Never underestimate the power of fungus!
Fungal skin infection of the foot (tinea pedis) is commonplace but looking through the literature recently I was interested by papers focussing on its presence in diabetic foot ulcers. This has probably come about as there is increased scientific interest in studying biofilms and the general microbial community of wounds (also known as the “microbiome”). This article summarises recent papers in our understanding of them and the role of fungi.
It has been long known that one of the factors that stops wounds from healing is the presence of infection. Consequently, one of the main principles of wound healing is to ensure the ulcer is clean and free of infection as the presence of microbes in the wound is likely to impair or delay healing. Microbes may reside in wounds, not as free-floating organisms, but in highly organised “micro-fortresses”. Much like a castle, they are biological structures built to be a protective enclave within a wound. Known as biofilms, they are recognised as major barriers to wound healing. These micro communities of multiple microbes that reside together in a highly structured protective extracellular matrix are difficult to eradicate. In early work, science had identified these biofilms as bacterial colonies – multiple strains of different bacteria living together in a protected citadel. It is only in the last few years, when moving away from traditional petri-dish culture, towards the more powerful DNA fingerprinting technologies that the full contents of the biofilm has been more thoroughly examined.
The surprising discovery from this technique is the biofilm is far from just being a bacterial haven - fungi has also been discovered residing in these biofilms alongside their bacterial counterparts. This may not be quite be a major revelation as early work has already hinted at this. In 2001, a study by Heald et al., demonstrated the presence of Candida species in a series of non-healing diabetic foot ulcers (1) which subsequently improved following the instigation of antifungal therapies. A few years after, Missoni et al., (2) studied the microbiology of 509 diabetic foot ulcers and found nearly 15% of them contained fungus. Again, the types involved tended to be of the Candida family. However, things looked quite different in 2016, as Kalan and colleagues (3) profiled 100 diabetic foot ulcers. While only 5% of wound swabs cultured fungi in the lab, using more modern DNA analysis, 80% were actually found to contain fungus. The most prevalent species were Candida (22%) and Cladisporidium (41%) with regular dermatophytes in less than 4% of the specimens examined. Interestingly, the types of fungi was seen to change in profile in individuals as antibiotics were used.
The idea of fungus living on the feet is not one you need to prove, dermatophytes are so common as the leading cause of tinea pedis. Moreover, their presence in patients with diabetes and vascular compromise can increase the risk of complications such as secondary, bacterial infection (4). However, it is interesting to note that in patients with diabetes and ulcers that their wound infection can include less common fungal pathogens of the feet such as Candida and other rarer species. Much more work is needed to examine the role of fungus in wounds and the synergy between fungi and bacteria but a paper in 2016 has documented that Candida is able to co-exist and interact with a range of bacteria including Staphylococcus, Pseudomonas and Streptococcus (5). Moreover, Candida can provide a hyphal scaffold onto which bacteria can colonise and help establish biofilms (6). These structures can then be a formidable barrier to penetration by conventional antibiotics.
Where does that leave us? Should we consider using antifungals as well as antibacterial when treating infected lesions? Well that would depend on the patient, the microbiology and full clinical picture. One study published in 2012 (7) did show that the addition of oral fluconazole as an antifungal added to the standard regime (glycaemic control, antibiotics and off-loading) did increase healing rates of diabetic foot ulcers which showed both bacterial and fungal positive cultures. Before we all rush to prescribe antifungals though, this study represents just one piece of work and may not be the true picture. An earlier study looked at the interaction between Candida with Staphylococcus epidermidis in biofilms (8). This work suggested a converse effect where the presence of Staphylococcus in the biofilm conferred protection from fluconazole – the Candida remained viable. This may not represent a true drug resistance but as another study highlighted, may demonstrate how the biofilm can act as an impermeable or limiting barrier reducing drug penetration and effect (9).
So, before antifungals are prescribed for all non-healing foot ulcer patients more work is needed to unravel this mystery, identify viable antimicrobial regimes which may improve wound healing rates and not adversely affect the wound and, more importantly the patient.
1. Heald AH, O'Halloran DJ, Richards K, Webb F, Jenkins S, Hollis S, et al. Fungal infection of the diabetic foot: two distinct syndromes. Diabet Med. 2001;18(7):567-72.
2. Missoni EM, Kalenic S, Vukelic M, De Syo D, Belicza M, Kern J, et al. [Role of yeasts in diabetic foot ulcer infection]. Acta Med Croatica. 2006;60(1):43-50.
3. Kalan L, Loesche M, Hodkinson BP, Heilmann K, Ruthel G, Gardner SE, et al. Redefining the Chronic-Wound Microbiome: Fungal Communities Are Prevalent, Dynamic, and Associated with Delayed Healing. MBio. 2016;7(5).
4. Bristow IR, Spruce MC. Fungal foot infection, cellulitis and diabetes: a review. Diabet Med. 2009;26(5):548-51.
5. Allison DL, Willems HM, Jayatilake JA, Bruno VM, Peters BM, Shirtliff ME. Candida-Bacteria Interactions: Their Impact on Human Disease. Microbiol Spectr. 2016;4(3).
6. Förster TM, Mogavero S, Dräger A, Graf K, Polke M, Jacobsen ID, et al. Enemies and brothers in arms: Candida albicans and gram-positive bacteria. Cell Microbiol. 2016;18(12):1709-15.
7. Chellan G, Neethu K, Varma AK, Mangalanandan TS, Shashikala S, Dinesh KR, et al. Targeted treatment of invasive fungal infections accelerates healing of foot wounds in patients with Type 2 diabetes. Diabet Med. 2012;29(9):e255-62.
8. Adam B, Baillie GS, Douglas LJ. Mixed species biofilms of Candida albicans and Staphylococcus epidermidis. J Med Microbiol. 2002;51(4):344-9.
9. Al-Fattani MA, Douglas LJ. Penetration of Candida biofilms by antifungal agents. Antimicrob Agents Chemother. 2004;48(9):3291-7.