Flow Pharma Edura Gentamicin Microsphere Technology Under Development for Surgcal Site Infection Prevention

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 (µg/mL) 1457 (263-2938) 462 (97-2258) 271 (48-732) 128 (37-311)
• Serum drug levels:
– Day 1: 20% detection, average level 1.6 µg/mL (range 0.7 – 5.9)
– Days 2 – 3: 6% detection, serum levels not reported
– ISDA guideline: Keep trough above 10 µg/mL to avoid resistance 4
– S. aureus in vitro MIC commonly ranges from <0.5 – 2 µg/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 (µg/mL) 1457 (263-2938) 462 (97-2258) 271 (48-732) 128 (37-311)
• Serum drug levels:
– Day 1: 20% detection, average level 1.6 µg/mL (range 0.7 – 5.9)
– Days 2 – 3: 6% detection, serum levels not reported
– ISDA guideline: Keep trough above 10 µg/mL to avoid resistance 4
– S. aureus in vitro MIC commonly ranges from <0.5 – 2 µg/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, α: 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 µg/mL)
– Trough level ideally kept >10 µg/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

26. Edura Gentamicin Advantage

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; 49:325–7
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; Feb10–14, 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.