Clinical trial NCT03560232: Noninferiority Comparison of Prophylactic Open Fracture Antimicrobial Regimens
Official title: A Randomized Controlled Trial Assessing Noninferiority of Three Antimicrobial Regimens for the Treatment of Grade III Open Fractures
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Open Fracture
Post-Op Wound Infection
Keywords: Open Fracture
Wound Infection
Antimicrobial Prophylaxis
Cefazolin
Gentamicin
Ceftriaxone
Ampicillin/Sulbactam
Clindamycin
Piperacillin/tazobactam
Lead sponsor: Mercy Health Ohio
Sponsor class: OTHER
First posted: 2018-06-18
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open-label
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Post-surgical site wound infections
timeFrame: 1 year
Secondary outcomes:
measure: Incidence of acute kidney injury
timeFrame: Hospital admission
measure: Average cost of antibiotic therapy per patient
timeFrame: Hospital admission
measure: Time to antibiotic therapy
timeFrame: Hospital admission
Other outcomes:
Locations:
city: Warren
country: United States
facility: St. Joseph Warren Hospital
state: Ohio
city: Youngstown
country: United States
facility: St. Elizabeth Youngstown Hospital
state: Ohio
Study officials:
affiliation: MercyHealth Youngstown
name: Natalie I Rine, PharmD
role: STUDY_CHAIR
affiliation: MercyHealth Youngstown
name: Paul T Miller, PharmD
role: STUDY_CHAIR
affiliation: MercyHealth Youngstown
name: Tyson T Schrickel, MD
role: STUDY_CHAIR
affiliation: MercyHealth Youngstown
name: Stuart Drew, DO
role: STUDY_CHAIR
affiliation: MercyHealth Youngstown
name: David J Gemmel, PhD
role: STUDY_CHAIR
affiliation: MercyHealth Youngstown
name: Chad W Donley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MercyHealth Youngstown
name: Allison R Lauver, PharmD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.