ORIGINAL ARTICLE
OTA HIGHLIGHT PAPER
Time-Dependent Effectiveness of Locally Applied
Vancomycin Powder in a Contaminated Traumatic
Orthopaedic Wound Model
David J. Tennent, MD,* Stefanie M. Shiels, PhD,* Carlos J. Sanchez Jr, PhD,* Krista L. Niece, PhD,*
Kevin S. Akers, MD,* Daniel J. Stinner, MD,* and Joseph C. Wenke, PhD*
Objectives: To evaluate the effectiveness of locally applied
vancomycin powder at different times postinfection in a contami-
nated traumatic animal model.
Methods: This study used an established segmental defect rat
femur model contaminated with Staphylococcus aureus UAMS-1
followed by treatment at 6 or 24 hours postinfection. Three treat-
ments were evaluated: debridement and irrigation alone (control
group) or in combination with either vancomycin powder or
vancomycin-impregnated poly(methyl methacrylate) beads. Serum
vancomycin levels were determined at scheduled time points over
14 days; bone, surrounding muscle, and implants were harvested for
bacterial and inammatory analyses.
Results: Locally applied vancomycin powder and impregnated
beads signicantly reduced bacteria both within the bone and implant
when treatment was performed at 6 hours. Delaying treatment to 24
hours signicantly reduced the therapeutic efcacy of locally applied
vancomycin of both groups. Serum vancomycin levels were detectable
in all animals treated with vancomycin powder at 24 hours, but
absorption was negligible from beads. At 14 days, vancomycin was
detectable in the surrounding musculature of all animals and in serum
of 20% of animals treated with vancomycin powder.
Accepted for publication April 14, 2016.
From the *United States Army Institute of Surgical Research, TX; and
Department of Orthopaedics, San Antonio Military Medical Center, TX.
Supported by a grant from the Orthopaedic Trauma Association.
Presented at the MHSRS August 1720, 2015, Fort Lauderdale, FL, the
Annual Meeting of the Orthopaedic Trauma Association, October
10, 2015, San Diego, CA, and at the SOMOS Annual Meeting
December 711, 2015, St. Petersburg, FL.
S. M. Shiels, and C. J. Sanchez were supported by an appointment to the
Postgraduate Research Participation Program at the US Army Institute of
Surgical Research administered by the Oak Ridge Institute for Science
and Education through an interagency agreement between the US
Department of Energy and USAMRMC. The other authors report no
conict of interest.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journals Web site (www.jorthotrauma.com).
The opinions or assertions contained herein are the private views of the author
and are not to be construed as ofcial or as reecting the views of the
Department of the Army or the Department of Defense.
Reprints: David J. Tennent, MD, San Antonio Military Medical Center, Fort
Sam Houston, TX (e-mail: david.j.tennent.mil@mail.mil).
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BOT.0000000000000617
J Orthop Trauma  Volume 30, Number 10, October 2016
Copyright 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Conclusions: This study suggests that vancomycin powder is
a promising adjunctive therapy for preventing infection in traumatic
wounds when treatment is performed early. This time-dependent
effectiveness of vancomycin powder is similar to that observed with
systemic and other local delivery adjuncts, which is likely attribut-
able to biolm formation after contamination, conferring intrinsic
recalcitrance to antimicrobials.
Key Words: infection, vancomycin, open fracture
(J Orthop Trauma 2016;30:531537)
INTRODUCTION
High-energy open fractures have infection rates ranging
from 8% to 52% and are associated with signicant cost to the
patient and the health care system.16 Although systemic anti-
biotics are the standard of care, traumatic orthopaedic wounds
frequently have compromised vascularization and extensive
soft tissue injury resulting from their primary injury that can
limit the ability of systemic antibiotics to efciently eradicate
bacterial contamination. Consequently, local application of
antibiotics may be advantageous in addition to systemic
delivery as it ensures a high concentration of antibiotics at
the site of contamination without relying on tissue perfusion
and greatly reduces the risk of systemic toxicity.713 Current
management often relies on delivery vehicles such as bone
cement, including poly(methyl methacrylate) (PMMA), to
provide prolonged, concentrated antibiotic over time. How-
ever, these materials may become an additional source of
infection because of the retained foreign body after antibiotic
depletion and often necessitate removal before denitive
wound closure.
Locally applied antibiotic powders have recently re-
emerged as an adjunct to systemic antibiotics to decrease
surgical site infections in posterior spinal fusions and
trauma.1321 Initial reports indicate that the prophylactic use
of local antibiotic powder has decreased the incidence of deep
surgical site infections from 2.6% to 0.2% while providing
a substantial cost savings of an estimated $3000 per surgery.15
Although the use of locally applied vancomycin powder in
clean orthopaedic surgery has shown success, infections in
traumatic orthopaedic fractures are multifactorial and pro-
longed exposure to contamination may initially predispose
these injuries to a higher infection risk. In these instances,
this extended exposure time to bacterial contaminants may
www.jorthotrauma.com | 531
Tennent et al
allow for the formation of biolms, which are intrinsically
resistant to antibiotics and complicate clinical manage-
ment.2225 The purpose of this study was to evaluate the
effectiveness of locally applied vancomycin powder to
decrease the bacterial burden in a contaminated traumatic
orthopaedic fracture model at different times that resemble
different clinical scenarios. We hypothesize that the local
application of vancomycin powder would decrease bacterial
load in this contaminated fracture model.
MATERIALS AND METHODS
Study Design
This study was conducted in compliance with the
Animal Welfare Act, the implementing Animal Welfare
Regulations, and in accordance with the principles of the
Guide for the Care and Use of Laboratory Animals. All
procedures were performed in a laboratory accredited by the
Association and Accreditation of Laboratory Animal Care
following a protocol approved by our Institutional Animal
Care and Use Committee.
Fifty-four Lewis rats were rst randomly assigned into
treatment groups: debridement and irrigation (D and I)
without local antibiotics (Standard Treatment, n = 18);
D and I with 4 vancomycin-loaded PMMA beads (n = 18);
or D and I with 50 mg local vancomycin powder (n = 18),
which is a sufcient application to coat the entirety of the
wound bed before closure. The rats were then assigned to
a time-to-treatment group: 6 hours (early treatment) (n =
10) or 24 hours (late treatment) (n = 8). The 24-hour treatment
time was chosen as previous in vitro work with Staphylococ-
cus aureus has shown reliable biolm formation at 24
hours.2628 At the specied time-to-treatment point, all ani-
mals underwent D and I with placement of their previously
assigned local antibiotic treatment. All animals were killed 2
weeks after treatment placement and samples analyzed.
Antibiotics and Preparation of PMMA Beads
Vancomycin hydrochloride hydrate powder (Sigma-
Aldrich, St. Louis, MO) was used without modications.
To prepare the antibiotic-loaded PMMA beads, 40 g of
Palacos R (Zimmer, Warsaw, IN) powder was hand mixed
with 6 g vancomycin hydrochloride powder under sterile
conditions. Twenty milliliters of methyl methacrylate mono-
mer was added to the powder mixture as per manufacturer
instructions to create 10% wt/wt vancomycin-impregnated
PMMA. The PMMA was placed in a 3-mm antibiotic bead
mold to create cylindrical beads. Each bead contained
approximately 2 mg vancomycin.25
Procedure
As described previously, critically sized (6 mm) defects
were created in 54 Lewis rat femurs (Harlan Laboratories,
Indianapolis, IN) with a mean weight of 310 6 25 g and
supported by poly acetyl plates and threaded K-wires
(Fig. 1).25,29 Each animal was given sustained-release bupre-
norphine, anesthetized with isourane, and the right hind limb
prepared for surgery. A 3-cm incision was made over the
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J Orthop Trauma  Volume 30, Number 10, October 2016
lateral right thigh and the femoral shaft exposed. A 24-mm
poly acetyl plate was xed to the femur with six 0.9-mm
threaded K-wires, and a 6-mm segment of bone was removed
with a saw under saline irrigation. Each animal was then
inoculated with 1.2 106 6 1.9 105 colony-forming units
(CFUs) of UAMS-1, a clinical S. aureus osteomyelitis isolate,
through a bovine collagen matrix (Sigma-Aldrich), and the
wounds closed.
After the initial procedure, all animals were recovered
and allowed food and water ad libitum. At their designated
time-to-treatment point, the animals were again anesthetized,
the wound reopened, debrided, and irrigated with 60 mL of
sterile normal saline. The assigned treatment was then placed
into the wound, either 50 mg vancomycin powder or four
6-mm vancomycin-impregnated beads as described above
(Fig. 1), the wound closed in layers, and the animal recov-
ered. Beginning at the time of debridement, each animal
received systemic antibiotics for 3 days consisting of twice-
daily subcutaneous injections of cefazolin (5 mg/kg). Four-
teen days after debridement, the animals were anesthetized
and killed with sodium pentobarbital. The plates and wires,
bone, beads, and the surrounding muscle were taken and
analyzed for microbial colonization, inammatory cytokines
[interleukin 6 (IL-6) and tumor necrosis factor a (TNFa)],
and local antibiotic concentration.
Bacterial Enumeration
At euthanasia, the femurs, implants (plates and wires),
and beads were removed. The femurs were ash frozen in
liquid nitrogen, crushed to a ne powder, and resuspended
in normal saline. The implants and beads were suspended in
normal saline and sonicated for 15 minutes to remove
attached bacteria. Serial dilutions of the supernatants were
plated onto 5% sheeps blood agar plates (Remel, Lenexa,
KS) and incubated overnight at 378C. CFUs were counted
and normalized to the weight of explanted material.25
Quantification of Inflammatory Markers
Enzyme-linked immunosorbent assays were performed
using premade kits, as per manufacturers instructions, to
quantify cytokine levels within bone homogenates for TNFa
and IL-6 (Abcam, Cambridge, MA). Supplemental Digital
Content 1 (see Appendix A, http://links.lww.com/BOT/A680).
Measurement of Local and Systemic
Antibiotic Concentrations
To evaluate the levels of local and systemic antibiotic
concentrations of vancomycin after the different treatments,
local tissues and blood were collected. Antibiotic quantica-
tion was completed by high-performance liquid chromatog-
raphy (HPLC) on a Dionex 3000 HPLC system (Dionex,
Thermo Fisher Inc, Sunnyvale, CA) with UV detection.
Blood was drawn through a tail vessel at 6 hours, 24 hours,
7 days, and 14 days into heparin-coated tubes. Plasma was
isolated by centrifugation at 1200 rpm for 10 minutes. Muscle
was collected at the time of sacrice, ash frozen, and
homogenized in phosphate-buffered saline supplemented with
2.5 mM calcium chloride and 0.1 mg/mL of 325 U/mg
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J Orthop Trauma  Volume 30, Number 10, October 2016
FIGURE1. A, Radiographic repre-
sentation of a 6-mm segmental
defect in the rat femur immediately
after the defect creation and bacte-
rial inoculation; (B) Placement of the
vancomycin powder after D and I;
(C) Radiographic representation of
a 6-mm segmental defect in the rat
femur with 4 vancomycin beads
within the wound; (D) placement of
the vancomycin beads before
wound closure. Editors Note: A
color image accompanies the online
version of this article.
collagenase (Sigma-Aldrich). Vancomycin was extracted
from plasma or muscle homogenate and concentrations were
measured by HPLC using UV detection at 210 nm.
Statistics
An infection was dened as detectable bacteria greater
than 103 CFU/g tissue as this level is approximately 1-log
CFU greater than the level of detection and represents the
bacterial burden where bone and implant are expected to
show detectable levels of bacteria.25 Fisher exact test using
absolute bacterial counts was performed comparing the treat-
ment groups with the standard treatment of those animals
infected ($103 CFU/g) and not infected (,103 CFU/g). Stu-
dent t test was used to compare vancomycin concentrations in
the muscle. A 2-way analysis of variance with Bonferroni
t test was used to compare local inammatory markers. Sta-
tistical signicance was set at P , 0.05. All values are ex-
pressed as mean 6 SEM.
RESULTS
All bone and implant samples taken from control
animals developed infection at 6 and 24 hours (Figs. 2A
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Locally Applied Vancomycin
and B). Locally applied vancomycin powder reduced bacteria
both within the bone (Fig. 2A) and on the implants (Fig. 2B)
compared with the standard D and I treatment alone when
local vancomycin treatment was applied 6 hours after con-
tamination (P , 0.001). Similar results were seen for the
vancomycin bead group when treatment was performed at 6
hours (P , 0.05). However, when local vancomycin applica-
tions were delayed until 24 hours after the initial bacterial
inoculation, the vancomycin beads and powder both failed
to decrease infection (P = 1). Bacterial counts on the implants
in those animals treated at 6 hours were signicantly lower
only in the powder group (P , 0.001). Furthermore, there
were no signicant differences in bacteria between the pow-
der and bead groups when treatment was given at either 6 or
24 hours on bone (P = 0.016 and P = 0.564, respectively) or
implants at 24 hours (P = 0.0679).
Vancomycin was detectable in the blood of all vanco-
mycin powder animals at 6 and 24 hours after application,
with an average of 23.5 6 4.0 and 8.6 6 1.8 mg/mL, respec-
tively. These levels declined over time, with less than 30% of
the animals having detectable quantities of vancomycin in the
serum by day 14 (Fig. 3A). In contrast to the vancomycin
powder group, vancomycin beads resulted in negligible
www.jorthotrauma.com | 533
Tennent et al J Orthop Trauma  Volume 30, Number 10, October 2016

FIGURE 2. A, Bacterial enumeration

(log CFU/g) of Staphylococcus
aureus strain, UAMS-1, within the
femur. B, Bacterial enumeration (log
CFU/g) of S. aureus UAMS-1 on the
excised implant. The dotted line
represents the threshold for infec-
tion (.103 CFU/g). *P , 0.05 and
#P , 0.0001 represent significant
differences compared with D and I
alone. Editors Note: A color image
accompanies the online version of
this article.

vancomycin being detected in serum at 6 or 24 hours; how-
ever, low levels of vancomycin became detectable in serum at
days 7 and 14 in those animals treated with vancomycin beads
(Fig. 3A). Vancomycin was also detectable in the adjacent
musculature for both beads, 2.87 (SEM: 1.14) and powder
groups, 5.67 (SEM: 2.53), at 14 days after treatment
(Fig. 3B), indicating persistent antibiotic presence in the sur-
rounding musculature at the time of sacrice.
Consistent with the previous results, measurable levels
of local proinammatory markers, IL-6 and TNFa, corre-
sponded with reductions in microbial burden in all groups
at each time point (Figs. 4A and B), with an exception of

FIGURE 3. Antibiotic concentration

within tissues. A, Vancomycin con-
centrations in serum after the appli-
cation of vancomycin powder; (B)
Vancomycin concentrations in local
muscle tissues. There were no signif-
icant differences in vancomycin con-
centrations in the muscle between
groups (Student t test, P = 0.377).
Editors Note: A color image ac-
companies the online version of this
article.

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J Orthop Trauma  Volume 30, Number 10, October 2016 Locally Applied Vancomycin

FIGURE 4. Levels of local inflammatory proteins IL-6 and TNFa. A, When compared with the standard treatment, there was
a decrease in IL-6 for both vancomycin beads and vancomycin powder at 6 hours. There was also a decrease in IL-6 among the
vancomycin beads at 24 hours. B, There was a significant decrease in TNFa in both vancomycin beads and vancomycin powder at
6 hours but not at 24 hours. *P , 0.05; #P , 0.001. Editors Note: A color image accompanies the online version of this article.

IL-6 of the vancomycin bead group at 24 hours. There was no
difference in levels of IL-6 or TNFa between vancomycin
beads and vancomycin powder groups at 6 hours (P =
0.999 and P = 0.061, respectively) or 24 hours (P = 0.116
and P = 0.133). Lastly, whereas those animals receiving treat-
ment at 6 hours showed little clinical evidence of infection,
including purulence and necrotic tissue, 5 of 8 in the vanco-
mycin bead group and 5 of 8 in the vancomycin powder
group showed purulence and tissue necrosis when the treat-
ment was delayed 24 hours.
DISCUSSION
Using a well-established contaminated orthopaedic
wound model, this study found that the local application of
vancomycin powder was an effective treatment to decrease
infection rates when treatment was performed at 6 hours.
Although the antibiotic beads reduced the infection rate when
administered at 6 hours postcontamination, it is interesting
that there was a dichotomous treatment response; half of the
wounds had large amount of bacteria within the wound and
half were not infected. In contrast, this was not seen within
the antibiotic powder group at the early time point where all
animals displayed an approximately 5-log CFU reduction in
bacteria when compared with D and I alone which were
similar to the corresponding decreases in inammatory
markers in those groups that had decreased levels of intra-
wound bacteria. Vancomycin was also shown to be present at
signicant levels up to 2 weeks after application in the
surrounding musculature in those animals assigned to the
vancomycin powder group. Furthermore, both the local and
serum vancomycin levels were similar between the antibiotic
bead and powder groups 14 days after application. Lastly, it is
interesting to note that there were no differences in bacteria
load between vancomycin powder and beads groups at 6
hours or 24 hours, at 24 on the implants or in inammatory
markers at 6 hours or 24 hours. This may imply that
vancomycin powder is a viable, more cost-effective alterna-
tive to beads that can allow immediate closure of a traumatic
wound when additional procedures are not required.
Previous studies have demonstrated that early antibiotic
administration decreases infection rates when administered
sooner after injury; however, the application of local anti-
biotics has historically relied on secondary delivery mecha-
nisms, such as PMMA, calcium sulfates, or other absorbable
materials.24,25,3038 Much like the spine literature where van-
comycin powder has been used successfully when placed in
a clean surgical wound before closure, vancomycin powder
drastically reduced evidence of infection only when used
early.1421,39 This time-dependent decrease in effectiveness
seen with vancomycin powder is consistent with previous
preclinical studies evaluating the early treatment of contami-
nated wounds and the need for early treatment, presumably
before mature biolm formation could occur, which has
been shown to be within the rst 510 hours after contam-
ination for some organisms.24,25,28,33,34 Furthermore, the
presence of vancomycin powder in the surrounding mus-
culature at 2 weeks seen in this study is similar to the
previous literature showing continued vancomycin pres-
ence in spine wound exudates several days after applica-
tion.15 This time dependency stresses the limitations of
current treatment interventions and the importance of having
other antiinfective agents at the surgeons disposal with
increased effectiveness against biolms when treatment is
delayed or if there is clinical concern for persistent infection,
such as rifampin which has shown in vitro effectiveness at

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Tennent et al
eradicating established biolms of both methicillin-resistant
and methicillin-susceptible S. aureus (MRSA/MSSA).28 The
variability within the group that was treated at 6 hours with
vancomycin beads may have been due to several reasons.
First, PMMA beads are an antibiotic depot and rely on both
elution of the antibiotic and diffusion throughout the wound,
and the vancomycin may not have diffused throughout the
entire wound.36,37 Second, PMMA beads only elute a small
proportion of the antibiotic (generally 10%20%), which
may not have been enough to kill the bacteria within all areas
of the wound.3840
This study, as is inherent to all preclinical animal
studies, has several limitations. Because rodents were
used, the serum vancomycin levels seen in this study
may not translate to human data because of the size of the
animals relative to the amount of vancomycin placed
within the wound. However, this study and previous ones
show that intrawound vancomycin powder is systemically
absorbed and can result in a clinically measurable concen-
tration of serum vancomycin.15 The size of the wound
created in this model is much smaller than a high-energy
contaminated orthopaedic wound. However, we did
attempt to mimic the clinical use of intrawound vancomy-
cin powder and antibiotic-loaded PMMA beads using sim-
ilar amounts of vancomycin powder and beads as has been
described previously.1417,1921,39 This study also did not
measure the potential effect that the vancomycin powder
has on bone healing. Although previous work has shown
that some local antibiotics can affect bone healing, vanco-
mycin is one of the least harmful antibiotics to human
cells. It has been shown to have very little toxicity to
osteoblasts, does not impair bone healing, and has been
used safely in patients undergoing spinal fusion without
signicant complications.4144 Lastly, although this study
only evaluated treatment at 6 or 24 hours, these times were
chosen to represent scenarios of early and delayed initia-
tion of treatment.
This study suggests that the local application of
vancomycin is a promising, cost-effective adjunct for pre-
venting infection in a traumatic wound model when treatment
is not delayed more than 6 hours. The time-dependent
effectiveness of vancomycin is similar to what has been
observed with both systemic and other local delivery
adjuncts. This temporal effect is likely due to biolm
formation after contamination, which causes the bacteria to
become recalcitrant to some antimicrobials, including vanco-
mycin.31 Although this study provides insight into how van-
comycin powder can be used in the orthopaedic trauma
setting, further investigation in clinical studies is needed to
validate this approach in humans. This study also highlights
the need for future preclinical studies to examine alternative
therapies which may prove more effective than vancomycin
against established infections.
ACKNOWLEDGMENTS
The authors thank Charnae Williams and Rebecca
Garcia for their technical assistance in quantication of the
vancomycin levels and cytokine levels.
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J Orthop Trauma  Volume 30, Number 10, October 2016
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Locally Applied Vancomycin
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