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The skin is a milieu for controlled bacterial growth. Skin supports the growth of commensal bacteria, which protect the host from pathogenic bacteria. Environmental and local factors, host immunity, and organism adherence and virulence are intricately related to cutaneous infection. Resident gram- positive bacteria include Staphylococcus, Micrococcus, and Corynebacterium sp. Staphylococcus aureus and Strepto coccus pyogenes are notoriously pathogenic in the skin. In order for bacteria to be pathogenic, they must be able to adhere to, grow on, and invade the host. Bacteria possess numerous virulence genes that allow for growth in these privileged niches. Epidermal infections caused by S. aureus and S. pyogenes include impetigo and ecthyma. Dermal infections consist of erysipelas, cellulitis, and necrotizing fasciitis. The pilosebaceous unit is involved in folliculitis, furunculosis, and carbunculosis. Moreover, S. aureus and S. pyogenes produce toxins that may elicit a superantigen response, causing massive release of cytokines. Staphylococcal scalded skin syndrome, toxic shock syndrome, and scarlet fever are all superantigen-mediated. Gram-negative organisms such as Pseudo monas aeruginosa, Pasteurella multocida, Capnocytophaga canimorsus, Bartonella sp., Klebsiella rhinoscleromatis, and Vibrio vulnificus are not typical resident skin microflora but may cause cutaneous infection.
The skin is a barrier that limits invasion and growth of pathogenic bacteria. The cutaneous antimicrobial defense mechanisms include the mechanical rigidity of the stratum corneum and its low moisture content, stratum corneum lipids, production of lysozyme, acidity (pH 5), and defensins (
). Specifically, most areas of skin are dry, creating an unfavorable environment for bacterial replication. Dead keratinocytes slough and physically remove colonizing bacteria. Skin is cooler than normal body temperature and slightly acidic; most bacteria grow best at a neutral pH and at 37°C. If organisms can evade cutaneous host defenses, the next line of protection involves the inunune system, or skin-associated lymphoid tissue (SALT).
The skin as a milieu for bacterial growth
The skin is an intricate habitat for many bacteria. A sterile milieu prenatally, human skin soon becomes host to resident bacteria after birth. The type and density of bacteria are determined by anatomic location, local humidity, the amount of sebum and sweat production, and the host's hormonal status and age (
). Bacterial skin flora are commensal, symbiotic, or parasitic relative to the host; although alterations in host immune status are known to have a significant impact, the type of relationship established is often inherent to the bacteria. Persistent colonization is the result of the ability of bacteria to adhere to skin epithelium, grow in a relatively dry and acidic milieu, and rapidly re-adhere during the normal process of desquamation (
Skin supports the growth of commensal bacteria, which protect the host from pathogenic bacteria both directly and indirectly. Direct effects include bacteriocin production, production of toxic metabolites, induction of a low reduction oxidation potential, depletion of essential nutrients, prevention of adherence of competing bacteria, inhibition of translocation, and degradation of toxins. Commensal bacteria compete for nutrients, niches, and receptors. For example, Staphylococcus epidermidis bind keratinocyte receptors and inhibit adherence of virulent S. aureus (
). Commensals can release species-specific antibiotic substances known as bacteriocins. For example, S. aureus strain 502A release bacteriocins that inhibit other virulent staphylococcal organisms (
). Indirectly, bacteria can induce the host to enhance antibody production, stimulate phagocytosis and clearance mechanisms, and augment interferon and cytokine production. For example, Propionibacterium acnes release fatty acids from lipid breakdown, acidifying the milieu and inhibiting growth of Streptococcus pyogenes (
Staphylococcus sp. are gram-positive cocci that aggregate in clusters. Commensal Staphylococcus sp. are distinguished by their inability to produce coagulase, an important virulence-associated enzyme. There are 32 species of coagulase-negative staphylococci, of which 15 are exclusive to humans, and 10 routinely isolated from normal glabrous skin. Staphylococcus epidermidis and S. hominis are the most prevalent coagulase-negative commensals. Occasionally, these organisms cause nosocomial infections in patients with indwelling foreign bodies such as heart valves and intravenous catheters (
Micrococcus sp. are also gram-positive cocci, distinguished from staphylococci by the inability to produce acid anaerobically from glycerol. Moreover, Micrococcus sp. are not lysed by lysostaphin and nitrofuran. At least eight species have been isolated from human skin, the most common being M. luteus.
Coryneforms are gram-positive pleomorphic bacilli. Skin commensals include Corynebacterium sp., Propionibacterium sp., Dermabacter sp., and Brevibacterium sp. Corynebacteria are classified as either lipophilic or nonlipophilic. Lipophilic organisms colonize areas rich in lipids or sebum such as the axilla and include Arcanobacterium haemolyticum, C. xerosis, C. minutissimum, and C. striatus. These organisms do not produce toxins and are nonmotile. Propionibacterium acnes is the dominant anaerobic coryneform on the skin. Unlike most commensals, its anaerobic requirements favor growth deep in adnexal structures as opposed to squamous epithelium. Dermabacter and Brevibacterium sp. prefer glabrous, humid skin such as the toewebs. The production of methane thiol by Brevibacterium sp. is the cause of “foot odor”.
Gram-negative bacteria
Gram-negative organisms do not normally reside in the dry environment of normal skin. Occasionally, moist intertriginous areas allow for the growth of Acinetobacter sp.
Pathogenicity and virulence factors
For an organism to become a pathogen, it must be able to circumvent normal host defense mechanisms. Perhaps the best-studied cutaneous pathogen is S. aureus, yet relatively little is known regarding the pathogenic mechanisms employed. Staphylococcus aureus readily adheres to all mammalian cell types, including keratinocytes (
; Murakawa, unpublished data). Teichoic acids mediate the binding of S. aureus to nasal epithelial cells as well as to fibronectin. Staphylococcus aureus binds most efficiently to well-differentiated keratinizing cells, and there is an increased affinity for keratinocytes derived from patients with atopic dermatitis (
). Other S. aureus virulence factors include catalase, hyaluronidase, and β-lactamase.
Our laboratory is investigating the interactions of S. aureus with keratinocytes and other components of the skin. Staphylococcus aureus is an ideal cutaneous pathogen to study because of its clinical relevance, well-delineated genome, and ability to grow on both liquid and solid media. Using plate assays, we have characterized the ability of S. aureus to adhere to, invade into, and grow on mammalian cells. Adherence assays are performed by incubating bacteria with mammalian cells, washing with PBS to remove nonadherent bacteria, and lysing the mammalian cells to free adherent or intracellular bacteria. Subsequently, the bacteria are diluted, plated, and counted to determine adherence. Intracellular bacteria are identified similarly, except that prior to lysing, the samples are treated with lysostaphin, a cytotoxic agent that specifically targets all extracellular bacteria. Using these assays, we have shown that S. aureus adhere to all mammalian cells (including macrophages and keratinocytes) efficiently and immediately (20%-60% within 15 min). Additionally, S. aureus invade macrophages efficiently and immediately (20%-50% in 30 min), but invade keratinocytes poorly (1%-4% in 4 h) (Figure 1). Morphologic studies using light and electron microscopy have confirmed these results, and intracellular bacteria reside within vacuoles.
Figure 1Invasion and adherence assays using S. aureus with mammalian cells. (A) Macrophage adherence; (B) macrophage invasion; (C) keratinocyte adherence; (D) keratinocyte invasion. As shown in (A) and (B), S. aureus adhere to macrophages and keratinocytes efficiently and immediately (20%-60%) within 15 min. As shown in (C) and (D), S. aureus invades macrophages efficiently and immediately (20–50%) within 30 min, but invade keratinocytes poorly (1%-4% in 4 h).
We have further characterized the interactions of S. aureus with skin by using skin equivalents (SE). Collagen and fibroblasts are combined to form a dermal matrix, and keratinocytes are subsequently added atop the matrix and allowed to differentiate, forming the SE. Bacteria readily adhere to and grow on the SE, but do not penetrate deeply into the epidermis or dermis (data not shown).
Infections caused by s. aureus and s. pyogenes
Staphylococcus aureus is the most common cause of cutaneous and systemic infections. It may transiently colonize the skin of newborn infants, the anterior nares in 20%-40% of healthy individuals, and the skin of atopic patients (
). Staphylococcus aureus is the most common cutaneous bacterial pathogen in HIV-infected patients, causing superficial and deep dermal pathology that can lead to life-threatening complications (
). In part, the susceptibility of HIV-infected patients to S. aureus may be a consequence of ongoing and increased nasal carriage of this organism. Recurrence after therapy is extremely common.
As with S. aureus, Streptococcus sp. are notoriously pathogenic in the skin. Streptococcus Groups A, B, C, D, and G (based on the Lancefield classification that segregates Streptococcus sp. according to M-protein serotype) are frequent human pathogens. M-protein is a virulence antigen that confers bacterial resistance to phagocytosis. Streptococcus pyogenes is not typically a cutaneous resident, but is asymptomatically carried in the throat of 15% of school-aged children (
). Non-bullous impetigo typically occurs on the face or extremities following minor cutaneous trauma. Erythematous papules, pustules, or vesicles develop into erosions covered by characteristic honey-colored crust. Lesions are usually painless, and there may be associated lymphadenopathy and leukocytosis. Cellulitis, lymphadenitis, scarlet fever, and guttate psoriasis are rare sequelae. Bullous impetigo is characterized by flaccid bullae that rupture easily, leaving a thin collarette of scale. There is usually no associated lymphadenopathy. Bullous impetigo is mediated by exfoliative toxin, which also causes staphylococcal scalded-skin syndrome (SSSS).
Ecthyma is a deeper form of impetigo in which ulcerations form beneath crusted plaques. The lower extremity is the most common site of involvement, and scarring is common. Streptococcus pyogenes or S. aureus are the usual culprits.
). Sharply demarcated, tender, erythematous plaques with an elevated advancing border occur on the lower extremities or face following an inflammatory dermatosis or traumatic insult. Vesicles and bullae may develop, resulting in local gangrene. Lesional cultures are usually negative. Constitutional symptoms and leukocytosis are common. A devastating complication of erysipelas is cavernous sinus thrombosis (
). There is usually a background of chronic edema and stasis dermatitis, and tinea pedis is most common portal of entry associated with leg cellulitis. The edematous, warm plaques of cellulitis are poorly demarcated, and lymphangitis occurs less frequently than with erysipelas. Constitutional symptoms are mild, and the causative organism is difficult to isolate. Local abscesses, necrotizing fasciitis, and septicemia may occur.
Two forms of cellulitis occurring in children deserve special mention. Perianal cellulitis caused by S. pyogenes presents in young children as perianal erythema, which may be associated with painful defecation and blood-tinged stool (
). Perianal cellulitis may be a trigger for guttate psoriasis. Haemophilus influenzae, a gram-negative rod, causes a facial cellulitis in children 3 mo to 4 y of age characterized by violaceous, indurated plaques. Meningitis is a feared complication. The advent of the H. influenzae vaccine has dramatically reduced the incidence of this form of cellulitis.
Necrotizing fasciitis is a potentially life-threatening infection of the subcutaneous fascia (
). Within 48 h, erythema, pain, and edema progress to violaceous, dusky plaques that quickly necrose. Anesthesia of the involved skin is characteristic. The most common cause is S. pyogenes, but S. aureus, coliforms, enterococci, Pseudomonas sp., and Bacteroides sp. have also been culprits.
). Folliculitis, caused by S. aureus, is characterized by discrete, follicular-based pustules. Carriage of S. aureus in the nares may lead to sycosis barbae in young men, presenting as inflammatory plaques in the beard area.
Deeper infections of hair follicle can lead to furuncles or carbuncles. A furuncle, or boil, is a nodule in a hair-bearing area that discharges purulent, necrotic debris. Carbuncles are multiple furuncles that coalesce to form large, deep, interconnected abscesses. Staphylococcus aureus is the cause in nearly all cases.
Miscellaneous infections
Acute paronychia, caused by S. aureus, presents as purulent tender swellings of the nailfold (
). Blistering distal dactylitis, caused by S. pyogenes and occasionally S. aureus, is characterized by tense blisters on an erythematous base over the volar fat pad of the phalanx of a finger (
). Botryomycosis is a granulomatous and suppurative infection caused by S. aureus, presenting on the lower extremity as crusted granulomatous plaques, ulcers, and sinus tracts draining purulent material.
Toxin-Mediated S. Aureus and S. Pyogenes Syndromes (Table III)
Staphylococcus aureus and S. pyogenes produce several toxins that can cause localized destruction or systemic symptoms (
). Systemic symptoms are mediated by superantigens (SA). Conventional antigens are expressed on the cell surface of antigen-presenting cells in association with the major histocompatibility type II complex (MHC II). Interaction with the T cell receptor occurs in a very specific, antigen-restricted fashion. Superantigens circumvent this process, interacting directly with a portion of the MHC II complex and with only the V-β section of the T cell receptor, without antigen (
). These cytokines lead to the clinical findings of fever, emesis, erythematous rash, hypotension, tissue injury, and shock. Physical signs common in toxin-induced staphylococcal and streptococcal syndromes include strawberry tongue, acral erythema with subsequent desquamation, and perineal erythema.
Table IIIStreptococcus pyogenes and S. aureus toxins
). There is sparing of the palms, soles, and mucous membranes. Generalized exfoliation quickly ensues, and the Nikolsky's sign is positive. Group 2 S. aureus, most commonly phage type 71, can be isolated from mucous membranes (skin erythema and desquamation are due to remote effects of the toxin). Exfoliative toxins A and B (ETA and ETB) have been implicated in the pathogenesis of SSSS, along with δ-hemolysin (
Toxic shock syndrome (TSS) is a multisystern illness caused by S. aureus or S. pyogenes. Clinically, diffuse macular erythema is followed by desquamation, especially of palms and soles. Staphylococcal TSS is typically associated with tampon use (
). Cases associated with S. pyogenes usually involve a soft-tissue infection. Most cases of staphylococcal TSS are mediated by TSST-1, although S. aureus strains expressing entero toxins B and C (SEB, SEC) have been isolated. Streptococcal TSS is primarily associated with SPE-A, although SPE-B, SPE-C, streptococcal superantigen, and mitogenic factor have been occasional culprits (
Scarlet fever, caused by S. pyogenes, occurs shortly after an episode of pharyngitis and is characterized by a papular erythematous “sandpaper” rash on the trunk and extremities accompanied by perioral pallor (
). A linear petechial eruption (Pastia's lines) occurs in flexural areas. A white coating on the tongue with hypertrophied projecting papilla leads to the so-called “white strawberry tongue”. Currently, SPE-B and SPE-C are the toxins most frequently isolated. Staphylococcal scarletina mimics classic scarlet fever, but the strawberry tongue is not seen.
Other gram-positive bacterial skin infections
Corynebacteria are normally found in intertriginous areas, where growth is enhanced by hyperhidrosis. Erythrasma, caused by C. minutissimum, is characterized by sharply defined, brown, slightly scaling plaques in intertriginous areas (
). Characteristic coral-red fluorescence is due the production of porphyrin. Pitted keratolysis presents as discrete coalescing crater-like pits on the plantar surface of the feet. In trichomycosis axillaris, concretions on axillary or pubic hair shafts occur.
Erysipelothrix rhusiopathiae is a gram-positive aerobic bacillus that causes erysipeloid, a localized cellulitis typically on the hands (
). Clinical findings include bright-red or violaceous, well-demarcated, polygonal plaques, often with central clearing. Erysipelothrix rhusiopathiae is present on dead matter of animal origin. Infection following trauma is seen in fish, meat, and poultry handlers, as well as farmers.
Bacillus anthracis is a nonmotile, gram positive aerobic rod that is capable of forming spores, and can produce both a localized cutaneous and a systemic infection (
). Cutaneous anthrax accounts for 95% of all anthrax infections in the USA, and typically develops in patients with a history of occupational contact with animals or animal products.
Gram-negative bacterial skin infections
An atypical form of cellulitis occurring in HIV-infected patients is caused by Helicobacter cinaedi (
). Red-brown or copper plaques with minimal warmth are characteristic. The cellulitis may be multifocal and recurrent.
Pseudomonas aeruginosa is an aerobic gram-negative rod found in moist environments. Ecthyma gangrenosum occurs primarily in immunosuppressed patients in the setting of Pseudomonas sepsis (
). Hemorrhagic bullae progress to deep ulcerations with eschar. “Hot tub” folliculitis presents as pruritic, discrete erythematous papules and pustules on the trunk and buttocks 8–48 h after water immersion. It is a self-limited disease resolving within 7–10 d; however, immunocompromised patients may develop ecthyma gangrenosum. Other diseases caused by P. aeruginosa include gram-negative toe web infections and green nail syndrome. Pseudomonas aeruginosa is also an important cause of morbidity and mortality in burn victims.
Pasteurella multocida is a gram-negative coccobacillus that is part of the commensal flora in dogs and cats (
). Following an animal bite, a rapidly progressive cellulitis with gray-colored serous drainage develops. Local complications including septic arthritis are common.
Bartonella sp. are aerobic, fastidious gram-negative bacteria. Bartonella henselae causes cat scratch disease (CSD) and bacillary angiomatosis (BA), B. quintana causes trench fever and BA, and B. bacilliformis causes verruga peruana and Oroya fever. CSD develops at the site of trauma, usually in the head and neck area, and is associated with unilateral lymphadenopathy. BA and verruga peruana are characterized by vascular skin lesions resembling pyogenic granulomas. Patients with trench fever and Oroya fever present with systemic symptoms but no cutaneous lesions (
in: Freedberg I.M. Eisen A.Z. Wolff K. Austen K.F. Goldsmith L.A. Katz S.I. Fitzpatrick T.B. Dermatology in General Medicine 5th edn. New York,
McGraw-Hill1999: 2249-2256
Capnocytophaga canimorsus, formerly referred to as DF-2, is a gram-negative rod that is commensal flora of dog and cats. Human infection is characterized by necrotizing eschar at the site of the bite. Alcoholics and patients who have undergone splenectomy are particularly predisposed to severe septicemia following the bite (
). Patients present with infiltrative and destructive granulomatous plaques that may lead to life-threatening complications. Transmission is by nasal secretions.
Consumption of raw seafood or seawater exposure may lead to infection with Vibrio vulnificus (
). Erythematous, indurated plaques studded with hemorrhagic bullae, pustules, petechiae, and areas of gangrene are found on the lower extremities.
In summary, the skin is a poor media for bacteria given the large number of inherent defense mechanisms; however, when altered or breached or under moist occlusive conditions, the skin can support the growth of both commensal and pathogenic bacteria. Although the bacteria–host interactions have been studied in depth, much remains unknown regarding the pathogenic mechanisms that bacteria employ and the host defense mechanisms to counteract infections.
ACKNOWLEDGMENTS
Dr. Murakawa was supported by the Howard Hughes Medical Institute, Dermatology Foundation Research Grant and National Institute of Arthritis, Musculoskeletal and Skin Diseases K-08 AR02068-02.
References
Aly R.
Cutaneous microbiology.
in: Orkin M. Maibach H.I. Dahl M.V. Dermatology. Los Altos,
Appleton & Lange1991: 22-25
in: Freedberg I.M. Eisen A.Z. Wolff K. Austen K.F. Goldsmith L.A. Katz S.I. Fitzpatrick T.B. Dermatology in General Medicine 5th edn. New York,
McGraw-Hill1999: 2249-2256
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