Acute Application Of Intrawound Antibiotic Powder In Open Extremity Fracture Wounds
Phase: PHASE4
Conditions: Fractures, Open, Wounds and Injuries--Infections, Anti-Bacterial Agents, Fractures, Bone, Extremity Fracture Lower, Extremity Fractures Upper
Sponsor: University of Colorado, Denver

 
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                      COMIRB Protocol 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW 
BOARDCAMPUS BOX F-490    TELEPHONE:  303-724 
1055 Fax: 303-724-0990 
 
 
 
Protocol #: 20-2957 
Project Title: Acute application of intrawound antibiotic powder in open extremity fracture 
wounds 
Principal Investigator: Nicholas Alfonso, M.D. 
Version Date: 5 March 2021 
 
  
 
I. 
Hypotheses and Specific Aims: 
 
We aim to investigate the effectiveness of preoperative intrawound antibiotic powder in preventing 
infection and reducing bacterial burden after open fracture. Our primary outcome is the incidence of 
surgical site infection after open fracture with and without antibiotic powder application in the 
preoperative setting. Secondary outcomes will be based on culture and PCR quantitative analysis. . 
We hypothesize that the subjects who receive preoperative intrawound antibiotic powder will have 
fewer superficial and deep surgical site infections compared to subjects who do not receive the 
antibiotic powder. We also anticipate that the application of the antibiotic powder to open fracture 
wounds preoperatively will decrease the bacterial burden. 
 
Specific Aim 1: To compare the incidence of surgical site infection across the three study groups, 
standard of care, vancomycin antibiotic powder, and tobramycin antibiotic powder. 
Hypothesis 1: There will be a significant decrease in the incidence of surgical site infection in the 
groups that receive the antibiotic powder relative to the standard of care group. 
 
Specific Aim 2: To compare changes in open fracture wound bacterial burden between the pre and 
intra-operative timepoints.  
Hypothesis 2: There will be larger decrease in bacterial load as measured by the Shannon index in 
the antibiotic groups relative to the control group. 
 
Specific Aim 3: To compare changes in the presence of bacterial species commonly associated with 
open fracture surgical site infection between the pre and intra-operative time points. 
Hypothesis: There will be a significant group*time interaction. Changes in the presence of bacterial 
species commonly associated with surgical site infection will significantly depend on group.   
 
II. 
Background and Significance:  
Current open fracture management involves expedited administration of systemic antibiotics which 
has been shown to reduce infection rate1-3, yet infection remains the most common and significant 
complication after high-energy fractures, with rates ranging from 15% to 40%4-7. Rehospitalization 
rates for complications after severe open fractures have been reported as high as 57% and one of the 

 
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major drivers of hospital readmission is deep infection5,8. Deep infection is a common problem in 
combat casualties with open fractures as well6. Furthermore, surgical site infections are associated 
with poor long-term outcomes and is considered one of the most common potentially preventable 
post-operative complication5,8,9. 
The issue with systemic intravenous therapy alone is that the antibiotic concentration in critically 
injured tissues is often less than the desired therapeutic level10. Furthermore, the open fracture wound 
is exposed to the outside environment and even nosocomial bacteria before systemic therapy can be 
initiated. These factors offer great opportunity for bacteria to attach to soft tissues and bone, and 
initiate biofilm production, a recognized source of chronic infections4,11. Given this dilemma, 
multimodal antibiotic therapies are being increasingly used by surgeons to prevent biofilm 
development, with evidence in the literature supporting combined systemic and local 
administration12,13. 
Antibiotic powder has gained substantial interest in infection prevention in orthopedic surgery, with 
the majority of research in spine literature. It has been found to be safe and effective in decreasing the 
infection burden in a local manner, with low systemic risk in prior studies14-23. It is also inexpensive 
and easy to use. Although there is a growing interest and use of antibiotic powder in the trauma 
setting, supporting research is limited24.  
An additional past study conducted at Denver Health Medical Center reviewed the utilization of 
antibiotic powder applied in the operative setting. A sample of 614 independent surgeries in 514 
patients were reviewed in which 152 (25%) patients received topical antibiotic powder based on the 
discretion of the attending surgeons. Patients received either Vancomycin alone (53 patients) with the 
median dose of 1 g (1 g to 2 g) or Vancomycin/Tobramycin (97 patients) with a median dose of 2 g 
(1 g to 2 g)/1.2 g (1.2 g to 1.2 g) respectively. This project supports a successful methodology of 
antibiotic powder application in the acute orthopedic trauma population and more importantly, 
supports that intrawound powdered antibiotics at the proposed dosages do not pose a greater risk than 
that of the standard of care25. 
 Of the studies available on this topic, all of them investigate the effect of antibiotic powder in the 
intra-operative setting.  To date, there is no known study investigating the effects of antibiotic powder 
in reducing infection risk when applied to an open fracture wound in the emergent setting, before the 
patient is taken to the operating room.  
Orthopedic trauma surgeons continue to face a significant rate of infection related complications 
associated with open fractures. Patients who experience these complications often face multiple 
surgeries and poor outcomes resulting in a significant burden to both the patient and the health care 
system. By identifying ways to help decrease infection rates in open fractures, we can strive for 
improved patient care and outcomes. 
III.      Preliminary Studies/Progress Report 
 
A preliminary project has been conducted at the University of Colorado Hospital in conjunction with 
National Jewish Health Genomics Core Laboratory to test the effectiveness and utility of the 
proposed culture collection and next-generation quantitative PCR analysis of bacteria from open 
wounds. Three subjects were enrolled with intrawound specimen swabs collected in the (1) 

 
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emergency department, (2) before prepping in OR, (3) after standard operative prepping, and (4) a 
tissue sample collected intraoperatively as well. A sterile, flocked swab was utilized to collect a 
sample from the wound bed and was then stored in a proprietary buffer solution for storage and 
analysis. This pilot project demonstrated feasibility in the collection process and the analysis using 
16S metagenomics of both DNA and RNA. This protocol will support the proposed project and 
demonstrates validity of the methods that will be utilized to address the secondary outcome measure.  
 
An additional past study conducted at Denver Health Medical Center reviewed the utilization of 
antibiotic powder applied in the operative setting. A sample of 614 independent surgeries in 514 
patients were reviewed in which 152 (25%) patients received topical antibiotic powder based on the 
discretion of the attending surgeons. Patients received either Vancomycin alone (53 patients) with the 
median dose of 1 g (1 g to 2 g) or Vancomycin/Tobramycin (97 patients) with a median dose of 2 g 
(1 g to 2 g)/1.2 g (1.2 g to 1.2 g) respectively. This project supports a successful methodology of 
antibiotic powder application in the acute orthopedic trauma population and more importantly, 
supports that intrawound powdered antibiotics at the proposed dosages do not pose a greater risk than 
that of the standard of care. 
 
 
IV.     Research Methods 
 
A.  Outcome Measure(s):   
 Primary outcome 
Incidence of surgical site infection during the post-operative follow-up period 
 Secondary outcome 
- 
Shannon’s index measure of bacterial diversity based on wound cultures (see 
Figure XX). 
- 
Simpson index measure of bacterial diversity based on the wound cultures. 
- 
Presence of bacterial species commonly attributed to surgical site infections based 
on would cultures including: Staph, enterococcus, acinetobacter, enterobacter, e. 
coli, klebsiella, and pseudomonas. 
 
B. Description of Population to be Enrolled:   
 
Inclusion Criteria for Subjects: 
 
 Subject or proxy willing and able to provide written informed consent. 
 Age between 18 years and 80 years (inclusive), with an upper or lower extremity 
Gustilo Type II, IIIA, or IIIB open fractures requiring debridement and internal 
fixation. 
 Open extremity fractures 
 Time from injury to study intervention 24 hours or less 
 
Exclusion Criteria for Subjects: 
 Individuals under the age of 18 years or over 80 years 
 
Type I or IIIC open fractures 
 
Over 24 hours from time of injury 

 
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 Subjects who have received acute operative care of the open fracture at an outside 
facility prior to presenting at the Emergency Department. 
 
Open fractures distal to the wrist and midfoot 
 
History of chronic infection in the extremity involved. 
 
Subjects who are currently pregnant 
 Subjects who are Prisoners 
 
Subjects with a known allergy to vancomycin or tobramycin 
 
Subjects with a condition or social circumstances that would reduce adherence and 
follow-up.  
 Subjects Participating in other clinical research involving investigational antimicrobial 
products within 30 days of randomization. 
 
 
Subjects meeting the study criteria will be consented for debridement and fixation along with 
enrollment in the study if possible before proceeding to the operating room. Based on trauma registry 
data from both institutions, we estimate to have 105 enrolled participants in 18 months, which 
includes an anticipated ten percent failure to enroll. Each arm of the study will enroll approximately 
35 subjects each, See Power and Sample Size 
 
C. Study Design and Research Methods   
 
A randomized clinical cohort study will be utilized to investigate the efficacy of pre-operative 
intrawound antibiotic powder to decrease bacterial burden and subsequent infection after open 
fractures. The study will be performed at two collaborative Level 1 Trauma Centers in a large, urban 
community (University of Colorado Hospital and Denver Health Medical Center). Both institutions 
have orthopedic trauma research teams with experience in the application of antibiotic powder and 
the collection of biologic samples from open wounds.  
 
The intervention will have three treatment arms: standard open fracture wound care (no powder), 
standard of care along with 1.0 gram vancomycin powder application to the open wound in the 
emergency department, or standard or care along with 1.2 gram tobramycin powder application to the 
open wound in the emergency department. This will be a single-blind study as only the participant 
will be blinded to the treatment. The clinical and research teams will be aware of the treatment arm 
for each participant. Subjects will be randomized to the three arms using a blocked stratified 
randomization scheme. Randomization strata will be defined by the fracture severity (type II vs type 
III open fractures). Investigators will be blinded to block size to preserve integrity of the 
randomization strategy. Randomization assignments will be created using the proc plan procedure 
within SAS.   
 
All subjects will receive standard open fracture care in the form of tetanus update (if needed), 
intravenous antibiotics, and splinting/traction as indicated. Gustilo Type II open fractures will receive 
intravenous first generation cephalosporin. Gustilo Type IIIA and IIIB open fractures will receive 
intravenous first generation cephalosporin and aminoglycoside. Intravenous penicillin will be added 
for anaerobic coverage as indicated. In the emergency department, prior to any antibiotic 
introduction, a swab of the wound bed will be collected and stored. 
Arms of the study are as follows: 

 
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Arm 1 – Open fracture wounds are dressed with damp saline-soaked gauze and given standard 
open fracture care. This group will act as internal control.  
Arm 2 – Same as Arm 1, with addition of 1 gram of vancomycin powder applied to the wound 
bed before the dressing is applied. 
Arm 3– Same as Arm 1, with addition of 1.2 grams of tobramycin powder applied to the 
wound bed before the dressing is applied. 
Before proceeding with surgical debridement in the operating room, swabs of the wound bed and 
tissue samples will be obtained. Samples will be collected as described in the METRC Bioburden 
study.4 Additional samples may be obtained for microbiology analysis as part of the standard of care 
and results will be utilized as a comparison for the identification of bacteria present in the wound. All 
treating surgeons will be fellowship trained orthopedic traumatologists and will be trained in proper 
sample collection technique. Subjects will be prospectively followed through their electronic medical 
record to track infection occurrence and other adverse events for six months following final 
debridement and fixation.  
Samples will be vortexed for 1 minute or agitated manually for 3 minutes immediately following 
specimen collection and submersion into the appropriate buffer solution. All manually agitated 
specimens will be vortexed for 1 minute prior to centrifuge. Samples will then be centrifuged at 
1000rpm for 15 seconds and stored in a -80C freezer for temporary storage. 
 
Samples will be analyzed at the National Jewish Health Genomics Core Laboratory using the 16S 
metagenomics sequencing on the Illumina platform. Both RNA and DNA extracts will be utilized to 
identify and quantify the bacteria load in the wound bed at the time immediately prior to surgical 
debridement. Total RNA and genomic DNA will be isolated using standard kits from Qiagen 
(Valencia, CA, USA). The isolated total RNA and genomic DNA will be processed for next-
generation sequencing (NGS) library construction for analysis with a Life Technologies (Carlsbad, 
CA, USA) Ion Gene Studio S5 Prime NGS platform. An Ion Ampliseq Pan-Bacterial Research Panel 
(Carlsbad, CA, USA) will be used to target more than 400,000 bacterial 16s regions. These 16s 
regions can then be used to identify bacteria at the genus and species level. Library construction will 
start from isolation of total RNA and genomic DNA, followed by reverse transcription using random 
priming (RNA), target amplification, adaptor ligation, amplification, and bead templating. Once 
validated, the libraries will be sequenced as barcoded-pooled samples on a 550 chip, as routinely 
performed by the NJH Genomics Facility. Once sequencing is finished, the data will be analyzed 
through the Pan Bacterial Analysis Plug-In through the Torrent Suite software. 
 
The Ion Ampliseq Pan-Bacterial Research pipeline will allow us to identify the bacterial species 
present in the wound cultures. The vegan R package will be used to calculate the Shannon index and 
the Simpson index of biodiversity. This information will allow us to determine whether changes in 
biodiversity differ across the study arms. The purpose of this proof of concept method will be to 
confirm that the bacterial powder causes quantifiable changes in the presence of bacterial species 
relative to the standard of care (no powder group). We acknowledge that diversity is an overly broad 
approach. Changes in diversity may not necessarily reflect changes in the bacterial species commonly 
associated with surgical site infection. Therefore, we will also test for differences in the presence of 
bacterial species commonly associated with surgical site infection before and after antibiotic powder 
treatment. Due to differences in antibiotic coverage between the two antibiotics, we expect changes 
in these species will depend on group (group*time interaction). Together the three aims will provide 
valuable information about the feasibility of the proposed study allowing us to more appropriately 
design a definitive RCT to test the efficacy of antibiotic powder treatment. 

 
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The investigational drug service pharmacy team covering these institutions will be working with the 
study team in dispensing the antibiotic powder. Both institutions participating in this study have 
pharmacy personnel in the emergency department for efficient access to antibiotic powder. All 
orthopedic trauma team members will be trained on a standard application of the antibiotic powder 
and sample collection to ensure consistent therapy and method of sample collection respectively. 
 
 
D.   Description, Risks and Justification of Procedures and Data Collection Tools: 
On presentation to the ER, the Subjects will undergo the standard of care as outlined above. The 
application of local antibiotic powder to the open fracture wound is very low risk as detailed in the 
significance and background section. Potential risks include allergic reaction, systemic absorption of 
antibiotic causing known side effects from both tobramycin and vancomycin such as acute kidney 
injury. However, these risks are very low and well detailed in the literature. 
 
Five samples will be collected as follows: 
 
P1_Swab_1: ED Pre Antibiotics Patient 1 
P1_Swab_2: OR Pre Prep Patient 1 
P1_Swab_3: OR Debridement Patient 1 
P1_Swab_4: Closure Patient 1 
P1_Tissue: Tissue at debridement 
 
P2_S1: ED Pre Sterilization Patient 2 
Etc: Follow Patient 1 order for Patient 2, 3…. 
 
 
When collecting samples, we will be using a cotton tipped swab which will not cause further injury to 
the soft tissues or bone surrounding the open fracture. Samples will be obtained intra-operatively as 
well by similar methods and the risk of further soft tissue damage is extremely low.  
 
Steps for Collection: Swab 
1. Swab patient. 
2. Immediately submerge swab in respective tube. 
3. Cut handle of swab low enough so it can fit in the tube, and the cap can be closed completely. 
4. Begin vortexing tube immediately. Vortex tube for 1 minute. If tube cannot be immediately 
vortexed, begin agitating by inversion for 3 minutes. Once a vortexer is available vortex 
for 1 minute. 
5. Spin down sample in centrifuge at 1000rpm for 15 seconds. 
6. Place sample in -20C or -80C freezer as soon as possible. (Sample is stable at room temp for a 
significant amount of time; however, immediate freezing will guarantee the best results). 
7. Keep sample frozen and deliver to NJH on dry ice. 
 
Steps for Collection: Tissue 
1. Cut tissue ~1 cubic centimeter. 
2. Immediately submerge tissue in respective tube with colored dot. 

 
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3. Begin vortexing tube immediately. Vortex tube for 1 minute. If tube cannot be immediately 
vortexed, begin agitating by inversion for 3 minutes. Once a vortexer is available vortex 
for 1 minute. 
4. Spin down sample in centrifuge at 1000rpm for 15 seconds. Be sure tissue is completely 
submerged in buffer before freezing. 
5. Place sample in -20C or -80C freezer as soon as possible. (Sample is stable at room temp for a 
significant amount of time; however, immediate freezing will guarantee the best results). 
6. Keep sample frozen and deliver to NJH on dry ice. 
 
The procedures in the previous section are the most invasive portion of our study. The data collection 
and analysis performed by National Jewish has no direct risk to the patient’s health or ability to heal 
their fracture. The risks associated with the data analysis by National Jewish are similar for other 
studies dealing with protected health information. All patient’s information will be de-identified and 
placed into a secured database (REDCap) with a randomized study participant ID.   
Subjects will be consented by proxy if they do not have the ability to consent at the time 
of arrival to the emergency department. This will be indicated in instances where the 
subject is intubated or unconscious due to trauma. 
 
Subjects or their proxy will be able to elect to remove themselves from the study at any 
time. They will be provided with the primary investigators phone number and may reach 
out at any time to have their data and specimens destroyed. At the time of notification, all 
patient data will be removed from the REDCap database. If patient swabs or culture 
tubes are still present, the respective laboratory will be notified to destroy and dispose of 
the specimen properly.  This process will be described in the consent.  
 
 Planned Duration of the Entire Study 
The study grant is for 24 months between January 1, 2021 and December 31, 2022. 
Enrollment and data collection will take place for about a year and six months. Final analysis 
will occur subsequently. 
 
E.   Potential Scientific Problems:   
Potential problems with this study include the execution of the methodology when the patient comes 
into the emergency department. Potential issues including obtaining the antibiotic powder in a timely 
fashion once the injury is identified, standardization of obtaining samples in the ER, and consent of 
subjects involved in poly-traumas who are unable to provide consent for the study in the emergent 
setting. 
 
To address the ability to obtain the antibiotic powder, there will be a specific order placed into EPIC 
to streamline the process for both orthopedic team member, ER team, and pharmacy. This order will 
be of the desired antibiotic powder with the correct dose with instruction to not re-constitute the 
powder and to directly provide the bottle to the orthopedic team member for administration.  
 
In regard to timing, pre-made kits will be available in the ER for the orthopedic team member that 
will include all supplies for the protocol including swab sticks, test tube vials, 4x4s, chloraprep stick 
etc. and an instruction sheet that will include a QR code that is scannable by any mobile device with a 
camera.  This QR code will allow the orthopedic team member to enter the patient’s MRN into a box 

 
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which will populate into a secure redcap database and randomize the patient into the correct arm of 
the study which will then allow the provider to order the correct antibiotic powder.  
 
For standardizing the protocol, there will be a formal training on how to perform the protocol in the 
ER to all orthopedic team members participating in the study. In addition, there will be detailed 
instructions within the pre-made kits. This will help to standardize the collection of samples and 
administration of antibiotics. 
 
Given many patients have other associated injuries with open fractures, we will absolutely have 
subjects who are obtunded, altered, or unable to provide consent in the emergency department setting. 
Given the critical timing of managing open fractures and the procedures involved in managing these 
injuries, such as stabilization of the fracture in a splint and identifying other potentially life-
threatening injuries, we will be requesting the use of consenting by proxy for specific circumstances 
at the time of consent for surgery.  
 
F.   Data Analysis Plan:   
Samples obtained from the wound bed will be analyzed as detailed above by National 
Jewish. In addition, we will be sending cultures to the site’s laboratories for standard 
aerobic, anaerobic, acid-fast bacilli, and fungal cultures.  
 
The post-operative data observing the presence of surgical site infection will be collected 
and placed into the secure redcap database. 
 
Sample Size and Power:  
The anticipated sample size in the current study is fixed based on study constraints including funding 
availability, funding duration, and patients eligible for the study during the funding period. Based on 
typical clinical volume, we anticipate we will be able to enroll approximately 117 subjects into the 
study. Assuming attrition is approximately 10% (reasonable assumption given most of data is 
collected at surgery and/or within 90 days of surgery), we anticipate a total sample size of 105 
available for analysis. We simulated data, 100,000 iterations, to evaluate the power available to test 
our primary aim, infection risk, assuming a sample size of 35 individuals per group. We evaluated 
several scenarios to explore power available in the current study. The parameters used in the 
simulation studies including the anticipated infection rate in the standard of care group, were based 
on a recent systematic review that reported the incidence of infection in lower extremity fractures that 
underwent operative treatment ranged between 5 and 40%. The incidence of infection was highest 
among open fractures, and thus we assumed the infection rate in the current study will be closer to the 
higher range of the infection estimates. As outlined below, assuming a common effect in the two 
antibiotic groups, 15% risk of infection, and a higher infection risk in the standard of care group, 40% 
risk of infection, the current study will have >80% power to reject the null hypothesis of no 
difference in infection risk between groups (antibiotic groups vs standard of care). As outlined in the 
table below, power decreases if there is heterogeneity in antibiotic effect and/or if the treatment effect 
is modest.  
 
Study Power Available Under Different Scenarios 
Consistent Treatment Effect 
Heterogeneous Treatment Effect 
Infection 
Rate
Power: Antibiotics 
vs Standard of Care
Infection 
Rate
Power: Vancomycin vs 
Tobramycin vs Standard of Care

 
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Large Treatment Effect
Vancomycin
15% 
81.8% 
15% 
61.7% 
Tobramycin
15% 
20% 
Standard of Care
40% 
40% 
Moderate Treatment Effect
Vancomycin
15% 
45.8% 
15% 
26.1% 
Tobramycin
15% 
20% 
Standard of Care
30% 
30% 
 
 
Statistical Methods:  
Descriptive statistics will be used to summarize group characteristics in the two study groups. Due to 
the small sample size, standardized mean differences will be used to screen for imbalance in relevant 
covariates. Covariates unequally distributed across groups will be adjusted for in subsequent analyses 
using multivariable models. To address aim 1, to test for differences in the incidence of post-
operative infection risk, Chi-Square tests will be used to test for differences in infection risk during 
the first 90 days post-operatively across the study arms. We will first test for differences between 
groups assuming a common effect among the two antibiotics groups. We will test the null hypothesis 
of no difference between antibiotics arms relative to the control group. In order to account for 
randomization strata (fracture severity type II vs type III), we will calculate the common risk 
difference and 95% confidence intervals using the Mantel-Haenszel method. Alternatively, if there is 
heterogeneity in the incidence of infections across the three groups, we will test for pairwise 
differences in infection risk between groups. To address aim 2, changes in wound culture diversity 
indices, linear mixed models will be used to compare changes in diversity indices between the pre- 
and intra-operative time points. A random intercept model will be used to account for clustering of 
multiple observations within subjects. We will test the null hypothesis that the difference between 
time points depends on group (group*time interaction). To address aim 3, changes in presence of 
bacterial species commonly associated with surgical site infection, generalized linear mixed models 
will be used to test for changes in presence of bacterial species, binary yes vs no, before and after 
application of the antibiotic powder. We will test whether changes in the bacterial species depends on 
group. We will account for multiple sources of clustering, multiple bacterial species (Staph, 
enterococcus, acinetobacter, enterobacter, e. coli, klebsiella, and pseudomonas) and time (pre-
operative and intra-operative prior to wound debridement). In this analytic framework, we will test 
the average of the bacterial species-specific binary outcome variables. We will also consider testing 
whether the changes in time points between groups depends on species (group*time*species 
interaction).  
 
Alternative Approaches: The primary analysis assumes that follow-up 
will be consistent across the three groups. Cox proportional hazards 
regression analyses will be considered if subjects are not routinely followed 
for 90 days. 
 
G.  Summarize Knowledge to be Gained:   
Overall, this study will allow us to identify the utility of using antibiotic powder in open 
fracture wounds at the time of presentation. We will be able to either support or refute 
the use of these antibiotics and their ability to decrease surgical site infection in open 
fractures. Given the prevalence of surgical site infection in open fractures, this study may 

 
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change the management of open fractures within the orthopedic community in both 
civilian and military populations. This study if successful will lead to further multi-center 
national studies to be performed. 
 
H. References: 
 
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America. 2017. 
 
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4. Bosse MJ, Murray CK, Carlini AR, Firoozabadi R, Manson T, Scharfstein DO, et al. Assessment 
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