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Looking for Clues in the Search for Wound Infection
For further reading, check out the Infection Topic Center on the Wound Care Learning Network.
Infection is the presence of micro-organisms that damage body tissues and elicit a host defensive inflammatory response. Timely diagnosis is critical to get the infection in check and prevent the sequalae of infection-associated complications and their associated costs to the patient and health system. Yet diagnosis can be a puzzle, even for the most experienced wound clinician, with many factors we must consider.
Factors that contribute to the development of infection include: the circumstances of the “host” or patient, the challenges concurrently present in the wound environment (which include all aspects of wound treatment), and the microorganisms themselves and their potential to resist treatment or work together to exacerbate infection. The details of these factors and how each contributes to the battle between the host and the microbes are enough to fill a textbook, but a summary of the key elements is described in Figure 1.
Current practice promotes the clinical appearance of infection as the primary method of diagnosing infection, and when available, the use of microbiological analysis to aid in diagnosis. However, the clinical appearance of infection can be variable and bacterial loads themselves have been difficult to assess accurately. Total reliance on either of these methods is not a reliable indicator of infection. So, what else can the astute clinician look out for to provide additional clues when investigating infection?
Clue #1: Is It Truly Infection or Inflammation Due to Another Trigger?
An important consideration when investigating wound infection is the fact that infection is just one of several triggers of the host inflammatory response and as such, infection is not always the cause of inflammation. Inflammation is the body’s general defensive vascular response to harmful physical stimuli including cell damage, irritants, or tissue invasion by microbial pathogens. The classic criteria used to identify wound infection are based on the Tetrad of Inflammation, which includes: calor, dolor, tumor and rubor.1 However, these criteria are also observed in chronic inflammatory conditions such as stasis dermatitis (Figure 2). Despite these limitations, these classic infection criteria have been featured in many clinical guidelines, including the most recent guidelines by the International Working Group of the Diabetic Foot for the management of diabetic foot infection.2
To make matters worse, the appearance of the inflammatory response (redness) in any diabetic patient with arterial disease (not just in aging patients) can be blunted due to impaired perfusion to the tissue. This can lead to a delay or absence of treatment. For example, a patient with diabetes may have concomitant vascular insufficiency and poor glucose control, both of which may contribute to a diminished or even absent inflammatory response to the invasion of foreign pathogens.3,4 This can potentially delay diagnosis of infection and/or inappropriate use of antibiotics and other treatments. So, are these “classic” signs and symptoms really the strong indicators of infection they purport to be? With the rising prevalence of diabetes and obesity and growth of aging populations, we must consider that total reliance on classic clinical signs and symptoms may not be a dependable marker of wound infection.
Clue #2: Is the Infection Covert or Overt?
In a 2001 paper, Gardner and colleagues describe localized infection in two categories: secondary (or covert) clinical signs of infection and classic (overt) clinical signs of infection.5 The covert signs of infection (e.g., delayed wound healing, excessive exudate, and wound breakdown) are thought to be key indicators of hindered wound healing and biofilm6 while overt infection includes the Tetrad of Inflammation (Figure 3). In vivo studies have shown that biofilm maturation promotes a lower-grade host inflammatory response7 than a classic or overt infection. This can be an investigational clue to the wound clinician to aid in avoiding misuse of antibiotics and ensure better wound outcomes.
For example, a wound with clinical signs of secondary/covert infection may not require a systemic antibiotic. Instead, a biofilm based wound care strategy such as Wound Hygiene8 may be effective in shifting the wound to a healing trajectory. Just like regular oral hygiene is necessary to prevent periodontal disease and decay, Wound Hygiene involves a consistent multimodal care routine that will address the root cause of the biofilm related pathology. The Wound Hygiene protocol utilizes mechanical or sharp wound debridement to disrupt biofilm and expose the more susceptible planktonic phenotype. The protocol also includes cleaning with a noncytotoxic antiseptic to clear newly exposed microbes and opening or refashioning of wound edges.8
Clue #3: What is the Significance of Wound Microbial Load?
The classic signs of infection reflect the host immune response to invasion by foreign bacterial pathogens.9 However, as alluded to earlier, the manifestation of these signs of infection may be highly variable and subject to host or environmental factors, including comorbid conditions such as diabetes that can blunt the expression of the immune response. Therefore, we have long relied on objective measures of bacterial burden to aid in the assessment of infection and provide more clues to guide the decision making of the wound practitioner. Early studies elegantly demonstrate a link between high bacterial counts (>105 CFU per mL of wound exudate) and greater risk of infection or impaired healing.10,11
More recently, studies have suggested that tissue bacterial loads exceeding 104 CFU per unit of measure are associated with a slowdown of wound healing processes12; wound healing is further impaired as the load increases.13-15 Often, these clinically significant microbial loads are present even in the absence of classic or overt signs and symptoms of infection. In a recent clinical trial of 350 chronic wounds, microbial loads of >104 CFU/g were observed in >80% of wounds, and in 37% of wounds, loads >107 CFU/g were observed.16 However, few of those wounds presented with overt signs and symptoms of infection.16
If infection is suspected but uncertainty exists, many clinicians may respond with “let’s take a swab” and turn to microbiological analysis to gain insight.17 Finding the area of the wound bed to collect a specimen can be a matter of luck because we simply cannot see microbes with the naked eye. Swabs may also underestimate infection as they mainly collect bacteria from the surface of the wound. Even if sample collection conditions are ideal, the microbiological techniques used to determine bacterial loads are fraught with challenges. For example, bacteria protected in biofilm are unlikely to grow in cultures from standard swab or even biopsy samples. In a recent study of 428 biopsies that compared semi-quantitative analysis to gold-standard quantitative analysis, almost half (44.3%) of the semi-quantitative cultures showing “light growth” (a clinically insignificant finding) had quantitative bacterial loads of >105 CFU/g (considered to be clinically significant).18
A report of “light” would have steered the wound detective in the wrong direction! Yet, implementation of quantitative analysis is not practical due to practice-related challenges associated with who can collect a tissue specimen, as well as the extensive processing techniques required for quantitative analysis that can be more difficult and costly than semi-quantitative cultures.
Variation in technique and analysis related to tissue specimen collection have made many clinicians weary to pursue microbial load as a clue in the hunt for infection. However, microbial load is an important consideration as it can offer insight into the status of the wound before more severe complications associated with infection arise.
Fortunately, advances in point-of-care technology have made it easier for clinicians to gather more clues when determining whether infection is present. Handheld systems like the MolecuLight i:X fluorescence imaging device (MolecuLight Inc. Toronto, Canada) enable immediate identification of regions with elevated bacterial loads (>104 CFU/g) in wounds, in essence providing a map to their locations. The non-contact and non-contrast reimbursable imaging procedure uses safe violet light to visualize fluorescence from bacteria and wound tissues.
Fluorescence from bacteria is visually different from tissue on the images. The unique fluorescence signatures from bacteria and tissue offer many insights for the wound detective. Due to matrix components within tissue, skin and slough appear some shade of green (e.g., fibrinous slough tends to appear a bright green) that varies in shade due to patient skin tone. Most bacteria (at least 28 wound pathogens) emit a bright red signal, but this appears a softer pink or blush color when bacteria are located subsurface19,20, a clue that surface cleansing will not be sufficient to address bacterial burden in those wounds. Pseudomonas aeruginosa appears a cyan color, a distinctive clue from this unique surface pathogen that is highly prone to forming virulent biofilms21. If biofilm forms, knowing where to focus efforts aimed at disrupting and removing biofilm can greatly diminish any potential negative impacts of biofilm on wound healing.
Having objective information on bacterial loads and locations, and in some cases even bacterial depth, while treating the patient is a stark contrast to the days (or weeks!) long wait for microbiology results to which we are accustomed. Now we can use our “map” of bacterial burden-laden regions straight away while employing our Wound Hygiene strategies or other treatments to eradicate the bacterial burden. There is no doubt that the ability to immediately see whether employed hygiene strategies are effective and map the location of bacteria in wound could lead to more thorough bacterial removal. Indeed, a recent retrospective analysis evaluating the impact of fluorescence imaging in care of foot ulcers observed a 23% increase in 12-week wound healing rates, resulting from enhanced Wound Hygiene.22 Consistent with these findings, 96% of wound care experts participating in an international Delphi consensus on fluorescence imaging also reported improved wound healing rates with fluorescence imaging.23
Can These Infection Clues Reduce Antibiotic Abuse?
The more clues available to aid in the diagnosis of acute infection, the greater chance we have of avoiding misuse of antibiotics. Confirmation of bacterial load prior to evidence of acute infection can help to control over prescribing of antibiotics. Overuse of antibiotics is an urgent global concern, particularly in wound care where patients with wounds are significantly more likely to receive antibiotics than age- and gender-matched patients without wounds.24 Accurate infection diagnosis is essential to ensure that antibiotics are employed only when warranted and to prevent antibiotic resistance resulting from ineffective exposure of microbes to antibiotics.25,26 The U.S. Centers for Disease Control and Prevention (CDC) reported that up to 50% of antibiotic subscriptions in this country are not needed or are inappropriately prescribed.27-29 The most common factors found to contribute to antibiotic misuse in wound care are clinician’s fear of bad outcome, patient demands, and uncertainty about when antibiotics are required.30 Given the challenges of diagnosing infection laid out in this article, this “just in case” approach is unsurprising, but is dangerous, nevertheless.
There is cause for hope; published evidence from our UK counterparts shows that with objective imaging clues to alert the clinician to bacterial loads at the point-of-care and support more thorough wound hygiene strategies as a first approach, there is a marked reduction in antibiotic usage.22 U.S. colleagues have proposed applying this objective information as a foundation of their stewardship programs.31 We need to be using all the investigational tools at our disposal to eliminate our antibiotic over-prescribing tendencies.
Point-of-care Detection of Elevated Levels of Bacteria
Patients with diabetes are prone to developing recurrent infection of foot ulcers, but infection is often challenging to detect due to presence of other comorbidities (e.g., neuropathy, vascular insufficiency). To stay on top of bacterial load before acute infection develops, I include fluorescence scans as part of my wound assessment process, particularly if the wound has been present for a long time or the patient has a history of infection.
Figure 5 and Figure 6 are of a diabetic foot ulcer I had been treating. On initial assessment, the wound lit up bright red, indicating concerning levels of bacteria present in the wound (denoted by red arrows). I opted to debride the wound to remove the bacteria. After debriding the wound, I took another fluorescence image to determine how effective my debridement was. While evaluating that image I noticed a new area of high bacterial load between the toes! I did not detect any signs or symptoms of acute infection, but the fluorescence scan revealed red fluorescence in the toe webspace (red circle) providing a clue that helped me spot this emerging wound between the toes before the wound was obvious. I applied a topical antiseptic to the webspace and was able to remove the bacteria before the wound split open, effectively preventing an acute infection and avoiding the need for systemic antibiotics. If I had relied on clinical assessment alone, I would have likely missed this discovery!
Conclusion
When we take a closer look, we see that many additional clues exist to aid in our diagnosis of infection. We now know that there are two distinct types of “infection,” covert and overt, with distinguishable clinical signs. Along with attention to covert and overt signs of infection, we must also consider microbial load to get the full picture on infection risk. Years of research have confirmed that bacterial load is directly linked to infection risk and healing delays. However, unreliability of semi-quantitative analysis and the cost and practice limitations associated with quantitative analysis further confirm that reliance on such methods can handicap our well-intentioned efforts for accurate wound infection investigation and confounds efforts to promote more judicious use of antibiotics.
With the advent of more reliable, objective diagnostic methods, additional clues are now available to aid clinicians in their quest to identify and contain the source of infection and prevent the progression of wound infection.
Jenny Hurlow, RN, MSN, GNP-BC, CWCN, is a consultant and Wound Care Specialized Nurse Practitioner in Memphis, TN.
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References
1. Ciaccia L. Fundamentals of Inflammation. Yale J Biol Med. 2011;84(1):64-65.
2. Lipsky BA, Senneville E, Abbas ZG, et al. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3280.
3. Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29(6):1288–1293.
4. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132–173.
5. Gardner SE, Frantz RA, Doebbeling BN. The validity of the clinical signs and symptoms used to identify localized chronic wound infection. Wound Repair Regen. 2001;9(3):178–186.
6. Haesler E, Swanson T, Ousey K, Carville K. Clinical indicators of wound infection and biofilm: reaching international consensus. J Wound Care. 2019;28(Sup3b):s4–s12.
7. Gurjala AN, Geringer MR, Seth AK, et al. Development of a novel, highly quantitative in vivo model for the study of biofilm-impaired cutaneous wound healing. Wound Rep Regen. 2011;19(3):400–410.
8. Murphy C, Atkin L, Swanson T, et al. Defying hard-to-heal wounds with an early antibiofilm intervention strategy: wound hygiene. J Wound Care. 2020;29(Sup3b):S1–S26.
9. International Wound Infection Institute. Wound infection in clinical practice. Wounds International. Published Nov. 11, 2016.
10. Krizek T. Bacterial growth and skin graft survival. Paper presented at: Surg Forum, 1967.
11. Bendy R. Relationship of quantitative wound bacterial counts to healing of decubiti. Effect of topical gentamicin. Antimicrob Agents Chemother. 1964;4:147–155.
12. Caldwell MD. Bacteria and antibiotics in wound healing. Surg Clin North Am. 2020;100(4):757–776.
13. Majewski W, Cybulski Z, Napierala M, et al. The value of quantitative bacteriological investigations in the monitoring of treatment of ischaemic ulcerations of lower legs. Int Angiol. 1995;14(4):381–384.
14. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol. 1978;114(12):1765–1768.
15. Robson MC, Heggers JP. Delayed wound closure based on bacterial counts. J Surg Oncol. 1970;2(4):379–383.
16. Le L, Baer M, Briggs P, et al. Diagnostic accuracy of point-of-care fluorescence imaging for the detection of bacterial burden in wounds: results from the 350-patient Fluorescence Imaging Assessment and Guidance Trial. Adv Wound Care (New Rochelle). 2021;10(3):123–136.
17. Cutting K. Wound infection conundrum. Br J Nurs. 2013;22(20):S3.
18. Serena TE, Bowler PG, Schultz GS, D’souza A, Rennie MY. Are semi-quantitative clinical cultures inadequate? Comparison to quantitative analysis of 1053 bacterial isolates from 350 wounds. Diagnostics. 2021;11(7):1239.
19. Jones LM, Dunham D, Rennie MY, et al. In vitro detection of porphyrin-producing wound bacteria with real-time fluorescence imaging. Future Microbiology. 2020;15(5):319–332.
20. Rennie MY, Dunham D, Lindvere-Teene L, Raizman R, Hill R, Linden R. Understanding real-time fluorescence signals from bacteria and wound tissues observed with the MolecuLight i:X™. Diagnostics (Basel). 2019;9(1).
21. Raizman R, Little W, Smith AC. Rapid diagnosis of Pseudomonas aeruginosa in wounds with point-of-care fluorescence imaging. Diagnostics. 2021;11(2):280.
22. Price N. Routine fluorescence imaging to detect wound bacteria reduces antibiotic use and antimicrobial dressing expenditure while improving healing rates: Retrospective analysis of 229 foot ulcers. Diagnostics 2020;10:927.
23. Oropallo A, Andersen C, Abdo R, Hurlow J, et al. Guidelines for point-of-care fluorescence imaging for detection of wound bacterial burden based on Delphi consensus. Diagnostics. 2021; 11(7):1219.
24. Howell-Jones RS, Price PE, Howard AJ, Thomas DW. Antibiotic prescribing for chronic skin wounds in primary care. Wound Repair Regen. 2006;14(4):387–393.
25. Shrivastava SR, Shrivastava PS, Ramasamy J. Responding to the challenge of antibiotic resistance: World Health Organization. J Res Med Sci. 2018;23:21–21.
26. Ciofu O, Rojo-Molinero E, Macia MD, Oliver A. Antibiotic treatment of biofilm infections. APMIS. 2017;125(4):304–319.
27. Shapiro DJ, Hicks LA, Pavia AT, Hersh AL. Antibiotic prescribing for adults in ambulatory care in the USA, 2007-09. J Antimicrob Chemother. 2014;69(1):234–240.
28. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among us ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864–1873.
29. Centers for Disease Control and Prevention. Office-related antibiotic prescribing for persons aged ≤14 years—United States, 1993–1994 to 2007–2008. MMWR Morb Mortal Wkly Rep. 2011; 60(34):1153–6.
30. Lipsky BA, Dryden M, Gottrup F, Nathwani D, Seaton RA, Stryja J. Antimicrobial stewardship in wound care: a position paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association. J Antimicrob Chemother. 2016;71(11):3026–3035.
31. Serena TE. Incorporating point-of-care bacterial fluorescence into a wound clinic antimicrobial stewardship program. Diagnostics (Basel). 2020;10(12).
