Pages 126 - 129 Volume 91, Issue 2
Trophic leprosy ulcers – what is a secondary infection?
Cite this article
Roderick Hay;
Trophic leprosy ulcers – what is a secondary infection?; Leprosy Review; 2020; 91; 2; 126-129; DOI: 10.47276/lr.91.2.126
Leprosy Review
British Leprosy Relief Association
Colchester, UK
Open skin wounds and ulcers, whether they are caused by trauma or underlying disease, often persist despite appropriate nursing care to encourage the formation of granulation tissue, a key prelude to re-epithelialisation. The factors that determine poor healing are multiple and include vascular or neurological damage, the presence of pathogenic microbes, repeated trauma or micro trauma and surface pressure. These factors are not constant and vary with different underlying medical conditions. Diabetic foot ulcers for instance are thought to be more prone to surface invasion by bacteria such as Staphylococcus aureus. But, as with other ulcers, there is a central practical dilemma in management – whether and when it is beneficial to use antibiotics. In order to address the similar problem posed by microorganisms in trophic ulcers in leprosy and highlighted by two papers in this issue of Leprosy Review,1,2 it is relevant to consider recent findings from the study of other skin ulcers.
Most guidelines on the indications for antimicrobial treatment of micro-organisms in ulcers are limited by a small body of scientific evidence from wound healing studies. The application of simple clinical indicators is, therefore, a common strategy for deciding whether the microbes detected are contributing to the pathology, a necessary first step in order to decide which patients will benefit from antibiotics. For instance, antibiotic use in the UK National Institute for Health and Care Excellence (NICE) guidelines for assessing and treating infection in leg ulcers (venous or stasis ulcers) is triggered by a simple clinical definition of infection.3 Clinical symptoms and signs of leg ulcer infection are cellulitis (defined as reddening and swelling), fever, increased pain, rapid extension of the area of ulceration, malodour and increased exudate. A similar approach has been adopted for foot ulcers in diabetics (diabetic foot). The definition of infection used for commencing antibiotic treatment in diabetic ulcers is similar and includes the presence of the classic signs of inflammation (redness, warmth, swelling, tenderness, or pain) or purulent secretions, but also additional or secondary signs such as non-purulent secretions, friable or discoloured granulation tissue, undermining of wound edges and foul odour.4 In addition, because the risk of deep infection in the diabetic foot is high, imaging studies and, if necessary, bone biopsies may also form part of the investigation which will determine use of antibiotics.
Current advice on the recognition of infection in trophic leprosy ulcers is also largely based on clinical parameters as in the paper from Hyderabad, published in this issue.1 Advice published in 2012 on the use of systemic antibiotics, oral or parenteral, suggested that, in leprosy ulcers, these are only required in the presence of signs of acute infection such as cellulitis or failure of a properly treated wound to heal.5 These clinical signs of infection again include purulent secretions, two or more signs of inflammation (e.g. pain, redness, erythema, warmth, tenderness and induration), foul odour and presence of necrotic tissue; in other words they are similar to the standard of care in diabetes, referred to previously.
Most studies of ulcer infections have focused on bacteria in the lesion and interpretation of the role of fungi in inhibiting healing of ulcers is more problematic. There is less supportive microbiological information, and this is largely based on the use of conventional culture techniques rather than genomics. Few fungal species have been consistently associated with a pathogenic role in ulcers, but these include Fusarium spp in diabetics, where there is histopathological evidence of deep invasion suggesting more than surface contamination.6,7 Other fungi found to cause penetrating infection of ulcers in diabetics include Candida species;8 mucoromycetes such as Rhizopus microsporus var rhizopodiformis9 or Aspergillus species10 can cause skin ulceration in immunocompetent patients. But these are rare occurrences. A further aid to diagnosis in fungal infection involves taking a biopsy from the ulcer base which will show deep penetration by fungal cells. But recent work suggests an alternative approach might be helpful as one study in diabetic ulcers has shown that the empiric – without guidance from microbiological samples – addition of fluconazole, an antifungal, to standard wound care significantly improved the healing rate of ulcers.11 The most common fungus isolated in this study was Candida parapsilosis, which is often not regarded as a significant pathogen except in the severely ill. Candida tropicalis and C. albicans were the next most common yeasts identified. A potential, explanation for this improved healing was provided by an in vitro study of microorganisms in biofilms, which form over an ulcer base, where the use of antibacterial antibiotics increased the numbers of Candida species whereas the addition of fluconazole decreased these significantly. Yeasts in biofilms were found to increase the colonisation rate by bacteria.12 The paper from Sudan in this issue contributes to our understanding of possible implications for leprosy ulcers by identifying fungal species.2 The commonest fungus was Aspergillus flavus which is generally sensitive to the oral antifungal, itraconazole; Candida species were isolated infrequently. It is not known whether empiric use of antifungal in this situation might improve healing. Treating fungal infections in ulcers presents a further practical problem as some of the major pathogenetic strains associated with wound penetration, e.g. Fusarium species, are only sensitive to the more costly or parenteral antifungals, some of which require supervised care.
Further recent findings from the study of other ulcers are relevant. Specific genetic strains of bacterial species, such as Staph aureus, are associated with infection in ulcers and, in parallel, the formation of a biofilm increases the risk of non-healing in many ulcers.13 This evidence is largely based on the ability to carry out genetic microbiome analysis, assess the presence or absence of biofilms and the detailed composition of the mix of bacteria in the wound. Bacteria and fungi in biofilms behave differently to those in free growth, from their ability for intermicrobial communication to changes in physiological and pathogenetic properties, such as expression of virulence factors and resistance genes.14 In diabetes, metagenomic shotgun sequencing has revealed that strain-level variation within the single species, Staphylococcus aureus, and genetic signatures of biofilm formation were both associated with poor healing. Cultured wound isolates of Staph. aureus produced differential clinical responses in mouse models and these corresponded with what had been observed in patients’ outcomes; the presence of wound ‘bystanders’ such as Corynebacterium striatum and Alcaligenes faecalis, that are considered to be commensals or contaminants, also had a significant impact on wound severity and healing.13 The authors also found that the composition of ulcer microbiome was profoundly affected by interventions other than antibiotic therapy such as debridement.
How does this help us to manage infection in leprosy ulcers? Firstly, it draws attention to the fact that this is a field that has been neglected by research using modern genetic techniques for microbial identification and analysis and this deficiency should be clearly identified as a research priority. Secondly, we need to understand a lot more about the relationship between different microorganisms in the leprosy ulcer biofilm and whether using an appropriate antibacterial or antifungal can improve long term healing rates and reduce disability. The studies discussed in this section suggest that, in other neuropathic ulcers, either an empiric antimicrobial approach or, at least, one that does not rely on the current clinical definitions of secondary infection of an ulcer might be beneficial. Does this also apply to patients with leprosy? In order to take this forward, interventions with antibiotics or antifungals should be correlated with simple clinical indicators that allow those treating leprosy ulcers to identify clearly which patients will benefit from antimicrobials. The paper by Ebineshan and co-workers1 has shown that leprosy ulcers do contain biofilm producing bacteria and that their antimicrobial resistance is increased, similar to diabetic foot ulcers. This evidence supports the need for further studies on the mixed microbial populations in leprosy patients. Yet until there is more information, those caring for patients with trophic leprosy ulcers will have to rely on the current clinical definitions of secondary infection in ulcers, unsatisfactory as they may be, to guide the use of antimicrobials, always bearing in mind the vital role of other, non-pharmacological, aspects of good ulcer care.
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