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Noninferiority Comparison of Prophylactic Open Fracture Antimicrobial Regimens

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ClinicalTrials.gov Identifier: NCT03560232
Recruitment Status : Recruiting
First Posted : June 18, 2018
Last Update Posted : September 5, 2019
Sponsor:
Information provided by (Responsible Party):
Mercy Health Ohio

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.

Condition or disease Intervention/treatment Phase
Open Fracture Post-Op Wound Infection Drug: Ceftriaxone Drug: Ampicillin/sulbactam Drug: Piperacillin/tazobactam Drug: Cefazolin + Gentamicin Drug: Clindamycin + Gentamicin Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, open-label
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Randomized Controlled Trial Assessing Noninferiority of Three Antimicrobial Regimens for the Treatment of Grade III Open Fractures
Actual Study Start Date : July 9, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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
Drug: Cefazolin + Gentamicin
See arm description
Other Name: Ancef + Garamycin

Active Comparator: 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
Drug: Ceftriaxone
See arm description
Other Name: Rocephin

Active Comparator: 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
Drug: Ampicillin/sulbactam
See arm description
Other Name: Unasyn

Active Comparator: 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
Drug: Piperacillin/tazobactam
See arm description
Other Name: Zosyn

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
Drug: Clindamycin + Gentamicin
See arm description
Other Name: Cleocin + Garamycin




Primary Outcome Measures :
  1. Post-surgical site wound infections [ Time Frame: 1 year ]
    The primary outcome for this study is the number of post-surgical site wound infections, defined as initiation of antibiotics for surgical-site infection and/or need for surgical debridement of site. The acceptable infection rate per Trauma Practice Management Guidelines states a rate less than 20%.


Secondary Outcome Measures :
  1. Incidence of acute kidney injury [ Time Frame: Hospital admission ]

    Incidence of acute kidney injury during hospital admission will be collected and compared to the other antibiotic regimens.

    Acute kidney injury is defined as (per KDIGO guidelines):

    • An increase in SCr by 0.3 mg/dL within 48 hours OR
    • Increase in SCr to 1.5 times baseline within the previous 7 days OR
    • Urine volume less than 0.5 mL/kg/h for 6 hours

  2. Average cost of antibiotic therapy per patient [ Time Frame: Hospital admission ]
    Cost per patient of each antibiotic therapy will be calculated and compared to the other antibiotic regimens

  3. Time to antibiotic therapy [ Time Frame: Hospital admission ]
    Time from arrival to receiving first dose of antibiotic therapy will be collected (Goal within 30 minutes of arrival).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • Water-borne injury
  • Farm-related injury

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03560232


Contacts
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Contact: Chad W Donley, MD 330-480-3667 chad_donley@mercy.com
Contact: Allison R Lauver, PharmD 330-480-3829 allison_lauver@mercy.com

Locations
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United States, Ohio
St. Joseph Warren Hospital Recruiting
Warren, Ohio, United States, 44484
Contact: Chad Donley, MD    330-841-4029    chad_donley@mercy.com   
Principal Investigator: Chad Donley, MD         
St. Elizabeth Youngstown Hospital Recruiting
Youngstown, Ohio, United States, 44501
Contact: Chad Donley, MD    330-480-3667    chad_donley@mercy.com   
Principal Investigator: Chad Donley, MD         
Sponsors and Collaborators
Mercy Health Ohio
Investigators
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Study Chair: Natalie I Rine, PharmD MercyHealth Youngstown
Study Chair: Paul T Miller, PharmD MercyHealth Youngstown
Study Chair: Tyson T Schrickel, MD MercyHealth Youngstown
Study Chair: Stuart Drew, DO MercyHealth Youngstown
Study Chair: David J Gemmel, PhD MercyHealth Youngstown
Principal Investigator: Chad W Donley, MD MercyHealth Youngstown
Study Chair: Allison R Lauver, PharmD MercyHealth Youngstown

Publications:

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Responsible Party: Mercy Health Ohio
ClinicalTrials.gov Identifier: NCT03560232     History of Changes
Other Study ID Numbers: 17-028
First Posted: June 18, 2018    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Mercy Health Ohio:
Open Fracture
Wound Infection
Antimicrobial Prophylaxis
Cefazolin
Gentamicin
Ceftriaxone
Ampicillin/Sulbactam
Clindamycin
Piperacillin/tazobactam
Additional relevant MeSH terms:
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Ampicillin
Wound Infection
Surgical Wound Infection
Fractures, Bone
Fractures, Open
Infection
Wounds and Injuries
Postoperative Complications
Pathologic Processes
Clindamycin
Clindamycin palmitate
Clindamycin phosphate
Gentamicins
Ceftriaxone
Cefazolin
Tazobactam
Piperacillin
Piperacillin, Tazobactam Drug Combination
Sulbactam
Sultamicillin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
beta-Lactamase Inhibitors