg Am. 2010 Aug 18;92(10):1921-6. doi: 10.2106/JBJS.I.00547. Epub 2010 Jul 21.

Reference Type: BACKGROUND

PMID: 20660225 (View on PubMed)

Other Identifiers

17-028

Identifier Type: -

Identifier Source: org_study_id