The Wound Infection Continuum and Its Application to Clinical Practice

M any wounds healing by secondary intention become indolent, extending periods of patient discomfort and inconvenience and increasing healthcare costs and staff workload. Although wounds cease to heal for many reasons, perhaps the most common emanates from the effects of wound bioburden,1 due to invasive infection, the sheer quantity of colonizing microbes, the mixture of species in the wound base, or the effect of their toxins. The indiscriminate use of antibiotics, either systemic and topical, for all open wounds would raise healthcare costs and contribute to the development or selection of multi-resistant micro-organisms; therefore, systemic antibiotics are not an option for prophylactic use in all open wounds and are reserved for proven cases of wound infection. However, proof of infection is fundamentally restricted to acknowledging clinical signs and symptoms in collaboration with qualitative microbiology. The use of qualitative microbiology alone is flawed because the relative impact of bacteria in any particular context on the body must be considered, creating the potential for either over-treatment or under-treatment depending on the diagnostic skills of the clinician. Based on the results of an audit, nurses'2 and other clinicians'3 ability to diagnose is highly variable, suggesting that wounds that become indolent due to bioburden (ie, critical colonization) but that do not exhibit the classically considered signs of infection may go untreated, even though they might benefit from a topical or systemic antimicrobial strategy. It should be noted that the term critical colonization - defined as a transition state between bacterial surface colonization that does not impair the healing process and invasion of the bacteria into viable tissue - is largely conceptual, although Fumal and colleagues4 have shown supportive evidence . Additionally, understanding the intricacies of the microbiology of open wounds is further complicated by the need to interpret laboratory results in various contexts. The wound's anatomical position, duration, shape, or presentation; the patient's level of health and control of underlying pathologies; the presence of infection-potentiating factors such as foreign bodies, hematoma, and necrotic tissue; the sources and frequency of exogenous contamination; the considered virulence of the individual micro-flora species; and the potential synergism between different species all require consideration. Add to this the complicated task of correctly identifying tissue types and interpreting the reasons why the wound is exhibiting certain signs and symptoms and the range of opinions on how to proceed clinically becomes self-evident. The Healing Process The wound healing process can be divided into three phases: inflammation, proliferation, and maturation. Each stage has signature events or cells. Inflammation includes coagulation through fibrin mesh and platelet plug, vasodilation and release of pro-inflammatory markers, platelet degranulation and release of proliferative growth factors, and the rapid infiltration of neutrophils (polymorphonuclear white cells) for non-specific bacterial killing. Monocytes also enter the wound and activate to become macrophages with a longer lifespan than the neutrophils; these are able to phagocytose damaged tissue, contaminating microbes and spent neutrophils. Macrophages also send out cytokines to attract fibroblasts necessary for the proliferative stage. In the proliferative stage, fibroblasts deposit collagen and, along with a massive influx of new blood vessels and ground substance of proteoglycans and glycosaminoglycans, form granulation tissue. During this time, myofibroblast activity is believed to incite wound contraction, significantly reducing the area to be filled. Keratinocytes change their phenotype and start moving across the granulation to form a new epithelium. At the end of this stage, epithelialization is complete and the wounded person is protected from the possibility of infection from exogenous microbes during the third stage, maturation. To achieve complete healing (signified by a strong functional scar), the wound "remodels." Collagen fibers, previously deposited unaligned, are made parallel and collagen subtypes are exchanged and cross-linked. This process of ordering flattens the scar, and the new network of blood vessels essential to proliferation is dismantled to a more normal level for skin as the healing process nears completion and the scar tissue pales. A fuller but still brief overview can be found in Kingsley, Trudgian, and Shorney.5 The maturation process may be the body's hurried response to the breach in its integrity. At risk for infection (and potentially, for death), the body's emphasis is on fast closure, even though this reaction may not produce the best functional result. Subsequent to closure, the body's natural priority changes to reorganizing the tissues to produce the best result possible. The impact of infection. A high bioburden can disrupt the orderly healing sequence, producing a chronic inflammatory wound. A wound that dwells too long in this state increasingly risks cellular dysfunction and biochemical imbalance. To appreciate the role of microbes in abnormal healing, a number of considerations need to be addressed. The first is the interplay between the aerobe and anaerobe species within wounds. Open wound pathogens are commonly considered to be aerobic (oxygen tolerant organisms), essentially Staphylococci and Streptococci species. But anaerobic species are also now thought to have a role to play because the frequency of their isolation increases in clinically infected chronic wounds. Hence, chronic infected wounds are polymicrobial and of mixed aerobe/anaerobe populations, making it impossible to designate the pathogens.6 Although competition through cohabitation on intact skin appears to decrease the virulence of an individual species, the polymicrobial nature of the open wound is likely to provide opportunities for synergism, producing infection or delayed healing. Another consideration is the effect of specific species on the wound. Beta hemolytic Streptococci, notably Streptococcus pyogenes (Group A Streptococci), are pathogenic at numbers that are significantly lower than many other species. Other species (eg, Staphylococcus aureus, Proteus, and Escherichia coli) may have a positive effect by provoking a fuller inflammatory response, accelerating wound repair by stimulating blood flow.7-9 Increased angiogenesis produced by a low bioburden has a positive effect, but uncontrolled angiogenesis is linked to excessive scar formation. The acceleration stimulus also may be paralleled by an increased strength in the wound because of increased collagen production. On the other hand, the outcome of high bioburden is often decreased strength. In clinical practice, the main focus is on reducing high levels of the organisms causing problems; trying to maintain a low level through prophylaxis is tempting if it could be achieved without toxicity to healing cells or inducing bacterial resistance. The issue of quantity of micro-organisms has two major aspects- the sheer weight of numbers present and the number of different species. The magic number 10⁵ organisms per mL of exudate or gram of tissue serves as a reasonable threshold for infection in a closed surgical wound that tends toward predictability. However, although the open wound often can tolerate much more bacteria (eg, 10⁶) without showing signs of deterioration,10-12 the response is dependent on a number of elements - predominantly, the adequacy of the host immune response and potentiating factors such as foreign bodies that reduce the quantitative threshold of infection. Trengove et al13 support the notion that the presence of multiple species (four or more) delays healing. In general, fewer species and numbers are better for normal healing progress. Simplistically, the outcome - both positive and negative - from wound organisms is a story of quantity and can be illustrated as an infection continuum (see Figure 1). The quantity and diversity of microbes representing the states of colonization, critical colonization, and infection are unique and related to the quality of the host immune response. Some wounds progress quickly from colonization to infection via a clinically indistinct critical colonization state. Other wounds stop at the critical point and become indolent. Wounds at this point on the continuum become increasingly chronic, cellular cascades become disordered, and biochemical imbalance follows. In addition, such wounds can prove resistant to adjustment using traditional care protocols and emerging therapies such as protease inhibitors, extracellular matrix components, and topical growth factors. Thus, early recognition of disordered healing, commonly caused in whole or in part by microbes, is vital to achieving good outcomes. The wound infection continuum can be expanded to demonstrate wound healing outcomes from the different states and include recommended actions to improve delayed or deteriorating wounds (see Figure 2).14 Infection can be defined as the process by which organisms bind to tissue, multiply, and then invade tissue and elicit a marked immune response. Alternatively it can be shown as an equation: [(Inoculum x Virulence) + Potentiating factors]/ Host resistance outcome = Infection/no infection The development of infection also can be diagrammatically depicted as scales. Immunocompetence and the positive effects of good wound care tips the scales in the direction of healing, counterbalanced against the quantity and mix of species and potentiating factors for infection such as hematoma, necrotic tissue, and foreign bodies that can drag the scales towards a balance point that favors indolence or below the level to favor infection (see Figure 3).15 Micro-organisms and Infection Potential As already mentioned, aerobic cocci (S. aureus and hemolytic Streptococci [Lancefield Groups A, C, G and occasionally B]) are the most frequently identified pathogens causing invasive wound infection and must include methicillin-resistant S. aureus (MRSA). In the not too distant future, the variants described as glycopeptide intermediate-resistant S. aureus (GISA), denoting a partial resistance to vancomycin, and glycopeptide resistant S. aureus (GRSA), fully resistant to vancomycin, will enter common parlance. The role of anaerobes, including species such as Peptostreptococcus, Prevotella, Porphyromonas, and Bacteroides, is currently being reconsidered; they may act synergistically to invade the tissue even if they themselves do not penetrate far into the deep wound compartment.16 Recent in vitro research17 shows how anaerobic species cause healing delay by inhibiting fibroblast and keratinocyte proliferation, keratinocyte wound repopulation and endothelial tubule formation. The foul odors produced by anaerobes also may require treatment for the holistic well being of the patient and caregivers. Odor can be debilitating and cause anxiety and social isolation, leading to psychological depression that is linked to poor healing. Therefore, antimicrobial strategies in the critically colonized or infected wound may need broad spectrum aerobe/anaerobe activity. However, bearing in mind that anaerobes inhabit necrotic tissue and anoxic pockets or sinus tracts, removing that habitat by sharp debridement and providing adequate drainage are antimicrobial strategies that need no chemoprophylaxis. A third group of organisms, Gram-negative bacilli (eg, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella, Proteus, Acinetobacter, and Enterobacter species) tend to appear in the open wound at approximately 4 weeks from initiation. This group generally does not penetrate, but adds to the large numbers of organisms in the wound bioburden. Gram-negative bacilli possess antiphagocytic and adherence mechanisms, endotoxins, and some exotoxins, making them difficult to remove and kill and allowing the toxins to prolong the inflammatory response into a chronic disordered process. Pseudomonas exotoxin (pyocyanin) - the blue/green stain - can cause wound extension without cellulitis. At a certain quantity, these organisms may start quorum sensing or communicating chemically and turn on expression of virulence factors and the production of biofilm, causing a great deal of fuss and bother but not classic cellulitic infection in the open wound. Antimicrobial methods to kill bacteria seem sensible in critical colonization and infected states, but Gram-negative organisms will release endotoxin at that point, exacerbating or at least continuing the chronic inflammatory process. Thus, products that kill the bacteria as well as remove their endotoxins are considered advantageous. The Diagnostic Value of Microbiology in Clinical Practice Microbiological samples are valued for either quantitative or qualitative results. The gold standard microbiological method is the biopsy, which is both quantitative and qualitative. Tissue-penetrating species and their numbers are identified and calculated. Because extra skill and time for collecting and processing are required (making it less convenient than swab methodology), this invasive method is not commonly used in routine clinical practice. Although the quantitative swab also requires skill to perform, it correlates reasonably well with the gold standard.18 A semi-quantitative surface swab providing an estimate of bioburden correlates reasonably with the quantitative swab19 and may be sufficient to provide data for clinical action. Thus, if a clinical delay (refractory to topical antiseptics in a suitable slow release formulation) or an obvious infection occurs (a clinical rather than microbiological diagnosis), a swab should be sent for analysis and an empiric antibiotic strategy immediately initiated to prevent further deterioration or indolence of the wound. By the time the clinician receives the results, the data already will be out of date as regards numbers of bacteria; what remains valuable is the identification of resistant species such as MRSA. Two things should be clinically obvious by the time the result is received: 1) whether the antibiotic dose is sufficient in the context of this individual patient, taking into particular account the blood flow in the wound area, and 2) whether the correct antibiotic for the sensitivities of the problem organisms was selected. If the wound is showing signs of improvement, the antibiotics are likely the right ones in the right quantity. If the wound is not improving, either the antibiotics are not being given in sufficient quantity or by the right route to achieve timely therapeutic values or the organisms responsible for the clinical problems are resistant. The real value of microbiological data to the clinician is in checking empiric antibiotic choice. In addition, a result of "no growth" from a swab taken from an open wound that has been clinically diagnosed "delayed" or "infected" despite appropriate wound care is not proof of absence of infection - rather, this strongly suggests a false negative, as microbes might not survive the collection storage transportation and processing stages for many reasons.20 Clinical Diagnosis of Infection Local signs. Abscess. Abscess (a collection of pus) is obvious in a previously unwounded area but less obvious in a pocket at the base of an open wound that does not drain easily. Pus can be difficult to determine in the inflammation phase of an open wound because exudate may be very pus-like. Cellulitis. Cellulitis, the collective term for a visible host tissue response, presents as redness, pain, swelling, and heat - signs that are also indicative of a normal inflammatory response to injury. The difference is in degree or timing of the sign present - for example, redness extending beyond the immediate wound margin, and more pain than previously experienced or inflammation beyond the expected normal inflammatory stage for normal healing such as after approximately the first 5 days. Necrosis. Necrosis appearing suddenly within the margins of a previously healing wound represents infection from a localized high bioburden. Great variation (heterogeneity) exists in habitats and mixture of species within the same wound. Conducive local conditions may lead to infection, producing the black spot phenomenon, which can be addressed in a number of ways, including topical antiseptic agents and/or sharp debridement. Gardner et al21 validated signs of chronic wound infection originally put forward by Cutting and Harding22 and matched the signs to quantitative microbial analysis. In that report, pain was the greatest predictor of infection. Systemic signs of infection may contribute to diagnosis if no other indications (eg, pyrexia, neutrophilia, and raised C-reactive protein) for why these signs may be present exist. In the elderly patient, confusion or malaise may be present as a response to infection before or instead of other systemic symptoms. Critical colonization. A diagnosis of critical colonization is made from two main signs: cessation/ delay in healing (despite receiving what would normally be considered effective therapy) and the absence of cellulitis. In addition, corroborative signs include a wet rather than moist wound, abnormal smell, change in exudate color (often to a green/blue staining), dull dark red or overly bright red discoloration of granulation, a pale edematous wound base that does not have a granular appearance, and more pain or different pain than usual. Knowledge of these signs and what stage they represent on the wound infection continuum can be utilized in a simple algorithm to guide practice (see Figure 4). The concept of x + 2 in the Figure 4 algorithm is a method of clinical titration used to determine the necessary amount of systemic antibiotics to give a patient with an infected wound. In this concept, x represents the number of days the visible signs of infection are present, and 2 represents an additional 2 days of therapy. Giving antibiotics in this way is tailored to the host immune response and ensures that any residual microbes present at the end of the treatment period can easily be contained by the host immune response. A standard concept such as this may be adapted for topical antiseptics to provide continuing prophylaxis and for example, might be x + 10 or x times 2, where topical antimicrobials are administered concurrent to systemic therapy and then continued after the systemic therapy is complete. This approach also might prove useful in standardizing research into the efficacy of different topical antimicrobials, allowing easier comparison of relative practical value for the clinical setting. The rule also could be used as part of decision support data in electronic patient record systems to encourage conformity among prescribers to local policy. Implications for Practice In current clinical practice, the infection continuum can guide practitioners into early therapy for the critical colonization state using topical antiseptic products. The goal is early return to healing, prevention of chronicity, prevention of overt infection, and judicious use (and probable reduction in use) of antibiotics, resulting in potentially improved clinical outcomes and lowered costs. One study23 shows that on average, nurses in North Devon (UK) ensure antibiotics are medically prescribed 45% of the time and any type of antimicrobial used 41% of the time only after positive microbiological swab results are obtained. Depending on microbiological testing process requirements and the time elapsed before receiving a paper copy result, appropriate wound care actions to deal with infection are delayed 2 to 5 days, while the patient experiences increased pain and suffering and the wound may enlarge. The disrupted healing process leads to long-term chronicity and ultimately increased costs of care. The potential positive clinical practice implications from using the wound infection continuum are improved care and reduced cost. The wound infection continuum concept makes logical sense as it is based on an understanding of the current paradigm of microbiology in wounds married to experience from clinical care. It simplifies a complex subject for a wide audience of professionals, most of whom are not wound care specialists. While proper scientific validation is still necessary to prove the concept, it may be immediately useful in clinical practice as a way to standardize existing care. Validation will likely involve a combination of microbiology, clinical diagnosis of infection continuum states, and response to antimicrobial strategies. The concept will almost certainly need to be implemented and documented in "real world" situations and multicenter studies for it to be properly accepted or rejected. Conclusion Wound care currently is predominantly about the removal of negatives or barriers to healing. These negative influences include the cause of wounding (such as pressure or venous hypertension), necrotic debris, excess exudates, high bioburden, high blood sugar, contamination from incontinence, pain, anxiety, excess proteases, nutritional deficits, and so on. Wound care is moving into an era of therapy where positive factors are introduced that might enhance healing beyond its normal maximal inherent rate through the use of growth factors, extracellular matrix components, living skin equivalents, and bio-absorbable collagen scaffolds. To ensure good results with these techniques, controlling the effects of high bioburden will remain a priority; therefore, treatment must conform to sound principles - in particular, rapid debridement; systemic antibiotics perhaps used in tandem with topical antiseptics; and topical antiseptics in safe formulations for critically colonized wounds. Gram-positive aerobic cocci cause infection sometimes aided and abetted by anaerobes, Gram-negative aerobic bacilli contribute to critical colonization, and anaerobes cause odor. Good wound care outcomes rely on practitioners who know what to expect of a wound in terms of the stages, tissue types, and timing of normal healing; observe the wound closely and interpret what they see correctly; and are empowered to initiate prompt treatment when healing is problematic. Putting knowledge into practice will achieve early resolution of wounds that would otherwise all too easily become complex and stop healing. - OWM

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