Biofilms no sign of infection but still not healing? <<Clinical Specialist>>

Biofilms no sign of infection but still not healing? <<Clinical Specialist>>

Chronic wounds Chronic wounds are increasing in prevalence as the population ages and the number of people living with multiple comorbidities that put them at risk of developing wounds rises 1. As the number of older people increases, the prevalence of chronic wounds will also continue to grow. 2

Chronic wounds Wounds represent a significant cost to patients as well as to the health economy 6. Chronic wounds are often hard to heal, resulting in a cycle of pain, anxiety and reduced quality of life for the patients as well as considerable treatment costs 6.

Chronic Wounds life is dominated by care Impact on daily life Reduced wellbeing Will it ever heal? 39072 Pain & discomfort Loss of work Decreased mobility Depression/anxiety My wound Smells Is it infected? Exudate levels Dressing changes

Hard to heal/stalled chronic wounds So you ve managed underlying comorbidities and addressed any obvious infection but the wounds still fails to progress.. WHY? BIOFILMS!

What do you know about Biofilms?

What is a biofilm? Biofilms are bacteria and or fungi that stick to surfaces and each other embedded within a matrix 1 Bacteria within this community can communicate and work cooperatively with each other The protective matrix shields bacteria from external threats like antimicrobial treatments or the body s immune response 1 4 1. Donlan RM and Costerton JW. Clin Microbiol Rev 2002;15:167 193. 2 Phillips PL, et al. Int Wounds J 2013. 3. Cochrane DMG and Brown MRW. J Med Microbiol 1988; 27: 255 261. 4. Hall Stoodley L and Stoodley P. Cell Microbiol 2009; 11(7):1034 1043.

How do biofilms form? 1 Stages of Biofilm formation 1 A. Bacteria loosely attach to a surface B. Bacteria multiply allowing them to irreversibly attach to the surface and form microcolonies C. Bacteria are embedded in a matrix (containing both bacteria and host components) called Extracellular Polymeric Substance (EPS). Cells continue to multiply within this protected community D. Bacteria can disperse from the edges of the biofilm to colonise new surfaces and cause recurrent infections Image adapted from 1. 1. Stoodley, P et al. Annu. Rev. Microbiol. 2002; 56: 187 209.

How quickly do wound biofilms form? Wolcott et al. (2010) 1 assessed antibiotic susceptibility of biofilms over 72 h from inoculation* or post debridement $ oin vitro: drip flow reactor, porcine ex vivo* oin vivo: delayed healing mouse model* oclinical: case study (n=3) following debridement $ Results showed: Increasing tolerance to antibiotics by 24 h Bacteria became resistant to treatment by 48/72 h Conclusions Treatment window with antibiotics up to 48h following debridement Antibiotic failure against mature (>48 h) biofilms Factor into treatment regimes and test model interpretation 1. Wolcott, RD et al. J. Wound Care 2010; 19: 320 328. * In vitro/ animal models $ Clinical evaluation

Biofilms and disease Strong link between Biofilms and chronic/persistent infections in the body 1 Biofilms are medically important and linked to many hospital acquired infections accounting for around 80 percent of persistent microbial infections 2 Reservoir for recurrent infection 1 Minimal treatment options Increased tolerance to antimicrobials (antibiotics and antiseptics) 3 6 Compromised immune response 7 9 1. Costerton JW et al. Science; 1999; 284: 1318 1322. 2. National Institutes of Health. Minutes of the National Advisory Dental and Craniofacial Research Council 153rd Meeting 1997. Report. 3. Phillips PL et al. Int Wounds J 2013; 1 15. 4. Singh R et al. J. Antimicrob. Chemother 2010; 65:1955 1958. 5. Anderl JN et al. Antimicrob. Agents Chemother 2000; 44: 1818 1824. 6. Stewart PS et al. J. Appl. Microbiol 2001; 91, 525 32. 7. Jesaitis AJ et al. J. Immunol. 2003; 171: 4329 4339. 8. Bjarnsholt T et al. Microbiology 2005; 151, 373 383. 9. Cochrane DM et al. J. Med. Microbiol 1988; 27: 255 61.

What evidence links biofilms and nonhealing chronic wounds? Five studies have highlighted; Clinical evidence of biofilms in 60% chronic wounds 1,2 Biofilm in wounds has been demonstrated to delay normal wound healing 2 4 Chronic inflammation from recurrent bacterial infections and immune cell lysis on biofilm affects ability to heal 5 1. James G, et al. Wound Repair Regen. 2008; 16: 37 44. 2. Roche ED, et al. Wound Repair Regen 2012; 20: 537 43. 3. Schierle CF, et al. Wound Repair Regen. 2009;17: 354 9. 4. Zhao G. et al. Wound Repair 2012; 20: 342 352. 5. Bjarnsholt T et al. Wound Repair Regen 2008; 16: 2 10.

How do you know it s a biofilm? No routine biofilm diagnostic tool available Not visible to the eye Non uniform distribution across the wound and presence in deeper tissues creates sampling issues 1,2 Clinician needs to look for indirect signs and symptoms Signs and symptoms of a biofilm presence are less obvious than those of overt acute infections therefore can be overlooked When presented with a combination of these markers biofilm should be suspected and biofilm based wound care initiated 1. Kirketerp Møller, K. et al. J. Clin. Microbiol. 46, 2717 22 (2008). 2. Fazli, M. et al. J. Clin. Microbiol. 2009. 47, 4084 9.

Can you see the Biofilm? With permission from Matthew Malone

Can you see the Biofilm?

Can you see the Biofilm? With permission from Matthew Malone

Biofilm signs and symptoms 1 7 Biofilm Recurrent infections Antimicrobial therapy failure Delayed wound healing infection Immune response to biofilm: low level inflammation and damage to surrounding tissue Physical/ mechanical intervention helps treat Infection symptoms may be obvious 1.Costerton JW et al. Science 1999; 284:1318 1322. 2. Roche ED, et al. Wound Repair Regen 2012; 20: 537 543. 3. Schierle CF, et al. Wound Repair Regen. 2009;17: 354 359. 4. Zhao, G. et al. Wound Repair 2012; 20: 342 352. 5. Bjarnsholt T, et al. Wound Repair Regen 2008; 16: 2 10. 6. Cochrane DM et al. J. Med. Microbiol. 1988; 27: 255 61. 7. Wolcott RD, et al. J. Wound Care 2010; 19, 320 328.

Options for biofilm attack Physical disruption and removal Regular/maintenance debridement can help disrupt and reduce wound biofilm and planktonic bacterial levels 1,2 Debridement weakens the biofilm creating a time dependant window where increased susceptibility to antimicrobials is reported 1,3 Topical antimicrobials Mature biofilms are tolerant to the effects of many antibiotics and topical antimicrobials 4 7 Some topical antimicrobials are proven to rapidly kill biofilm bacteria over a sustained period (in vitro) 4 Multifaceted approach required: Sharp debridement to disrupt and weaken the biofilm 1 Antimicrobials to prevent re growth 1 1.Wolcott RD et al. J. Wound Care 2009; 18: 54 56. 2. Schwartz JA, et al. Int. Wound J. 2013; 10: 193 9. 3. Wolcott RD et al J. Wound Care 2010; 19: 320 8. 4. Phillips PL et al. Int Wounds J 2013:1 15. 5. Singh R et al. J Antimicrob Chemother. 2010; 65: 1955 1958. 6. Anderl JN et al. Antimicrob Agents Chemother 2000; 44, 1818 1824. 7. Stewart PS et al. J Appl. Microbiol 2001; 91, 525 532.

Biofilms are tolerant to many topical antimicrobials Silver Silver is not as effective against mature biofilms 1,3 Ag+ is the active agent in most silver dressings Charged antimicrobials more easily neutralised by negatively charged biofilm 2 Concentration of silver required to eradicate biofilm found to be 10 100 x higher than planktonic bacteria (concentration of silver in currently available wound dressings is much too low for treatment of chronic biofilm wounds) 3 3 day old PAO1 biofilm cultured on 12 mm porcine explants. Results mean CFU/ml, n=9 4 Silver dressings are effective against planktonic bacteria and can prevent biofilm re formation 4 1. Phillips, et al. Int Wounds J; 2013:1 15. 2. Stewart, P. S. et al. J. Appl. Microbiol. 2001. 91, 525 32. 3. Bjarnsholt et al. APMIS 2007.115: 921 8. 4. Driffield, K. et al. Poster presentation in SAWC (2007).

Biofilms are tolerant to many topical antimicrobials Iodine Iodine is highly effective against planktonic bacteria 1 Antimicrobials which are less reactive are less likely to be bound to the negatively charged EPS and are hypothesised to have more effect against biofilm bacteria 2 Older formulations of Iodine such as Povidone Iodine (PVP I) have a fast but rapidly decaying antibacterial action 3 3 day old PAO1 biofilm cultured on 12 mm porcine explants. Results mean CFU/ml, n=9 4 Need sustained activity to be effective against biofilm e.g. Cadexomer Iodine 4 1. McDonnell G et al. Clin Microbiol Rev 1999; 12: 147 179 2. Stewart, P. S. et al. J. Appl. Microbiol. 2001. 91, 525 32. 3. Hendley JO, et al. Antimicrob. Agents Chemother 1991; 35, 627 631. 4. Phillips, et al. Int Wounds J; 2013:1 15.

IODOFLEX and the barriers to healing 1. Edwards R and Harding KG, Curr Opin Infect Dis. 2004;17:91 96. 2. Lipsky BA and Hoey C, Clin Infect Dis. 2009;49:1541 1549. 3. WUWHS. Principles of Best Practice A World Union of Wound Healing Societies Initiative Wound infection in clinical practice: An international consensus. 2008. London: MEP Ltd. 4. Menke NB, et al. Clin Dermatol. 2007;25:19 25. 5. Phillips P, Int Wound J. 2013:1 15. 6. Schierle CF, et al. Wound Repair Regen. 2009;17:354 9. 7. Costerton J, et al. Science. 1999;284:1318 22. 8. Cochrane DM, et al. J Med Microbiol. 1988;27:255 61. 9. WUWHS. Principles of best practice: Wound exudate and the role of dressings. A consensus document. 2007. World. 10. Bucalo B, et al. Wound Repair Regen. 1, 181 186 (1993). 11. Salman H, Leakey A. A report to Smith & Nephew Medical Ltd. Report number 194 03 01. March 2001. 12. Woodmansey E, IODOSORB Antimicrobial effectiveness list. Asset 45285. 2013. 13. Troëng T, et al. E. A. in Cadexomer Iodine, (eds. Fox, J. & Fisher, H.) Schattauer Verlag. 1983:43 50. 14. Lindsay G, et al. Acta Ther. 1986;12:141 148. 15. Johnson A. Prof. Nurse. 1991;7:60, 62, 64. 16. Skog E, et al. Br. J. Dermatol. 1983;109:77 83. 17. Mertz P, et al. Wounds. 1994;6:184 193. 18. Falanga, V. Ostomy Wound Manage. 1999;45: 33S 43S, quiz 44S 45S. 19. Schwartz J, et al. Int. Wound J. 2013;10:193 199. 20. Drolshagen C and Schaffer D. Poster. 1999. SAWC Anahiem. 21. Smith & Nephew Data on file #091101. 2009. 22. Drosou A, et al. Reduces bioburden 1 4 Disrupts biofilm 5 Manages exudate 1,8 12 Overcomes slough 1,8 10 Highly effective antimicrobial against a broad spectrum of bacteria including MRSA (in vitro) 11 19 Wounds. 2004;15:149 166. 23. Sundberg J, et al. Wounds A Compend Clin Res Pract. 1997;9:68 86. 24. Ormiston MC and Fox JA. Br. Med. J. (Clin. Res. Ed). 1985;291:1424 1425. 25. Akiyama H, et al. J. Dermatol. 2004;31:529 34. 26. Hansson C, et al. Int. J. Dermatol. 1998;37:390 396. 27. Holloway, G. A., et al. West. J. Med. 1989; 151:35 38. 28 Zhou LH, et al. Br. J. Dermatol 2002;146, 365 74.. Clinical activity against common wound pathogens 12 Sustained release of iodine 16,20,21 Minimal toxicity 28 Shown to kill mature biofilms of Pseudomonas aeruginosa and Staphylococcus aureus (in vitro) 17,18 Prevents and kills mixed species of biofilm bacteria typical of chronic wounds (in vitro) 19,20 Absorbs bacteria into cadexomer matrix 21 Tested in a variety of biofilm models High absorption capacity to help establish moisture balance 13 15,22 24 Provide effective desloughing 23 26 Cleanses wound bed via absorption of excess slough and debris to prepare for effective healing 13,27 The only antimicrobial proven at the highest level of evidence: The Cochrane Review states cadexomer iodine generates higher healing rates than standard care in venous leg ulcers 8 1. Edwards R and Harding KG, Curr Opin Infect Dis. 2004;17:91 96. 2. Lipsky BA and Hoey C, Clin Infect Dis. 2009;49:1541 1549. 3. WUWHS. Principles of Best Practice A World Union of Wound Healing Societies Initiative Wound infection in clinical practice: An international consensus. 2008. London: MEP Ltd. 4. Menke NB, et al. Clin Dermatol. 2007;25:19 25. 5. Phillips P, Int Wound J. 2013:1 15. 6. Schierle CF, et al. Wound Repair Regen. 2009;17:354 9. 7. Costerton J, et al. Science. 1999;284:1318 22. 8. Cochrane DM, et al. J Med Microbiol. 1988;27:255 61. 9. WUWHS. Principles of best practice: Wound exudate and the role of dressings. A consensus document. 2007. World. 10. Bucalo B, et al. Wound Repair Regen. 1, 181 186 (1993). 11. Salman H, Leakey A. A report to Smith & Nephew Medical Ltd. Report number 194 03 01. March 2001. 12. Woodmansey E, IODOSORB Antimicrobial effectiveness list. Asset 45285. 2013. 13. Troëng T, et al. E. A. in Cadexomer Iodine, (eds. Fox, J. & Fisher, H.) Schattauer Verlag. 1983:43 50. 14. Lindsay G, et al. Acta Ther. 1986;12:141 148. 15. Johnson A. Prof. Nurse. 1991;7:60, 62, 64. 16. Skog E, et al. Br. J. Dermatol. 1983;109:77 83. 17. Mertz P, et al. Wounds. 1994;6:184 193. 18. Falanga, V. Ostomy Wound Manage. 1999;45: 33S 43S, quiz 44S 45S. 19. Schwartz J, et al. Int. Wound J. 2013;10:193 199. 20. Drolshagen C and Schaffer D. Poster. 1999. SAWC Anahiem. 21. Smith & Nephew Data on file #091101. 2009. 22. Drosou A, et al. Wounds. 2004;15:149 166. 23. Sundberg J, et al. Wounds A Compend Clin Res Pract. 1997;9:68 86. 24. Ormiston MC and Fox JA. Br. Med. J. (Clin. Res. Ed). 1985;291:1424 1425. 25. Akiyama H, et al. J. Dermatol. 2004;31:529 34. 26. Hansson C, et al. Int. J. Dermatol. 1998;37:390 396. 27. Holloway, G. A., et al. West. J. Med. 1989; 151:35 38. 28 Zhou LH, et al. Br. J. Dermatol 2002;146, 365 74..

IODOFLEX : Cadexomer Iodine IODOFLEX is easy to apply and remove 10 IODOFLEX is an effective deslougher 7 which helps cleanse the wound bed and prepare it for effective healing. IODOFLEX has high absorption capacity 7 which assists with debridement by absorbing excess slough and debris. 7,8 IODOFLEX provides sustained release of iodine 10,11 has broad spectrum antimicrobial activity (in vitro) 9,10 and accelerates healing 7 Helping to reduce the barriers to healing Local slow release of iodine 7,10 Effective against a broad range of bacteria (in vitro) 10 Changes colour when ready to be removed 12 (On average 2 to 3 times per week) 7.Sundberg J and Meller R. A retrospective review of the use of cadexomer iodine in the treatment of chronic wounds. Wounds (1997), 9(3): p 68 86. 8. Troëng T, Skog E, Arnesjö B et al., In Cadexomer iodine. Fox JA, Fischer H (eds) (1983) p43 50. 9. Smith & Nephew (2006). Data On File Report reference 0607023. 10. Skog E, Arnesjö B, Troëng T, et al., A randomized trial comparing cadexomer iodine and standard treatment in the outpatient management of chronic venous ulcers. British Journal of Dermatology. (1983): 109, 77 83. 11. Drolshagen C and Schaffer D. Use of an absorbent antimicrobial and a viscous hydrogel to manage ulcers secondary to peripheral vascular disease. Poster presented at the (1999) Symposium on Advanced Wound Care, Anahiem. 12. Demonstrable 77054

IODOFLEX and IODOSORB formats 50% cadexomer iodine powder 48% polyethylene glycol and 2% polaxomer 1g of IODOSORB ointment absorbs 3mls of exudate IODOSORB Ointment 60% cadexomer iodine powder 40% polyethylene glycol 1g of IODOSORB absorbs 3.6mls of exudate IODOFLEX 100% cadexomer iodine powder 1g of IODOSORB powder absorbs 6mls of exudate IODOSORB Powder Trademark of Smith & Nephew. All Trademarks acknowledged. 77054

Biofilms key messages Biofilms A natural form of protection for bacteria Linked to delayed healing Found to be present in at least 60% chronic wounds experts suggest to be much higher Clinical symptoms not as obvious as an infection Have increased tolerance to many antibiotics and antimicrobial treatments and also the host immune response Biofilm treatment Needs a multifaceted approach regular debridement and antimicrobials Most antimicrobials alone will fail Some antimicrobials shown to be effective in vitro i.e. IODOFLEX