Wound Care

Critical Colonization—the Concept Under Scrutiny

a report by

R i c h a rd Wh i t e , P h D , M B i o l 1 and Ke i t h F C u t t i n g , M S c , R N , D i p N , C e r t E d 2
1. Senior Research Fellow, Tissue Viability, Grampian NHS Trust, Scotland, and 2. Principal Lecturer, Wound Care Management, Buckinghamshire Chilterns University College

The term ‘critical colonization’ was first coined by Davis. Using case studies, Davis demonstrated how delayed healing in wounds could be reversed through the appropriate use of topical antiseptics. She also defined the condition of the wound in relation to bacterial presence and defined critical colonization as “multiplication of organisms without invasion but interfering with wound healing.”1 The presence of pathogens—with or without host reaction—can interfere with healing.2,3 Currently, the absence of a host response is viewed as a fundamental link to understanding the concept of critical colonization. Although the concept of critical colonization is not universally accepted, clinicians and researchers generally agree that the term needs definitive characterization in order to validate its consideration in infection management.4,5 Trengove et al.6 have shown that the number of bacterial species and the number of organisms are important in the development of infection. However, these findings have yet to be clinically validated. In a theoretical hypothesis, Heinzelmann et al.7 submit that the host response is a key factor in the development of infection. Critical colonization occurs when wound healing is delayed without the overt signs and symptoms of infection8 and despite ‘optimum’ treatment.9 In a retrospective review of patients, Drosou et al.10 provide an additional perspective, stating that it is likely that subclinical damage to tissue as a result of bacterial contamination exists, citing Hermanns et al.11 in support of the premise. Clinically, host response to wound infection is recognized by the classic signs and symptoms of inflammation—i.e. redness, swelling, warmth, and pain. However, not all erythematous reactions are necessarily generated immunologically. Recent findings from a series of clinical cases have shown that a Morganella species—Morganella morganii—commonly found in wounds expresses histamine in physiologically significant amounts.12 Therefore, periwound erythema could be attributable to M. morganii colonization. However, M. morganii is not routinely considered in bacterial samples acquired from wounds. Hansson et al.13 found M. morganii (identified as Proteus morganii) in 23% of venous leg ulcers (n=58). Conversely, Bowler and Davis14 found this bacterium in infected (n=44) but not non-infected (n=30) leg ulcers. Delayed healing has been intimately linked with ‘uncontrolled inflammation’15 or immunopathology.16 Three or more potential bacterial ‘modes of action’ are described in the literature, whereby delayed healing can be associated with microbial factors without eliciting an obvious host response. These are: the expression of immuno-evasion;17 biofilm formation;18 and suppression of cellular wound healing responses.19 These modes have been identified following in vitro work and can occur when the wound is colonized by certain specific bacteria.

An organism commonly found in chronic wounds20 and associated with chronic infection,21 Pseudomonas aeruginosa is known to form biofilms22 and secrete immuno-evasive factors23 that are active against polymorphonucleocytes (PMNs). To this effect, activation of the type III secretion system—a recently identified virulence determinant of P. aeruginosa—has been reported from in vitro study using clinical isolates.24 It has been postulated that P. aeruginosa is likely to be of far greater significance to wound chronicity, tissue invasion, and infection than previously recognized.17-19,25 As indicated in a summary of clinical and microbial findings,26 experienced wound clinicians have long noticed occasional green coloration in chronic wounds and have associated this with the presence of P. aeruginosa and delayed healing. The green pigment, pyocyanin, is a phenazine—a highly diffusible exotoxic metabolite.27 Pyocyanin has been shown to inhibit many cell functions and impair host defenses through apoptosis.21 In vitro laboratory research on clinical samples28 has shown that many pathogens—including P. aeruginosa— induce inappropriate or premature apoptosis of immune cells such as macrophages and neutrophils, which can be pro-inflammatory.29 P. aeruginosa has evolved immuno-evasive strategies, by which it affects host immunity.30 Pyocyanin and other similar phenazines have a pro-apoptotic action on human neutrophils.23 P. aeruginosa has been shown to be a phenotypically unstable pathogen, particularly in chronic infection,31 with

Richard White, PhD, MBiol, is Senior Research Fellow in Tissue Viability in Grampian NHS Acute Trust Aberdeen, Director of Medical Communications (UK) Ltd., and Professor of Tissue Viability at the University of Worcester. He has 17 years of experience in research in UK teaching hospitals, with lecturing and supervision responsibilities, as well as 12 years of experience in the medical devices industry in clinical research. Dr White studied at the Universities of Dundee and Liverpool and is qualified in biochemistry and experimental dermatology.

Keith Cutting, MSc, RN, DipN, Cert Ed, is Principal Lecturer in Wound Care Management at Buckinghamshire Chilterns University College, UK. He is an editorial board member of the Journal of Tissue Viability and Clinical Editor of the Wounds UK Journal. Dr Cutting is also an International Board Member for the Association for the Advancement of Wound Care (AAWC) and a presenter at national and international conferences. He has a keen interest in wound infection and works with a number of international wound care companies and other medical agencies on a consultancy basis. E: info@healthdirections.co.uk

© TOUCH BRIEFINGS 2007

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Wound Care

virulence controlled by an N-acyl homoserine lactone (AHL)- dependent quorum-sensing system. The organism has the capability to modulate its own quorum-sensing-dependent pathogenic potential through an AHL-acylase enzyme.32 This may in part explain how P. aeruginosa may be a delayer of wound healing under certain circumstances, while under other circumstances it may be an infecting organism. Other aerobes and anaerobes can also downregulate the immune response. Bowler et al.33 summarised the role of succinate (a short-chain fatty acid, or SCFA) produced by aerobes and anaerobes, and Rotstein et al.34,35 have demonstrated how succinate may increase the risk of infection by impairing host-cell function. Staphylococcus aureus also interferes with host-cell functions. Impaired healing is often observed in S. aureus-infected wounds where the extracellular adherence protein has been implicated36 and shown to be a potent anti-inflammatory37 and anti-angiogenic agent, preventing recruitment of inflammatory cells to the wound site as well as inhibiting neovascularization.38 Chronic wound malodour is linked to SCFAs.20 These volatile compounds are the metabolic by-products of anaerobic bacterial metabolism.39 Organisms known to generate SCFAs are Bacteroides spp. and anaerobic cocci.40 Stephens et al.19 demonstrated in vitro that Peptostreptococci-generated SCFA inhibited the growth of the key cells—keratinocytes, fibroblasts, and endothelial cells— responsible for wound healing. If translated to the in vivo situation, this could result in delayed healing from uncomplicated colonization (i.e., no perceived clinical or cellular effects) without the bioburden necessarily reaching a theoretical infection threshold. Hansson et al.13 found Peptostreptococcus species—identified as P. magnus, P. asaccharolyticus, and P. prevotii) in 30% of venous leg ulcers. This is a clinically significant level of species-specific colonization and indicates the importance of anaerobic involvement in chronic wound bacteriology. Studies of SCFAs have shown that they play a part in impairing neutrophil chemotaxis and phagocytosis.19 The low pH of all chronic wounds facilitates succinate activity and provides a milieu that down regulates neutrophil function.34,35 A chronic wound colonized but not infected with one or more certain bacteria—among them Morganella spp., P. aeruginosa, and Peptostreptococcus spp.—may exhibit erythema and delayed healing without a traditional or otherwise evident host response. Scenarios involving these

organisms and possibly others yet to be identified have been used to postulate the concept of critical colonization. The critical nature of colonization takes on a far greater significance when viewed in this light. A low level of colonization may be all that is required to delay healing and is far removed from that required for local infection to be diagnosed in terms of the level of bioburden and the demonstration of signs of infection (host response). It has yet to be determined how frequently delayed healing can be attributed to a microbiological cause or to other factors. In chronic wounds, the fact that colonization is the norm should precipitate the conclusion that delayed healing is more likely than not to be microbiological in origin. When encountered clinically, delayed healing may be perceived as an idiosyncratic event that defies rational explanation. We suggest that, in the absence of firm evidence to explain delayed healing—e.g. malnutrition, smoking, comorbidities, or less than optimal care—critical colonization should be considered not as a confounding feature but as a clinical probability. To put this into context, many clinicians have seen an indolent wound improve following topical antimicrobial treatment, retrospectively confirming the diagnosis of critical colonization. While wound infection is a cause of morbidity and subsequent increased patient management costs, delayed healing also presents cause for concern. Healing delays affect patient quality of life and are used as justification for expensive modern wound treatments. The term critical colonization describes the situation of delayed healing with a microbial cause. It should be viewed microbiologically, quantitatively, and qualitatively, where its manifestation is dependent on the species present and by the expression of virulence determinants. The goal in such situations is to consider treatment such as topical antiseptics that manage the bioburden in order that healing may proceed. This being the case, recognizing that critical colonization is a distinct, clinically important stage in the wound infection continuum is important; failing to acknowledge that critical colonization is a cause of delayed healing (even without a traditional host response) impedes early diagnosis. Additional studies need to ascertain the point at which a wound is critically colonized, as well as to find the appropriate treatment to provide at that juncture in order to avoid additional morbidity and care costs. ■ This is an edited version of an article that was first published in Ostomy Wound Management, 2006;52(11):50–56.

1. 2.

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4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Davis E, 2nd Joint meeting of the Wound Healing Society and the European Tissue Repair Society, Boston, US, 1996. Danielson L, Proceedings, 4th European Wound Management Association (EWMA) conference on advances in Wound Management, Sept 6–9, 1994, Copenhagen. Trengove NJ, Stacey MC, McGechie D, et al., Proceedings, 4th EWMA Conference on Advances in Wound Management Sept 6–9, 1994, Copenhagen. Ovington L, Ostomy Wound Manage, 2003;49(7)Suppl A:8–12. Cutting KF, White RJ, Ostomy Wound Manage, 2005;51,1:28–34. Trengove NJ, Stacey MC, et al., J Wound Care, 1996;5(6);277–80. Heinzelmann M, Scott M, Lam T, Am J Surg, 2002;183:179–90. Cutting KF, EWMA Journal, 2003;3,1:17–19. Kingsley AR, Ostomy Wound Manage, 2003;49(Suppl 7A):1–7. Drosou A, Kirsner RS, Welsh E, et al., J Cutan Med Surg, 2003;7,5:3823–86. Hermanns JF, Paquet P, Arrese JE, et al., Rev Med Liege, 1999;54(7):600–5. Cooper RA, Morwood S, Burton N, J Infect, 2004;49:39. Hansson C, et al., Acta Derm Venereol, 1995;75:24–30. Bowler PG, Davies, BJ, Int J Dermatol, 1999;38:101–6. Moore K, J Wound Care, 1999;8,7:345–52.

16. Page KR, Scott AL, Manabe YC, Cell Microbiol, 2006;8(2):185–96. 17. Allen L, Dockrell DH, Pattery T, et al., J Immunol, 2005;174:3643–9. 18. Serralta VW, Harrison-Balestra C, et al., Wounds, 2001;13(1):29–34. 19. Stephens P, Wall IB, Wilson MJ, et al., Brit J Dermatol, 2003;148(3):456–66. 20. Bowler PG, Davies BJ, Jones SA, J Wound Care, 1999;8(5):216–18. 21. Lau GW, Hassett DJ, et al., Trends Mol Med, 2004;10(12):599–606. 22. Costerton JW, Trends Microbiol, 2001;9(2):50–52. 23. Usher LR, Lawson RA, et al., J Immunol, 2002;168:1861–8. 24. Dacheux D, Epaulard O, de Groot A, et al., Infect Immun, 2002;70(7):3973–7. 25. White RJ, More research is needed before we can accurately define and understand critical colonisation, Letter Wounds UK, 2006;2(2):86–8. 26. Hamilton Jakobsen B, Danielsen L,, Ugeskr Laeger, 1997;159(19):2836–40. 27. Denning GM, Iyer SS, Reszka KJ, et al., Am J Physiol Lung Cell Mol Physiol, 2003;285(3):584–92. 28. Zychlinsky A, Sansonetti P, J Clin Invest, 1997;100(3):493–5.

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Zychlinsky A, Sansonetti P, Trends Microbiol, 1997;5(5):201–4. Buret A, Cripps AW, Am Rev Respir Dis, 1993;148(3):793–805. Speert DP, Front Biosci, 2002;7:354–61. Sio CF, Otten LG, Cool RH, et al., Infect Immun, 2006;74,3:1673–82. Bowler PG, Duerden BI, Armstrong DG, Wound microbiology and associated approaches to wound management, Clin Microbiol Rev, 2001;14:244–69. Rotstein OD, Nasmith PE, Grinstein S, Infect Immun, 1987;55,4:864–70. Rotstein OD, Vittorini T, Kao J, et al., Infect Immun, 1989;57,3:745–53. Athanasopoulos AN, Economopoulos M, Orlova V, et al., Blood, 2006;107(7);2720–27. Chavakis T, Hussain M, Kanse SM, et al., Nat Med, 2002;8(7):687–93. Haggar A, Ehrnfelt C, Holgersson J, Infect Immun, 2004;72(10):6164–7. Reed PJ, Sanderson P, J Clin Path, 1979;32(12):1203–5. Bowler PG, Wounds, 1998;10:170–78.

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