The impact of biofilms in dermatology: The fortified enemies

Abhineetha Hosthota1, Niti Khunger2, Anila Sara Tampi1, Anjana Ravi1, Shreya Sethunath1, Leena Hanumappa Narayanaswamy1

1Department of Dermatology, The Oxford Medical College, Hospital & Research Centre, Bangalore, Karnataka, India, 2Vardhman Mahavir Medical College & Safdarjang Hospital, New Delhi, India

Corresponding author: Prof. Abhineetha Hosthota, M.B.B.S., M.D, E-mail: abhineethahosthota@yahoo.com
How to cite this article: Hosthota A, Khunger N, Tampi AS, Anjana R, Sethunath S, Leena HN. The impact of biofilms in dermatology: The fortified enemies. Our Dermatol Online. 2025;16(2):186-194.
Submission: 04.03.2024; Acceptance: 21.05.2024
DOI: 10.7241/ourd.20252.17

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© Our Dermatology Online 2025. No commercial re-use. See rights and permissions. Published by Our Dermatology Online.

ABSTRACT

The role of biofilms is an emerging topic in the field of dermatology. Recent evidences show association of biofilm in a wide range of dermatological disorders such as chronic wounds, atopic dermatitis, hidradenitis suppurativa, acne vulgaris, onychomycosis, candidiasis, and in dermal fillers. Biofilms create a favorable environment to protect microorganisms from external perturbations through microbial communication, enhanced virulence, and nutrient supply. This helps organisms to sustain and survive in an unfavorable environment, overcoming the host immune system and antibiotics. They exhibit an altered phenotype making their detection with routine culture techniques extremely difficult. Thus, they pose a huge challenge to clinicians due to their persistent nature and resistance to conventional antimicrobial therapy. Despite recent developments, the eradication of biofilms in dermatological disorders remains a challenge. However, novel treatment armamentaria have been attempted and tested with varying degrees of efficacy, ranging from topical agents to lights and lasers.

Key words: Biofilm; Acne vulgaris; Antibiotic tolerance; Biofilm eradication agents

INTRODUCTION

Biofilms are complex sessile microbial communities that consist of one or more bacterial species surrounded by extracellular polymeric substances (EPS) [1]. EPS is a complex composition of polysaccharides, proteins, extracellular DNA, and even host-produced factors. Apart from viscoelastic structural functions of EPS, it also plays an informative, redox-active, and nutritive role in biofilms. [2] These bacterial communities attach to biological and nonbiological surfaces with altered phenotypes and growth characteristics. Biofilms are now thought to be the predominant bacterial phenotype on both healthy and diseased human skin. [1]

In bacterial biofilm communities, the metabolic activity is modified by a reduction in the growth rate, an increased rate of EPS production, and the alteration of genes associated with biofilm emergence. Biofilms protect microorganisms from altered pH, osmolarity, nutrient scarcity, mechanical, and shear forces and also block antibiotics and access to the host’s immune cells [3]. Thus, biofilm matrix gives scope to tolerate a harsh host environment leading to the persistence of infections.

BIOFILM FORMATION

Biofilm formation progresses over five main stages: 1) Reversible attachment: individual planktonic cells migrate and adhere to a surface. 2) Irreversible attachment: adherent cells exude an extracellular polymeric substance (EPS) and become irreversibly attached to the surface, which results in cell aggregation and matrix formation. 3) Stage of EPS production: the biofilm begins to mature by developing microcolonies in addition EPS holds the biofilm cell community in close proximity, thereby enabling cell-to-cell communication (quorum sensing) and facilitating the exchange of genetic material through horizontal gene transfer. 4) Stage of maturation: the fully mature biofilm reaches its maximum cell density and is now considered a three-dimensional community. 5) Stage of dispersal: the mature biofilm releases microcolonies of cells from the main community, which are free to migrate to new surfaces to spread infections [2,4] (Fig. 1).

Figure 1: Stages of biofilm production.

QUORUM SENSING (QS)

It is a density-dependent form of cell–cell communication that represents a feedback loop regulating bacterial growth [1]. QS allows microorganisms to sense the critical bacterial concentrations and then suppress further multiplication by producing and releasing molecular signals that affect the host, other bacterial cells, and producer cells [5]. There are two distinct groups of QS signaling molecules such as Auto Inducing Peptides (AIP) by Gram-positive and N-acyl-homoserine lactones by Gram-negative bacteria. Once the specific cell density is reached, these signaling molecules bind to autoinducer receptors leading to repression or activation of several target genes. They exert their effect by regulating the expression of genes involved in the production of virulence factors, sporulation, DNA uptake, and biofilm formation. Thus, QS modulation process allows bacteria to behave more like a multicellular organism [4].

ADVERSE EFFECTS OF BIOFILMS

Biofilms have a huge impact on human healthcare. Approx. 80% of chronic and recurrent microbial infections in the human body are due to bacterial biofilms [3]. Biofilm-related infections may be divided into two types. a) The biofilms on the abiotic surfaces causing nosocomial infections. b) Biofilms causing chronic infections secondary to host tissue related factors and antibiotic resistance [3]. In the healthcare setup, biofilms may develop on surfaces of medical devices (e.g., catheters, prosthetic heart valves, pacemakers, shunts, implants, contact lenses) dead tissues (e.g., sequestra of bones), and inside living tissues (e.g., lung parenchyma, teeth facets) [6]. In addition, they cause life-threatening infections and diseases such as osteomyelitis, cystic fibrosis (CF), periodontitis, infective endocarditis (IE), chronic wounds, and otitis media [7].

ROLE OF ANTIBIOTIC TOLERANCE

Biofilm antibiotic tolerance has been defined as the ability of the biofilm residing bacteria to survive antimicrobial treatment by utilizing their existing complement of genes [4]. Organisms within biofilms have shown 10–1000 times more antibiotics resistance than the planktonic cells [8]. Bacterial biofilm communities survive under antibiotics stress either by stationary phase (slow or non-growth phase of the bacterial life cycle) or viable-but-nonculturable state (state of latency) [9]. Multiple factors are thought to contribute to biofilm antibiotic tolerance, which may be divided into two categories: innate (due to growth in biofilm) and induced (due to a response to antimicrobial treatment). Some of the responsible factors have been briefly described below [1,4].

  1. Physical barrier: The extracellular matrix of the biofilm prevents diffusion of antibiotics through the biofilm matrix [1].
  2. Altered growth and metabolism: Growth, protein synthesis, and metabolic activity are stratified in biofilms. The highest level of activity happens at the surface with slow growth in the center due to lack of nutrients or oxygen. Most antimicrobials have minimal effect on non-reproducing sessile organisms [1].
  3. Phenotype switch: Sessile bacteria possess regulatory genes that switch to more tolerant phenotypes upon environmental stresses such as an increase in bacterial density or alteration in temperature and pH [10].
  4. Persister cells: Biofilms contain ‘persister cells’, which are spore-like cells that produce proteins that shut down antibiotic targets [11].
  5. Increased mutation frequency: It is caused by oxidative stress resulting from a deficient antioxidant system with slow diffusion and limited release of reactive oxygen species [12].
  6. Horizontal gene transfer: Horizontally acquired DNA segments frequently integrated in the vicinity of tRNA genes. These account for up to 10% of bacterial genome leading to rapid changes in biofilm virulence potential. Thus, contributing to the evolution of the genome of multiple bacterial species [3].
  7. Role of eDNA: eDNA is produced by cell lysis and active secretions, which promote microbial adhesion, inhibition of antimicrobial diffusion, and chelate cations, and also suppress innate immunity. It has been reported that eDNA contributes to cation gradients, genomic DNA release, and induces antibiotic resistance [13].
  8. Efflux pumps: Efflux pumps are proteinaceous active transporters embedded within cytoplasmic membranes. These induce antibiotic resistance to microorganisms by pushing intracellular toxins including antibiotics away from intracellular targets back into extracellular space. It is in planktonic bacteria and is upregulated in biofilms leading to multidrug resistance [13].
  9. Role of antibiotic-modifying enzymes of the matrix: Lyases, group transferases, hydrolases, and redox enzymes are the reported classes of antibiotic-modifying enzymes. These enzymes enhance virulence and induce resistance against antibiotics, by either cleaving chemical bonds necessary for the functioning or restricting antibiotics binding to specific targets [13].

BIOFILMS IN DERMATOLOGICAL DISEASES

Human skin tissue surface covers approx. 1.8 m2. Human skin along with hair follicles, sebaceous glands and other appendages, provides a habitat for > 1010 microbes. One million microbes are present per one cm2, which includes bacteria, eukaryotes, and viruses, and their distribution depend on skin-surface environmental conditions. Propionibacterium, Corynebacterium, and Staphylococcus represent the three most dominant genus of microbes in the skin microbiota, with sebaceous sites dominated by the Propionibacterium species [14]. Newer molecular techniques have given better insight into the topographical diversity of the human skin microbiome, hence prompting us to understand the biofilm structure and shift our focus toward a targeted therapeutic approach. Biofilms have been known to exist on the epithelial surface and be associated with various cutaneous diseases. Thus, it is vital for the clinical dermatologists to understand the concept of biofilms, their role, and impact on cutaneous disorders.

ACNE VULGARIS

Acne vulgaris is a common cutaneous disorder mostly affecting teenagers. It is due to hyperplasia of the pilosebaceous ducts with the formation of keratinaceous plugs and subsequent colonization of the follicle by C. acnes. It is a commensal, lipophilic, rod-shaped, Gram-positive bacterium that colonizes sebaceous glands, which provide an ideal anaerobic, lipid-rich environment for growth [15,16]. It also possesses enzyme systems to detoxify oxygen to sustain on the skin surface [16].

Biofilms of C. acnes are found in vitro and in vivo on medical devices. Biofilm was detected more frequently in non-inflammatory comedones compared with inflammatory lesions or unaffected skin. Comedones are significantly enriched in Staphylococcus when compared to healthy skin. This observation suggests that C. acnes has a mutualistic relationship with the Staphylococcal species. So, biofilm in acne may occur as a polymicrobial community, which includes Cutibacterium, Malassezia, and Staphylococcus. Comedones contain a unique microbial habitat including biofilm, which creates an environment that allows Staphylococcus and other potential microbes to flourish, and vice versa [17]. C. acnes biofilms in follicles are one of the key elements in the cohesiveness and inflammatory process of acne. Polymorphonuclear leucocytes may permeate through biofilm yet cannot efficiently phagocytose individual bacteria. This dysfunctional phagocytosis results in increased quantity of inflammatory cytokines that contribute to inflammation of the surrounding tissues, which also promotes antimicrobial resistance and treatment failure [18].

ATOPIC DERMATITIS (AD)

AD is a chronic skin disorder associated with abnormalities in skin barrier function and allergen sensitization [1]. S. epidermidis and S. aureus colonizes the healthy and atopic dermatitis skin respectively [19] (Fig. 2). Katsuyama et al. confirmed the presence of S. aureus biofilm in the stratum corneum of their patients with AD [20]. Correspondingly, Akiyama et al. using confocal laser scanning microscopy observed the formation of S. aureus strains biofilm isolated from AD lesions both in vitro and in vivo [21].

Figure 2: Biofilm in atopic dermatitis.

HIDRADENITIS SUPPURATIVA (HS)

It is defined as a chronic, inflammatory, recurrent, debilitating, follicular skin disease that presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland bearing areas such as axillae, inguinal, and anogenital region [22]. HS affects mostly women, middle-aged, obese, and smokers. Deep-seated HS nodules, dilated hair follicles, and sinus tracts constitute small anoxic cavities providing ideal settings for the growth of anaerobic bacteria. In addition, deposition of scattered intradermal corneocytes, keratin-debris, and hair fragments in HS lesions may act as nidus, thus promoting the formation of biofilm and intensifying the pathogenic properties of commensal bacteria [23]. Chronic course, punctuated by acute exacerbations, localized to specific anatomic regions, and temporarily responsive, yet ultimately refractory to conventional antibiotic therapy are the characteristics highly suggestive of HS as a bacterial biofilm based disease [22].

IMPETIGO AND FURUNCLES

Impetigo and furuncles are acute infections associated with sessile bacterial colonies. Impetigo is a superficial skin infection caused by group A streptococci or S. aureus. Furuncles are perifollicular abscesses caused by S. aureus [1]. Studies have demonstrated the formation of glycocalyx by S. aureus isolated from furuncle and impetigo lesions in vivo [24,25]. S. aureus cell strains isolated from impetigo and furuncle was inoculated and observed the formation of membranous structure. It was more prominent with S. aureus strains isolated from impetigo (coagulase types I · V origin than with S. aureus strains isolated from furuncle (coagulase type IV origin) (p < 0.05) in the plastic tissue-culture coverslip in human plasma after 72 hours [24].

In non-bullous impetigo lesions, S. pyogenes and S. aureus biofilms in vivo were found. S. pyogenes cells microcolonies encircled by glycocalyx in the outer walls of the lesions that existed independently from microcolonies of S. aureus were found using confocal laser scanning microscopy [25].

MILIARIA

Miliaria is caused by obstruction of the eccrine ducts leading to sweat retention in different layers of the epidermis. Mowad et al. reported that the EPS-producing strains of Staph. epidermidis induce miliaria. These sweat glands were obstructed by EPS of S. epidermidis, thus confirming its ability to form biofilms [26]. In nonatopic skin, biofilms form in the eccrine ducts due to water, salt, and other materials such as ethanol and play a role in the etiopathogenesis of miliaria.

Onychomycosis

Onychomycosis is a common chronic nail infection caused by Trichophyton rubrum, T. mentagrophytes, and some Candida spp. [1]. The chronic nature of onychomycosis could be attributed to host anergy, biofilms, development of increased virulence, multidrug resistance efflux pump, drug malabsorption, and degradation by microsomal enzymes [27]. Trichophyton rubrum is known to form biofilms on nails leading to chronic infection, which is recalcitrance to treatment. To address this, antibiofilm treatment through enzymes and exogenous treatments such as photodynamic therapy or SAW (use of low-frequency surface acoustic waves) is suggested in combination with antifungals [27]. Some success has been observed with cationic antimicrobial peptides and antibody guided alpha radiation [28].

CANDIDIASIS

C. albicans is a healthy human microbe asymptomatically colonizing the oral cavity, skin, and female reproductive tract. Infections range from superficial infections to disseminated systemic infections associated with mortality. Variations in the local pH or nutrition, use of antibiotics, and immunosuppression lead to disturbances in microbiome, enabling C. albicans to proliferate rapidly and form biofilms [29]. C. albicans is a leading cause of hospital-acquired infections, which includes 15% of cases of sepsis, and 40% of bloodstream infections in clinical settings [30]. C. albicans biofilm formed on an implanted medical device acts as a reservoir for pathogenic cells, resistant to drugs and the host immune system. It has the potential to cause dissemination through circulation, leading to invasive systemic infections.

DERMAL FILLERS

The increased demand and popularity of dermal fillers for aesthetic appeal have raised the incidence of complications. When a filler implant is present, 100 organisms per gram of tissue is required to cause clinical infection. It may follow direct injection of skin flora or bacteria may be seeded through contiguous direct extension or hematological spread. Transient bacteremia coupled with the skin’s physiological immune dysbiosis may lead to infection [31].

Numerous adverse reactions such as acute infection, nodules, abscesses, sinuses, and type IV delayed reactions have been reported after the administration of fillers. They develop within weeks and often persist for months as erythematous, mild, tender nodules [32]. Although these adverse reactions may occur with long-acting and hydrophilic fillers. Inadequate disinfection of the skin, poor injection technique, presence of patients’ own microflora may act as potential pathogens. Reduced host immunity, past permanent implants existence at the injection site are the risk factors for bacterial infections. When these bacteria adhere to the surface of the implants and aggregate into communities to form biofilms, they become resistant to the host immune system and antimicrobials [33].

Proper preparation of the skin with inexpensive 70% topical alcohol or topical chlorhexidine is inherently critical for the prevention of infection. Antibiotics should be initiated before any attempts to remove the granuloma with hyaluronidase, steroid 40 mg/mL, or fluorouracil (5-FU) 50 mg/mL injections; laser lysis; or surgical excision. Infectious disease consultations may be necessary for infections involving atypical mycobacteria or fungus [34].

ECTHYMA GANGRENOSUM (EG)

Ecthyma gangrenosum (EG) is a critical dermatologic condition presenting with hemorrhagic pustules, which progress into necrotic ulcers. P. aeruginosa is the most commonly associated pathogen (74%) and is associated with a high mortality rate of 38% to 77% [35]. It is usually seen in immunocompromised or neutropenic patients who require invasive device support or prolonged hospitalization. P. aeruginosa forms dense matrices of EPS, which provide resistance to host defense systems, antibiotics, disinfectants, and other external stressors [36].

In prolonged hospitalized patients, an implantable port will provide a scaffold for biofilm formation and propagation of strains of P. aeruginosa with variable antibiotic resistance patterns. This is due to higher cellular levels of cyclic dimeric GMP, gradients of nutrients and oxygen in biofilms, which allows faster propagation of heterogenous bacterial population and mutagenesis when compared to planktonic variety of microbes. This emphasizes the importance of immediate removal of any indwelling foreign bodies such as implantable ports and prompt initiation of antipseudomonal antibiotic therapy [35,36].

SKIN AND SOFT-TISSUE INFECTION

Skin and soft-tissue infections (SSTIs) involve the invasion of microbes into the layers of the skin and underlying soft tissues. Clinically they manifest in a wide range of etiologies and presentations varying from erythema, edema, tenderness to the affected, dysfunctional area. Depending on infection severity and associated comorbidities, they may transform into a rapidly advancing life-threating infection [37]. The main causative agent of SSTI is Staph aureus. Other causal agents of a high percentage are Pseudomonas aeruginosa and Enterobacteriaceae [1].

A combination of medical and surgical lines of management is essential to treat complicated SSTI. Lately, due to the emergence of biofilm, management has become more challenging with increasing frequency and severity of infections [37]. This has led to adverse consequences such as prolonged hospitalization, overburdened health system and increased mortality rates. Newer promising therapeutics such as PDT along with systemic antibiotics would be a better approach to fight against SSTI diseases.

BIOFILM ERADICATION AGENTS

A biofilm-specific environment such as EPS or anaerobic conditions triggers the development of tolerant subpopulations, which constitute a large fraction of the biofilm. Thus, antibiotic tolerance means bacterial colonies that survive treatment with bactericidal antibiotics without having acquired antibiotic resistance determinants [36]. Hence, for the successful treatment of biofilm-associated infections, we have to find alternative approaches, some of which are described below (Fig. 3):

Figure 3: Biofilm eradication agents.
  1. Biofilm matrix degrading enzymes: eDNA, biofilm matrix and exopolysaccharides are degraded by DNase I, Dispersin B (DspB), and a-amylase, correspondingly. Degradation of biofilm structural component allows the increased penetration and efficiency of antibiotics [38].
  2. Inhibitors/compounds disturbing the QS signaling cascade: Attenuation of QS signaling by halogenated furanone isolated from Delisea pulchra (marine algae), ginseng extract, garlic extract and usnic acid [9]. Coenye et al. identified icariin, resveratrol, and salidroside in plant extracts with C. acnes biofilm-eradication properties [39]. Likewise, Feuillolay et al. found that a combination of antibiotics and Mediterranean myrtle extract led to a reduction in biofilm [40]. Sivasanker et al. found that a combination of ellagic acid (natural phenol antioxidant) and tetracycline led to 80–91% inhibition of biofilms [41].
  3. Nanoparticles: These are ultrafine particles 1–1000 nm in diameter with improved antibacterial and wound-healing properties. Their ability to penetrate into the deeper areas of biofilm may improve the efficacy of drugs, effectively target infectious cells, and significantly increase the concentration of antibiotics around bacterial colonies [42]. In recent years, organic and inorganic nanoparticle combinations have been used as antimicrobial and antibiofilm agents [43].
  4. Photodynamic therapy (PDT): It selectively binds to the membranes of pathogenic cells and with accurate delivery of light to the affected tissue causes maximal damage to microbes and minimal damage to the host. It sufficiently reduces drug-resistant Gram-positive and Gram-negative bacteria [3,37,44].
  5. Anti-microbial peptides (AMPs): These are ubiquitous compounds, produced in plant, invertebrate, and animal species varying in size and molecular mass (1–5 kDa). Their activity is linked to cytoplasmic membrane disruption and inhibition of protein folding or enzyme activity [45]. A human cathelicidin-derived broad-spectrum AMP, which has a promising effect on both Gram-negative and Gram-positive organisms with low human cell toxicity [46]. However, most AMPs display a strong anti-biofilm action by inhibition.
  6. Nitroxide functionalized antibiotics: Recently, Fairfull-Smith et al. have developed nitroxide functionalized antibiotics. These are highly potent, low μM range, and exhibit a broad spectrum of activity with low mammalian cytotoxicity, making them attractive BEAs [47].
  7. Natural products: Methanolic extract of a coral-associated actinomycete, 4-phenylbutanoic acid, Azadiracta indica (Neem), and Acacia extracts show high antibiofilm activity against Gram-positive and Gram-negative bacteria with an antimicrobial effect [3].

FUTURE SCOPE

The understanding of skin microbiome has evolved, yet its mechanism of attachment, survival, and propagation on the skin is still partially understood. In the future, studies on biofilm-related genes in various diseased skin lesions and evaluation of keratinocytes response to the effects of toxins and metabolites secreted by biofilms will help in overcoming biofilm-related morbidities in chronic skin diseases. Inducing biofilm growth in in vitro or in vivo skin models helps to study the physiological and molecular adaptations undergone by host cells and organisms. The use of the proteomics method to analyze the characteristics of microbial biofilms on the skin will be useful. The above scope of research may further heighten the understanding of the relationship between skin diseases and biofilms and, thus, lead to the development of the best therapeutic armamentarium.

CONCLUSION

Bacterial biofilms are serious global health concerns due to their ability to tolerate antibiotics, host defense systems, and external stressors. Newer molecular and genome analyses have provided opportunities to understand the role of biofilm in the pathogenesis of cutaneous disorders. Biofilm is the predominant bacterial phenotype on the skin that alters host immunity and antibiotic susceptibility. Therefore, in the near future, researchers will have to rewrite its role in the etiopathogenesis of cutaneous diseases. Inappropriate use of antibiotics may enhance biofilm formation. Thus, better understanding of biofilm composition and structure will lead to the development of better therapeutic strategies.

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Notes

Source of Support: This article has no funding source.

Conflict of Interest: The authors have no conflict of interest to declare.

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