Jan V. Hirschmann MD1
Professor of Medicine
1University of Washington School of Medicine; Assistant Chief, Medical Service, Puget Sound Veterans Affairs Medical Center
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Despite its large surface area and constant exposure to the environment, the skin resists infection well. The most important protective factor is an intact stratum corneum, the tough barrier of protein and lipid formed on the cutaneous surface by the underlying epidermis.1This barricade impedes invasion by environmental pathogens, and its dryness discourages colonization and growth of the many organisms that require moisture to survive, such as gram-negative bacilli. Furthermore, the constant shedding of cells of the epidermis impedes most microbes from establishing permanent residence.
Some organisms, however, can attach to skin cells and reproduce there; the normal cutaneous flora comprises primarily aerobic, gram-positive cocci and bacilli in densities ranging from about 102 organisms/cm2 on dry skin to 107 organisms/cm2 in moist areas, such as the axilla.2 This resident population inhibits harmful organisms from colonizing the skin by occupying binding sites on the epidermal cells, competing for nutrients, producing antimicrobial substances, and maintaining the skin surface at a low pH (about 5.5). Anaerobes are sparse except in areas with abundant sebaceous glands, such as the face and chest; in the deeper portions of these sites, as well as in hair follicles, anaerobes reach concentrations of 104 to 106 organisms/cm2.
Cutaneous infections occur when the skin's protective mechanisms fail, especially when trauma, inflammation, maceration from excessive moisture, or other factors disrupt the stratum corneum. The organisms causing infection may originate from the victim's own resident flora, either on the skin or on adjacent mucous membranes, but many come from other people, animals, or the environment.
Dermatophytes are fungi (molds) that can infect the skin, hair, and nails. These organisms, which include Trichophyton, Microsporum, andEpidermophyton species, are classified as anthropophilic, zoophilic, or geophilic, depending on whether their primary source is humans, animals, or the soil, respectively.3 Geophilic dermatophyte infections occur sporadically, primarily among gardeners and farm workers. Zoophilic dermatophytes (Trichophyton and Microsporum species) may have a restricted range of hosts (e.g., M. persicolor infects only voles) or may afflict many different animals (e.g., T. mentagrophytes can infect mice and other rodents, dogs, cats, and horses). Human infections with zoophilic species have occurred after exposure to dogs, cats, horses, cattle, pigs, rodents, poultry, hedgehogs, and voles.
Anthropophilic dermatophytes are the most common cause of fungal skin infections in humans. Transmission of these infections occurs from direct contact between people or from exposure to desquamated skin cells present in the environment—arthrospores can survive for months. Direct inoculation of the spores through breaks in the skin can lead to germination and subsequent invasion of the superficial cutaneous layers.
Dermatophyte infections occur more frequently in certain ethnic groups and in people with impaired cell-mediated immunity. Many of the anthropophilic dermatophyte infections occur more often in one gender or age group.4
Infection of the scalp, for example, is primarily a disease of children. Involvement of the feet and groin is most common in adolescents and young adults, especially males, but is unusual in children. Nail infection is more frequent in both men and women of advancing age. The reasons for these differences are unknown.
The anthropophilic dermatophytes also have unique geographic distribution patterns. The most common cause of scalp infection in the United States, for example, is T. tonsurans, but in Southeast Asia and the Middle East, it is T. violaceum. These differences may relate to climatic or racial factors.
The various forms of dermatophytosis, also called ringworm, are named according to the site involved. These infections include tinea capitis (scalp), tinea corporis (body), tinea barbae (beard area of men), tinea faciei (face), tinea cruris (groin), tinea pedis (feet), tinea unguium (nails), and tinea manuum (hands). The characteristic skin lesion is an annular scaly patch [see Figure 1], though the clinical appearance varies not only with the site involved but also with the host's immune status and the type of infecting organism. In general, anthropophilic species elicit little inflammation and cause chronic infections. Zoophilic and geophilic species, however, often provoke intense inflammation, which sometimes leads to eradication of the organisms and healing without treatment.
Figure 1. Classic annular lesion of tinea corporis shows a raised or vesicular margin with central clearing.
Tinea capitis occurs primarily in children but may develop in adults—especially the elderly, those who are unkempt, and the impoverished. Transmission can occur between humans by the sharing of combs, brushes, or headgear. Only Microsporum and Trichophyton species cause tinea capitis. Infection begins with invasion of the stratum corneum of the scalp skin. The hairs then become infected, in one of three microscopic patterns: ectothrix, endothrix, or favus. In ectothrix, the spores are outside the hair shaft and destroy the cuticle; in endothrix, they lie within the hair and do not affect the cuticle; and in favus, broad hyphae and air spaces form within the hair, but spores are absent. In all three types, scaling, hair loss, and inflammation of varying degrees are present.5
Figure 2. A typical kerion presenting as a zoophilic Microsporum canis infection of the scalp (tinea capitis).
Tinea corporis typically appears as a single lesion or multiple circular lesions with scaling, well-delineated margins and a raised, erythematous edge. Often, the lesions have an area of central clearing. The amount of inflammation varies; when the inflammation is intense, pustules, vesicles, and even bullae may occur. Sometimes, involvement of the hair follicles in the middle of a patch of scaling erythema leads to perifollicular nodules, a condition called Majocchi granuloma. This infection usually occurs on the legs of patients infected with T. rubrum; it can be precipitated by topical corticosteroid therapy. In immunocompromised hosts, subcutaneous abscesses may develop.
Tinea barbae occurs in adult men and involves the skin and coarse hairs of the beard and mustache area. The usual cause is a zoophilic species, primarily T. verrucosum or T. mentagrophytes; these species commonly infect cattle and horses. Patients are generally farm workers, and the infection usually causes erythema, scaling, and follicular pustules. Many hairs become loose and are easily removed with a forceps.
Tinea faciei occurs as an infection of the face in women and children and infection of the area outside the mustache and beard in men. The usual causes are T. rubrum and T. mentagrophytes; these organisms reach the face through direct inoculation or by spreading from another site of infection on the body. Patients often complain of itching and burning, and symptoms may worsen after exposure to sunlight. The lesions may be scaly, annular erythematous patches, but often they are indistinct red areas with little or no scaling.
Tinea cruris, infection of the groin, is much more common in men than women and is often associated with infection of the feet. T. rubrumand E. floccosum are the most common causes. The lesions are usually red, scaling, sharply demarcated areas with raised, erythematous borders. The infection, which affects the medial portion of the upper thighs but consistently spares the scrotum, may extend to the buttocks, abdomen, and lower back. Vesicles, nodules, pustules, and maceration may be present.
Tinea pedis is most frequently caused by T. rubrum, E. floccosum, and T. mentagrophytes. The most common form consists of fissuring, scaling, and maceration in the interdigital spaces, especially between the fourth and fifth toes. A second type involves scaling, hyperkeratosis, and erythema of the soles, heels, and sides of the feet. In this kind of tinea pedis, the lesions occur in a so-called moccasin distribution pattern [see Figure 3a]. The plantar skin may become very thick and scaly. A third form demonstrates an inflammatory pattern characterized by vesicles, pustules, or even bullae, usually on the soles [see Figure 3b].
Figure 3 (a). The scaling of tinea pedis appears between and under the toes and on the plantar surface. (b) Tinea pedis may also present as vesicles.
An important complication of tinea pedis is streptococcal cellulitis of the lower leg. Streptococci do not ordinarily survive on normal skin, but the presence of interdigital fissuring, scaling, or maceration from fungal disease or other causes apparently permits streptococci of various groups, including A, B, C, and G, to colonize the toe webs.6 From this location, these bacteria may invade the skin damaged by the tinea pedis or migrate to locations higher up the leg and enter the skin through any defects.
Nail involvement usually occurs from adjacent fungal infection of the hands or feet. The organisms typically invade the nail from the distal or lateral borders, and infection spreads proximally. The nails are thickened, opaque, and yellowish to brownish. They may crack or crumble, and often, subungual hyperkeratosis lifts the nail plate from the underlying bed (a condition known as onycholysis) [see Figure 4]. Splinter hemorrhages are common.
Figure 4. Nails are usually thickened, cracked, and crumbly in tinea unguium; subungual debris may be present, as shown.
Tinea manuum is an infection of the hands. Most cases have accompanying involvement of the feet; inexplicably, usually only one hand is affected (so-called two-feet, one-hand disease). The most common finding is scaling or hyperkeratosis of the palms and fingers. Occasionally, vesicles, papules, or follicular nodules form on the dorsal surface of the hands.
Clinicians should suspect dermatophyte infection in patients with any scaling, erythematous eruption and in patients whose nails exhibit the characteristics of tinea unguium (see above). The diagnosis can be confirmed by microscopy or culture of properly obtained specimens. The optimal method of obtaining specimens from the skin is by scraping the scaly lesions; specimens from the nails are best obtained by taking fragments of subungual debris.
The specimen is prepared for microscopic examination by first placing it on a glass slide and treating it with potassium hydroxide (KOH), which digests the keratin of the skin, nails, and hair, and then heating it to hasten the process. The basic culture medium for isolating dermatophytes is an agar containing Sabouraud medium, often combined with antibiotics to eliminate bacteria and with cycloheximide to inhibit saprophytic fungi. Growth is usually apparent in 3 to 14 days. A dermatophyte test medium culture can be used in the office and is both accurate and inexpensive.7 When both KOH preparations and cultures are negative, a biopsy may be useful in identifying the infecting organism, usually by special tissue stains such as periodic acid-Schiff or Gomori methenamine-silver stains. As an alternative to cultures, a biopsy may be used as the primary method for establishing the diagnosis.
Tinea corporis, tinea cruris, tinea pedis, and tinea faciei respond to topical agents applied once or twice daily to the affected area, usually for 2 to 4 weeks. Good choices include azoles (e.g., miconazole, econazole, or clotrimazole) or terbinafine. The cost of the preparation can dictate which agent to recommend; many are available without prescription. Tinea pedis often recurs after effective therapy, especially in cases of the moccasin form of the disease. When infection reappears, the previous therapy can be resumed without loss of effectiveness.
Oral therapy is necessary for extensive lesions, for infection involving the hair or hair follicles (e.g., tinea capitis and tinea barbae), for tinea unguium, and, often, for tinea manuum and various forms of dermatophytoses in immunocompromised hosts. Five oral agents are currently available: griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. Griseofulvin, a fungistatic agent, is the oldest oral treatment available and is still useful, primarily in infections not involving the nails. Griseofulvin reduces the serum levels of barbiturates and warfarin. Some patients receiving griseofulvin note a diminished tolerance to alcohol.
The azoles include ketoconazole, itraconazole, and fluconazole; like griseofulvin, they are fungistatic. Ketoconazole is usually well tolerated, but hepatotoxicity occurs in about 1 in 10,000 patients, typically after several weeks of use. Fluconazole and itraconazole provide protracted levels of antibiotic in the nails, allowing short or intermittent courses of therapy for tinea unguium. Both fluconazole and itraconazole can cause gastrointestinal disorders, rashes, and, occasionally, hepatotoxicity and can have serious interactions with several medications, including cyclosporine, digoxin, and quinidine. Ketoconazole, itraconazole, and fluconazole can interact with other medications; pharmacologic sources should be consulted for potential interactions.
Terbinafine, an allylamine, is fungicidal, unlike both griseofulvin and the azoles, which are fungistatic. High levels of terbinafine penetrate the nails, and the drug persists for many weeks to exert antifungal effects long after discontinuance. Its few side effects include gastrointestinal reactions and, occasionally, skin rashes. Hepatotoxicity and hematologic abnormalities are rare, and drug interactions are uncommon. These oral antifungals are quite effective for tinea capitis. The adult dosage for griseofulvin is 500 mg twice daily for 8 weeks. The other agents are effective when given for 1 to 3 weeks. Daily doses are as follows: itraconazole, 200 mg; fluconazole, 200 mg; and terbinafine, 250 mg. Of these, griseofulvin is the least expensive, but some T. tonsurans isolates are resistant to it. All these medications are effective in cases of tinea barbae; Majocchi granuloma; extensive tinea corporis; and tinea manuum that is unresponsive to topical agents. Griseofulvin and terbinafine appear to be superior to fluconazole and itraconazole for the treatment of tinea capitis.8
Tinea unguium is difficult to eradicate, particularly in the toenails. The most effective agent is terbinafine, administered at a dosage of 250 mg daily for 6 weeks for fingernail infections and for 12 weeks for toenail involvement.9 The terbinafine regimens produce short-term eradication of infection in about 70% to 90% of patients with fingernail infection and in about 50% to 80% of patients with toenail infection. Relapse is common, and patients often require a second course of treatment. About 75% of patients who receive one or more courses of terbinafine will have a clinical cure 5 years later. This medication is expensive, and clinicians must decide in each case whether its use is warranted.
Yeasts are unicellular fungi that reproduce by budding. They may form filamentous projections, which, unlike the hyphae of molds, do not contain separate cells. Accordingly, they are called pseudohyphae. Candida species are not part of the normal skin flora, but they commonly reside in the oropharynx, vagina, and colon. From these locations, they may cause infections in adjacent traumatized skin. Alternatively, with reduction in the other flora or with impaired host defense mechanisms, these yeasts may proliferate in large numbers to produce lesions on the mucosal surfaces of the mouth and vagina.
Malassezia furfur (also called Pityrosporum orbiculare or P. ovale) is a yeast that requires lipids for growth. It normally colonizes the skin of adults, especially the scalp and upper trunk, where the presence of sebum is highest. For unknown reasons, these organisms, which are ordinarily commensals, can become pathogenic and cause tinea versicolor (also known as pityriasis versicolor) or folliculitis. Cogent evidence suggests that these organisms also cause seborrheic dermatitis and dandruff.
One form of oral candidiasis, thrush, appears as white to gray patches (pseudomembranes) on the tongue, soft palate, gingiva, oropharynx, and buccal mucosa. Removing the material from the mucosal surface reveals an underlying erythematous base. Predisposing factors in adults include diabetes mellitus, use of systemic or local corticosteroids, use of broad-spectrum antibiotics, use of radiotherapy or chemotherapy, and impaired cell-mediated immunity, especially from HIV infection. Acute atrophic candidiasis especially follows antibiotic therapy and causes painful, red, denuded lesions of the mucous membranes; the tongue may have erythematous areas with atrophic filiform papillae. In chronic atrophic candidiasis, con-tamination of dentures with Candida causes painful, red, and sometimes edematous lesions with a shiny, atrophic epithelium and well-demarcated borders where the dentures contact the mucous membranes. Poor dental hygiene and prolonged use of dentures are common predisposing factors. Some patients with these predisposing factors have angular cheilitis (perleche), characterized by erythema and fissuring of the corners of the mouth. Other contributing conditions are maceration from excessive salivation or licking, poorly fitting dentures, and a larger fold from diminished alveolar ridge height. Candida is present in most, but not all, patients with this disorder.
Chronic hyperplastic candidiasis (candidal leukoplakia) consists of irregular, white, persistent plaques on the tongue or mucous membranes that are difficult to remove; this form of candidiasis occurs especially in male smokers. Soreness, burning, and roughness of the affected areas are the usual symptoms. Candidiasis of the tongue can also take the form of median rhomboid glossitis, a diamond-shaped area of atrophic papillae in the central portion of the lingual surface.
Candida infection may occur in any skin fold, causing soreness and itching. Obese patients are especially vulnerable. Commonly affected areas include the groin, inframammary regions, and folds of the abdominal pannus. The lesions are patches of bright erythema accompanied by maceration and an irregular, scalloped border, beyond which papules and pustules (satellite lesions) commonly form [see Figure 5].
Figure 5. Prominent satellite lesions of discrete vesicles are seen in a patient with candidiasis.
Candidal vulvovaginitis and balanitis
Most women with candidal vulvovaginitis have no underlying disease, but candidal vulvovaginitis may accompany diabetes mellitus and HIV infection. It also occurs as a complication of therapy with certain antibiotics. Candidal vulvovaginitis causes white plaques on a swollen, red vaginal mucosa; a creamy vaginal discharge; and erythema, sometimes with pustules, on the vulvar skin. Soreness and burning are common symptoms. Male sexual partners of women with candidal vulvovaginitis—especially male sexual partners who are uncircumcised—may develop balanitis, characterized by erythema, pustules, and erosions on the glans of the penis. Balanitis may occur spontaneously as well.
Candidal paronychia and nail infection
Maceration of the tissue surrounding the nail, typically caused by excessive moisture, may cause paronychia, which is characterized by erythema, swelling, and pain of the nail fold with loss of the cuticle [see Figure 6]. Candida organisms often colonize the area but are probably pathogenic only when pus forms. With chronic colonization, nail involvement may occur, producing yellowish discoloration and separation of the nail plate from the nail bed (onycholysis). For chronic paronychia without purulence, topical cortico-steroids, such as triamcinolone cream applied twice daily for 3 weeks, are the best therapy.10
Figure 6. In a Candida paronychia, seen on this patient's thumb, the nail fold becomes red, swollen, and painful. Nail dystrophy is also seen.
Scrapings from cutaneous or mucous membrane lesions may be mixed with KOH solution and examined under the microscope to identify budding yeasts with pseudohyphae. Gram stains of the same specimen are easier to evaluate because they disclose very large, oval, gram-positive organisms that may demonstrate budding or pseudohyphal formation. These yeasts are much larger than bacteria and are much easier to see on Gram stain than on KOH preparations. Culture of specimens may be useful if the microscopy is normal or ambiguous. These organisms grow rapidly on both fungal and conventional bacterial media.
For oral candidiasis, topical nystatin suspension, 200,000 to 400,000 units three to five times a day, is usually effective; an alternative treatment is clotrimazole troches. For patients in whom topical treatment is ineffective or poorly tolerated, systemic therapies include ketoconazole (200 mg/day), fluconazole (100 mg/day), and itraconazole (100 mg twice a day). Angular cheilitis usually responds to an azole cream, such as miconazole or clotrimazole. Dentures should be cleaned carefully with an effective disinfectant, such as chlorhexidine.
Candidal intertrigo and balanitis
Candidal intertrigo and balanitis respond to a topical azole cream, such as miconazole or clotrimazole.
Treatment of vulvovaginitis includes a topical azole in the form of a cream, suppository, or ointment, administered intravaginally, typically once daily for 7 days. A cream may be used for vulvar involvement. An alternative to suppositories is treatment with a single oral dose (150 mg) of fluconazole, which is at least as effective as topical therapy and is often preferred by patients.
Patients with candidal paronychia should keep their fingers dry; when wet work is unavoidable, patients should use cotton liners under rubber gloves. Prolonged topical therapy with creams or solutions of various azole preparations, such as clotrimazole, is often necessary to eradicate the infection.
Tinea versicolor (pityriasis versicolor)
Because the term tinea traditionally refers to dermatophyte infection, some clinicians prefer the term pityriasis, which means scaling, for this yeast infection. Usually asymptomatic, tinea versicolor may cause itching or skin irritation. The lesions are small, discrete macules that tend to be darker than the surrounding skin in light-skinned patients and hypopigmented in patients with dark skin. They often coalesce to form large patches of various colors (versicolor) ranging from white to tan [see Figure 7]. Scratching the lesions produces a fine scale. This infection most commonly involves the upper trunk, but the arms, axillae, abdomen, and groin may also be affected. Most lesions fluoresce a yellowish color under a Wood light.
Figure 7. Tinea versicolor appears on the chest of this patient as oval, hypopigmented, finely scaling macules.
Malassezia folliculitis (Pityrosporum folliculitis)
In folliculitis, inflammation of the hair follicle causes red papules and pustules that surround individual hairs. One cause of folliculitis is various Malassezia species. Lesions appear predominantly on the trunk but occasionally occur on the arms as well. The lack of comedones distinguishes the lesion from acne. Pruritus and stinging may be present.
In patients with tinea versicolor, KOH preparations of scrapings from the lesions demonstrate pseudohyphae and yeasts, which resemble spaghetti and meatballs. This finding is sufficient to establish the diagnosis. The yeast form prevails in folliculitis and is easily seen on Gram stain of purulent material from a pustule, appearing as a large, oval, gram-positive organism that is much larger than bacteria. Biopsies of these lesions show yeasts around and within the hair follicle, with accompanying neutrophilic inflammation. The yeasts are best seen with periodic acid-Schiff or Gomori methenamine-silver stain. Because these yeasts form part of the normal cutaneous flora, growth of the organism on cultures from scrapings of the skin surface is not very helpful diagnostically. Culture of the yeast from the pus of folliculitis is definitive; however, it requires special media, such as Sabouraud agar with olive oil, to provide the necessary lipids for growth. Growth typically occurs in 3 to 5 days.
Simple treatment of tinea versicolor and Malassezia folliculitis involves applying selenium sulfide shampoo from the chin to the waist and from the shoulders to the wrist, allowing the shampoo to dry, and then washing it off after 10 to 15 minutes. Repeating this regimen after 1 week is usually effective; reapplication once every few weeks as necessary should prevent relapses, which are otherwise common. With tinea versicolor, scaling resolves promptly, but the pigmentary changes may take weeks to months to disappear. Topical azoles, such as ketoconazole, miconazole, and clotrimazole, are also effective, but they are more expensive. For patients who have difficulty applying a topical agent because of physical disabilities or other factors, oral ketoconazole or fluconazole in a single 400 mg dose is an effective alternative. This oral program can be repeated for recurrences.
SKIN INFECTIONS CAUSED BY STREPTOCOCCI, STAPHYLOCOCCI, OR BOTH
Initially a vesicular infection of the skin, nonbullous impetigo rapidly evolves into pustules that rupture, with the dried discharge forming honey-colored crusts on an erythematous base [see Figure 8]. The lesions are often itchy. Nonbullous impetigo characteristically occurs on skin damaged by previous trauma, such as abrasions or cuts. Exposed areas are most commonly involved, typically the extremities or the areas around the mouth and nose. Nonbullous impetigo is usually a disease of young children and is more frequent in hot, humid climates than in temperate ones.
Figure 8. Vesicopustules or bullae of impetigo rupture quickly and leave an erythematous base covered with a thin, seropurulent exudate. The exudate dries, forming layers of honey-colored crusts.
The usual cause of nonbullous impetigo is Staphylococcus aureus, but sometimes, Streptococcus pyogenes (group A streptococci) is also present; occasionally, S. pyogenes is the sole organism cultured.11 Some strains of S. aureus elaborate a toxin that causes a split in the epidermis and the development of thin-roofed bullae. In this disorder, known as bullous impetigo, superficial, fragile, and flaccid vesiculopustules form and then rupture, with the exudate drying into a thin, brown, varnishlike crust. Sometimes, the vesiculopustules are not apparent, and erythematous erosions, often surrounded by a collar of remnants from the roof of the ruptured bulla, are the only evident disturbance. Gram-positive cocci in clusters are usually evident on a Gram stain of the fluid or pus from the bullae or from the surface of the erosions. Culturing S. aureus from these specimens establishes the diagnosis of bullous impetigo. Growth of S. aureus, S. pyogenes, or both from the skin lesions of nonbullous impetigo confirms the diagnosis of nonbullous impetigo, but cultures are unnecessary in characteristic cases. For treatment of sparse, nonbullous lesions, topical mupirocin ointment applied three times daily for 7 days is as effective as oral antimicrobials. Systemic antibiotics active against both S. aureus and S. pyogenes, such as cephalexin or dicloxacillin (250 mg orally four times a day for 7 days), represent an alternative to topical treatment. For extensive lesions, these antibiotics are preferred to topical therapy, and they are the treatment of choice for bullous impetigo. Because of the superficial nature of these infections, the lesions heal without scarring.
Ecthyma is a deeper infection than impetigo. As with nonbullous impetigo, S. aureus, S. pyogenes, or both may be the cause. Ecthyma commonly occurs in patients with poor hygiene or malnutrition or patients who have had skin trauma. The lesions, which are often multiple and are most common on the lower extremities, begin as vesicles that rupture, creating circular, erythematous lesions with adherent crusts. Beneath the scabs, which may spontaneously slough, are ulcers that leave a scar when healing occurs. Culture of the ulcer base yields the causative organisms. Treatment should be with an oral antistaphylococcal agent, such as dicloxacillin or cephalexin (250 mg orally four times a day for 7 days).
SKIN INFECTIONS CAUSED BY STREPTOCOCCI
Cellulitis and Erysipelas
Cellulitis and erysipelas are acute, spreading infections of the skin caused by streptococci of various groups, including A, B, C, and G. Erysipelas involves the superficial dermis, especially the dermal lymphatics, and cellulitis affects the deeper dermis and subcutaneous fat. Erysipelas has an elevated, sharply demarcated border, but differences in the clinical appearances of erysipelas and cellulitis are unimportant and often unclear. The most common sites of infection are the face and lower extremities. The causative organisms may enter the skin at obvious areas, such as traumatic wounds and leg ulcers, or through cutaneous inflammation (e.g., eczema); often, however, no point of entry is apparent. Edema from any cause, including venous insufficiency, hypoalbuminemia, and lymphatic damage, is a predisposing factor. Infection commonly occurs on skin that has been permanently damaged by burns, trauma, radiotherapy, or surgery. For example, cellulitis may occur at the site of a saphenous vein removal for cardiac or vascular surgery months to years after the procedure.12An important predisposing factor in patients with cellulitis or erysipelas is toe intertrigo (fissuring and maceration between the toes); streptococci that colonize these areas can invade the skin between the toes or can migrate to more proximal locations on the leg and enter through abnormal skin. Obesity is also a predisposing condition.13
Cutaneous findings include rapidly expanding erythema and swelling of the skin [see Figure 9], sometimes accompanied by proximal streaks of redness, representing lymphangitis, and tender, enlarged regional lymph nodes. Vesicles, bullae, petechiae, and ecchymoses may occur. The cutaneous surface may resemble the skin of an orange (peau d'orange) because the hair follicles remain tethered to the deeper structures, keeping their openings below the surrounding superficial edema and creating the characteristic dimpling of the skin. On the face, the typical location is on one or both cheeks, with a butterfly pattern of erythema and swelling. Extension to the eyelids, ears, or neck is common. Systemic symptoms, such as fever, headache, and confusion, can accompany these infections; sometimes, such symptoms precede by hours any cutaneous findings on examination. Other patients have no systemic features despite severe skin abnormalities.
Figure 9. Erythema, edema, and sharp demarcation of the lesion from the normal surrounding skin characterize facial erysipelas.
The diagnosis is largely clinical; in a typical case, cultures are unnecessary and usually unrewarding. Needle aspiration of the lesion yields an isolate in about 5% to 20% of specimens. Blood cultures in febrile patients are positive in fewer than 5%. Because of their low yield, blood cultures are unnecessary in typical cases of cellulitis.14 Punch biopsies of the skin are culture-positive in about 20% of cases.15 These results, together with serum antibody tests for streptococci16 and immunofluorescent studies of skin biopsies,17 indicate that streptococci cause the vast majority (probably about 90%) of cases of cellulitis and erysipelas. S. aureus is often suspected but rarely implicated in cellulitis in the absence of an abscess or penetrating injury, including needle sticks from the injection of illicit drugs. Additional circumstances in which organisms other than streptococci are likely to be responsible for cases of cellulitis include immunodeficiency, penetrating trauma, immersion injuries in freshwater or saltwater, granulocytopenia, and animal bites or scratches. Cultures are appropriate in these situations.
Treatment consists of elevation of the affected area to help reduce edema and administration of systemic antibiotic therapy. For patients who do not have serious systemic illness, oral treatment is satisfactory. Penicillin is the drug of choice for streptococcal infections; for outpatients who may not take an oral medication as prescribed, I.M. benzathine penicillin G in an adult dose of 1.2 million units provides a complete course. Instead of penicillin, many clinicians prescribe an antistaphylococcal agent—either a first-generation cephalosporin or a penicillinase-resistant penicillin—because of concerns about S. aureus. Patients often get worse shortly after therapy, with further extension of the cellulitis, higher fever, greater toxicity, and increased white blood cell counts, presumably because rapid killing of the organisms releases potent enzymes, such as streptokinase and hyaluronidase, that cause many of the clinical features. One study showed that oral prednisolone, taken for 8 days in doses of 30 mg, 15 mg, 10 mg, and 5 mg, with each dose taken for 2 days, decreases the duration of cellulitis and shortens hospital stay; it is a reasonable treatment for those with no contraindications to systemic corticosteroids.18
In patients with leg cellulitis, treatment of tinea pedis is useful in preventing further episodes, which are likely to cause permanent lymphatic damage and can lead to lymphedema and further risk of infection. Other measures to diminish the frequency of future attacks, which occur in about 5% to 10% of patients annually, include control of edema by diuretics or mechanical means, such as elastic stockings, and, for those with frequent episodes, prophylactic antibiotics. The easiest approach is the administration of oral penicillin or erythromycin, 250 mg twice daily.19,20
INFECTIONS DUE TO STAPHYLOCOCCUS AUREUS
A furuncle (or boil) is a deep-seated inflammatory nodule with a pustular center that develops around a hair follicle [see Figure 10]. With involvement of several adjacent follicles, a mass called a carbuncle may form, with pus discharging from multiple follicular orifices. This infection typically develops on the back of the neck and appears more commonly in patients with diabetes than in the general population. Moist heat is usually adequate for small furuncles, which ordinarily drain spontaneously. Incision and drainage are appropriate for large or multiple furuncles and for all carbuncles. Systemic antibiotics are unnecessary unless there is fever or substantial surrounding cellulitis.
Figure 10. A furuncle, or boil, occurs as an acute, painful, localized staphylococcal abscess surrounding a hair follicle.
Recently, in many areas throughout the world, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major cause of community-acquired skin and soft-tissue infections.21 These organisms differ from hospital-associated MRSA in molecular biology, clinical manifestations of infection, and antimicrobial resistance. Most isolates have genes that cause production of Panton-Valentine leukocidin, a toxin that destroys neutrophils and produces tissue necrosis. Many of the reported infections have occurred in outbreaks among groups living together or having close physical contact (e.g., soldiers or sporting teams), but isolated cases are common.
Most of the cases involve furuncles or cutaneous abscesses that often begin as painful red papules, with variable surrounding erythema, that develop purulent or necrotic centers. Many patients interpret the lesions as spider bites. The appropriate therapy is incision and drainage, which often yields minimal pus and primarily necrotic material. Antimicrobials are usually unnecessary. Some patients continue to develop new lesions, even without evidence of staphylococcal nasal carriage. In these patients, the organisms may remain on various skin sites, and antimicrobial therapy may be useful in terminating the recurrences. Oral agents to which most isolates are susceptible include doxycycline (100 mg orally two times a day), clindamycin (150 mg orally four times a day), sulfamethoxazole-trimethoprim (1 double-strength tablet two times a day), and fluoroquinolones (e.g., ciprofloxacin, 500 mg two times a day).
Some patients have recurrent episodes of furunculosis. Although a few patients have definable abnormalities in host defenses, such as neutrophil disorders, most are otherwise healthy people who, like 20% to 40% of the population, carry S. aureus in the anterior nares. From this site or occasionally from the perineum or axilla, organisms can spread and enter the skin, presumably through minor, usually inapparent, trauma. Successful prevention of recurrent infection requires eradication of these bacteria from their site of residence, but most systemic antibiotics do not achieve adequate levels of drug in the anterior nares. An exception is clindamycin, which, when given as a single daily dose of 150 mg for 3 months, is very effective in preventing subsequent episodes.22 A less effective alternative is mupirocin ointment, applied in the anterior nares twice daily for 5 days each month.23
SKIN INFECTIONS CAUSED BY THE RESIDENT CUTANEOUS FLORA
The normal cutaneous flora helps prevent infection by other organisms through the mechanisms mentioned above: occupying available sites of residence, competition for nutrients, establishment of a low pH, and the elaboration of antibacterial substances. Occasionally, however, the resident skin flora causes cutaneous infections, especially with trauma or alterations in the stratum corneum. Examples are erythrasma, pitted keratolysis, trichomycosis axillaris, and most cases of cutaneous abscesses.
Cutaneous abscesses are collections of pus within the dermis and deeper skin tissues. They probably occur as a result of trauma. Sites of trauma associated with cutaneous abscesses may be apparent, as with sites of injections in illicit-drug users,24 or they may be minor and unnoticed. S. aureus, usually in pure culture, causes about 25% of cutaneous abscesses, especially in the axillae, on the hand, and on the breasts of women after childbirth.25 In other sites, however, the predominant organisms are anaerobes. Anaerobes occur either alone or in the mixture of anaerobes and aerobes that constitutes the normal regional flora; they are sometimes accompanied by microbes from adjacent mucous membranes. In anogenital infections, such as scrotal, inguinal, vaginal, buttock, and perirectal abscesses, the organisms are commonly fecal bacteria, including streptococci, anaerobic gram-positive cocci, and anaerobic gram-negative bacilli, such as Bacteroides fragilis. On the extremities, trunk, neck, and head, the usual microbes include coagulase-negative staphylococci, anaerobic gram-positive cocci, and Propionibacterium acnes, an anaerobic gram-positive bacillus. These organisms ordinarily possess little virulence, but when introduced into the dermis or subcutaneous tissue by trauma or through a disrupted cutaneous surface, they may become pathogenic.
Cutaneous abscesses usually cause a painful, fluctuant, red, tender swelling, on which may rest a pustule. Treatment is incision and drainage of the area. Gram stain and culture of the pus are ordinarily unnecessary, as are topical antimicrobials. Systemic antibiotics are reserved for patients with extensive surrounding cellulitis, neutropenia, cutaneous gangrene, or systemic manifestations of infection, such as high fever.
Porphyrin-producing coryneform bacteria, which are gram-positive bacilli that constitute part of the normal cutaneous flora, cause a superficial, usually asymptomatic, skin disorder called erythrasma. One particular species, Corynebacterium minutissimum, has often been cited as the sole cause of this infection, but its precise role, if any, remains unclear. The most common site of erythrasma is between the toes, especially in the fourth interdigital space, where it causes fissuring, maceration, and scaling, resembling tinea pedis. Other locations are intertriginous areas, such as the axillae, groin, submammary area, and intergluteal cleft. In these regions, the lesions are usually scaly, brownish-red, sharply circumscribed patches. In hot, humid climates, more extensive disease may occur. The definitive diagnostic technique is examination of the skin with a Wood light, which, because the organisms produce porphyrins, reveals a coral-red fluorescence. Culture of the lesions, which requires special media, is unnecessary. Because they possess some activity against gram-positive bacteria, topical azoles, such as miconazole and clotrimazole, are effective in the treatment of this infection. Topical erythromycin or clindamycin is also effective. Oral erythromycin (250 mg q.i.d. for 2 weeks) is an alternative.26
Coryneform bacteria, Kytococcus sedentarius (a gram-positive coccus), and Dermatophilus congolensis (a gram-positive bacillus) together or individually cause a disorder called pitted keratolysis that affects the soles—typically in pressure-bearing areas, occasionally, the palms.27Pitted keratolysis consists of small pitted erosions about 0.7 to 7 mm in diameter that may be present on reddened plaques and are often more apparent after soaking in water for a few minutes. This infection occurs with increased moisture, such as caused by excessive sweating, occlusive footwear, or frequent contact with water. It appears more commonly in hot, humid climates than in more temperate ones. An impressive malodor of the feet is often apparent, presumably from the production of sulfur-compound by-products. Although the disorder may cause no symptoms, some patients complain of itching, tenderness, or sliminess of the feet, which often results in the feet sticking to socks. As in erythrasma, topical azoles, such as clotrimazole and miconazole, are effective, as are topical erythromycin, clindamycin, and mupirocin. With treatment, the problem usually clears within 3 to 4 weeks.
Trichomycosis axillaris is characterized by colored concretions of axillary hair that result from infection of the hair shafts by large colonies of various species of Corynebacterium. The nodules may be yellow, black, or red; and because the organisms may invade the cuticle, the hair can become brittle. The same process occasionally affects the facial or pubic hair.28 Excessive sweating, poor hygiene, and failure to use an axillary deodorant are predisposing factors. Shaving the hair is effective treatment; other options include topical erythromycin or clindamycin.
INFECTIONS DUE TO OTHER BACTERIA
Necrotizing fasciitis, a necrotizing infection of the subcutaneous tissue, can be caused by streptococci; more often, however, the responsible organisms are a combination of aerobic bacteria—such as gram-negative enteric organisms (e.g., Escherichia coli) and gram-positive cocci—and anaerobes, including B. fragilis.29 Occasionally, cases have occurred from infection with community-acquired MRSA.30 Necrotizing fasciitis often occurs after a penetrating wound to the extremities. The injury is typically deep, but sometimes, infection occurs after apparently trivial trauma, such as abrasions or lacerations. The necrotizing process may develop from extension of an adjacent infection, especially in the second most common location, the anogenital area. There, infection typically arises from a perianal abscess; as an extension of a periurethral gland infection, especially in men with urethral strictures; through retroperitoneal suppuration from perforated abdominal viscera; or as a complication of a preceding surgery. Necrotizing infection involving the genitalia is called Fournier gangrene.
These infections typically begin with fever, systemic toxicity, severe pain in the affected site, and the development of a painful, red swelling that rapidly progresses to necrosis of the subcutaneous tissue and overlying skin. Early on, the pain may appear disproportionate to the clinical findings. In some cases involving S. pyogenes infection, the characteristics of the streptococcal toxic-shock syndrome may appear31[see 7:I Infections Due to Gram-Positive Cocci]. When anaerobes or certain aerobic gram-negative bacilli cause the infection, gas may form in tissues, evident as crepitus on physical examination or visible on radiographic studies. Although the disease may resemble uncomplicated cellulitis, the following signs and symptoms should suggest the presence of a necrotizing subcutaneous infection: edema extending beyond the erythematous border; rapid development of bullae and ecchymoses; cutaneous gangrene; fluctuance; crepitus; loss of sensation in the affected area; and radiographically visible gas. Computed tomography or magnetic resonance imaging may be helpful in some cases in detecting the infection and defining its extent. Aspiration of the affected tissue may yield purulent fluid, which on Gram stain demonstrates only gram-positive cocci in chains when S. pyogenes is responsible, gram-positive cocci in clumps when S. aureus causes the infection, or a variety of many different organisms when a mixed infection is present. The findings on Gram stain and culture of the pus should dictate antibiotic choice, but a good initial program is ampicillin-sulbactam (3 g intravenously every 6 hours) combined with clindamycin (600 mg intravenously every 8 hours). For patients with severe penicillin allergies, an alternative to ampicillin-sulbactam is a fluoroquinolone, such as ciprofloxacin (400 mg intravenously every 6 to 8 hours). Vancomycin (1 g intravenously every 12 hours) is appropriate when S. aureusinfection is suspected. Most important is incision and drainage of the affected area, which should include removal of any necrotic tissue. Often, the amount of disease revealed at surgery is much greater than was apparent on the preoperative clinical examination, because the infection typically extends far beyond the borders of cutaneous inflammation. Repeat operation after 24 hours is typically prudent to drain new areas of infection and remove necrotic tissue.
Folliculitis is an inflammation at the opening of the hair follicle that causes erythematous papules and pustules surrounding individual hairs [see Figures 11a and 11b]. The most common location is the trunk. The initiating factor seems to be occlusion of the opening of the follicle, which may occur from contact with chemicals, such as oils or cosmetics; overhydration of the skin from excessive moisture; or repetitive trauma, such as friction from tight-fitting clothing, which elicits hyperkeratosis and follicular plugging. Subsequently, inflammation develops, which may be provoked by bacteria, yeast, or other nonmicrobial substances trapped beneath the occluded ostium.
Figure 11. Folliculitis is a superficial or deep inflammation of the hair follicles, appearing at follicular openings as small pustules surrounded by erythema (a). Folliculitis may also occur as an isolated lesion (b).
Among bacteria, S. aureus is often suspected but rarely found, except in cases of folliculitis of the nasal hairs. When bacteria are present in the pustules, Gram stain and culture usually reveal normal skin flora. In these patients, doxycycline (100 mg orally two times a day) may be effective in eradicating the lesions. Another cause is Malassezia species; Malassezia are yeasts that normally reside on the skin. In Gram stain of pus, these yeasts are visible as large gram-positive oval organisms that can bud [see Malassezia Folliculitis, above]. In some patients, Gram stain and culture of the pus reveal no organisms, and the avoidance of oily substances on the skin or tight clothing leads to resolution of the problem.
Occasionally, Pseudomonas aeruginosa causes folliculitis, as a consequence of inadequate disinfection of hot tubs, swimming pools, or whirlpools.32 This gram-negative bacillus grows well in hot water. Outbreaks occur an average of 48 hours after exposure, with a range of several hours to several days. Erythematous, pruritic papules, often with a pinpoint central pustule, appear in areas exposed to the contaminated water; papules are particularly numerous in regions occluded by tight-fitting swimming suits. The lesions disappear spontaneously over several days, leaving no scars; ordinarily, no topical or systemic therapy is necessary. Some patients have sore throat, rhinitis, earache, and headache, but fever or bacteremia is very rare. Cultures of the skin lesions and the contaminated water usually yield the organism. Adequate disinfection of the source of the contaminated water is critical in preventing recurrences.
Spores of Bacillus anthracis sent through the mail in the fall of 2001 as an act of bioterrorism caused cases of inhalational and cutaneous anthrax in several states. Otherwise, anthrax has been very rare in the United States over the past few decades. Ordinarily, this bacterium resides in the soil, where it forms spores that can persist for years. When ingested—primarily by herbivores (e.g., cattle, horses, sheep, and goats) grazing on contaminated land—these spores may cause infection. This veterinary disease is most frequent in tropical and subtropical areas, but extensive vaccination of livestock can markedly diminish its frequency.
Except for cases associated with bioterrorism [see 8:V Bioterrorism], humans usually develop anthrax from exposure to affected animals or their products, such as hides. Occasional laboratory-acquired cases also occur. The cutaneous form develops when spores enter the skin through abrasions and then transform into bacilli, which produce toxins that cause local tissue edema and necrosis. Macrophages can transport spores to regional lymph nodes, but bacteremia is uncommon. After an incubation period of about 1 to 7 days, a painless, pruritic papule forms at the entry site, most commonly the head, neck, and extremities. Over the next few hours, the lesion enlarges, and a ring of erythema may form around it. In 1 to 2 days, vesicles appear, surrounding the papule and containing numerous bacteria but few neutrophils. Painless, gelatinous, nonpitting edema then encircles the lesion, often spreading extensively to adjacent skin and soft tissue [see Figure 12]. This pronounced edema is especially characteristic of anthrax. After enlarging, the vesicles become hemorrhagic and rupture. In the depressed center of the lesion, a black eschar forms and sloughs within 1 to 2 weeks, leaving a shallow ulcer that heals with minimal, if any, scarring. In the early days of illness, patients commonly have headache, malaise, and fever. Regional lymph nodes often enlarge, causing pain and tenderness.
Figure 12. Cutaneous anthrax lesion, seen on the seventh day after infection.
The treatment of cutaneous anthrax that is not associated with bioterrorism is penicillin V (500 mg q.i.d. orally) or amoxicillin (500 mg t.i.d. orally) for mild cases and, for more severe disease, penicillin G (6 to 8 million units I.V. daily). For penicillin-allergic patients or cases arising from bioterrorism, the recommended therapy is oral ciprofloxacin (500 mg b.i.d.) or doxycycline (100 mg b.i.d). Antibiotic therapy does not alter the course of eschar formation and healing, but it does decrease the risk of systemic disease. Ordinarily, the duration of therapy is 7 to 10 days, but the recommended regimen for cases associated with bioterrorism is 60 days because of the possibility of simultaneous aerosol exposure.33
Warts, or verrucae, are caused by human papillomaviruses (HPVs), a subgroup of DNA-containing papovaviruses, of which there are numerous types. Humans are the only known reservoir; transmission probably occurs from close contact with infected people or possibly from exposure to sloughed, infected epidermal cells. The virus presumably enters through small breaks in the skin. The incubation period is difficult to discern but is probably several months. Autoinoculation from one portion of the body to another also occurs. Cell-mediated immunity appears important in controlling these infections, which can be very extensive and refractory to treatment in immunocompromised patients.
Verrucae vary according to location. They include the common, elevated wart (verruca vulgaris), typically appearing on the hands; the flat wart (verruca plana), on the face and legs; the moist wart (condyloma acuminatum), in the anogenital area; and the callus-covered plantar wart (verruca plantaris), on the sole of the foot. A histologic feature that distinguishes a wart from other papillomas is the presence in the upper epidermis of large, vacuolated cells that contain numerous viral particles.
The common wart consists of single or multiple skin-colored papules, which often have a hyperkeratotic, papillary surface. They are commonly present on the fingers. The estimated nationwide prevalence of hand warts is 3.5% for people 18 to 64 years of age; the greatest frequency (5.5%) occurs in men 18 to 24 years of age. The warts may be filiform, with a small base and a thin projection of several millimeters, especially on the face.
Liquid nitrogen is a common initial treatment of choice for many warts. Administered with a cotton-tipped applicator or cryospray device, liquid nitrogen freezes the lesion, causing it to blister and subsequently dissolve. More than one application at 2- to 3-week intervals may be necessary for large or periungual warts. Electrodesiccation and curettage or laser surgery is effective for persistent or recurrent lesions. Use of duct tape is an alternative, patient-conducted treatment that involves application of the tape for 6 days, its removal, soaking the area in water, debridement of the wart with an emery board or pumice stone, and reapplication of the tape for 6 day-intervals. One randomized study demonstrated results superior to cryotherapy.34
The flat wart is a skin-colored or light-brown, slightly elevated, smooth papule commonly seen on the face and the dorsum of the hand. These may be difficult to treat, but freezing with liquid nitrogen, application of trichloroacetic acid, or painting the lesions with 10% salicylic acid and 10% lactic acid in flexible collodion may be effective.
The plantar wart is often painful and disabling. A mosaic wart, a variant of verruca plantaris, consists of multiple discrete or confluent superficial lesions and is often difficult to treat. A plantar wart that is covered by a callus can be distinguished from an ordinary callus by paring off the surface keratin; multiple, pinpoint dots, representing thrombosed vessels, or bleeding points from surface capillaries will become apparent if it is a wart. Paring of the wart can be followed by immediate treatment with liquid nitrogen, the application of strong acid (50% trichloroacetic acid), or the nightly administration of salicylic acid in plasters, an acrylic vehicle, or collodion.
Anogenital warts consist of skin-colored or gray, discrete or confluent cauliflower-like excrescences that may cause no symptoms or produce itching, burning, pain, or tenderness [see Figure 13]. The incidence is highest in young adults; most often, it is a sexually transmitted disease, though some anogenital warts may develop from autoinoculation or may be acquired in other ways.35
Figure 13. Condyloma acuminatum may appear as a large cauliflower-like mass that resembles a malignant tumor.
Infection with some types of HPV predisposes to malignancy. Most cases of squamous carcinoma of the cervix are caused by HPV, especially HPV-16 and HPV-18, but fortunately, these types represent only a small percentage of the isolates from anogenital warts. Genital verrucous carcinoma, also called giant condyloma acuminatum of Buschke-Löwenstein, is a low-grade genital malignancy caused by HPV-6 and HPV-11. Squamous carcinoma of the anus is associated primarily with HPV-16. The Food and Drug Administration recently approved an HPV vaccine (Gardasil), which is reported to be 95% to 100% effective against HPV-6, HPV-11, HPV-16, and HPV-18.36 The vaccine is approved for use by girls and women 9 to 26 years of age; it is recommended that the vaccine be administered before the start of sexual activity. More studies are needed to determine the period of protection offered by the vaccine.
Anogenital warts may be difficult to eradicate, and several treatments are often necessary.35 Therapies administered by clinicians include liquid nitrogen, podophyllin resin, trichloroacetic or bichloroacetic acid, surgical removal, laser therapy, or intralesional interferon. Patient-applied treatments are podophyllotoxin, which the patient applies twice daily for 3 days, or imiquimod cream, used at bedtime three times a week for up to 16 weeks. Another approach involves fluorouracil (5-FU) cream administered twice daily for 1 to 3 weeks. This medication is particularly suitable for large wart plaques and warts of the urethral meatus, but side effects, including discomfort and painful erosions, are common.
Bowenoid papulosis consists of benign-appearing erythematous or pigmented papules in the anogenital area that histologically resemble Bowen disease (squamous cell carcinoma in situ) [see Figure 14]. Its course, however, is not aggressive, and the papules should be treated as anogenital warts (see above). HPV-16 is a common cause, however, and malignancy does occasionally develop, especially in women.
Figure 14. Benign lesions of bowenoid papulosis, as seen on the shaft of the penis, may histologically resemble carcinoma in situ.
Figure 12 Centers for Disease Control and Prevention Public Health Image Library.
Editors: Dale, David C.; Federman, Daniel D.