¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Prurigo nodularis and atopic dermatitis are chronic, inflammatory skin conditions characterized by significant pruritus that disrupts daily life. They also involve dysfunction of the T-helper 2 immune response, leading to the over secretion of interleukin-31 (IL-13) in the dermis and serum. Nemolizumab is a new IL-31 receptor antagonist that has shown high efficacy in the treatment of prurigo nodularis (PN) and atopic dermatitis (AD) in multiple phase 3 trials, with a good safety profile. A brief overview of PN and AD including highlights of the findings from three trials of nemolizumab in treating these disorders will be presented herein.

Keywords: atopic dermatitis, interleukin-31, nemolizumab-ilto, prurigo nodularis, pruritus

Introduction

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized mainly by pruritus, leading to a disruption of sleep and daily activities.^1,2 The pruritus is often intense, lasting over 6 weeks, and may also present with a burning or stinging sensation.^3,4 Diagnosis is primarily made by clinical examination of the lesions and through the patient’s history, revealing clusters of nodules commonly located on the extremities or trunk.³ Biopsy can also help to confirm the diagnosis in unusual cases, which typically reveals hyperkeratosis, hypergranulosis and increased fibroblasts.³

PN disproportionally impacts individuals of African ancestry and the elderly, although it can affect patients of any age.⁴ Men and women are equally susceptible.⁵ A significant number of patients also suffer from anxiety, depression, and suicidal ideation due to the severity of the condition.^2,4,5 In 2022, dupilumab became the first US Food and Drug Administration approved treatment for PN.⁶ Other conventional treatments have typically been less effective, involve off-label uses of medications and mainly aim to reduce itching by targeting the neural and immunologic aspects of the condition.³

Similarly, atopic dermatitis (AD) is also an inflammatory cutaneous disease commonly manifesting with erythema, papules, edema, and crusting.^7,8 AD most commonly affects the pediatric population, with 90% of cases first presenting with symptoms under the age of 5 years, persisting with episodical outbreaks in adulthood.⁸ AD is highly variable in presentation and current management of the condition depends on its severity.^7,9 First-line therapy involves the use of topical corticosteroids, along with emollients and regular bathing.⁹ Systemic therapies are also commonly used, including ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil.¹⁰ Other treatments include calcineurin inhibitors, crisaborole, rofumilast, ruxolitinib, ultraviolet B phototherapy, and, more recently, dupilumab, tralokinumab, abrocitinib, and upadacitinib, which may be used in more severe or treatmentresistant AD.⁹

IL-31 Pathway and Mechanism of Nemolizumab

T-helper 2 (Th2) cells are primarily responsible for the release of interleukin-31 (IL-31), with CD4+, CD8+, and mast cells also producing IL-31 in the presence of allergens of pathogens.^4,11-13 This leads to the stimulation of eosinophils and contributes to the itching in AD, as well as other inflammatory skin disorders.¹¹ There are multiple proposed mechanisms as to how IL-31 leads to the pruritus in AD and PN, such as the abundance of IL-31 receptors in the dorsal root ganglia (DRG) of cutaneous sensory nerves.¹¹ IL-31 may also activate receptors present in keratinocytes, which subsequently activate unmyelinated C fibers, leading to pruritus.¹¹ Transient receptor potential cation channels in the DRG and chemokine release by keratinocytes due to IL-31 are possible additional mechanisms.¹¹

Both PN and AD are inflammatory cutaneous conditions that involve impaired IL-31 signaling.⁴ PN skin lesions form as a result of the chronic scratching induced by immunologic and neural dysfunction.⁴ Skin biopsy reveals the presence of T lymphocytes, mast cells, and eosinophils that release IL-31, tryptase, and histamine.⁴ There is also increased nerve fiber density, along with neuropeptides such as substance P and calcitonin gene-related peptide in the dermis, which contribute to the pathogenesis of pruritus in PN.^3,4 Similarly, IL-31 serum levels increase with higher severity of AD, and gene polymorphisms have been linked with the development of the disease.^4,11-13 Nemolizumab is an IL-31 receptor alpha antagonist that has shown potential in treating both PN and AD in multiple phase 3 clinical trials.⁴ These investigations demonstrated that treatment with nemolizumab reduced itch intensity, improved lesion healing and inhibited Th2 (IL-13) and Th17 (IL-17) cells.⁴

Phase 3 Clinical Trials for Prurigo Nodularis

A phase 3 clinical trial of nemolizumab in PN enrolled 274 patients, aged 18 years and older, from 68 sites and 9 different countries, for a 16-week treatment period and subsequent 8-week follow-up.⁵ Patients were selected based on a history of PN for ≥6 months and pruritus classified as severe by the Peak Pruritus Numerical Rating Scale (PP-NRS).⁵ This scale ranges from a score of 0 (no itch) to 10 (worst itch), where a score of 7 or greater is severe and qualified patients for enrollment in the trial.⁵ Patients were also selected for the presence of 20 or more nodules, and a score of 3 or 4 on the Investigator’s Global Assessment (IGA), which assesses the severity of the disease on a scale of 0-4 by the type, size and quantity of lesions.^5,14 Patients with active AD, neuropathic or psychogenic pruritus, or pruritus due to causes other than PN were excluded from the study.⁵

183 patients were randomly chosen to receive nemolizumab and another 91 patients were given a placebo.⁵ Participants were administered an initial dose of 60 mg of nemolizumab, followed by 30 mg or 60 mg based on their starting weight, every 4 weeks over a period of 16 weeks.⁵ Overall, both groups were similar and balanced prior to treatment; only 4.4% of participants were Black.⁵

19.7% and 35% of the nemolizumab group achieved almost complete itch relief at 4 weeks and 16 weeks, respectively.⁵ In the placebo group, 2.2% and 7.7% reported similar itch relief after 4 weeks and 16 weeks, respectively.⁵ 37.2% and 51.9% of patients receiving nemolizumab achieved a decrease in sleep disturbance by 4 and 16 weeks, respectively.⁵ In contrast, only 9.9% and 20.9% of the placebo group reported a clinically significant decrease in sleep disturbance.⁵ 16 week after treatment, 56.3% of the nemolizumab group and 20.9% of the control group achieved a significant decrease in itch intensity, defined as a 4 or greater point decrease on the PP-NRS.⁵ Patients who received nemolizumab demonstrated significant improvements in skin lesions, pruritus, sleep disturbance, pain, global disease assessment, quality of life, and anxiety and depression symptoms compared to the control group.⁵ Improvements in itch, skin lesions, sleep disturbance, and quality of life continued through week 52, with more than two-thirds of patients becoming itch-free or nearly itch-free and 90% reporting clinically meaningful improvement in quality of life.¹⁵ Quality of life was assessed using the Dermatology Life Quality Index (DLQI), which is composed of 10 questions designed to evaluate how patients perceive the impact of their skin condition on different areas of their life, including symptoms/feelings, daily activities, leisure, work/school, personal relationships, and treatment.⁵

61.2% of participants that received nemolizumab and 52.7% of placebo experienced at least one adverse event (AE) (Table 1).⁵ In the treatment group, most AEs were common side effects and included mild AD and headache.⁵ Peripheral or facial edema and asthma were more common in patients receiving nemolizumab, while infections were more prevalent in the control group.⁵ One case of bullous pemphigoid was reported in the nemolizumab group, and a case of generalized exfoliative dermatitis was recorded in the placebo group.⁵ In addition, a higher number of placebo patients required rescue therapy (15.4%) compared to those receiving nemolizumab (4.9%).⁵ 2.2% of patients in each group withdrew from the trial due to adverse reactions.⁵ Long-term data over a 52- week extended study remained consistent with the safety profiles in phase 3 trials.¹⁵

In patients with no history of asthma, 6 of 156 in the nemolizumab group and 2 of 77 in the placebo group had decreased expiratory flow below 80% during the treatment period.⁵ In those with a history of asthma, 5 of 22 patients receiving nemolizumab showed peak expiratory flow under 80% of the predicted value during the treatment period, however, only 2 of these were confirmed as worsening asthma.⁵ In comparison, 1 of 13 patients with a history of asthma in the placebo group experienced a peak expiratory flow under 80% of the expected value during the treatment period.⁵ An increased eosinophil count was reported in 7.7% of the nemolizumab group and 4.4% of the placebo group.⁵ Moreover, 5.8% of nemolizumab patients developed antidrug antibodies.⁵

Table 1.

Phase 3 Clinical Trials for Atopic Dermatitis

In two identical phase 3 trials of nemolizumab for the management of AD, ARCADIA 1 and ARCADIA 2, 1142 patients over the age of 12 years received 30 mg of nemolizumab (after a loading dose of 60 mg), while 586 participants were given a placebo every 4 weeks over a period of 16 weeks.¹⁶ The Eczema Area and Severity Index (EASI), which assesses the surface area of the skin affected by AD and the severity of lesions, as well as the IGA, were used to characterize the severity of AD.^16,17 Primary endpoints were defined as an IGA score of 0 or 1 with a ≥2-point improvement from baseline and at least 75% improvement in EASI.¹⁶ Patients in the nemolizumab group who successfully achieved these endpoints were then randomly reassigned in a 1:1:1 ratio.¹⁶ They were to receive either 30 mg of nemolizumab every 4 weeks, 30 mg of nemolizumab every 8 weeks, or a placebo every 4 weeks in a maintenance period.¹⁶

In the nemolizumab group, 36% of patients in ARCADIA 1 and 38% in ARCADIA 2 achieved IGA success, compared to 25% (ARCADIA 1) and 26% (ARCADIA 2) of patients in the control group.¹⁶ 75% improvement in EASI was observed in 44% (ARCADIA 1) and 42% (ARCADIA 2) of patients in the nemolizumab group, compared to 29% (ARCADIA 1) and 30% (ARCADIA 2) of those receiving placebo.¹⁶ Improvements in pruritus were observed from week 1 in the nemolizumab group, with additional improvements reported in quality of life, sleep, and a decrease in pain by 16 weeks.¹⁶ Additionally, clinically meaningful improvements in itch, skin lesions, and sleep disturbance persisted through week 56 of an extended study.¹⁸ Overall, the study showed that a statistically significant proportion of patients with moderate to severe AD achieved clinically meaningful improvements in symptoms of pruritus and inflammation with nemolizumab (Table 2).¹⁶

Table 2.

In terms of safety, 50% of patients in ARCADIA 1 and 41% in ARCADIA 2 receiving nemolizumab reported an AE, with serious effects occurring in 1% and 3% of patients in each respective trial.¹⁶ Worsening of AD was the most commonly reported adverse effect, occurring in a total of 112 patients receiving nemolizumab from both trials, compared to 49 patients in the control group. Worsening of asthma was reported in 1% of patients in ARCADIA 1 and 5% of patients in ARCADIA 2 in the nemolizumab group; however, there was no significant difference compared to those receiving placebo.¹⁶ Serious drug-related AEs were rare, reported in 5 patients in ARCADIA 2, and included infection, peripheral edema, eosinophilic colitis, and small intestinal obstruction.¹⁶ Additionally, AEs resulting in treatment discontinuation occurred in a total of 24 patients in the nemolizumab group, compared to 6 patients in the control group across both trials.¹⁶ Safety results of nemolizumab after 56 weeks aligned with previous findings, supporting its use in adolescents and adults with moderate-to-severe AD.¹⁸

Conclusion

Nemolizumab demonstrated high efficacy in the treatment of PN and AD in phase 3 trials, yielding marked improvements in symptom control with an overall favorable safety profile.^5,16 In the PN trial, a significant number of patients receiving nemolizumab exhibited improvements in pruritus, sleep disturbances, and quality of life based on the DLQI compared to the control group.⁵ The most common side effects were nasopharyngitis, AD, and headaches.⁵ In the AD trials, similar improvements in pruritus, sleep quality, and a decrease in pain levels were observed with the most common side effect being worsening of AD.¹⁶ Overall, nemolizumab has shown promising results in reducing pruritus and is particularly useful in treating severe or therapy-resistant PN and AD.^4,5,16

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¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX USA
³Dermatology Department, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
A biofilm is a diverse community of microorganisms enclosed in an extracellular matrix. Although this organization of cells exists naturally in healthy skin, it is also involved in the pathogenesis of multiple skin disorders, such as acne and atopic dermatitis. Because biofilms provide microorganisms with a survival advantage and increased resistance to traditional antibiotics, they can be very difficult to treat, particularly when the goal is to also preserve the natural skin microbiota. This review aims to provide an overview of the role of biofilms in various dermatological diseases, as well as the conventional and newly developed therapies that can be used in their treatment.

Keywords: acne, atopic dermatitis, biofilms, dermal fillers, hidradenitis suppurativa, onychomycosis, chronic wounds

Introduction

Biofilms are a collection of microbial cells encased in a polymeric substance matrix.^1,2 Biofilms can range in population from tens of cells to hundreds of thousands, and can encompass multiple species of organisms.³ The first step in its formation involves the attachment of the microorganism to a living or abiotic surface.³ The cells can then begin secreting extracellular components of the matrix, including polysaccharides, DNA, proteins, and lipids.^3,4 This is followed by a maturation stage, with the formation of a stable, three-dimensional community that allows for the movement of nutrients and signaling particles within the biofilm.⁵

Biofilms provide cells with increased protection from desiccation, chemical perturbation, and invasion from other microorganisms.⁶ They can also reduce the susceptibility of bacteria to antibiotics by up to 1000 fold, due to reduced antibiotic penetration and the presence of metabolically dormant, antibiotic resistant persister cells, which can recolonize the biofilm following antibiotic administration.⁷ Biofilms can also alter the growth kinetics of bacteria, where cells deeper within the polymer are in a stationary phase of growth, which β‐lactam antibiotics are less effective against.⁷ These factors provide bacteria and certain species of fungi with a survival advantage compared to organisms in the planktonic state, which is the free floating state of microorganisms.³

Acne

The pathogenesis of acne is complex, involving inflammation of the pilosebaceous unit, as well as hyperkeratinization, androgen induced increase in sebum, and colonization of the follicle by Cutibacterium acnes (C. acnes).^8,9 The C. acnes genome was shown to encode genes for the synthesis of extracellular polysaccharides, an essential component of biofilms.³ In one study, over 50% of antibiotic treated patients were found to be colonized with erythromycin and clindamycin resistant strains, and over 20% of them had tetracycline resistant acne.⁸ Biofilms are one factor for this increased resistance to antibiotics observed in patients with severe acne.⁸ For example, in vitro studies showed that significantly higher concentrations of cefamandole, ciprofloxacin, and vancomycin were needed to inhibit C. acnes biofilms compared to free floating bacteria.⁸ In another study, C. acnes biofilms were less sensitive compared to planktonic bacteria to a range of antimicrobials, such as 0.5% minocycline, 1% clindamycin, 0.5% erythromycin, 0.3% doxycycline, 0.5% oxytetracycline and 2.5-5% benzoyl peroxide.⁸

One hypothesis for the pathogenesis of acne is the formation of the comedone, which is a collection of keratin and sebum in the pilosebaceous unit caused by the hyperproliferation of keratinocytes in the follicular lining.⁹ Biofilms are thought to increase the cohesiveness between keratinocytes, which promotes the formation of the comedone and enables C. acnes to strongly attach itself to the follicular epithelium.⁹ Following the hyperproliferation of keratinocytes, the comedone grows with debris and releases its immunogenic contents into the surrounding dermis.⁹ As a result, proinflammatory cytokines can infiltrate the pilosebaceous unit and promote the development of inflamed pustules and papules seen in acne.⁹

In addition to certain antibiotics and antimicrobial peptides, agents that can specifically target biofilms in acne include surfactants such as rhamnolipids, which are produced by Pseudomonas aeruginosa (P. aeruginosa) and can dysregulate biofilms by creating central hollow cavities.^9,10 Surfactants can also be used to weaken the adhesion of biofilms to surfaces and promote their dispersal.¹¹ Quorum sensing (QS) plays an important role in the formation and maintenance of biofilms.¹¹ By altering microbial gene expression, they can promote the transformation from the planktonic state into a sessile form.¹¹ The use of QS inhibitors such as azithromycin, bergamottin, usnic acid, quercetin, and ellagic acid may help inhibit C. acnes virulence factors and biofilm formation.^9,10 Moreover, dispersin B and deoxyribonuclease (DNase) can be employed to degrade biofilm proteins, while metal chelators can be used to bind to magnesium and calcium in the outer cell wall, which disrupts the stability of the biofilm.¹⁰ Nitric oxide generating agents can also be used to decrease intracellular cyclic dimeric guanosine monophosphate levels, which leads to a favoring of the planktonic state over the formation of biofilm.¹⁰ Finally, bacteriophage therapy specifically directed against C. acnes, has proved to be successful in the animal model and is an exciting new therapy that has been studied more extensively in other diseases such as meningitis, but not in the treatment of skin conditions.¹⁰

Atopic Dermatitis

Atopic dermatitis (AD) is present in 10% of children and 7% of adults in the United States. Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) are the two most commonly found bacteria in AD lesions, and are also known to form biofilms^12-14 In a study of 40 patients with AD, 93% of biopsied lesions contained staphylococci, with 85% being strong producers of biofilms.¹⁵ Bacteria naturally colonize the epidermis, forming biofilms between squamous epithelial cells even in healthy skin.¹² In AD however, S. aureus and other pathogens enhance inflammation and weaken the skin barrier.^12,13,16 Although staphylococci natrally colonize the skin, those associated with biofilms have only been found in AD lesions.¹² Moreover, S. aureus can cause keratinocytes to undergo apoptosis when present as biofilms but not in the planktonic state.¹² This is significant to the pathogenesis of AD, as damaged keratinocytes release double-stranded RNA (dsRNA), which initiates the toll-like receptor (TLR)-3-mediated secretion of thymic stromal lymphopoietin (TSLP), a cytokine that causes a strong itch response.¹² TSLP also activates dermal dendritic cells and recruits T helper 2 cells, which subsequently produce interleukin (IL)-4 and IL-13, leading to the inhibition of adenosine monophosphate (AMP) and further weakening immunity against pathogens.¹² Bacterial biofilms can also result in the blockage of eccrine sweat glands and ducts, causing further inflammation or potentially inducing the inflammation and pruritus observed in AD.^12,17

Traditional treatment of AD does not typically involve the use of antibiotics due to their insufficient specificity and risk of promoting antibiotic resistant bacteria.¹⁸ In terms of reducing inflammation in AD, a major goal of treatment is the improvement of dysbiosis, which involves reducing the population of S. aureus.¹⁸ Sodium hypochlorite bleach baths are helpful for improving clinical AD symptoms by limiting bacterial colonization and restoring skin surface microbiome. In vitro and in vivo investigations have provided evidence of efficacy, with one study demonstrating significant anti-staphylococcal and anti-biofilm activity when used at a concentration of 0.02% compared to the standard recommendation of 0.005%.^18,19 There is also evidence supporting the topical use of farnesol and xylitol in supressing the formation of biofilms.^14,20 Additionally, use of emollients can improve skin hydration and decrease pH, which may play a role in preventing S. aureus proliferation, with some studies suggesting a decreased incidence of AD in susceptible individuals after consistent emollient use.¹⁹ One of the novel treatments currently being developed to specifically target S. aureus in AD lesions is Staphefekt™, an engineered bacteriophage endolysin with bactericidal activity towards S. aureus.¹⁸ Other potential new therapies include synthetic antimicrobial peptides that target staphylococci as well as their biofilms, and omiganan, an indolicidin analog was found to improve microbial dysbiosis as well as clinical scores in phase II trials in the treatment of AD lesions.¹⁸ Finally, dupilumab and ultraviolet-B (UVB) therapy also exhibited efficacy in decreasing S. aureus colonization, while increasing the bacterial diversity in AD patients.¹⁸

Wounds

Wounds are particularly susceptible to the formation of biofilms due to the absence of the protective covering of the skin.²¹ S. aureus, P. aeruginosa, and the Clostridiales family are among the most common biofilm-forming bacteria found in wound infections.^4,22 In chronic wounds, the healing process is impaired due to multiple factors that result in a constant state of inflammation.^23,24 These wounds are characterized by the presence of proinflammatory cytokines such as tumor necrosis factor alpha and IL-1 alpha.²³ One element that contributes to this state of chronic inflammation and recruits inflammatory cells is biofilm formation in the initial wound.^23,25 These inflammatory cells then secrete proteases and reactive oxygen species that delay the healing process.²³ In some cases, extensive use of antimicrobials, particularly in doses under the minimum inhibitory concentrations required for the infectious agent, promotes biofilm formation.⁴

Debridement is essential in the initial management of chronic wounds, including the removal of necrotic tissue and biofilms.^23,26 This should be followed by the administration of antimicrobials such as polyhexamethylene biguanide, acetic acid, and iodine.²³ Silver and hypochlorous acid have also shown therapeutic potential against biofilms when tested in vitro, exhibiting bactericidal activity against multiple microorganisms, including Pseudomonas and Staphylococcus.²⁷ Low-frequency ultrasound, lasers, and photodynamic therapy are also potential options for biofilm breakdown.²⁰

Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by painful nodules, abscesses and pus-discharging sinus tracts or fistulas known as tunnels.^28,29 Microscopic analysis of HS lesions typically reveals inflammatory infiltrates that can partially be explained by the presence of biofilms in most cases of HS.²⁸ This is particularly evident in the late stages of HS pathogenesis.³⁰ Although HS is not an infectious disease itself, some studies have demonstrated the presence of slow-growing microbial agents.^28,31 One study of the microbiome of sinus tracts in patients with moderate to severe HS found that they were predominantly colonized by anaerobic species, such as Prevotella and Porphyromonas.³⁰ The deposition of intradermal corneocytes and hair fragments provides a suitable environment for the formation of biofilm by commensal bacteria.²⁸ This is supported by the consistent detection of anaerobic species in HS lesions, which can grow in the anoxic environment created by deep-seated HS nodules, dilated hair follicles, and sinus tracts.²⁸ In one study, 67% of sampled HS lesions contained biofilms.²⁸ Moreover, the difficulty in detecting these pathogens using traditional culturing techniques, which identify the planktonic state of bacteria, may be due to the presence of biofilms, especially in chronic lesions.²⁸

Conventional treatment of HS lesions continues to be tetracyclines, while second-line therapy involves a combination of clindamycin and rifampicin, which work synergistically and reduce risks of antibiotic resistance.³⁰ However, when administered as monotherapy, 65.7% and 69.3% of bacterial cultures from HS patients were found to be resistant to clindamycin and rifampicin, respectively.³⁰ Dapsone can also be used as a third-line treatment in mild to moderate HS, however, evidence supporting its use is weak.^30,32 Other therapeutic options include metronidazole or ertapenem in severe cases, with the latter exhibiting resistance rates of less than 1%.³⁰ Patients with HS often experience flare ups of the disease, which can also be partially attributed to biofilm formation.^28,33

Dermal Fillers

Injectable dermal fillers are the second most common nonsurgical cosmetic procedure performed in the United States.¹⁷ Adverse effects include erythema and nodules, which although heavily disputed, have recently been attributed to biofilm formation.^17,34 Conventional treatment of these side effects can involve the use of steroids, though when used at high doses can worsen the infection and symptoms.^17,34 In one study that investigated the role of dermal fillers in biofilm formation, the presence of as few as 40 bacteria was enough to cause infection.³⁵ Bacterial colonies in human skin contain up to 105 bacteria, which make them a potential source of needle contamination during skin penetration if proper precautions are not taken.³⁵

Treatment of dermal filler biofilms includes broad-spectrum antibiotics such as ciprofloxacin, amoxicillin or clarithromycin.³⁶ Dermal fillers composed of hyaluronic acid, one of the most common substances used in fillers, should also be treated with hyaluronidase.³⁶ This serves to lyse the gel and remove the mechanical support of the biofilm.³⁶ 5-fluorouracil, laser lyses, and surgical resection can also be employed in more severe, treatment-resistant cases.^17,36 Importantly, the conventional use of steroids, non-steroidal anti-inflammatory drugs, and antihistamines should be avoided.^17,36

Onychomycosis

Onychomycosis is a fungal infection of the nails that is associated with the formation of biofilms.^37-39 It is typically therapy resistant and relapses are common.³⁷ Trichophyton rubrum, Trichophyton mentagrophytes and the Candida family are all fungi that can cause onychomycosis, and are also potentially capable of producing biofilms.⁴ These biofilms are hypothesized to be responsible for the treatment resistance and infection recurrence observed in onychomycosis.³⁸ Multiple studies of patients with onychomycosis support the formation of fungal biofilms in vitro and ex vivo.³⁸ Amphotericin B and echinocandins are usually effective in clearing free existing fungi as well as biofilms, especially when combined with biofilm-targeted treatments such as cationic antimicrobial peptides and antibody-guided alpha radiation.³⁷ Antibody-mediated inhibition of matrix polysaccharides has been found to prevent biofilm formation in Cryptococcus neoformans.⁴⁰ Other biofilm-specific therapies being investigated aim to inhibit the extracellular matrix or matrix polysaccharides and increase antifungal penetration, including gentian violet, DNases, and quorum-sensing molecules.³⁷

Conclusion

The skin is colonized by a wide variety of microorganisms, which can aggregate and form biofilms.^3,41 In some conditions, these biofilms can play a significant role in the pathogenesis of multiple skin diseases such as acne, atopic dermatitis, and hidradenitis suppurativa.^8,12,28 With the growing concern of antibiotic resistance in dermatology, it is essential to consider the role of biofilms in the treatment of cutaneous disorders.^42,43 Recently developed treatments, such as bacteriophage therapy, that have been used extensively in other fields of medicine but not yet in dermatology, should also be investigated for their utility in the management of skin conditions.¹⁰

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