Transcript Postoperative spinal wound infections occur at a rate

Postoperative spinal infection prevention with
gentamicin microspheres.
Kornelis A. Poelstra MD PhD*, Alexander R. Vaccaro MD#, Steven Lampro BS#,
Christopher Adams PhD#,Reid Rubsamen MD%, Todd J. Albert MD#
* Department of Orthopaedics, University of Maryland – Shock Trauma, Baltimore MD
Rothman Institute, Thomas Jefferson University, Philadelphia, PA. % John Muir Medical Center, Walnut Creek, CA
Results:
Introduction:
Postoperative spinal wound infections occur at a rate of 15% in the non-compromised patient population undergoing
elective posterior spinal surgery. Due to numerous systemic
and local factors, this infection with primarily
Staphylococcus aureus in the traumatized spine occurs at 612%.
Returns to the operative room for irrigation and
debridements added to the need for long term intravenous
antibiotics lead to significant morbidity for the patient and
pressures healthcare facilities with tremendous costs.
Local hematoma harboring bacteria at the end of a
procedure, combined with systemic malnutrition, tissue
hypoxia and compromised skin under a brace or due to
long-term supine positioning are important factors for this
increased risk of infection.
Local delivery of PLGA gentamicin-microspheres resulted in controlled
bactericidal levels of 20μg/ml hematoma for 72hrs, while powdered delivery
of equal amounts of gentamicin resulted in cytotoxic ‘burst’-levels above
130μg/ml for the first 24hrs (Figure 4).
After 24hrs, powdered antibiotic levels tapered off rapidly to sub-therapeutic
local concentrations, which could encourage antibiotic-resistance in
remaining organisms. Systemic levels of gentamicin stayed < 0.2μg/ml in the
serum.
After establishing a reliable infection in 78% of all challenged control sites
using 103 CFU S.aureus (Figure 5), gentamicin-microsphere treatment
reduced incidence of infection by 50% (p<0.01 – Chi-square; Figure 6).
Also the severity of infection in the sites that did get infected was reduced in
the treated sites compared to controls by 1.5log values (p=0.03 – paired T-test
Figure 7) for bacterial growth.
Placebo
Two treatment sites and one
control site can be created in a
single animal, increasing
significance of outcomes (via
paired T-tests) and therewith
reducing the number of
animals needed for the study.
Methods:
After pharmacokinetics of the release were studied in-vitro
and in-vivo, three non-contiguous sites (two treatment
sites and one control site; Figure 2) were created in the
spine of each rabbit, and wounds were challenged with S.
aureus (ATCC 23593).
After 7 days, postoperative wound infection was assessed
using standard tissue sampling and bacterial
quantification techniques (fascia, hematoma and bone) to
test our hypothesis that both incidence as well as severity
of postoperative spinal wound infection can be reduced
using controlled, local delivery of gentamicin (Figures 3a
& 3b) using PLGA microsphere technology.
Powdered delivery, however, leads to cytotoxic levels
of aminoglycosides (>100μg/ml) and is of only short
duration. Gentamicin-microsphere controlled delivery
successfully reduced the incidence and severity of
S.aureus postoperative spinal wound infection while
local bactericidal levels of gentamicin remained at
20μg/ml for a prolonged period of time. Minimal
systemic penetration was detected, reducing sideeffects and clearance.
Inoculum
-without antibiotics (placebo)
or
-with 440 μg gentamicin
(right).
Significant growth inhibition
was seen for up to 5-days
afterwards.
Total sites
Infected
Notinfected
Percentage
infected
101
4
0
4
0
102
4
1
3
25
(CFU S.aureus)
103
9
7
2
78
104
7
7
0
100
105
9
9
0
100
Total
33
24
9
73
Treatment
Total sites
Gentamicin
160
Figure 3a:
FloSeal® (Baxter) hemostatic
agent on a blood-agar plate
incubated with
Staphylococcus aureus.
Floseal® mixed with
microspheres (PLGA, 6-23
μg):
Placebo
Gentamicin
140
120
100
toxic level
80
60
40
20
0
0:00
2:00
4:00
10:00
23:59
Time postop (hrs)
Reference:
Poelstra KA, Barekzi NA, Gristina AG, Grainger DW, Schuler TC. A novel spinal implant infection model in rabbits.
Spine 2000;25;406-410
We developed a reliable, controlled release delivery
system for gentamicin to wounds and hematoma using
PLGA resorbable microspheres (Figure 1). The spheres (625 micrometers, resorbtion in 3-10 days) were tested
using a well published spinal infection model in 40 New
Zealand White rabbits.
Local delivery of antibiotics to wounds and hematomas
in the spine is an intuitively attractive option to sterilize
the local environment where intravenous antibiotic
prophylaxis cannot reach (hypoxic, devitalized tissue
and pooled hematoma lacking vascular flow).
All animals survived the procedure and no surgical complications occurred.
Figure 2:
New Zealand White rabbit
infection model with three noncontiguous infection sites per
animal.
Figure 1:
Poly-L-Glycolic Acid microspheres
after production.
They measure 6-23 μm each.
Conclusion:
ug/ml Gentamicin
#
Infected
Notinfected
Percentage
infected
Control
11
11
0
100
Gent-Spheres
22
11
11
50
Likelihood ratio
11.5
P-value:
0.001
Pearson Chi2
8.25
P-value:
0.004
Figure 5:
Establishing an ID-80
using a variety of
concentrations.
103CFU gave a
reliable infection rate
of ~80% without use
of a spinal implant.
Treatment
Control
Gent-Spheres
Figure 3b:
Postoperative day 7; Spine sites
with placebo and gentamicin
microspheres side-by-side…
Average
(log10)
St.Dev
(log10)
7.59
0.73
6.88
1.0
Paired
T-test
(P-value)
Figure 4:
Postoperative
pharmacokinetics for
gentamicin inside the wound.
= powdered gentamicin
= microspheres (duplicate)
20μg/ml = bactericidal
Figure 7:
Gentamicin microspheres significantly
reduced also severity of postoperative
S.aureus wound infection in the spine
in sites that did get infected despite the
local microsphere treatment.
0.003
TAKE HOME
Figure 6:
Gentamicin microspheres significantly
reduced incidence of
postoperative
S.aureus wound
infection in the spine
by 50%.
INFECTION
1. Occurs at a high rate after posterior spine surgery; especially after trauma.
2. Patient factors typically cannot be changed
3. Local wound milieu is compromised:
- dead-space defect fills with hematoma, often harboring bacteria,
- hypoxia due to lengthy supine positioning postoperatively and bracing
MANAGEMENT
1. Meticulous surgical technique.
2. Proper antibiotic prophylaxis and re-dosing during lengthy procedures.
3. Local application of microspheres for controlled release of antibiotics could
become significant to sterilize the hematoma…
5. circumventing shelf-life complications with implant coatings while
distributing local prophylaxis over much greater wound-surface area to…
6. Reduce bacterial adhesion and surface colonization of hardware.