Fresh from the press: Updated best practices in Surgical Site Infection Preve...
LoftinAH _Smart_ Coatings for Spine Implant-Related Infection
1. A novel implant coating
to deliver antibiotic
through an active trigger
mechanism in a spine
infection mouse model
UCLA Department of
Orthopaedic Surgery
“Smart”
Coatings: Amanda
H. Loftin
AALAS Annual Meeting
Wednesday Nov. 4th, 2015
2. Despite advances in
aseptic surgical
technique &
perioperative
antibiotic
use...
Chahound
et.
al.
Front
Med.
2014
.5 -18.8% of patients
post-
operative
infection is
reported to still
occur in approximately
Undergoing spine surgeries.
3. Surgical site
infection
following
spine surgery
is a dreaded
complication
with
significant:
Negative outcomes
for the patient
Detrimental effects on
the healthcare system
Economic burden
1
2
3
Stavrakis et. al. Front Med. 2015
6. This amounts to huge costs,
with the treatment of a single
implant-associated spinal wound
infection potentially costing
more than $900,000
Stavrakis
et
al.
Front
Med.
2015
8. 1 year post-op
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from http://
www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
9. 1 year post-op
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from
http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
10. Staphylococcus aureus
remains that leading agent of spine implant
infections, responsible for around 50% of cases1
1. Chahoud et al. Front Med. 2014
2. Stavrakis et. al. Front Med. 2015
Staphylococcus epidermidis
& Propionibacterium acnes
are also common pathogens 1-2
11. BIOFILM FORMATION
1. Attachment of
S. aureus to
implanted surface
2. Growth
Formation of an
extracellular matrix
that is not
susceptible to
antimicrobial killing.
3. Dispersal of
further
establishes the
biofilm making
treatment
extremely
difficult
Biofilms block penetration of immune cells and
antimicrobials, promoting bacterial survival
12. Orthopedic spinal implant infections are unique in that
the implant is typically retained to prevent destabilizing
the spine making treatment more challenging
Bardis, Alexander. (2014). Late Post-operative Spinal Infections
[PowerPoint Slide]. Retrieved from http://www.slideshare.net/
AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
13. 13
Implants provide
an avascular
surface for bacteria
to form biofilm1-3
1. Cappen DA et al Orthop. Clin North Am 1996
2. Massie JB et al C. O. R.R., 1992
3. Knapp DR et al C. O. R.R. 1988
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from
http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
14. The use of
instrumentation
increases the risk
of infection1-3
1. Cappen DA et al Orthop. Clin North Am 1996
2. Massie JB et al C. O. R.R., 1992
3. Knapp DR et al C. O. R.R. 1988
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved
fromhttp://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
15. The incidence of
spine implant related
infection is:
1. Stavrakis et. al. Front Med. 2015
2. Chahoud et a. Front Med. 2014
3. Smith et. al. Spine. 2011.
1% without instrumentation1
3.4-10% with instrumentation1
One study reports a 28% higher
infection rate with instrumentation
16.
Once biofilm is formed,
bacteria are 100-1,000 times
less susceptible to
antibiotics1
Olsen
et.
al.
J
Neurosurg.
2003
18. Modification of the host
is difficult and often
beyond the surgeons control
18
Reduction of preoperative risk factors is:
timely, requires extreme patient compliance,
and often impossible
20. Some surgical risk factors can
be modified by the surgeon
to decrease risk of infection,
but this may compromise the
intended benefit of the procedure
20
22. Current methods of
local antibiotic delivery
Short-lived
Vancomycin powder
Via passive release from suboptimal loading vehicles
Antibiotic loaded beads
23. 23
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from
ttp://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=2
24. 24
No antibiotic barrier is
present on the implant
itself to protect it from
bacterial colonization and
subsequent biofilm formation
25. 25
Develop a novel, non-toxic,
biodegradable poly (ethylene
glycol )-propylene sulfide (PEG-PPS)
polymer coating that can be used
As a vehicle to deliver antibiotics locally through
both a passive and active mechanism.
To actively release antibiotic in response to the
reactive oxygen cascade initiated by the presence of
bacteria, allowing the “smart” polymer to release
antibiotic where it is needed most.
27. Combines the use of bioluminescent bacteria and
genetically modified mice with advanced imaging to
noninvasively monitor infection and inflammation in real time,
without requiring euthanasia.
Provides a rapid, accurate, and inexpensive in vivo
preclinical screening tool to evaluate the efficacy
of potential strategies to prevent or treat implant
related spine infections.
Strengths of our model
28. 28
Postoperative evaluation of infection and inflammation
Bioluminescence
and fluorescence
imaging
PODs* 0, 1, 3,
5, 7, 10, 14, 18,
21, 28, 35
POD 35
24 lysEGFP mice
(12 wks., male)
POD 35
Evaluation of
bacterial burden
immune response
Visualization
of biofilm
on implant
Colony forming
units (CFUs)
harvested from
implant and
joint tissues
Variable Pressure
Scanning Electron
Microscopy
(VP-SEM)
ex vivo confirmation
of bacterial
burden
POD 0: Intraoperative
inoculation of
S. aureus Xen36
29. Provides a rapid, accurate, and
inexpensive in vivo preclinical screening
tool to evaluate the efficacy of
potential strategies to prevent or
treat implant related spine
infections.
32. PEG-PPS Coating
32
O
O
OH
m
O
O S
S
S
S N
m n
NaH
O
O
O
m
Br
AIBN
SH
O
O
O
O S
OS
O
O S
S
S
m n
N S
S N
1.
2.
NaOMe
star PEG-PPS
star PEG OH
OH
OH
OH
SH
Si
O
O
O
OH
SH
Si
OCH3
OCH3
H3CO
+
Implant
A B
33. Polyethylene glycol polymer
33
• Coating of optimal “timed” release
• Coating of targeted abx
!
S O
OOS
S
PPS PEG
Antibiotic
0.5% Star PEG-PPS
solution at 4°C
Dry coat at 37°C
Implant
Implant
!
!
Figure!7.!Antibiotic!loaded!implant!coating!process!using!star!
PEG6PPS!polymer.!A!solution!of!star!0.5%!PEG6PPS!with!
antibiotic!will!be!used!to!rapidly!coat!the!implant.!Metal!
34. Titanium
Pins
Uncoated
3%
PEG-‐PPS
6%
PEG-‐PPS
Polymer
is
low
profile:
nano-‐micro
scale
Covalent
linkage:
resistant
to
wear
39. Ex Vivo Bacterial Counts
39
0
1000
2000
3000
4000
5000
6000
ColonyFormingUnits
PEG Vanc Tig
Tissue Colony Forming Units Post-
Operative Day 21
40. 40
PEG-PPS is an optimal vehicle to deliver
antibiotics in the setting of spinal implants as
it passively delivers antibiotics above the
MIC and actively increases drug delivery in
the presence of bacteria.
The Vanc impregnated PEG-PPS coating
prevented implant colonization by bacteria and
prevented implant infection completely
This novel coating shows promise in the
prevention and/or treatment of orthopaedic
spine implant infections and further large animal
studies and biosafety studies are warranted.
41. Now that we have a vehicle to
deliver antibiotics,
can we redesign
antibiotics?
41
43. Special Thanks
43
Bernthal Lab
Alexandra Stavrakis
Yan He
Erik Dworsky
Jannifer Manegold
Los Angeles
Orthopaedic Hospital
Fabrizio Billi, PhD
CRUMP
INSTITUTE OF
MOLECULAR
IMAGING
David Stout, PhD
Center for Experimental
Medicine, University of
Tokyo, Japan
Yoichiro Iwakura, D. Sc,
Cedars-Sinai
George Liu, M.D., PhD
Moshe Arditi, M.D.
Caliper Life Sciences
Kevin Francis, Ph.D.Department of Biomedical
Engineering. UC. Davis
Scott Simon, Ph.D.
UCLA Orthopaedic
Hospital Research
Center
John Adams, MD
Jeff Miller, MD
UCLA Department of
Orthopaedic Surgery
Jeffrey Eckardt, MD
Gerald Finerman, MD
Department of
Microbiology and
Immunology.
Dartmouth Medical
School
Ambrose Cheung, MD
