Carmen Maria Salavastru1, Adelina Maria Sendrea2, Stefana Cretu3, and George Sorin Tiplica4
1 Pediatric Dermatology Unit, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
2 2nd Clinic of Dermatology, Colentina Clinical Hospital Developmental and Research Unit, Bucharest, Romania
3 2nd Clinic of Dermatology, Colentina Clinical Hospital, Bucharest, Romania
4 2nd Clinic of Dermatology, Colentina Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
Infections of the Skin Caused by Bacteria
Skin and soft tissue infections can be defined as clinical entities that involve the invasion of the skin and underlying subcutaneous tissue by pathogenic microbes . Bacteria are unicellular prokaryotic organisms and although most of them are not harmful to humans under regular conditions, the ones capable of causing diseases are called pathogens . In the US, skin and soft tissue infections represent the second most frequent type of infection requiring hospitalization .
In an update published in 2014, the Infectious Disease Society of America (IDSA) classified skin and soft tissue infections according to the presence of pus into purulent and non‐purulent, each subclassified as mild, moderate, or severe. Purulent infections include cutaneous abscesses, furuncles, carbuncles, and inflamed epidermoid cysts. Non‐purulent infections include cellulitis, erysipelas, and necrotizing fasciitis . Also, according to their extension skin and soft tissue infections can be classified into simple, also known as uncomplicated, confined to the skin and underlying superficial soft tissue; and complicated, affecting subcutaneous fat, fascial layers, and muscle tissue . In addition, they can be classified depending on host risk factors, leading to differences in disease management. Although young, previously healthy individuals are often affected, the patients with extreme ages and those with altered immune status are at higher risk for contracting skin and soft tissue infections and/or develop severe complications [4, 5].
The Importance of Biofilms
Biofilms are complex, dynamic aggregates of bacteria attached to a surface and embedded in an extracellular matrix . They adhere to the underlying surface and to each other by means of adhesins and extracellular polymers. The matrix material is produced by individual bacterial cell and acts as a protective envelope for the entire community. Inside this structure complex bacterial interactions take place, both commensal and competitive . Despite their presence in nature in various environmental settings, in the human body biofilms can be found forming dental plaque, on the skin’s surface, in chronic wounds, or in surgical sites, and can involve prosthetic materials or catheters. They are estimated to cause of over 60% of all human infections receiving treatment from physicians. Biofilms help bacteria survive and thrive inside their host, evading the attacks from the immune system and antibiotics. Although the exact mechanisms are not fully understood, researchers have identified several key properties leading to biofilm resistance to the action of antimicrobials. Amongst these are the structure of the biofilm, its composition, and the presence of altered phenotypes . Moreover, biofilms are an independent virulence factor apart from antibiotic resistance. In chronic wound settings, colonies involve several types of microbes, with weak or nonbiofilm producers associating with strong ones. The association between Staphylococcus aureus and Pseudomonas aeruginosa, two of the strongest biofilm producers, provides mutual benefit with regard to antibiotic resistance. They coexist with other bacteria, low biofilm producers, such as Klebsiella pneumoniae and Acinetobacter baumannii, or non‐biofilm producers. Moreover, through pyrosequencing techniques researchers have found that the chronic wound harbors more than 100 different bacteria generally belonging to strict and facultative anaerobes, which are generally not observed by standard culturing techniques. These findings suggest that bacterial communities act synergistically within the biofilm in order to promote wound chronicity .
Emotional, Mental, and Social Aspects
From a social perspective, mortality from severe soft tissue infections has decreased little in the last 30 years and approaches 100% in the absence of surgical treatment. Patients requiring surgery or stays in the intensive care unit (ICU) perceive these experiences as traumatic. Women and those with abdominoperineal involvement report more problems with regard to their body image one year after discharge . One study found that patients who received treatment in the ICU had a higher level of mean posttraumatic stress symptoms one year after discharge. The personality of the patient influenced how they perceived the event, as pessimism was a predictor of posttraumatic stress, anxiety, and depression symptoms. In other studies, the prevalence of anxiety ranges between 12% and 43%, for depression, between 10% and 30%, and posttraumatic stress disorder‐related symptoms had a prevalence between 5% and 64% depending on the study . From a mental point of view, altered mental health represents a risk factor for the development of bacterial skin infections. Patients with substance abuse disorders, depression, attention deficit/hyperactivity disorder, anxiety disorders, bipolar disorders, organic brain syndromes, and schizophrenia can often present with bacterial skin infections due to low self‐care, poor hygiene, malnutrition, and an overall decreased immune status. Also, infections of the skin caused by bacteria and their interaction with the host’s immune system can have an impact on the patient’s psyche. Raised inflammatory cytokines and markers of inflammation can play a role in the pathogenesis of depression. Antibodies against group A beta hemolytic Streptococcus can cross‐react with brain tissue in genetically susceptible children, leading to a subtype of obsessive‐compulsive symptom .
Environmental Changes and Their Impact
Because of global warming, travel, and migration, some bacterial infectious diseases affecting the skin have gained increasing importance in recent years. Such is the case of Gram‐negative bacillus Vibrio vulnificus, found only in some coastal areas but able to cause necrotizing fasciitis. Because of its rarity, the diagnosis and adequate treatment outside these areas are delayed, leading to a severe course of evolution and highly unfavorable outcomes for patients [13, 14]. Re‐emergence of some infectious diseases has been observed. One example is melioidosis, induced by Burkholderia pseudomallei found in soil and surface waters. Other examples are tick‐borne diseases like Lyme disease, caused by spirochetes members of the Borrelia spp. The disease has a three‐stage course of evolution, each with its particular skin findings. In the US, the disease is caused by Borrelia burgdorferi and by the recently discovered Borrelia mayonii. The former is transmitted by the Ixodes ricinus tick. In Europe, Borrelia afzelii, also suspected for the association with acrodermatitis chronica atrophicans, seems to be more frequent. On both continents Lyme disease is the most common tick‐borne infection. Also, infections caused by members of the Rickettsia spp, transmitted through various subspecies of the Dermacentor tick vector are increasingly more prevalent. In Europe, Rickettsia slovaca, and less often Rickettsia rioja and Rickettsia raouli, are responsible for the emergence of tick‐borne lymphadenopathy. In the US, there has been an increase in the number of cases of Rocky Mountain spotted fever, caused by Rickettsia rickettsii. Some researchers argue that ecological and climate changes are responsible for the increase in the number of tick‐borne diseases; others explain this increase through raised awareness of these conditions, diagnostic practices and reporting policies . With terrorism an increasing global threat, some bacteria with the potential to cause severe epidemics can be used as weapons for bioterrorism. They can cause conditions with skin manifestations and thus can present in dermatology settings. Examples of such bacteria are: Bacillus anthracis, a Gram‐positive spore‐forming rod that can cause infections through inhalation, ingestion, and skin contact; and Yersinia pestis, the Gram‐negative bacillus responsible for plague, the “Black Death” of the Middle Ages. Another example is the pathogen responsible for tularemia, Francisella tularensis. It is a Gram‐negative coccobacillus with extreme infectivity, easy dissemination, and the capacity to cause significant human morbidity and mortality .
Relationship with Stress
The immune system is the main defense against infections, including those caused by bacteria. Stress, through the release of neurotransmitters and hormones by the brain, has an important impact on the mechanisms involved in antimicrobial resistance. It can be briefly described as a series of events, perceived together as a stimulus, leading the organism to produce an adaptive response. Stress can be classified into negative or positive, acute, lasting for minutes to hours, or chronic, lasting from several hours a day to weeks or months. While acute stress can enhance the immune system, preparing the organism for fight or flight, chronic stress is suppressive for the immune system. Two of the main mechanisms involved in the body’s reaction to stress are the hypothalamic–pituitary–adrenal axis (HPA) and the sympathetic nervous system. The main hormones released in response to stress are cortisol and catecholamines (adrenaline and noradrenaline). Acute stress prepares the body to deal with immediate challenges, for example wounds or infections, and involves significant changes in the distribution of leukocytes. The body ensures that the right type and amount of immune cells are present at the right place . Stress seems to boost humoral immunity and suppresses the Th1 response, leading to a Th2 shift [17, 18]. Chronic stress, on the other hand, acts as a suppressor for the immune system through various mechanisms. For once, it can act as a means to preserve resources . It inhibits the cellular immune defense, which has a profound impact on the susceptibility to and/or the course of infections . For example, one study involving 608 healthy adult volunteers exposed to a common cold virus showed that elevated basal salivary cortisol was associated with a higher risk for infection and a longer period of viral shedding, indicating viral replication .
When it comes to treatment of skin and soft tissue infections, the following three therapeutic approaches are recommended: surgical drainage and debridement, wound culture and susceptibility testing, and early and appropriate empiric antibiotic therapy . However, skin infections caused by bacteria are often managed, both in hospital and outpatient settings, with inappropriately broad‐spectrum antibiotics and long courses of therapy, finally leading to antibiotic resistance. Many antibiotic exposures are avoidable .
Complementary and Alternative Treatments
With antibiotic resistance an increasing issue, there is an obvious need for alternative antimicrobials. One option for prevention and treatment of skin and soft tissue bacterial infections is the use of antiseptics. In a recent review povidone‐iodine use was analyzed. It has strong bactericidal activity, including against Methicillin‐resistant Staphylococcus aureus (MRSA), P. aeruginosa and highly resistant Enterococcus faecium. Compared with other antiseptics such as chlorhexidine gluconate, quaternary ammonium salts like benzethonium chloride, silver, or triclosan, it showed a longer and more intense antimicrobial effect and so far resistance was not detected. With a history of over 60 years, the safety profile of povidone‐iodine is well‐established. However, in long‐term use, systemic absorption of iodine is possible and it should not be used in patients with thyroid disease. If strictly indicated, it can be used during pregnancy and lactation, but it should be for as short a duration as possible [22, 23]. Especially in the context of wound management, the use of honey has gained increasing attention in recent years. Its use has been documented since ancient times, and several studies have tried to objectively assess its properties. In a recent Cochrane review, honey seemed to heal partial thickness burns and infected post‐operative wounds faster than conventional therapeutic modalities. However, for any other indication the evidence was considered of low and very low quality, mostly due to study design .
Infections of the Skin Caused by Viruses
Viruses represent a various group of small intracellular infectious agents, with either a RNA or DNA genome, encircled by a protective protein coat. Although some viruses encode a small number of enzymes, they don’t own cellular organelles (like functional ribosomes) and must depend on the host’s cells to replicate, often being referred to as “obligate intracellular parasites” . Cutaneous viral infections represent a large group of infections that have as etiologic agent a virus with cutaneous tropism.
Cutaneous lesions may be encountered in many diseases caused by viral agents, either caused by the direct replication of the virus in the epidermis (viral skin infections), or as a consequence of viral replication anywhere else in the body (viral systemic infections) . Viruses are divided into several viral families, taking into account multiple features, such as types of viral nucleic acid (RNA vs. DNA), size, or shape, with the viruses that are related to skin lesions being described in detail in Rook’s Textbook of Dermatology .
Emotional, Mental, and Social Aspects
Neuropsychiatric imbalances may significantly influence the course of any disease, taking into account that up to 14% of the burden associated with any chronic disease has been attributed to diseases of the neuropsychiatric spectrum . The relationship between emotional, mental, and social aspects and cutaneous viral infections is characterized by a bidirectional manner. Patients with certain viral infections – human immunodeficiency virus (HIV/AIDS), herpes simplex virus (HSV), varicella‐zosterian virus (VZV), or cytomegalovirus (CMV) – are more likely to develop mental and emotional disorders (like anxiety, depression, or posttraumatic stress disorder) and, at the same time, patients with pre‐existing neuropsychiatric illnesses are prone to manifest certain risky behaviors that may lead to certain viral infections with cutaneous manifestations (like HSV 2, HIV, human papilloma virus [HPV] or hepatitic viruses) . Furthermore, patients with pre‐existing emotional and mental disorders have the tendency toward poor treatment adherence and are less compliant.
Environmental Changes and Their Impact
Climatic and environmental changes are continually developing, and have a major impact on dermatological diseases, including viral skin infections, leading to changes in patterns and types of such certain diseases. The most discussed environmental change during the past years is the “global warming” phenomenon. Considering the continuous temperature increase, in association with humidity, some epidemic enteroviral diseases (like hand‐foot‐and‐mouth disease or herpangina) may develop prolonged and severe, intense disease courses . Aside from enteroviral diseases, arboviral diseases with skin manifestations (like infections caused by Chikungunya, dengue, Zika, or West Nile viruses) represent another disease category that is affected by environmental changes in terms of temperature, humidity, or precipitation, mostly by biologic and ecologic changes in the hosts and vectors, but also by expansion of geographical ranges into more northern latitudes . It has been observed that climate change is strongly linked to outbreaks of certain infectious arboviral diseases, such as Chikungunya and Zika reported in the southern part of the US , Dengue in Thailand and the southern United States [30, 31], and West Nile in southern Florida .
Relationship with Psychosocial Stress
Psychosocial stress is well known to contribute in both onset and exacerbation of some skin diseases, but it also has a role in the recurrence of certain dermatologic conditions. It has been proven that chronic stress leads to a suppression of the immune system (through an increase of the levels of catecholamines and suppressor type of T cells), which, in turn, leads to an increased risk of viral infections, including cutaneous ones . In some specific cases, psychosocial stress plays a well‐established role in the onset of certain viral cutaneous diseases (such as herpes simplex infections or shingles in persons who haven’t been vaccinated for varicella) or in the exacerbation or recurrence of such dermatological conditions . Regarding the specific case of HSV infections, Padget et al. have proven that stress causes reactivation of HSV1 infection in mice with latent disease in 40% of the cases , while Glaser et al. have shown that caregivers of patients suffering from dementia, which are supposed to be subjected to a high level of stress, have a much higher level of antibody titers to the total viral antigen and a significantly poorer HSV1‐specific T cell type response .
The allopathic approach of viral skin infections is very complex, ranging from simple supportive treatment (such as anti‐inflammatory agents, vitamin supplements, or even bed rest) to antiviral (Aciclovir, Ribavirin, etc.) or immunomodulatory agents (Interferon, Imiquimod), administered in topical or systemic regimens, taking into account which virus is needed to be managed. Also, there are several nonpharmacological, physical therapy techniques that have proved in recent years to have some beneficial implications in cutaneous viral infections management, like: photodynamic therapy (PDT), lasertherapy with pulse dye laser (PDL), liquid nitrogen cryotherapy, or electrocurettage. A synthesis of therapeutic modalities currently available for viral cutaneous diseases is listed in the following table.
Complementary and Alternative Treatments
Aside from the pharmacological and physical treatment methods listed in Table 14.1, there are some other complementary and alternative treatments that have proven successful in managing viral cutaneous infections. Psychotherapy, in its various types, can be extremely helpful in treating various virus‐related skin infections, mostly in cases where conventional treatments have failed. For example, hypnotherapy has proven effective in the treatment of warts, especially in cases that are refractory to conventional treatment or even cases with disseminated lesions in immunocompromised patients. Furthermore, herpetic mucocutaneous infections can be successfully treated through psychotherapy techniques like biofeedback or relaxation treatment, given the well‐known relationship between stress and this type of viral infection of the skin . Considering herpetic viral infections, there are several other alternative therapies for this disease category, starting with dietary changes that might help in preventing recurrences (like restricting refined‐sugar and high‐arginine foods intake, identifying and avoiding allergenic foods or emphasizing foods high in bioavailable lysine) and ending with natural remedies that can be used for both treatment and prophylaxis (like vitamins C, E, zinc, adenosine monophosphate, or even lemon balm) . Speaking of natural remedies, from ancient times it has been observed that herbals have great potential in treatment and prevention of several cutaneous disorders, among which viral infections represent a significant percentage. In India, for example, more than 80% of inhabitants rely strictly on traditional medicine, using plant‐derived products in the treatment of skin disorders. Hemp seed oil has proven to enhance skin resistance against bacterial, viral, and fungal infections. The effect that multiple plant‐derived products may exhibit against cutaneous papillomas was tested in animals or skin models, and the following assessments were concluded: garlic ingestion delays papilloma formation and decreases their size and number; orchid tree oil delays appearance and reduces the cumulative number of papillomas; saffron ingestion inhibits papilloma formation and reduces their size; topical applications of bitter gourd extract reduces the tumor burden, cumulative number of papillomas, and percentage of mice that develop papillomas. Aside from papillomas, other diseases determined by viruses with cutaneous tropism can benefit from the well‐known effects of herbal‐derived products, as follows: the MeOH extract and also saponin, alkaloid, and non‐alkaloid fractions obtained from the leaves of Devil’s horsewhip (Achyranthes aspera) have shown a significant inhibitory effect on the activation of the Epstein‐Barr virus early antigen induced by the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate; supplementation with echinacea, in conjunction with zinc, probiotics, and other antioxidants have shown to determine a significant reduction of warts; also, when it comes to warts, fig tree latex usage has shown beneficial effects, most probably through proteolytic activity of the latex enzymes; and henna (Lawsonia inermis) has provided significant improvement in patients with hand‐foot‐and‐mouth disease due to its anti‐inflammatory, antipyretic, and analgesic effects . But, when it comes to complementary treatments used for viral skin infections, not all have proven to be successful. For example, in a group of patients with genital warts managed through Reiki healing (which is a Japanese technique for stress reduction and relaxation that promotes healing), this type of complementary therapy hasn’t shown any effectiveness .
Table 14.1 Conventional therapy in viral infections of the skin.
|Treatment type||Antiviral agents||Immunomodulators||Physical treatments||Supportive treatment||Vaccine||Post‐exposure prophylaxis|
|Curettage (large lesions)|
|Human parvovirus 19||*||*|
Infections of the Skin Caused by Fungi
Fungi are complex eukaryotic organisms, with a great diversity. The number of species is estimated at 1.5 million . Approximately 300 are pathogenic to humans, leading to infections called mycoses . The skin and nails can be affected, forming the most numerous and widespread group of all mycoses . Also, hair and mucous membranes can be involved in fungal infections. Fungi can present as yeasts or molds. As a consequence of changes in their environment, some fungi, called dimorphic, can shift between these two forms . It is worth mentioning that apart from pathogenesis, fungi establish multiple relationships with humans, including commensal and symbiotic. Infection and disease appear when the balance between pro‐ and anti‐inflammatory signals is impaired .
Fungal infections of the skin can be classified according to the pathogen involved or to the depth of invasion [39, 40]. The latter classification comprises superficial mycoses, limited to the stratum corneum, hair, nails, and mucous membranes, subcutaneous mycoses, affecting the dermis and subcutaneous tissue and deep or systemic .
Emotional, Mental, and Social Aspects
Superficial fungal infections have the potential to negatively impact the patient’s quality of life. Onychomycosis is a chronic disease affecting the nails, with prevalence in the general population ranging between 3% and 13.8%. It accounts for up to half of all nail‐related disorders. The pathogens responsible for this condition are mostly dermatophytes, although Candida spp. and other molds can be involved [42, 43]. In addition to being cosmetically disagreeable, it is also associated with other symptoms such as pain or loss of dexterity. Patients suffering from this condition feel embarrassed, esthetically disfigured, and afraid that the infection might spread to other nails or people . Patients with onychomycosis also feel stigmatized, especially if the disease affects the fingernails. This feeling is more intense in young people and females . Moreover, the negative impact of the disease is higher in women, possibly due to the fact that socially there is more emphasis on their physical appearance than men. Also, the disease seems to have a more negative impact on blue‐collar workers and in patients with longer disease duration [14, 44]. Although onychomycosis affects the quality of life in a negative way, mostly in females and young patients, it raises a different problem in elderly men. One study found that fewer patients from the latter category identified the disease by themselves. This aspect influences patient addressability and management of the condition, with important individual and social consequences . Tinea capitis, often involving children, has a mild to severe negative impact on the psychosocial well‐being and as with onychomycosis, females are more affected . Tinea versicolor, caused by Malassezia furfur, also affects quality of life. Patients were mostly concerned with the negative influence the disease had on their appearance, recurrence, and risk of spread to the face. Patients suffer from associated depression and anxiety, which tend to be associated with longer duration of disease. As with other skin conditions, the greater the impact on the quality of life, the higher the level of depression and anxiety . Apart from their negative impact on patients’ quality of life and their emotional and psychosocial well‐being, recent research suggests that fungal infections might also influence the mental health of the patient. One study identified disseminated fungal infection, involving Candida spp. in most of the patients suffering from Alzheimer’s disease that they tested. The authors suggested that the disease might be in fact a fungal infection and the amyloid deposits might be the body’s antifungal response. As for other hypotheses concerning this disease’s etiology, the clinical symptoms and previous observations are in some aspects contradictory, but none can rule out the fungal etiology .
Environmental Changes and Their Impact
In the next decades the global temperature is expected to rise by 2–5 °C, leading to the disappearance of some habitats and species and to the thriving of others. Most fungi prefer lower temperature and although they can be pathogenic for some organisms, such as amphibians for example, they do not affect warm‐blooded animals, and hence, humans. However, the expansion of the geographic rage of some pathogenic species might increase the prevalence of some fungal infections in areas currently unaffected. Moreover, in their struggle to survive, species preferring cooler environments, but with significant pathogenic potential, might adapt and come to infect warm‐blooded animals and humans . Whether it involves traveling for short periods of time or massive population exodus due to famine or conflict, migration is another aspect with great impact on fungal infections of the skin. Some cutaneous mycoses regarded as tropical can now be seen in countries with temperate climates. For example, mycetoma, or Madura foot, is a chronic, subcutaneous mycosis, often involving the foot. It has a slowly progressive, destructive course and it can invade underlying muscles or bones. Mycetoma is caused by various fungi found in the soil or decaying plants and is increasingly more prevalent in temperate areas. Workers at risk include farmers and those exposed to penetrating trauma from thorns and splinters. Another example of a chronic, progressive infection once regarded as rare is paracoccidioidomycosis. Infection with the fungus Paracoccidioides brasiliensis occurs primarily in the lungs and it can disseminate and involve the skin. It has a long latency period, sometimes reaching 30 years. In European travelers, histoplasmosis, caused by Histoplasma capsulatum var. capsulatum is the most common acquired systemic mycosis. The fungus is found worldwide and contamination takes place through inhalation of spores. It is an infection frequently affecting patients with AIDS .
Relationship with Psychosocial Stress
Although studies directly linking fungal infections of the skin to psychosocial stress are missing, indirect evidence suggests that stress can modulate the immune system’s activity, and hence influence the development and course of cutaneous mycoses. The immune system works as a whole to fight fungal infection and to a greater or lesser extent, innate, cellular, and humoral immunity are all involved . On the one hand, stress, through the release of cortisone and catecholamines, has been proven to enhance IgG and IgM reactions and overall favor humoral immunity, inducing a predominantly Th2‐type response. On the other hand, it inhibits the Th1 response and the activity of natural killer cells (NK) . In dermatophyte infections researchers have identified several protective and nonprotective antibodies, providing some protection against the pathogen. However, in the eradication of fungal infections, Th1‐type response is predominant . Thus, stress could lead to a decrease in the antifungal defense. Interestingly, acute stress can enhance delayed type hypersensitivity reactions, which is important for the eradication of infection . However, in the case of fungal infections, hyperinflammation can prevent successful pathogen elimination . All in all, there is urgent need for more studies focusing on the complex interaction between stress, the immune system, and fungal infections of the skin.
The choice of therapy in fungal infections of the skin is guided by the level of involvement, the agent responsible, and immune status of the host.
Complementary and Alternative Treatments
Conventional antifungal agents are associated with various side effects. Azoles for example, act through the inhibition of the enzyme cytochrome P450 in both fungi and humans. This results in liver toxicity and interaction with other drugs inhibiting the same enzyme, such as rifampicin. Other agents, such as second‐generation triazoles have different mechanisms of action and are associated with lower toxicity. However, they are more expensive. In some cases fungi have developed resistance to the antimicrobial agents . These drawbacks to antifungal therapy have challenged researchers to identify alternative therapeutic agents. Blue light PDT, using as photosensitizer a substance isolated from the spice turmeric, called curcumin, encapsulated as nanoparticles, was effective in vivo against Trichophyton rubrum . Sertraline, a selective serotonin reuptake inhibitor (SSRI), commonly prescribed for the treatment of depression, has proven effective against Candida spp., Aspergillus spp., Cryptococcus spp., and Tricosporon spp. .