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Transcript
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.