Flow Pharma Edura Presentation 際際滷 Share
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Flow Pharma Edura Gentamicin Microsphere Technology Under Development for Surgcal Site Infection Prevention
Flow Pharma Edura Presentation 際際滷 Share
- 1. Instrumented Spine Surgical Site Infections (SSI) source: AAOS orthopaedic knowledge online
- 2. Contents Risk Factors for SSI Economic impact of SSIs SSI Isolates Presentation of SSI Current methods of prophylaxis Novel approaches for prophylaxis The Edura gentamicin advantage
- 3. Risk Factors Amy Cizket al. Bone and Joint, 2012. Retrospective analysis of 1532 pts over 1 year Inclusion: > 18yo, no prior SSI, invasiveness index > 0 Not statistically significant: age group (p = 0.16 0.60); smoking (p = 0.83); PVD (p = 0.17)
- 4. Risk Factors Amy Cizket al. Bone and Joint, 2012. Retrospective analysis of 1532 pts over 1 year Inclusion: > 18yo, no prior SSI, invasiveness index > 0
- 5. Risk Factors Summary Primary Impact Factor on SSIs: Surgical invasiveness Secondary Impact Factors on SSIs: Treating pre-existing disease Not operating on high risk patients
- 6. Economic Impact About 300,000 US spine fusion surgeries/year1 SSI rate about 6% overall2 Cost per SSI about $24,0002 Total annual spine fusion SSI cost = 0.06 X 300,000 X $24,000 = $432,000,000 Spine fusion SSI now an HAC for IPPS hospitals CMS bulletin May 2012 The hospitals pay
- 7. Analysis of SSI isolates Pullter Gunne et al. Spine, 2010. Retrospective cohort analysis of 3174 pts over 9 years Culture yields Isolated organisms* Diagnosed SSI: 132 (4.2%) Gram(+): 82 (68%) Deep component: 84 (64%) Gram(-): 27 (22%) Superficial only: _____________________________________________________________________________________________________________________________ _____________________________ 48 (36%) _____________________________________________________________________________________________________________________________ _____________________________ S. aureus: 63 (76%) Culture (+): 83 (63%) MSSA: 54 (86%) MRSA: 9 (14%) Culture (-): 38 (29%) _____________________________________________________________________________________________________________________________ _____________________________ E. faecalis: 12 (14%) Monomicrobial: 63 (77%) E. coli 9 (11%) Polymicrobial: 20 (24%) K. pneumoniae 6 (7%) * Percentages calculated as a function of the number of patients with culture growth
- 8. Analysis of SSI isolates Pullter Gunne et al. Spine, 2010. Retrospective cohort analysis of 3174 pts over 9 years Culture yields Isolated organisms* Diagnosed SSI: 132 (4.2%) Gram(+): 82 (68%) Deep component: 84 (64%) Gram(-): 27 (22%) Superficial only: _____________________________________________________________________________________________________________________________ _____________________________ 48 (36%) _____________________________________________________________________________________________________________________________ _____________________________ S. aureus: 63 (76%) Culture (+): 83 (63%) MSSA: 54 (86%) MRSA: 9 (14%) Culture (-): 38 (29%) _____________________________________________________________________________________________________________________________ _____________________________ E. faecalis: 12 (14%) Monomicrobial: 63 (77%) E. coli 9 (11%) Polymicrobial: 20 (24%) K. pneumoniae 6 (7%) * Percentages calculated as a function of the number of patients with culture growth
- 9. Presentation of SSI Pullter Gunne et al. Spine, 2010. Retrospective cohort analysis of 3174 pts over 9 years Median Time to Diagnosis (d) Signs & Symptoms Deep SSI: 15 (6 - 730) ESR 94.4% Superficial SSI: 18 (5 - 85) CRP 98.0% WBC 44 - 58% Microbial trends _____________________________________________________________________________________________________________________________ _____________________________ Drainage 88 (67%) Gram(-) isolates 4X as frequent Pain 36 (27%) in deep vs superficial SSI Fever 34 (26%) Erythema 24 (18%)
- 10. Current methods of prophylaxis IV 1st gen cephalosporin IV vanco non-superior3 Discectomy < 1% Antiseptic prep Decompression 1.5 2% Chlorahex / betadine / isopropanol Fusion 1 5% Ioban dressing Instrumentation 3 9% Laminar flow systems Trauma 8 13% Agency for Healthcare Research and Quality, 2004 Limited room traffic
- 11. Current methods of prophylaxis The economic impact of SSI is large Big spine surgeries are high risk for SSI Current methods are not effective The hospitals are paying for SSI care
- 12. Novel methods for SSI prophylaxis Intrawound Application of Vancomycin Powder Sweet et al. Spine, Nov. 2011. Retrospective cohort study of 1732 consecutive pts over 11 years
- 13. Vancomycin Powder Sweet et al. Objective: To examine safety, drug levels, efficacy Inclusion: Thoracic / lumbar posterior instrumented fusions Control: 2g IV Ancef: 2000 2006, (n = 821) Tx: 2g vancomycin powder adjunct: 2006 2011, (n = 911) Average follow-up: 2.5 years (1 7 year range)
- 14. Vancomycin Powder Sweet et al. Results drug levels Local drug levels, POD 0 3 (n = 178, consecutive) Post op day 0 1 2 3 Drug level (袖g/mL) 1457 (263-2938) 462 (97-2258) 271 (48-732) 128 (37-311) Serum drug levels: Day 1: 20% detection, average level 1.6 袖g/mL (range 0.7 5.9) Days 2 3: 6% detection, serum levels not reported ISDA guideline: Keep trough above 10 袖g/mL to avoid resistance 4 S. aureus in vitro MIC commonly ranges from <0.5 2 袖g/mL 5
- 15. Vancomycin Powder Sweet et al. Results drug levels Local drug levels, POD 0 3 (n = 178, consecutive) Post op day 0 1 2 3 Drug level (袖g/mL) 1457 (263-2938) 462 (97-2258) 271 (48-732) 128 (37-311) Serum drug levels: Day 1: 20% detection, average level 1.6 袖g/mL (range 0.7 5.9) Days 2 3: 6% detection, serum levels not reported ISDA guideline: Keep trough above 10 袖g/mL to avoid resistance 4 S. aureus in vitro MIC commonly ranges from <0.5 2 袖g/mL 5
- 16. Vancomycin Powder Sweet et al. Results infection rate Control: 21 infections (2.6%) 71% Staph spp. Treatment: 2 infections (0.2%) Clostridium septicum, 6 wks post-op, 1 wk s/p diverticulitis E. coli, 4 weeks post-op, immediately s/p E. coli urosepsis Statistical Analysis: Fisher exact test, power analysis Rates significant, with P < 0.0001, 留: 1%, power: 95%
- 17. Vancomycin Powder Issues No coverage of Gram(-) species Increased vancomycin resistance Systemic absorption in 20% of post-op pts (0.7 - 5.9 袖g/mL) Trough level ideally kept >10 袖g/mL to avoid resistance 4 MIC creep in S. aureus spp. 9 17% increase in MIC from 2001 2009 in one institution 10 Unpublished case reports: Vancomycin powder coagulating around nerve roots Localized red man syndrome c/ skin exfoliation
- 18. Novel methods for SSI prophylaxis Edura Gentamicin Microspheres Stall et al. Spine, 2009. Animal study (rabbit spinal implant model) Proof of concept, pharmacokinetic profile
- 19. Gentamicin Microspheres Stall et al. Biodegradable PLGA gentamicin microspheres Rabbit model of spinal fusion6 3 sites per rabbit 1 control, 2 treatment 106 CFU S. aureus inocculation All animals given IM ceftriaxone Exploration on POD 7 Endpoint: S. aureus present on implanted rod and 1 other local tissue sample
- 20. Hematoma Pharmacokinetic profile5 * *Edura = gentamicin microspheres
- 21. Results Stall et al. One Million CFU S. aureus inocculation 20mg/Kg Ceftriaxone pre-Rx 50% infection suppression in animal model
- 22. Vancomycin Powder Efficacy Profile Significant benefit in preventing instrumented spine SSIs No gram negative coverage 2/3 of spine SSIs are deep Deep infections are 4x more likely to be gram negative Safety Profile Very high dose to obtain duration of action Systemic absorption demonstrated Local toxicity reported Worsening drug resistance reported
- 23. Vancomycin Powder Opportunity Address Safety and Efficacy issues Need gram positive and gram negative coverage Need long duration of action without high dosing Need to minimize systemic absorption Need to minimize local toxicity Need to reduce concerns RE creating resistance
- 24. Edura Gentamicin Advantage Gram(-) and gram(+) including MRSA10 Longer duration above MIC7 No systemic absorption8 Dampened peak levels reducing toxicity7 Eliminates vancomycin resistance concern
- 25. Edura Gentamicin Advantage Multiple Issued US Patents 8,138,157 6,357,670 7,293,559 6,241,159 7,059,319 6,196,525 6,792,940 6,174,469 6,595,202 6,119,953 6,554,202 6,116,516 6,386,463
- 27. Edura Gentamicin Advantage Blocking Method Patent Issued
- 28. References 1. J Neurosurg Spine 2011 Jun;14(6):771-8 2. http://www.cms.gov/HospitalAcqCond 3. J Thorac Cardiovasc Surg. 2002 Feb;123(2):326-32. 4. Clinical Infectious Diseases 2009; 49:3257 5. Clin Biochem Rev. 2010 Feb;31(1):21-4. 6. Spine. 2000 Feb;25(4):406-10. 7. Poelstra et al. 53rd ORS Meeting; Feb1014, 2007 8. Spine. 2009 Sept;34(5):479-83. 9. Surg Infect. 2011 Jun;12(3):191-203. 10. J Microbiol Immunol Infect. 2012 May 7. 11. Clin Infect Dis. 2008 Jun 1;46(11):1637-46.
Editor's Notes
- #8: Gram(-) are usually polymicrobial, arent affected by vancomycin, and were present in 40.3% of all positive Deep SSI cultures, compared to only 10% in positive superficial SSI cultures. *** Skin flora is a known cause of late deep SSI, and skin flora is overwhelmingly Gram(+), so preventing early onset deep SSI means adequately targeting gram negatives as well
- #9: Gram(-) are usually polymicrobial, arent affected by vancomycin, and were present in 40.3% of all positive Deep SSI cultures, compared to only 10% in positive superficial SSI cultures. *** Skin flora is a known cause of late deep SSI, and skin flora is overwhelmingly Gram(+), so preventing early onset deep SSI means adequately targeting gram negatives as well
- #10: CRP is better than ESR, because at 15 days, CRP normalizes in normal pts, while ESR is still peaking in normal and infected ptsCommon
- #11: < 60% of clinical isolates from wound infections in the US are resistant to cephalosporins (Sweet et al.)Current IV prophylaxis with cephalosporins provides coverage for less than half of the staph organisms found in hospitals and is probably not an adequate prophylactic agent by itself. - SweetUnfortunately, intravenous vancomycin has not been shown to reduce surgical wound infection rates. [relative to cephalosporins] - Sweet
- #15: Clinical Infectious Diseases 2009; 49:3257 it is recommended that trough serum vancomycin concentrations always be maintained at 10 mcg/L to avoid the development of resistance. (Level of evidence, III; grade of recommendation, B.)
- #16: Clinical Infectious Diseases 2009; 49:3257 it is recommended that trough serum vancomycin concentrations always be maintained at 10 mcg/L to avoid the development of resistance. (Level of evidence, III; grade of recommendation, B.)