Noninferiority Comparison of Prophylactic Open Fracture Antimicrobial Regimens

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.

Inclusion Criteria:

- Age great than/equal to 18 years

- Diagnosis of Grade III open fracture

Exclusion Criteria:

- Water-borne injury

- Farm-related injury