Infectious skin diseases pose considerable treatment challenges, especially given the recent appearance of several highly virulent pathogens as well as the rising number of immunocompromised patients in the United States. This article discusses common bacterial, fungal, and viral skin infections with an emphasis on cellulitis, dermatophyte infections, and herpes simplex viral infections. Disease pathogenesis, treatment, and cost of treatment are addressed with an emphasis on therapeutic needs and future research directions. Common priorities for all infectious skin disease categories include increased disease surveillance, study of existing treatments, and efforts in drug development.
Infectious skin diseases encompass a vast array of conditions that range in severity from benign to life threatening. The clinical presentation of infectious skin diseases varies based on the type of pathogen involved, the skin layers and structures affected, and the underlying medical condition of the patient. Infectious skin diseases represent common diagnoses made by dermatologists, by primary care physicians, and in the emergency room. Between 1980 and 1996, 48 of every 1000 medical visits were attributed to infectious skin disease—a number that is rising, particularly with the appearance of virulent pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). Effective treatment of infectious skin disease requires timely identification or estimation of the offending pathogen, and selection of a treatment that is effective against the pathogen and is administered via the optimal route and dosing schedule.
Bacterial skin diseases
Bacterial skin and soft-tissue infections (SSTIs) are the most common type of infectious skin disease, and encompass an array of conditions that may be classified by the skin layers and structures they affect. Impetigo is a superficial, crusting epidermal skin infection that presents in bullous and nonbullous forms. Erysipelas is a streptococcal infection of the superficial dermal lymphatics that demonstrates sharply demarcated, raised borders. Cellulitis is an infection of the deeper dermis and subcutaneous tissue with poorly demarcated borders; the vast majority of cases are streptococcal in origin. Clinically the distinction between erysipelas and cellulitis is subtle and, given that both are predominantly streptococcal in origin, many experts consider them to be different presentations of the same disease. As such, these infection types are often grouped in clinical reporting and epidemiologic analyses. Cutaneous abscesses are collections of pus in the dermis and subcutaneous tissue. Folliculitis describes superficial infection of hair follicles with pus accumulation in the epidermis. Furuncles, or “boils,” represent deeper involvement of hair follicles in which the infection extends into the subcutaneous tissue. Carbuncles occur when adjacent furuncles coalesce to form a single inflamed area. Pus-forming infections tend to be staphylococcal in origin, except for periorificial abscesses, which are often anaerobic. Although all of the preceding are common, cellulitis accounts for the majority of serious bacterial SSTIs.
Cellulitis
General
Cellulitis represents an acute spreading infection of the dermis and subcutaneous tissue whose clinical appearance was classically described by Celsus in the first century using the terms “calor,” “rubor,” “tumor,” and “dolor,” or warmth, erythema, edema, and tenderness, respectively. Certain characteristics, such as pain out of proportion to physical findings, large bullae, crepitus, and anesthesia, suggest more serious infection. Cellulitis is most common in the lower extremities, but has been documented on all parts of the body. Cellulitis results from breaches in skin integrity that allow for the spread of organisms below the skin surface. Cutaneous disruption via skin trauma, ulceration, edema, surgical incision, preexisting fungal and other superficial infection, and dermatitis may predispose to cellulitis.
In recent years S aureus has become an increasingly important pathogen, and the emergence of community strains of MRSA has created a dilemma for physicians treating invasive bacterial infections. Although S aureus is commonly isolated from surface cultures, positive outcomes with β-lactam antibiotics suggest that even in the age of MRSA, the primary pathogens causing cellulitis remain Streptococcus species in Lancefield groups A, C, and G, especially group A β-hemolytic streptococci. The presence of erysipelas, lymphangitis, and rapid tissue spread suggest streptococcal infection, while purulence or concomitant abscesses and furuncles increase the probability of staphylococcal infection.
If staphylococcal infection is suspected, it is difficult to distinguish between methicillin-sensitive S aureus (MSSA) and MRSA based on clinical information alone. Certain factors increase the likelihood of MRSA infection, including a history of recurrent infections, young age, participation in athletic sports, and injection drug use. MRSA infection can be further divided into infection with community-acquired MRSA (CA-MRSA) and health care–associated MRSA (HA-MRSA). It may be clinically relevant to differentiate between the two types because HA-MRSA bacterial isolates display broader antibiotic resistance patterns than do CA-MRSA isolates. Nevertheless, the distinction between CA-MRSA and HA-MRSA infection is blurred as patients move between and community and hospital settings.
Incidence
Recent analyses have yielded incongruous results with regard to the changing incidence of SSTIs over the last 2 decades. One study endorses that the incidence of SSTIs increased from 32 to 48 clinical visits per 1000 persons per year between 1997 and 2005, which is attributed to the growing incidence of cellulitis and abscesses. Other studies endorse that the overall incidence of SSTIs has not increased over a similar time period, but confirm that visits for cellulitis and abscesses specifically have increased significantly. Although their conclusions regarding changing incidence differ, when taken together these studies demonstrate the relative commonness of SSTIs and the increasing incidence of cellulitis in particular. In addition, consensus opinion favors the view that emergency room visits for SSTIs have increased in recent years, nearly tripling between 1995 and 2005. This change is attributed to an increase in diagnoses of MRSA-related cellulitis and abscesses.
Treatment
Most cellulitis cases are treated on an outpatient basis with oral antibiotics. Antibiotics are typically selected empirically without diagnostic cultures, given the low yield of cultures for cellulitis. Aspiration and punch biopsies show varied results, yielding positive cultures in fewer than 40% of cases. In general, pus and tissue samples are most sensitive if collected before initiating antibiotic treatment. Blood cultures should always be obtained if patients demonstrate signs of systemic involvement. When systemic disease is suspected, patients are typically treated on an inpatient basis with intravenous (IV) antibiotics. Necrotizing infection requires emergent debridement and treatment with IV antibiotics. Between 1995 and 2005 approximately 14% of emergency room visits for SSTIs resulted in hospitalization. Recently, however, there has been a trend toward at-home administration of IV antibiotics for some patients.
The choice of antibiotics for cellulitis can be challenging. A recent Cochrane review cites lack of evidence from randomized controlled trials to guide antibiotic selection. Given the increasing prevalence of MRSA infection, some investigators suggest that providers assume bacterial antibiotic resistance and select empiric antibiotics active against CA-MRSA. This practice may produce suboptimal outcomes, however, as sulfa drugs and tetracyclines are not reliable against many pathogen types. Although the prevalence of inducible resistance to clindamycin is increasing, clindamycin remains an acceptable alternative to beta-lactam agents when clinical or epidemiologic factors suggest the possibility of MRSA infection. Linezolid is expensive, but has demonstrated good outcomes in life-threatening MRSA infections. Vancomycin achieves low intracellular levels and has demonstrated poorer outcomes in serious infections. Fluoroquinolone and macrolide resistance is now widespread. If patients are treated as outpatients, it is advisable to evaluate their response to treatment after 24 to 48 hours.
Cost of treatment
The cost of cellulitis treatment varies widely based on the severity of disease and the treatment mechanism. Data from 2005 to 2006 suggest a mean cost of $6800 for inpatient treatment of SSTI. There are relatively few United States data on the cost of outpatient treatment of cellulitis with oral medications, though data from other countries suggests that outpatient treatment is substantially less expensive. In the Netherlands, for example, outpatient costs account for only 20% of health care costs associated with cellulitis even though they represent 87% of patients treated for cellulitis.
To offset the cost of inpatient care and improve patient comfort, there has been a trend toward home administration of IV antibiotics, which is nearly half as expensive as inpatient management and produces the same patient outcome. Other analyses have explored the cost effectiveness of cultures, colonization surveillance, decolonization, and duration of antibiotic treatment. Cultures were found not to be cost effective for the majority of patients with uncomplicated infections, although they are recommended when serious pathogens are suspected. Data regarding the cost effectiveness and benefit of MRSA surveillance and decolonization are mixed.
Summary and Future Directions
The emergence of new pathogens will continue to affect health care use and the appropriate choice of antibiotics. CA-MRSA is a key example. This pathogen has become the most common cause of skin infections presenting to emergency departments, and its emergence has led to recommendations that first-line antibiotics be chosen for their MRSA coverage. This advice is premature, as most CA-MRSA infections are abscesses and can be treated surgically without the need for antibiotics. Outcomes data suggest that streptococci remain the principal pathogens involved in cellulitis and that β-lactam drugs still play an important role in the treatment of cutaneous infections. Sulfa and tetracycline antibiotics are both unreliable against streptococci. Ongoing monitoring for disease prevalence and antibiogram data are needed to inform future recommendations ( Table 1 ).
Surveillance | Treatment | Future Study |
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Fungal skin diseases
Cutaneous fungal infections may be divided into 3 categories: superficial, deep, and systemic infections. Superficial infections are confined to dead keratinous tissue, the epidermis, and hair follicles, and are caused by dermatophytes, nondermatophyte molds, and yeasts ( Candida and Malassezia species). Deep infections demonstrate involvement of all skin layers and often extend into the subcutaneous tissue. These infections occur via direct inoculation of the skin, and include infections such as sporotrichosis, mycetoma, and chromomycosis. Systemic infections with cutaneous manifestations are the least common and often occur in immunocompromised hosts. These infections are usually acquired through inhalation of spores with a primary pulmonary focus, even when skin lesions are the presenting finding. Histoplasmosis, blastomycosis, and coccidioidomycosis may occur in patients with normal immune function, whereas other infections such as cryptococcosis, aspergillosis, fusariosis, and mucormycosis present primarily in immunocompromised hosts.
Superficial Fungal Infections
General
The majority of fungal infections are superficial cutaneous infections, most of which result from dermatophyte infection. Dermatophytes are fungi that digest keratin as a nutrient source. These fungi colonize the highly keratinized stratum corneum, or outermost layer of the skin, as well as other keratinized structures such as the nail plate and hair follicles. Such fungi rarely invade viable tissue, and thus do not produce deep cutaneous or systemic infections, nor are they lethal. Although many infections demonstrate gross changes to the surrounding and underlying tissue suggestive of deeper infection, this usually represents an inflammatory host response to the overlying dermatophyte infection without true invasion.
Dermatophytes are divided into 3 genera: Trichophyton , Microsporum , and Epidermophyton . More than 40 different species of dermatophyte have been implicated in skin disease; however, most infections are caused by just a few species. Trichophyton rubrum is the most common dermatophyte, and it is estimated that 70% of the United States population will experience at least one T rubrum infection in their lifetime. Other common species in the United States include Trichophyton tonsurans and Trichophyton mentagrophytes . The distribution of dermatophytes is not static but instead ever-changing, especially in the era of international migration, travel, and commerce. Factors such as socioeconomic status, use of occlusive footwear, and urbanization also affect the varying distribution of pathogen types.
Tinea pedis, or “athlete’s foot,” represents a superficial fungal infection of the foot. This common infection occurs in 1 in 5 adults in the United States during their lifetimes. Worldwide incidence has increased in recent decades, especially with the use of occlusive footwear. Ninety-five percent of tinea pedis cases are caused by dermatophytes, with most infections caused by T rubrum and Trichophyton interdigitale (formerly Trichophyton mentagrophytes var. interdigitale ). Tinea pedis is classified into 3 primary clinical types: interdigital, moccasin, and vesiculobullous. Interdigital infection involves the toe web spaces and often presents with bacterial superinfection. Moccasin-type tinea pedis demonstrates thickening of the plantar and lateral foot with overlying scale. Vesiculobullous-type tinea pedis demonstrates plantar pustules and vesicles, which may become macerated and superinfected with bacteria.
Tinea unguium, or onchomycosis, is an infection of the nail plate or bed. Fungal infection of these structures leads to nail bed deformity (onchodystrophy) with thickening (hyperkeratosis) and discoloration. Eighty-two percent of tinea unguium cases are the result of dermatophyte infection, of which T rubrum is most common. Candida species and molds may also cause onchomycosis, particularly in tropical climates. Estimates vary regarding the prevalence of onchomycosis; however, most investigators endorse that these infections affect at least 5% of the adult population and increase in prevalence with age.
Tinea corporis is a superficial fungal infection of glabrous skin occurring most commonly on the trunk and limbs, whereas tinea facei affects the face. Both types are referred to as “ringworm” given their tendency to produce annular plaques or patches with a red, raised, scaling border. Tinea corporis and facei are most commonly caused by Trichophyton , particularly T rubrum , and Microsporum species.
Tinea cruris, or “jock itch,” describes infection of the groin region that occurs almost exclusively in adult men. It presents as an erythematous patch involving the inner thigh and inguinal folds while sparing the scrotum and penis. Tinea cruris is often associated with tinea pedis, and it is thought that infection occurs through self-inoculation from the foot. Most cases are caused by infection with T rubrum or T mentagrophytes , and may be secondarily infected with bacteria or yeast species.
Tinea capitis represents infection of the scalp and hair. Ninety-five percent of cases are caused by superficial infection with T tonsurans . Tinea capitis displays wide variation in presentation and is classified into 4 patterns. First, seborrheic-type demonstrates dandruff-like noninflammatory scaling. Next, “black-dot” tinea capitis produces hair breakage, leading to areas of alopecia with dark spots representing underlying hair follicles. Kerion-type tinea capitis involves the formation of a purulent inflammatory nodule. Finally the favus type, the rarest form, describes an inflammatory alopecia with honey-colored crusts.
Other common superficial fungal infections include candidiasis and tinea versicolor. Candidiasis is most commonly caused by Candida albicans and affects the skin, mucus membranes, nails, or gastrointestinal tract. Candidiasis is more common in women when accounting for vulvovaginal candidiasis, and in immunosuppressed patients. Tinea versicolor is a harmless skin disease most common in tropical regions, characterized by overgrowth of Malassezia species leading to the formation of hypopigmented or hyperpigmented patches with associated fine scale.
Incidence
Fungal skin infections are estimated to affect more than 20% of the world’s population. In the United States, prevalence is estimated at 10% to 20% of the population. Unlike bacterial skin infections, which must be recognized and treated promptly, fungal infections tend to follow a more indolent course and are less commonly life threatening. These infections are often difficult to treat, and persist despite optimal medical management. Furthermore, fungal remnants frequently remain after treatment; this and genetic predisposition result in a high rate of recurrent infection.
Given that cutaneous fungal infections affect up to 1 in 5 individuals in the United States and tend to follow a chronic, treatment-resistant course, it is not surprising that they account for a large number of physician visits each year. It is estimated that superficial cutaneous fungal infections account for more than 4 million outpatient visits annually, one-third of which are for onchomycosis specifically. Physician visits for fungal infections comprise 18% of outpatient visits for infectious skin diseases in the United States, or approximately 0.4% of all outpatient visits.
Treatment
The treatment of superficial fungal infections varies based on the type of infection and the suspected pathogen. For some infection types, including tinea corporis, tinea facei, tinea pedis, tinea cruris, tinea versicolor, and candidiasis, treatment with topical agents may be adequate. Nevertheless, many superficial fungal infections respond poorly to topical agents alone. For example, fewer than 20% of cases of tinea unguium respond to topical treatment, owing to poor penetration of the nail bed. For infections such as tinea unguium, tinea capitis, and other refractory or severe cutaneous fungal infections, use of systemic antifungal agents is the standard of care. Griseofulvin, terbinafine, and azoles such as fluconazole, itraconazole, and ketoconazole are the most widely used systemic antifungal therapies for cutaneous fungal infections. Use of some of these agents can be complicated by drug toxicities for which monitoring of hepatic and renal function is necessary. In recent years, several new drugs with more favorable side-effect profiles have been developed.
Cost of treatment
Estimates for the annual cost of treatment of cutaneous fungal infections in the United States vary widely. In a study using data from 1990 to 1994, it was estimated that cutaneous fungal infections account for approximately $220 million in office visit and medication expenses annually. In a 2004 study, the economic burden of cutaneous fungal infections was estimated to be much higher at $1.7 billion annually. This value accounted for the cost of physician visits as well as prescription drug costs, which represented 74% of the total. Despite the discrepancy in costs reported by these studies, it is indisputable that cutaneous fungal infections account for substantial annual health care expenditures in the United States.
Summary and Future Directions
The burden of fungal skin disease is high, and recurrence is common. Simple fungal infections serve as important portals of entry for bacterial sepsis in immunosuppressed patients. Given the aging population and increasing prevalence of immunosuppression, these pathogens will continue to represent a public health burden. Research priorities include improved prophylactic regimens, the feasibility of shorter courses of therapy, and the cost effectiveness of care in various populations ( Table 2 ).
Surveillance | Treatment | Future Study |
---|---|---|
|
|
|
Fungal skin diseases
Cutaneous fungal infections may be divided into 3 categories: superficial, deep, and systemic infections. Superficial infections are confined to dead keratinous tissue, the epidermis, and hair follicles, and are caused by dermatophytes, nondermatophyte molds, and yeasts ( Candida and Malassezia species). Deep infections demonstrate involvement of all skin layers and often extend into the subcutaneous tissue. These infections occur via direct inoculation of the skin, and include infections such as sporotrichosis, mycetoma, and chromomycosis. Systemic infections with cutaneous manifestations are the least common and often occur in immunocompromised hosts. These infections are usually acquired through inhalation of spores with a primary pulmonary focus, even when skin lesions are the presenting finding. Histoplasmosis, blastomycosis, and coccidioidomycosis may occur in patients with normal immune function, whereas other infections such as cryptococcosis, aspergillosis, fusariosis, and mucormycosis present primarily in immunocompromised hosts.
Superficial Fungal Infections
General
The majority of fungal infections are superficial cutaneous infections, most of which result from dermatophyte infection. Dermatophytes are fungi that digest keratin as a nutrient source. These fungi colonize the highly keratinized stratum corneum, or outermost layer of the skin, as well as other keratinized structures such as the nail plate and hair follicles. Such fungi rarely invade viable tissue, and thus do not produce deep cutaneous or systemic infections, nor are they lethal. Although many infections demonstrate gross changes to the surrounding and underlying tissue suggestive of deeper infection, this usually represents an inflammatory host response to the overlying dermatophyte infection without true invasion.
Dermatophytes are divided into 3 genera: Trichophyton , Microsporum , and Epidermophyton . More than 40 different species of dermatophyte have been implicated in skin disease; however, most infections are caused by just a few species. Trichophyton rubrum is the most common dermatophyte, and it is estimated that 70% of the United States population will experience at least one T rubrum infection in their lifetime. Other common species in the United States include Trichophyton tonsurans and Trichophyton mentagrophytes . The distribution of dermatophytes is not static but instead ever-changing, especially in the era of international migration, travel, and commerce. Factors such as socioeconomic status, use of occlusive footwear, and urbanization also affect the varying distribution of pathogen types.
Tinea pedis, or “athlete’s foot,” represents a superficial fungal infection of the foot. This common infection occurs in 1 in 5 adults in the United States during their lifetimes. Worldwide incidence has increased in recent decades, especially with the use of occlusive footwear. Ninety-five percent of tinea pedis cases are caused by dermatophytes, with most infections caused by T rubrum and Trichophyton interdigitale (formerly Trichophyton mentagrophytes var. interdigitale ). Tinea pedis is classified into 3 primary clinical types: interdigital, moccasin, and vesiculobullous. Interdigital infection involves the toe web spaces and often presents with bacterial superinfection. Moccasin-type tinea pedis demonstrates thickening of the plantar and lateral foot with overlying scale. Vesiculobullous-type tinea pedis demonstrates plantar pustules and vesicles, which may become macerated and superinfected with bacteria.
Tinea unguium, or onchomycosis, is an infection of the nail plate or bed. Fungal infection of these structures leads to nail bed deformity (onchodystrophy) with thickening (hyperkeratosis) and discoloration. Eighty-two percent of tinea unguium cases are the result of dermatophyte infection, of which T rubrum is most common. Candida species and molds may also cause onchomycosis, particularly in tropical climates. Estimates vary regarding the prevalence of onchomycosis; however, most investigators endorse that these infections affect at least 5% of the adult population and increase in prevalence with age.
Tinea corporis is a superficial fungal infection of glabrous skin occurring most commonly on the trunk and limbs, whereas tinea facei affects the face. Both types are referred to as “ringworm” given their tendency to produce annular plaques or patches with a red, raised, scaling border. Tinea corporis and facei are most commonly caused by Trichophyton , particularly T rubrum , and Microsporum species.
Tinea cruris, or “jock itch,” describes infection of the groin region that occurs almost exclusively in adult men. It presents as an erythematous patch involving the inner thigh and inguinal folds while sparing the scrotum and penis. Tinea cruris is often associated with tinea pedis, and it is thought that infection occurs through self-inoculation from the foot. Most cases are caused by infection with T rubrum or T mentagrophytes , and may be secondarily infected with bacteria or yeast species.
Tinea capitis represents infection of the scalp and hair. Ninety-five percent of cases are caused by superficial infection with T tonsurans . Tinea capitis displays wide variation in presentation and is classified into 4 patterns. First, seborrheic-type demonstrates dandruff-like noninflammatory scaling. Next, “black-dot” tinea capitis produces hair breakage, leading to areas of alopecia with dark spots representing underlying hair follicles. Kerion-type tinea capitis involves the formation of a purulent inflammatory nodule. Finally the favus type, the rarest form, describes an inflammatory alopecia with honey-colored crusts.
Other common superficial fungal infections include candidiasis and tinea versicolor. Candidiasis is most commonly caused by Candida albicans and affects the skin, mucus membranes, nails, or gastrointestinal tract. Candidiasis is more common in women when accounting for vulvovaginal candidiasis, and in immunosuppressed patients. Tinea versicolor is a harmless skin disease most common in tropical regions, characterized by overgrowth of Malassezia species leading to the formation of hypopigmented or hyperpigmented patches with associated fine scale.
Incidence
Fungal skin infections are estimated to affect more than 20% of the world’s population. In the United States, prevalence is estimated at 10% to 20% of the population. Unlike bacterial skin infections, which must be recognized and treated promptly, fungal infections tend to follow a more indolent course and are less commonly life threatening. These infections are often difficult to treat, and persist despite optimal medical management. Furthermore, fungal remnants frequently remain after treatment; this and genetic predisposition result in a high rate of recurrent infection.
Given that cutaneous fungal infections affect up to 1 in 5 individuals in the United States and tend to follow a chronic, treatment-resistant course, it is not surprising that they account for a large number of physician visits each year. It is estimated that superficial cutaneous fungal infections account for more than 4 million outpatient visits annually, one-third of which are for onchomycosis specifically. Physician visits for fungal infections comprise 18% of outpatient visits for infectious skin diseases in the United States, or approximately 0.4% of all outpatient visits.
Treatment
The treatment of superficial fungal infections varies based on the type of infection and the suspected pathogen. For some infection types, including tinea corporis, tinea facei, tinea pedis, tinea cruris, tinea versicolor, and candidiasis, treatment with topical agents may be adequate. Nevertheless, many superficial fungal infections respond poorly to topical agents alone. For example, fewer than 20% of cases of tinea unguium respond to topical treatment, owing to poor penetration of the nail bed. For infections such as tinea unguium, tinea capitis, and other refractory or severe cutaneous fungal infections, use of systemic antifungal agents is the standard of care. Griseofulvin, terbinafine, and azoles such as fluconazole, itraconazole, and ketoconazole are the most widely used systemic antifungal therapies for cutaneous fungal infections. Use of some of these agents can be complicated by drug toxicities for which monitoring of hepatic and renal function is necessary. In recent years, several new drugs with more favorable side-effect profiles have been developed.
Cost of treatment
Estimates for the annual cost of treatment of cutaneous fungal infections in the United States vary widely. In a study using data from 1990 to 1994, it was estimated that cutaneous fungal infections account for approximately $220 million in office visit and medication expenses annually. In a 2004 study, the economic burden of cutaneous fungal infections was estimated to be much higher at $1.7 billion annually. This value accounted for the cost of physician visits as well as prescription drug costs, which represented 74% of the total. Despite the discrepancy in costs reported by these studies, it is indisputable that cutaneous fungal infections account for substantial annual health care expenditures in the United States.
Summary and Future Directions
The burden of fungal skin disease is high, and recurrence is common. Simple fungal infections serve as important portals of entry for bacterial sepsis in immunosuppressed patients. Given the aging population and increasing prevalence of immunosuppression, these pathogens will continue to represent a public health burden. Research priorities include improved prophylactic regimens, the feasibility of shorter courses of therapy, and the cost effectiveness of care in various populations ( Table 2 ).
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