Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The skin acts as a barrier to pathogenic bacteria — research has shown that skin is effective at preventing growth and invasion of pathogenic organisms. Understanding how the microflora is invaded is important. In this article, authors George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D., offer an overview of how bacteria invade the normal microflora of the skin and discuss the common gram-positive and gram-negative bacterial infections that result. At the end of this article, you’ll find a 10-question exam you can dowload as a PDF. Mark your responses in the designated area, and fax page to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. Method of Participation: Physicians may receive two category 1 credits by reading the article and successfully answering the questions. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: April 2005 Expiration Date: April 2006 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: The North American Center for Continuing Medical Education (NACCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for the maximum of two category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: Drs. Murakawa and Aufiero have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. Dr. Murakawa receives grants/research support from Howard Hughes Medical Institute, NIH-NIAMS and the Dermatology Foundation. Learning Objectives: 1. Identify the type of microflora that inhabit skin. 2. Identify which skin disorders are associated with microbial infections. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None Microflora and Bacterial Infections of the Skin How bacteria invade the skin and an overview of the signs and symptoms of common gram-positive and gram-negative bacterial infections that result. By George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. T he skin serves as a restrictive environment for microorganisms and provides a barrier to pathogenic bacteria. And, while studies have shown that skin is highly effective at using multiple mechanisms to prevent the growth and invasion of pathogenic organisms, skin infections can and do occur. Here, we’ll discuss the normal function of the skin and the complex series of events that must occur in order for bacteria to invade the normal microflora of the skin and get enough of a foothold to cause a bacterial infection. We’ll highlight the common gram-positive and gram-negative bacterial infections that do occur when this happens, and discuss the typical signs and symptoms that present with these infections. The Skin Barrier The stratum corneum, the outermost layer of the epidermis, provides a rigid barrier to the external environment. The sloughing of dead keratinocytes interferes with bacterial colonization. The skin’s low moisture content and indigenous microflora are critical components of antimicrobial defense. Most bacteria, especially gram-negative bacilli, require a relatively moist environment for replication. The lack of moisture in most areas of skin limits bacterial growth. Indigenous microflora protect the skin from pathogens. The pH of the skin may play a role in suppressing bacterial growth. Free fatty acids formed during cornification contribute to an acidic environment (pH 5).1 Most bacteria, such as Staphylococcus aureus, prefer a neutral pH. Finally, naturally occurring substances, such as lysozyme, cathelicidins and defensins, have antibacterial effects.2 Resistance to skin infections in patients with psoriasis may be related to the production of beta-defensin 2. In contrast, studies suggest that the lack of antimicrobial peptides leads to increased susceptibility to S. aureus skin infections in patients with atopic dermatitis.3 The skin is a privileged site for growth of microorganisms, and few bacteria are capable of surviving the environment of the skin, forming the cutaneous microflora.4 In utero, the skin is sterile, and colonization by bacteria occurs after birth. Bacterial adherence is necessary for colonization and occurs through specific molecular structures called adhesins.5 The nature of bacterial growth is dependent on anatomic location, local humidity, sebum and sweat production, and the host’s hormonal status and age. Bacteria may develop a commensal, symbiotic, or parasitic relationship with the host. Microflora exert both direct and indirect effects on pathogenic bacteria. Commensals produce antimicrobial substances, such as bacteriocin and toxic metabolites, which directly inhibit pathogens. Furthermore, commensals compete with pathogens for nutrients, niches and receptors. Staphylococcus epidermidis binds keratinocyte receptors, blocking adherence by S. aureus, a process known as bacterial interference.6,7 Microflora also indirectly affect pathogens by stimulating the immune system. Their presence may enhance antibody production, stimulate phagocytosis and increase cytokine production. Gram-Positive Bacteria and Skin Flora Gram-positive bacteria form the major component of normal skin flora in humans.8,9 The three major groups of gram-positive bacteria found on skin are Staphylococcus, Micrococcus and coryneform bacteria (See table 1).10 These bacteria are able to survive the relatively dry environment of the skin. Gram-negative bacteria are rarely found on normal skin. Acinetobacter, which are gram-negative bacilli, may be present in intertriginous areas such as the axilla and perineum. Occlusion in these areas increases the relative humidity, permitting growth of gram-negative bacteria. Figure 1 shows bacterial growth from the arm and axilla. Bacterial growth was significantly greater from the axilla than from the arm. Staphylococcus are gram-positive cocci that occur in microscopic clusters resembling grapes. Species of Staphylococcus are categorized by their ability to produce coagulase, an enzyme that allows bacteria to resist phagocytosis. Staphylococcus found on skin are coagulase-negative and usually nonpathogenic. Coagulase-negative staphylococci may occasionally cause nosocomial infections in patients with indwelling catheters through adherence to the plastic. Staphylococcus epidermidis, S. hominis, and S. haemolyticus are the most abundant species on the skin. Micrococcus are gram-positive cocci that may be abundant on the skin in some individuals. Micrococcus are differentiated from Staphylococcus by resistance to lysostaphin and nitrofuran. The most common species is Micrococcus luteus. M. sedentarius is the causative agent of pitted keratolysis, but most species are nonpathogenic. Coryneforms are gram-positive bacilli. There are four genera that are found in the microflora: Corynebacterium, Propionibacterium, Dermabacter and Brevibacterium. Propionibacterium is an anaerobic coryneform, which, therefore, grows deep in adnexal structures. They are associated with acne vulgaris, but are not directly causal. Dermabacter and Brevibacterium are found in glabrous, humid skin such as the toewebs. Brevibacterium cause “foot odor” by the production of methane thiol. Pathogenesis of Skin Infections The basic tenet is that in order for skin infections to occur, pathogenic bacteria must be able to adhere to skin, invade the local environment (perhaps, intracellularly), and grow on the skin (see figure 2). Independently, the skin elicits a specific response toward the bacteria. Through specific receptors, bacteria activate a signaling pathway, which elicits a molecular response and subsequent acute and chronic cellular responses (see figure 2). Solitary or multiple pathways can be elicited simultaneously, and activation of a specific pathway is dependent on the pathogenic bacteria itself. Bacterial skin pathogens must compete against commensal bacteria and circumvent host defense mechanisms in order to cause skin infections. Pathogens compete, in part, by utilizing different host signaling pathways.11 The majority of cases are caused by bacteria such as S. aureus or Streptococcus pyogenes.4 Pathogens establish infection through the expression of virulence gene products that promote bacterial adherence and invasion. S. aureus mediates adherence to host cells through surface receptor molecules, some of which display techoic acid sensitivity.12 Many of the implicated receptors belong to the MSCRAMMs (microbial surface components recognizing adhesive matrix molecules)13-15 family of proteins, such as fibronectin-binding protein,16,17 collagen-binding protein18 and fibrinogen-binding protein.17,19,20 Plasmin-sensitive surface protein (Pls) adheres to keratinocyte lipids and glycoproteins,21 and protein A7,16 is involved in adherence. In fact, suggestive evidence indicates that more than one, and probably many, surface proteins are capable of mediating host cell attachment.16,22 Invasion by S. aureus requires the cooperation of the host cytoskeletal elements22,23 and long incubation times in certain host cells. The skin is comprised of several cell types, each of which has unknown potential to sponsor bacterial growth. Our laboratory studies the ability of S. aureus to adhere to and invade the skin cell types, including keratinocytes and macrophages. Adherence occurred within 5 minutes and was high in all skin cell types. S. aureus invasion displayed different characteristics that varied among cell types. Macrophages, which are professional phagocytes, ingested maximal levels of bacteria (30% to 35%) within a short period of time (5 minutes to 60 minutes). In contrast, fewer bacteria were found within keratinocytes (2% to 4% in 4 hours). These data indicate that skin cells found in the epidermis and dermis are potential targets for the establishment of S. aureus infection.22 Infections Caused by S. aureus and S. pyogenes Staphylococcus aureus is the most common cause of cutaneous bacterial infections (see table 2). It’s not part of the normal microflora of skin, but may transiently colonize the skin of newborn infants, the anterior nares (in 35% of the population), the perineum (20%), and the skin of atopic patients.24 HIV-infected patients are particularly susceptible to S. aureus infections, and this may be a consequence of increased nasal carriage. Streptococcus species are the second most common cause of cutaneous bacterial infections (see table 3).25 The Lancefield scheme, based on C carbohydrate antigens in the cell wall, classifies Streptococcus species into groups A to T. The major human pathogens belong to groups A, B, C, D and G. Group A streptococci are organized into subtypes based on their M-proteins, which are virulent antigens that interfere with phagocytosis, promote bacterial adherence to host cells and aid bacterial growth in human blood. Streptococcus pyogenes, the only member of group A, is the most invasive of this species. S. pyogenes is not part of the normal microflora, but may colonize the upper respiratory tract of children and adults. Impetigo is a superficial bacterial infection, occurring just below the stratum corneum.26 The most common causative agents are S. aureus in industrialized countries and S. pyogenes in developing countries. It frequently occurs in children as well as adults. There are two clinical variants: bullous and nonbullous. Nonbullous impetigo is the more common variant and occurs on the face and extremities. Infection only occurs after trauma to the skin because intact skin is resistant to colonization and impetiginization. The initial papules, pustules and vesicles evolve into honey-colored crusted erosions. Lesions are painless and constitutional symptoms are rare. Regional lymphadenopathy may be prominent. Acute glomerulonephritis is a complication in up to 5% of patients with streptococcal impetigo. Bullous impetigo is only caused by S. aureus (see upper left panel of figure 3). The lesions begin as flaccid bullae that rupture, leaving eroded plaques with a collarette of scale. Lymphadenopathy does not occur.4 The subcorneal pustules of bullous impetigo are caused by exfoliative toxin A, which cleaves desmoglein 1, a component of the desmosomes linking keratinocytes.27 Untreated impetigo may extend into the dermis, causing ecthyma. Crusted plaques develop into punched out ulcers with indurated margins. Ecthyma usually occurs on the lower extremities of children, the elderly, and patients with diabetes. Ecthyma is caused by S. aureus and S. pyogenes. Erysipelas is an acute dermal infection with significant dermal lymphatic vessel involvement. Group A Streptococcus is the most common etiologic agent. Rarely, group B, C, and G Streptococcus and S. aureus can cause erysipelas. The face and lower extremities are the most frequent sites of involvement. Lesions are tender, erythematous, edematous plaques with a sharply demarcated margin. Blisters may form in the involved area, leading to local gangrene. Systemic symptoms of malaise, fever, chills, and local pain are common. Erysipelas typically has an uncomplicated course. Rarely, abscess, septicemia and cavernous sinus thrombosis may occur. Cellulitis is a deep soft tissue infection involving the dermis and subcutaneous tissue. S. aureus and S. pyogenes are the most common causative agents, although the organism is rarely isolated. Impaired lymphatic drainage and stasis dermatitis are predisposing factors. Skin lesions, including psoriasic, eczema and tinea, provide portals of entry for pathogens. The leg is the most frequent site of involvement, followed by the arm and face. Cellulitis is characterized by warm, indurated plaques that lack distinct margins. Fluctuance and crepitus on palpation may be appreciated. Cellulitis may be accompanied by fever, chills, and regional lymphadenopathy. Complications include thrombophlebitis, local abscesses, necrotizing fasciitis, and septicemia. Two variants of cellulitis occur in children. Perianal cellulitis is caused by S. pyogenes, and presents with perianal erythema and pruritus. Perianal cellulitis may spread to adjacent perineal structures, causing painful defecation and blood-tinged stools. Perianal cellulitis has been known to lead to guttate psoriasis. Prior to the development of a vaccine, Haemophilus influenzae caused facial cellulitis in young children. Necrotizing fasciitis is a rapidly progressing infection of the subcutaneous fascia.28 Predisposing factors include penetrating injuries, surgical procedures, childbirth and burns. It is most commonly caused by S. pyogenes, when it is also known as streptococcal gangrene. S. aureus, coliforms, Enterococcus, Pseudomonas, and Bacteroides are other etiologic agents. The extremities are most frequently involved. The initial presentation is severe pain, erythema and edema. Lesions evolve into violaceous, dusky plaques and necrosis of the overlying skin (see upper right panel of figure 3). The involved area becomes anesthetic. Bacteria causing necrotizing fasciitis complicated by streptococcal toxic shock syndrome are known as “flesh-eating” bacteria. Folliculitis is an infection of the hair follicle or pilosebaceous unit. Superficial folliculitis, or Bockhart’s impetigo, presents as dome-shaped, follicular pustules in the scalp, beard area, axillae, extremities, and buttocks. S. aureus most commonly causes folliculitis. Deep folliculitis in the bearded areas of the face and upper lip is known as sycosis barbae. This is associated with S. aureus colonization in the nares. Bacterial skin infections are a common complication of intravenous drug abuse (IVDA). Infections such as cellulitis, abscesses, necrotizing fasciitis, and septic thrombophlebitis may present atypically in IVDA. Subcutaneous injection, or “skin-popping,” leads to a linear distribution of staphylococcal pyoderma (see lower right panel of figure 3). Additional bacterial infections of the skin are acute paronychia, blistering distal dactylitis, and botryomycosis. Acute paronychia is infection of the epithelium lateral to the nail plate, and is usually caused by S. aureus. It presents as tender erythema and edema in the nailfold. Blistering distal dactylitis presents as tense, purulent blisters on the volar skin pad of distal fingers and toes. It usually occurs in children and is caused by S. pyogenes and, less frequently, S. aureus. Botryomycosis is a chronic, purulent and granulomatous infection of the lower extremities. Typical lesions are verrucous plaques, abscesses, and ulcers. Sinuses and fistulas discharge granules of bacteria. Toxin-mediated S. aureus and S. pyogenes Syndromes Staphylococcal scalded-skin syndrome (SSSS) is caused by exfoliative toxins A and B.29,30 These toxins are usually produced by phage group II S. aureus. Bullous impetigo results from local action of exfoliative toxins, while SSSS occurs through hematogenous dissemination of toxins. At present, it is unclear whether exfoliative toxins are superantigens. SSSS typically presents in children following conjunctivitis, otitis media, or nasopharyngeal infection. Fever and skin tenderness are prominent features. Nikolsky’s sign, which is the ability to split the epidermis by lateral pressure, is positive. Initial erythema progresses to large, flaccid bullae in the axillae, groin, and periorificial regions. Palms, soles and mucous membranes are spared. The process resolves with superficial desquamation over 5 to 7 days. Toxic shock syndrome (TSS) is a life-threatening, multiorgan system illness. An outbreak occurred in the United States from 1979 to 1982, mainly in women using superabsorbent tampons. TSS may be caused by either S. aureus or S. pyogenes. S. aureus produces TSS toxin 1 (TSST-1) and S. pyogenes produces streptococcal pyrogenic exotoxins A, B and C (SPE-A, SPE-B and SPE-C), streptococcal superantigen, and mitogenic factor. These toxins are superantigens, which bypass the usual major histocompatibility complex (MHC)-restricted antigen recognition process. Superantigens instead bind directly to MHC II on antigen-presenting cells and interact with the variable region of the b chain on T-cell receptors. This leads to widespread T-cell activation of up to 30% of resting T cells and the massive release of cytokines such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and interleukin-6 (IL-6). Massive cytokine release causes fever, hypotension, and diffuse erythema. The rash resembles scarlet fever and progresses to desquamation, especially of the palms and soles. Conjunctival injection and strawberry tongue are additional features. Scarlet fever is caused by a delayed-type hypersensitivity to streptococcal antigens. Previous exposure sensitizes the patient. Scarlet fever is characterized by an erythematous rash with 1-mm to 2-mm punctate papules on the trunk and extremities, known as the sandpaper rash. The exanthem is prominent at sites of pressure, such as the buttocks (see lower left panel of figure 3). The rash occurs 1 to 2 days after S. pyogenes pharyngitis, primarily in children. Fever, nausea, vomiting, and headache may be prominent. The antecubital fossae and axillary folds show a linear petechial eruption called Pastia’s lines. The “white-strawberry” tongue of scarlet fever is characterized by a white coating with reddened, hypertrophied papillae. In recent decades, the toxins SPE-B and SPE-C have been responsible for scarlet fever. S. aureus causes a similar toxin-mediated syndrome called staphylococcal scarlatiniform eruption. Pharyngitis and strawberry tongue are not present. Other Gram-Positive Skin Infections Erythrasma is a superficial infection of intertriginous areas, occurring more commonly in tropical climates.31 Corynebacterium minutissimum is the causative agent. The typical lesions are well-demarcated, brown, slightly scaling plaques. Erythrasma may also occur as keratotic macerated plaques in the web spaces of the feet. Wood’s lamp examination shows a coral-red fluorescence due to bacterial production of porphyrin. Pitted keratolysis is a superficial infection of the web spaces and plantar surface of the feet. Micrococcus sedentarius is probably the cause of pitted keratolysis, although Corynebacterium and Dermatophilus congolensis have also been implicated. The disease presents as discrete, crateriform pits on the plantar foot and eroded plaques in the web spaces. Trichomycosis axillaris and pubis are infections of the hair shaft caused by Corynebacterium. Hair shafts exhibit tan concretions, which may be malodorous. The concretions are composed of bacterial colonies. Erysipeloid is a localized cutaneous infection caused by Erysipelothrix rhusiopathiae, a gram-positive aerobic bacillus. E. rhusiopathiae may contaminate or infect animals and fish, exposing fishermen, butchers, and veterinarians. The infection is acquired following minor trauma to the skin and manifests as well-demarcated, red plaques with central clearing, usually on the hands. Bacillus anthracis is a gram-positive soil organism capable of forming endospores. Exposure to endospores leads to cutaneous and systemic infections known as anthrax. In the United States, infection has occurred in workers who handled animals or animal products.32 B. anthracis has been used as a biological weapon because of its robust spores and virulence factors.33 The first cases of cutaneous and inhalational anthrax due to bioterrorism were reported in 2001 in the United States. Cutaneous anthrax occurs following exposure to spores in cuts or abrasions. The initial skin lesion is a painless, pruritic papule, which undergoes central necrosis and progresses to a depressed, black eschar. Surrounding nonpitting edema is caused by edema toxin produced by the bacteria. Cutaneous anthrax is effectively treated by antibiotics and complications are uncommon. Gram-Negative Skin Infections Pseudomonas aeruginosa is a ubiquitous gram-negative rod that causes multiple cutaneous infections. Patients with Pseudomonas septicemia may develop ecthyma gangrenosum.34 The lesion presents as a gray, infarcted plaque and becomes a deep ulcer with a black eschar. Common sites of involvement are the groin and axillary region. Ecthyma gangrenosum is a complication in immunocompromised patients. “Hot tub folliculitis” occurs after uses of whirlpools, hot tubs and swimming pools. The characteristic lesions are erythematous papules and pustules on the trunk, buttocks and extremities. Lesions develop 8 hours to 48 hours after exposure and resolve in 7 day to 10 days. P. aeruginosa is a rare cause of toe-web infections and “green nails.” Decubitus ulcers and thermal burns may be secondarily infected by P. aeruginosa. Pasteurella multocida is a gram-negative coccobacillus that is present in the nasopharynx of dogs and cats.35 Bites from these animals lead to a local cellulitis with lymphadenitis. Complications include septic arthritis, tenosynovitis, and osteomyelitis. Capnocytophaga canimorsus, a gram-negative rod present in the oral flora of cats and dogs, causes infection after animal bites. The most common presentation is overwhelming sepsis in a patient with a predisposing condition such as splenectomy, trauma or Hodgkin’s disease.36 Bartonella are aerobic, fastidious, gram-negative rods that lead to multiple diseases.37 Cat-scratch disease, caused by Bartonella henselae, is transmitted by the bite or scratch of a cat. A papule develops at the site of trauma, usually on the head and neck, with lymphadenopathy occurring an average of 2 weeks later. Bacillary angiomatosis (BA) occurs in immunosuppressed patients. B. henselae and B. quintana are the etiologic agents. BA presents with pyogenic granuloma-like papules and nodules and lymphadenopathy. A low CD4 count is typical in BA patients. Helping Patients While the skin typically acts as a barrier to most bacterial infections, it’s important to note that infections do happen. Knowing how the skin is compromised and what signs to look for to diagnose infection helps us know how to best treat our patients.
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CME #122Microflora and Bacterial Infections of the Skin
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The skin acts as a barrier to pathogenic bacteria — research has shown that skin is effective at preventing growth and invasion of pathogenic organisms. Understanding how the microflora is invaded is important. In this article, authors George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D., offer an overview of how bacteria invade the normal microflora of the skin and discuss the common gram-positive and gram-negative bacterial infections that result. At the end of this article, you’ll find a 10-question exam you can dowload as a PDF. Mark your responses in the designated area, and fax page to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. Method of Participation: Physicians may receive two category 1 credits by reading the article and successfully answering the questions. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: April 2005 Expiration Date: April 2006 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: The North American Center for Continuing Medical Education (NACCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for the maximum of two category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: Drs. Murakawa and Aufiero have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. Dr. Murakawa receives grants/research support from Howard Hughes Medical Institute, NIH-NIAMS and the Dermatology Foundation. Learning Objectives: 1. Identify the type of microflora that inhabit skin. 2. Identify which skin disorders are associated with microbial infections. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None Microflora and Bacterial Infections of the Skin How bacteria invade the skin and an overview of the signs and symptoms of common gram-positive and gram-negative bacterial infections that result. By George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. T he skin serves as a restrictive environment for microorganisms and provides a barrier to pathogenic bacteria. And, while studies have shown that skin is highly effective at using multiple mechanisms to prevent the growth and invasion of pathogenic organisms, skin infections can and do occur. Here, we’ll discuss the normal function of the skin and the complex series of events that must occur in order for bacteria to invade the normal microflora of the skin and get enough of a foothold to cause a bacterial infection. We’ll highlight the common gram-positive and gram-negative bacterial infections that do occur when this happens, and discuss the typical signs and symptoms that present with these infections. The Skin Barrier The stratum corneum, the outermost layer of the epidermis, provides a rigid barrier to the external environment. The sloughing of dead keratinocytes interferes with bacterial colonization. The skin’s low moisture content and indigenous microflora are critical components of antimicrobial defense. Most bacteria, especially gram-negative bacilli, require a relatively moist environment for replication. The lack of moisture in most areas of skin limits bacterial growth. Indigenous microflora protect the skin from pathogens. The pH of the skin may play a role in suppressing bacterial growth. Free fatty acids formed during cornification contribute to an acidic environment (pH 5).1 Most bacteria, such as Staphylococcus aureus, prefer a neutral pH. Finally, naturally occurring substances, such as lysozyme, cathelicidins and defensins, have antibacterial effects.2 Resistance to skin infections in patients with psoriasis may be related to the production of beta-defensin 2. In contrast, studies suggest that the lack of antimicrobial peptides leads to increased susceptibility to S. aureus skin infections in patients with atopic dermatitis.3 The skin is a privileged site for growth of microorganisms, and few bacteria are capable of surviving the environment of the skin, forming the cutaneous microflora.4 In utero, the skin is sterile, and colonization by bacteria occurs after birth. Bacterial adherence is necessary for colonization and occurs through specific molecular structures called adhesins.5 The nature of bacterial growth is dependent on anatomic location, local humidity, sebum and sweat production, and the host’s hormonal status and age. Bacteria may develop a commensal, symbiotic, or parasitic relationship with the host. Microflora exert both direct and indirect effects on pathogenic bacteria. Commensals produce antimicrobial substances, such as bacteriocin and toxic metabolites, which directly inhibit pathogens. Furthermore, commensals compete with pathogens for nutrients, niches and receptors. Staphylococcus epidermidis binds keratinocyte receptors, blocking adherence by S. aureus, a process known as bacterial interference.6,7 Microflora also indirectly affect pathogens by stimulating the immune system. Their presence may enhance antibody production, stimulate phagocytosis and increase cytokine production. Gram-Positive Bacteria and Skin Flora Gram-positive bacteria form the major component of normal skin flora in humans.8,9 The three major groups of gram-positive bacteria found on skin are Staphylococcus, Micrococcus and coryneform bacteria (See table 1).10 These bacteria are able to survive the relatively dry environment of the skin. Gram-negative bacteria are rarely found on normal skin. Acinetobacter, which are gram-negative bacilli, may be present in intertriginous areas such as the axilla and perineum. Occlusion in these areas increases the relative humidity, permitting growth of gram-negative bacteria. Figure 1 shows bacterial growth from the arm and axilla. Bacterial growth was significantly greater from the axilla than from the arm. Staphylococcus are gram-positive cocci that occur in microscopic clusters resembling grapes. Species of Staphylococcus are categorized by their ability to produce coagulase, an enzyme that allows bacteria to resist phagocytosis. Staphylococcus found on skin are coagulase-negative and usually nonpathogenic. Coagulase-negative staphylococci may occasionally cause nosocomial infections in patients with indwelling catheters through adherence to the plastic. Staphylococcus epidermidis, S. hominis, and S. haemolyticus are the most abundant species on the skin. Micrococcus are gram-positive cocci that may be abundant on the skin in some individuals. Micrococcus are differentiated from Staphylococcus by resistance to lysostaphin and nitrofuran. The most common species is Micrococcus luteus. M. sedentarius is the causative agent of pitted keratolysis, but most species are nonpathogenic. Coryneforms are gram-positive bacilli. There are four genera that are found in the microflora: Corynebacterium, Propionibacterium, Dermabacter and Brevibacterium. Propionibacterium is an anaerobic coryneform, which, therefore, grows deep in adnexal structures. They are associated with acne vulgaris, but are not directly causal. Dermabacter and Brevibacterium are found in glabrous, humid skin such as the toewebs. Brevibacterium cause “foot odor” by the production of methane thiol. Pathogenesis of Skin Infections The basic tenet is that in order for skin infections to occur, pathogenic bacteria must be able to adhere to skin, invade the local environment (perhaps, intracellularly), and grow on the skin (see figure 2). Independently, the skin elicits a specific response toward the bacteria. Through specific receptors, bacteria activate a signaling pathway, which elicits a molecular response and subsequent acute and chronic cellular responses (see figure 2). Solitary or multiple pathways can be elicited simultaneously, and activation of a specific pathway is dependent on the pathogenic bacteria itself. Bacterial skin pathogens must compete against commensal bacteria and circumvent host defense mechanisms in order to cause skin infections. Pathogens compete, in part, by utilizing different host signaling pathways.11 The majority of cases are caused by bacteria such as S. aureus or Streptococcus pyogenes.4 Pathogens establish infection through the expression of virulence gene products that promote bacterial adherence and invasion. S. aureus mediates adherence to host cells through surface receptor molecules, some of which display techoic acid sensitivity.12 Many of the implicated receptors belong to the MSCRAMMs (microbial surface components recognizing adhesive matrix molecules)13-15 family of proteins, such as fibronectin-binding protein,16,17 collagen-binding protein18 and fibrinogen-binding protein.17,19,20 Plasmin-sensitive surface protein (Pls) adheres to keratinocyte lipids and glycoproteins,21 and protein A7,16 is involved in adherence. In fact, suggestive evidence indicates that more than one, and probably many, surface proteins are capable of mediating host cell attachment.16,22 Invasion by S. aureus requires the cooperation of the host cytoskeletal elements22,23 and long incubation times in certain host cells. The skin is comprised of several cell types, each of which has unknown potential to sponsor bacterial growth. Our laboratory studies the ability of S. aureus to adhere to and invade the skin cell types, including keratinocytes and macrophages. Adherence occurred within 5 minutes and was high in all skin cell types. S. aureus invasion displayed different characteristics that varied among cell types. Macrophages, which are professional phagocytes, ingested maximal levels of bacteria (30% to 35%) within a short period of time (5 minutes to 60 minutes). In contrast, fewer bacteria were found within keratinocytes (2% to 4% in 4 hours). These data indicate that skin cells found in the epidermis and dermis are potential targets for the establishment of S. aureus infection.22 Infections Caused by S. aureus and S. pyogenes Staphylococcus aureus is the most common cause of cutaneous bacterial infections (see table 2). It’s not part of the normal microflora of skin, but may transiently colonize the skin of newborn infants, the anterior nares (in 35% of the population), the perineum (20%), and the skin of atopic patients.24 HIV-infected patients are particularly susceptible to S. aureus infections, and this may be a consequence of increased nasal carriage. Streptococcus species are the second most common cause of cutaneous bacterial infections (see table 3).25 The Lancefield scheme, based on C carbohydrate antigens in the cell wall, classifies Streptococcus species into groups A to T. The major human pathogens belong to groups A, B, C, D and G. Group A streptococci are organized into subtypes based on their M-proteins, which are virulent antigens that interfere with phagocytosis, promote bacterial adherence to host cells and aid bacterial growth in human blood. Streptococcus pyogenes, the only member of group A, is the most invasive of this species. S. pyogenes is not part of the normal microflora, but may colonize the upper respiratory tract of children and adults. Impetigo is a superficial bacterial infection, occurring just below the stratum corneum.26 The most common causative agents are S. aureus in industrialized countries and S. pyogenes in developing countries. It frequently occurs in children as well as adults. There are two clinical variants: bullous and nonbullous. Nonbullous impetigo is the more common variant and occurs on the face and extremities. Infection only occurs after trauma to the skin because intact skin is resistant to colonization and impetiginization. The initial papules, pustules and vesicles evolve into honey-colored crusted erosions. Lesions are painless and constitutional symptoms are rare. Regional lymphadenopathy may be prominent. Acute glomerulonephritis is a complication in up to 5% of patients with streptococcal impetigo. Bullous impetigo is only caused by S. aureus (see upper left panel of figure 3). The lesions begin as flaccid bullae that rupture, leaving eroded plaques with a collarette of scale. Lymphadenopathy does not occur.4 The subcorneal pustules of bullous impetigo are caused by exfoliative toxin A, which cleaves desmoglein 1, a component of the desmosomes linking keratinocytes.27 Untreated impetigo may extend into the dermis, causing ecthyma. Crusted plaques develop into punched out ulcers with indurated margins. Ecthyma usually occurs on the lower extremities of children, the elderly, and patients with diabetes. Ecthyma is caused by S. aureus and S. pyogenes. Erysipelas is an acute dermal infection with significant dermal lymphatic vessel involvement. Group A Streptococcus is the most common etiologic agent. Rarely, group B, C, and G Streptococcus and S. aureus can cause erysipelas. The face and lower extremities are the most frequent sites of involvement. Lesions are tender, erythematous, edematous plaques with a sharply demarcated margin. Blisters may form in the involved area, leading to local gangrene. Systemic symptoms of malaise, fever, chills, and local pain are common. Erysipelas typically has an uncomplicated course. Rarely, abscess, septicemia and cavernous sinus thrombosis may occur. Cellulitis is a deep soft tissue infection involving the dermis and subcutaneous tissue. S. aureus and S. pyogenes are the most common causative agents, although the organism is rarely isolated. Impaired lymphatic drainage and stasis dermatitis are predisposing factors. Skin lesions, including psoriasic, eczema and tinea, provide portals of entry for pathogens. The leg is the most frequent site of involvement, followed by the arm and face. Cellulitis is characterized by warm, indurated plaques that lack distinct margins. Fluctuance and crepitus on palpation may be appreciated. Cellulitis may be accompanied by fever, chills, and regional lymphadenopathy. Complications include thrombophlebitis, local abscesses, necrotizing fasciitis, and septicemia. Two variants of cellulitis occur in children. Perianal cellulitis is caused by S. pyogenes, and presents with perianal erythema and pruritus. Perianal cellulitis may spread to adjacent perineal structures, causing painful defecation and blood-tinged stools. Perianal cellulitis has been known to lead to guttate psoriasis. Prior to the development of a vaccine, Haemophilus influenzae caused facial cellulitis in young children. Necrotizing fasciitis is a rapidly progressing infection of the subcutaneous fascia.28 Predisposing factors include penetrating injuries, surgical procedures, childbirth and burns. It is most commonly caused by S. pyogenes, when it is also known as streptococcal gangrene. S. aureus, coliforms, Enterococcus, Pseudomonas, and Bacteroides are other etiologic agents. The extremities are most frequently involved. The initial presentation is severe pain, erythema and edema. Lesions evolve into violaceous, dusky plaques and necrosis of the overlying skin (see upper right panel of figure 3). The involved area becomes anesthetic. Bacteria causing necrotizing fasciitis complicated by streptococcal toxic shock syndrome are known as “flesh-eating” bacteria. Folliculitis is an infection of the hair follicle or pilosebaceous unit. Superficial folliculitis, or Bockhart’s impetigo, presents as dome-shaped, follicular pustules in the scalp, beard area, axillae, extremities, and buttocks. S. aureus most commonly causes folliculitis. Deep folliculitis in the bearded areas of the face and upper lip is known as sycosis barbae. This is associated with S. aureus colonization in the nares. Bacterial skin infections are a common complication of intravenous drug abuse (IVDA). Infections such as cellulitis, abscesses, necrotizing fasciitis, and septic thrombophlebitis may present atypically in IVDA. Subcutaneous injection, or “skin-popping,” leads to a linear distribution of staphylococcal pyoderma (see lower right panel of figure 3). Additional bacterial infections of the skin are acute paronychia, blistering distal dactylitis, and botryomycosis. Acute paronychia is infection of the epithelium lateral to the nail plate, and is usually caused by S. aureus. It presents as tender erythema and edema in the nailfold. Blistering distal dactylitis presents as tense, purulent blisters on the volar skin pad of distal fingers and toes. It usually occurs in children and is caused by S. pyogenes and, less frequently, S. aureus. Botryomycosis is a chronic, purulent and granulomatous infection of the lower extremities. Typical lesions are verrucous plaques, abscesses, and ulcers. Sinuses and fistulas discharge granules of bacteria. Toxin-mediated S. aureus and S. pyogenes Syndromes Staphylococcal scalded-skin syndrome (SSSS) is caused by exfoliative toxins A and B.29,30 These toxins are usually produced by phage group II S. aureus. Bullous impetigo results from local action of exfoliative toxins, while SSSS occurs through hematogenous dissemination of toxins. At present, it is unclear whether exfoliative toxins are superantigens. SSSS typically presents in children following conjunctivitis, otitis media, or nasopharyngeal infection. Fever and skin tenderness are prominent features. Nikolsky’s sign, which is the ability to split the epidermis by lateral pressure, is positive. Initial erythema progresses to large, flaccid bullae in the axillae, groin, and periorificial regions. Palms, soles and mucous membranes are spared. The process resolves with superficial desquamation over 5 to 7 days. Toxic shock syndrome (TSS) is a life-threatening, multiorgan system illness. An outbreak occurred in the United States from 1979 to 1982, mainly in women using superabsorbent tampons. TSS may be caused by either S. aureus or S. pyogenes. S. aureus produces TSS toxin 1 (TSST-1) and S. pyogenes produces streptococcal pyrogenic exotoxins A, B and C (SPE-A, SPE-B and SPE-C), streptococcal superantigen, and mitogenic factor. These toxins are superantigens, which bypass the usual major histocompatibility complex (MHC)-restricted antigen recognition process. Superantigens instead bind directly to MHC II on antigen-presenting cells and interact with the variable region of the b chain on T-cell receptors. This leads to widespread T-cell activation of up to 30% of resting T cells and the massive release of cytokines such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and interleukin-6 (IL-6). Massive cytokine release causes fever, hypotension, and diffuse erythema. The rash resembles scarlet fever and progresses to desquamation, especially of the palms and soles. Conjunctival injection and strawberry tongue are additional features. Scarlet fever is caused by a delayed-type hypersensitivity to streptococcal antigens. Previous exposure sensitizes the patient. Scarlet fever is characterized by an erythematous rash with 1-mm to 2-mm punctate papules on the trunk and extremities, known as the sandpaper rash. The exanthem is prominent at sites of pressure, such as the buttocks (see lower left panel of figure 3). The rash occurs 1 to 2 days after S. pyogenes pharyngitis, primarily in children. Fever, nausea, vomiting, and headache may be prominent. The antecubital fossae and axillary folds show a linear petechial eruption called Pastia’s lines. The “white-strawberry” tongue of scarlet fever is characterized by a white coating with reddened, hypertrophied papillae. In recent decades, the toxins SPE-B and SPE-C have been responsible for scarlet fever. S. aureus causes a similar toxin-mediated syndrome called staphylococcal scarlatiniform eruption. Pharyngitis and strawberry tongue are not present. Other Gram-Positive Skin Infections Erythrasma is a superficial infection of intertriginous areas, occurring more commonly in tropical climates.31 Corynebacterium minutissimum is the causative agent. The typical lesions are well-demarcated, brown, slightly scaling plaques. Erythrasma may also occur as keratotic macerated plaques in the web spaces of the feet. Wood’s lamp examination shows a coral-red fluorescence due to bacterial production of porphyrin. Pitted keratolysis is a superficial infection of the web spaces and plantar surface of the feet. Micrococcus sedentarius is probably the cause of pitted keratolysis, although Corynebacterium and Dermatophilus congolensis have also been implicated. The disease presents as discrete, crateriform pits on the plantar foot and eroded plaques in the web spaces. Trichomycosis axillaris and pubis are infections of the hair shaft caused by Corynebacterium. Hair shafts exhibit tan concretions, which may be malodorous. The concretions are composed of bacterial colonies. Erysipeloid is a localized cutaneous infection caused by Erysipelothrix rhusiopathiae, a gram-positive aerobic bacillus. E. rhusiopathiae may contaminate or infect animals and fish, exposing fishermen, butchers, and veterinarians. The infection is acquired following minor trauma to the skin and manifests as well-demarcated, red plaques with central clearing, usually on the hands. Bacillus anthracis is a gram-positive soil organism capable of forming endospores. Exposure to endospores leads to cutaneous and systemic infections known as anthrax. In the United States, infection has occurred in workers who handled animals or animal products.32 B. anthracis has been used as a biological weapon because of its robust spores and virulence factors.33 The first cases of cutaneous and inhalational anthrax due to bioterrorism were reported in 2001 in the United States. Cutaneous anthrax occurs following exposure to spores in cuts or abrasions. The initial skin lesion is a painless, pruritic papule, which undergoes central necrosis and progresses to a depressed, black eschar. Surrounding nonpitting edema is caused by edema toxin produced by the bacteria. Cutaneous anthrax is effectively treated by antibiotics and complications are uncommon. Gram-Negative Skin Infections Pseudomonas aeruginosa is a ubiquitous gram-negative rod that causes multiple cutaneous infections. Patients with Pseudomonas septicemia may develop ecthyma gangrenosum.34 The lesion presents as a gray, infarcted plaque and becomes a deep ulcer with a black eschar. Common sites of involvement are the groin and axillary region. Ecthyma gangrenosum is a complication in immunocompromised patients. “Hot tub folliculitis” occurs after uses of whirlpools, hot tubs and swimming pools. The characteristic lesions are erythematous papules and pustules on the trunk, buttocks and extremities. Lesions develop 8 hours to 48 hours after exposure and resolve in 7 day to 10 days. P. aeruginosa is a rare cause of toe-web infections and “green nails.” Decubitus ulcers and thermal burns may be secondarily infected by P. aeruginosa. Pasteurella multocida is a gram-negative coccobacillus that is present in the nasopharynx of dogs and cats.35 Bites from these animals lead to a local cellulitis with lymphadenitis. Complications include septic arthritis, tenosynovitis, and osteomyelitis. Capnocytophaga canimorsus, a gram-negative rod present in the oral flora of cats and dogs, causes infection after animal bites. The most common presentation is overwhelming sepsis in a patient with a predisposing condition such as splenectomy, trauma or Hodgkin’s disease.36 Bartonella are aerobic, fastidious, gram-negative rods that lead to multiple diseases.37 Cat-scratch disease, caused by Bartonella henselae, is transmitted by the bite or scratch of a cat. A papule develops at the site of trauma, usually on the head and neck, with lymphadenopathy occurring an average of 2 weeks later. Bacillary angiomatosis (BA) occurs in immunosuppressed patients. B. henselae and B. quintana are the etiologic agents. BA presents with pyogenic granuloma-like papules and nodules and lymphadenopathy. A low CD4 count is typical in BA patients. Helping Patients While the skin typically acts as a barrier to most bacterial infections, it’s important to note that infections do happen. Knowing how the skin is compromised and what signs to look for to diagnose infection helps us know how to best treat our patients.
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The skin acts as a barrier to pathogenic bacteria — research has shown that skin is effective at preventing growth and invasion of pathogenic organisms. Understanding how the microflora is invaded is important. In this article, authors George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D., offer an overview of how bacteria invade the normal microflora of the skin and discuss the common gram-positive and gram-negative bacterial infections that result. At the end of this article, you’ll find a 10-question exam you can dowload as a PDF. Mark your responses in the designated area, and fax page to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. Method of Participation: Physicians may receive two category 1 credits by reading the article and successfully answering the questions. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: April 2005 Expiration Date: April 2006 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: The North American Center for Continuing Medical Education (NACCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for the maximum of two category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: Drs. Murakawa and Aufiero have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. Dr. Murakawa receives grants/research support from Howard Hughes Medical Institute, NIH-NIAMS and the Dermatology Foundation. Learning Objectives: 1. Identify the type of microflora that inhabit skin. 2. Identify which skin disorders are associated with microbial infections. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None Microflora and Bacterial Infections of the Skin How bacteria invade the skin and an overview of the signs and symptoms of common gram-positive and gram-negative bacterial infections that result. By George J. Murakawa, M.D., Ph.D., and Barbara M. Aufiero, Ph.D. T he skin serves as a restrictive environment for microorganisms and provides a barrier to pathogenic bacteria. And, while studies have shown that skin is highly effective at using multiple mechanisms to prevent the growth and invasion of pathogenic organisms, skin infections can and do occur. Here, we’ll discuss the normal function of the skin and the complex series of events that must occur in order for bacteria to invade the normal microflora of the skin and get enough of a foothold to cause a bacterial infection. We’ll highlight the common gram-positive and gram-negative bacterial infections that do occur when this happens, and discuss the typical signs and symptoms that present with these infections. The Skin Barrier The stratum corneum, the outermost layer of the epidermis, provides a rigid barrier to the external environment. The sloughing of dead keratinocytes interferes with bacterial colonization. The skin’s low moisture content and indigenous microflora are critical components of antimicrobial defense. Most bacteria, especially gram-negative bacilli, require a relatively moist environment for replication. The lack of moisture in most areas of skin limits bacterial growth. Indigenous microflora protect the skin from pathogens. The pH of the skin may play a role in suppressing bacterial growth. Free fatty acids formed during cornification contribute to an acidic environment (pH 5).1 Most bacteria, such as Staphylococcus aureus, prefer a neutral pH. Finally, naturally occurring substances, such as lysozyme, cathelicidins and defensins, have antibacterial effects.2 Resistance to skin infections in patients with psoriasis may be related to the production of beta-defensin 2. In contrast, studies suggest that the lack of antimicrobial peptides leads to increased susceptibility to S. aureus skin infections in patients with atopic dermatitis.3 The skin is a privileged site for growth of microorganisms, and few bacteria are capable of surviving the environment of the skin, forming the cutaneous microflora.4 In utero, the skin is sterile, and colonization by bacteria occurs after birth. Bacterial adherence is necessary for colonization and occurs through specific molecular structures called adhesins.5 The nature of bacterial growth is dependent on anatomic location, local humidity, sebum and sweat production, and the host’s hormonal status and age. Bacteria may develop a commensal, symbiotic, or parasitic relationship with the host. Microflora exert both direct and indirect effects on pathogenic bacteria. Commensals produce antimicrobial substances, such as bacteriocin and toxic metabolites, which directly inhibit pathogens. Furthermore, commensals compete with pathogens for nutrients, niches and receptors. Staphylococcus epidermidis binds keratinocyte receptors, blocking adherence by S. aureus, a process known as bacterial interference.6,7 Microflora also indirectly affect pathogens by stimulating the immune system. Their presence may enhance antibody production, stimulate phagocytosis and increase cytokine production. Gram-Positive Bacteria and Skin Flora Gram-positive bacteria form the major component of normal skin flora in humans.8,9 The three major groups of gram-positive bacteria found on skin are Staphylococcus, Micrococcus and coryneform bacteria (See table 1).10 These bacteria are able to survive the relatively dry environment of the skin. Gram-negative bacteria are rarely found on normal skin. Acinetobacter, which are gram-negative bacilli, may be present in intertriginous areas such as the axilla and perineum. Occlusion in these areas increases the relative humidity, permitting growth of gram-negative bacteria. Figure 1 shows bacterial growth from the arm and axilla. Bacterial growth was significantly greater from the axilla than from the arm. Staphylococcus are gram-positive cocci that occur in microscopic clusters resembling grapes. Species of Staphylococcus are categorized by their ability to produce coagulase, an enzyme that allows bacteria to resist phagocytosis. Staphylococcus found on skin are coagulase-negative and usually nonpathogenic. Coagulase-negative staphylococci may occasionally cause nosocomial infections in patients with indwelling catheters through adherence to the plastic. Staphylococcus epidermidis, S. hominis, and S. haemolyticus are the most abundant species on the skin. Micrococcus are gram-positive cocci that may be abundant on the skin in some individuals. Micrococcus are differentiated from Staphylococcus by resistance to lysostaphin and nitrofuran. The most common species is Micrococcus luteus. M. sedentarius is the causative agent of pitted keratolysis, but most species are nonpathogenic. Coryneforms are gram-positive bacilli. There are four genera that are found in the microflora: Corynebacterium, Propionibacterium, Dermabacter and Brevibacterium. Propionibacterium is an anaerobic coryneform, which, therefore, grows deep in adnexal structures. They are associated with acne vulgaris, but are not directly causal. Dermabacter and Brevibacterium are found in glabrous, humid skin such as the toewebs. Brevibacterium cause “foot odor” by the production of methane thiol. Pathogenesis of Skin Infections The basic tenet is that in order for skin infections to occur, pathogenic bacteria must be able to adhere to skin, invade the local environment (perhaps, intracellularly), and grow on the skin (see figure 2). Independently, the skin elicits a specific response toward the bacteria. Through specific receptors, bacteria activate a signaling pathway, which elicits a molecular response and subsequent acute and chronic cellular responses (see figure 2). Solitary or multiple pathways can be elicited simultaneously, and activation of a specific pathway is dependent on the pathogenic bacteria itself. Bacterial skin pathogens must compete against commensal bacteria and circumvent host defense mechanisms in order to cause skin infections. Pathogens compete, in part, by utilizing different host signaling pathways.11 The majority of cases are caused by bacteria such as S. aureus or Streptococcus pyogenes.4 Pathogens establish infection through the expression of virulence gene products that promote bacterial adherence and invasion. S. aureus mediates adherence to host cells through surface receptor molecules, some of which display techoic acid sensitivity.12 Many of the implicated receptors belong to the MSCRAMMs (microbial surface components recognizing adhesive matrix molecules)13-15 family of proteins, such as fibronectin-binding protein,16,17 collagen-binding protein18 and fibrinogen-binding protein.17,19,20 Plasmin-sensitive surface protein (Pls) adheres to keratinocyte lipids and glycoproteins,21 and protein A7,16 is involved in adherence. In fact, suggestive evidence indicates that more than one, and probably many, surface proteins are capable of mediating host cell attachment.16,22 Invasion by S. aureus requires the cooperation of the host cytoskeletal elements22,23 and long incubation times in certain host cells. The skin is comprised of several cell types, each of which has unknown potential to sponsor bacterial growth. Our laboratory studies the ability of S. aureus to adhere to and invade the skin cell types, including keratinocytes and macrophages. Adherence occurred within 5 minutes and was high in all skin cell types. S. aureus invasion displayed different characteristics that varied among cell types. Macrophages, which are professional phagocytes, ingested maximal levels of bacteria (30% to 35%) within a short period of time (5 minutes to 60 minutes). In contrast, fewer bacteria were found within keratinocytes (2% to 4% in 4 hours). These data indicate that skin cells found in the epidermis and dermis are potential targets for the establishment of S. aureus infection.22 Infections Caused by S. aureus and S. pyogenes Staphylococcus aureus is the most common cause of cutaneous bacterial infections (see table 2). It’s not part of the normal microflora of skin, but may transiently colonize the skin of newborn infants, the anterior nares (in 35% of the population), the perineum (20%), and the skin of atopic patients.24 HIV-infected patients are particularly susceptible to S. aureus infections, and this may be a consequence of increased nasal carriage. Streptococcus species are the second most common cause of cutaneous bacterial infections (see table 3).25 The Lancefield scheme, based on C carbohydrate antigens in the cell wall, classifies Streptococcus species into groups A to T. The major human pathogens belong to groups A, B, C, D and G. Group A streptococci are organized into subtypes based on their M-proteins, which are virulent antigens that interfere with phagocytosis, promote bacterial adherence to host cells and aid bacterial growth in human blood. Streptococcus pyogenes, the only member of group A, is the most invasive of this species. S. pyogenes is not part of the normal microflora, but may colonize the upper respiratory tract of children and adults. Impetigo is a superficial bacterial infection, occurring just below the stratum corneum.26 The most common causative agents are S. aureus in industrialized countries and S. pyogenes in developing countries. It frequently occurs in children as well as adults. There are two clinical variants: bullous and nonbullous. Nonbullous impetigo is the more common variant and occurs on the face and extremities. Infection only occurs after trauma to the skin because intact skin is resistant to colonization and impetiginization. The initial papules, pustules and vesicles evolve into honey-colored crusted erosions. Lesions are painless and constitutional symptoms are rare. Regional lymphadenopathy may be prominent. Acute glomerulonephritis is a complication in up to 5% of patients with streptococcal impetigo. Bullous impetigo is only caused by S. aureus (see upper left panel of figure 3). The lesions begin as flaccid bullae that rupture, leaving eroded plaques with a collarette of scale. Lymphadenopathy does not occur.4 The subcorneal pustules of bullous impetigo are caused by exfoliative toxin A, which cleaves desmoglein 1, a component of the desmosomes linking keratinocytes.27 Untreated impetigo may extend into the dermis, causing ecthyma. Crusted plaques develop into punched out ulcers with indurated margins. Ecthyma usually occurs on the lower extremities of children, the elderly, and patients with diabetes. Ecthyma is caused by S. aureus and S. pyogenes. Erysipelas is an acute dermal infection with significant dermal lymphatic vessel involvement. Group A Streptococcus is the most common etiologic agent. Rarely, group B, C, and G Streptococcus and S. aureus can cause erysipelas. The face and lower extremities are the most frequent sites of involvement. Lesions are tender, erythematous, edematous plaques with a sharply demarcated margin. Blisters may form in the involved area, leading to local gangrene. Systemic symptoms of malaise, fever, chills, and local pain are common. Erysipelas typically has an uncomplicated course. Rarely, abscess, septicemia and cavernous sinus thrombosis may occur. Cellulitis is a deep soft tissue infection involving the dermis and subcutaneous tissue. S. aureus and S. pyogenes are the most common causative agents, although the organism is rarely isolated. Impaired lymphatic drainage and stasis dermatitis are predisposing factors. Skin lesions, including psoriasic, eczema and tinea, provide portals of entry for pathogens. The leg is the most frequent site of involvement, followed by the arm and face. Cellulitis is characterized by warm, indurated plaques that lack distinct margins. Fluctuance and crepitus on palpation may be appreciated. Cellulitis may be accompanied by fever, chills, and regional lymphadenopathy. Complications include thrombophlebitis, local abscesses, necrotizing fasciitis, and septicemia. Two variants of cellulitis occur in children. Perianal cellulitis is caused by S. pyogenes, and presents with perianal erythema and pruritus. Perianal cellulitis may spread to adjacent perineal structures, causing painful defecation and blood-tinged stools. Perianal cellulitis has been known to lead to guttate psoriasis. Prior to the development of a vaccine, Haemophilus influenzae caused facial cellulitis in young children. Necrotizing fasciitis is a rapidly progressing infection of the subcutaneous fascia.28 Predisposing factors include penetrating injuries, surgical procedures, childbirth and burns. It is most commonly caused by S. pyogenes, when it is also known as streptococcal gangrene. S. aureus, coliforms, Enterococcus, Pseudomonas, and Bacteroides are other etiologic agents. The extremities are most frequently involved. The initial presentation is severe pain, erythema and edema. Lesions evolve into violaceous, dusky plaques and necrosis of the overlying skin (see upper right panel of figure 3). The involved area becomes anesthetic. Bacteria causing necrotizing fasciitis complicated by streptococcal toxic shock syndrome are known as “flesh-eating” bacteria. Folliculitis is an infection of the hair follicle or pilosebaceous unit. Superficial folliculitis, or Bockhart’s impetigo, presents as dome-shaped, follicular pustules in the scalp, beard area, axillae, extremities, and buttocks. S. aureus most commonly causes folliculitis. Deep folliculitis in the bearded areas of the face and upper lip is known as sycosis barbae. This is associated with S. aureus colonization in the nares. Bacterial skin infections are a common complication of intravenous drug abuse (IVDA). Infections such as cellulitis, abscesses, necrotizing fasciitis, and septic thrombophlebitis may present atypically in IVDA. Subcutaneous injection, or “skin-popping,” leads to a linear distribution of staphylococcal pyoderma (see lower right panel of figure 3). Additional bacterial infections of the skin are acute paronychia, blistering distal dactylitis, and botryomycosis. Acute paronychia is infection of the epithelium lateral to the nail plate, and is usually caused by S. aureus. It presents as tender erythema and edema in the nailfold. Blistering distal dactylitis presents as tense, purulent blisters on the volar skin pad of distal fingers and toes. It usually occurs in children and is caused by S. pyogenes and, less frequently, S. aureus. Botryomycosis is a chronic, purulent and granulomatous infection of the lower extremities. Typical lesions are verrucous plaques, abscesses, and ulcers. Sinuses and fistulas discharge granules of bacteria. Toxin-mediated S. aureus and S. pyogenes Syndromes Staphylococcal scalded-skin syndrome (SSSS) is caused by exfoliative toxins A and B.29,30 These toxins are usually produced by phage group II S. aureus. Bullous impetigo results from local action of exfoliative toxins, while SSSS occurs through hematogenous dissemination of toxins. At present, it is unclear whether exfoliative toxins are superantigens. SSSS typically presents in children following conjunctivitis, otitis media, or nasopharyngeal infection. Fever and skin tenderness are prominent features. Nikolsky’s sign, which is the ability to split the epidermis by lateral pressure, is positive. Initial erythema progresses to large, flaccid bullae in the axillae, groin, and periorificial regions. Palms, soles and mucous membranes are spared. The process resolves with superficial desquamation over 5 to 7 days. Toxic shock syndrome (TSS) is a life-threatening, multiorgan system illness. An outbreak occurred in the United States from 1979 to 1982, mainly in women using superabsorbent tampons. TSS may be caused by either S. aureus or S. pyogenes. S. aureus produces TSS toxin 1 (TSST-1) and S. pyogenes produces streptococcal pyrogenic exotoxins A, B and C (SPE-A, SPE-B and SPE-C), streptococcal superantigen, and mitogenic factor. These toxins are superantigens, which bypass the usual major histocompatibility complex (MHC)-restricted antigen recognition process. Superantigens instead bind directly to MHC II on antigen-presenting cells and interact with the variable region of the b chain on T-cell receptors. This leads to widespread T-cell activation of up to 30% of resting T cells and the massive release of cytokines such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and interleukin-6 (IL-6). Massive cytokine release causes fever, hypotension, and diffuse erythema. The rash resembles scarlet fever and progresses to desquamation, especially of the palms and soles. Conjunctival injection and strawberry tongue are additional features. Scarlet fever is caused by a delayed-type hypersensitivity to streptococcal antigens. Previous exposure sensitizes the patient. Scarlet fever is characterized by an erythematous rash with 1-mm to 2-mm punctate papules on the trunk and extremities, known as the sandpaper rash. The exanthem is prominent at sites of pressure, such as the buttocks (see lower left panel of figure 3). The rash occurs 1 to 2 days after S. pyogenes pharyngitis, primarily in children. Fever, nausea, vomiting, and headache may be prominent. The antecubital fossae and axillary folds show a linear petechial eruption called Pastia’s lines. The “white-strawberry” tongue of scarlet fever is characterized by a white coating with reddened, hypertrophied papillae. In recent decades, the toxins SPE-B and SPE-C have been responsible for scarlet fever. S. aureus causes a similar toxin-mediated syndrome called staphylococcal scarlatiniform eruption. Pharyngitis and strawberry tongue are not present. Other Gram-Positive Skin Infections Erythrasma is a superficial infection of intertriginous areas, occurring more commonly in tropical climates.31 Corynebacterium minutissimum is the causative agent. The typical lesions are well-demarcated, brown, slightly scaling plaques. Erythrasma may also occur as keratotic macerated plaques in the web spaces of the feet. Wood’s lamp examination shows a coral-red fluorescence due to bacterial production of porphyrin. Pitted keratolysis is a superficial infection of the web spaces and plantar surface of the feet. Micrococcus sedentarius is probably the cause of pitted keratolysis, although Corynebacterium and Dermatophilus congolensis have also been implicated. The disease presents as discrete, crateriform pits on the plantar foot and eroded plaques in the web spaces. Trichomycosis axillaris and pubis are infections of the hair shaft caused by Corynebacterium. Hair shafts exhibit tan concretions, which may be malodorous. The concretions are composed of bacterial colonies. Erysipeloid is a localized cutaneous infection caused by Erysipelothrix rhusiopathiae, a gram-positive aerobic bacillus. E. rhusiopathiae may contaminate or infect animals and fish, exposing fishermen, butchers, and veterinarians. The infection is acquired following minor trauma to the skin and manifests as well-demarcated, red plaques with central clearing, usually on the hands. Bacillus anthracis is a gram-positive soil organism capable of forming endospores. Exposure to endospores leads to cutaneous and systemic infections known as anthrax. In the United States, infection has occurred in workers who handled animals or animal products.32 B. anthracis has been used as a biological weapon because of its robust spores and virulence factors.33 The first cases of cutaneous and inhalational anthrax due to bioterrorism were reported in 2001 in the United States. Cutaneous anthrax occurs following exposure to spores in cuts or abrasions. The initial skin lesion is a painless, pruritic papule, which undergoes central necrosis and progresses to a depressed, black eschar. Surrounding nonpitting edema is caused by edema toxin produced by the bacteria. Cutaneous anthrax is effectively treated by antibiotics and complications are uncommon. Gram-Negative Skin Infections Pseudomonas aeruginosa is a ubiquitous gram-negative rod that causes multiple cutaneous infections. Patients with Pseudomonas septicemia may develop ecthyma gangrenosum.34 The lesion presents as a gray, infarcted plaque and becomes a deep ulcer with a black eschar. Common sites of involvement are the groin and axillary region. Ecthyma gangrenosum is a complication in immunocompromised patients. “Hot tub folliculitis” occurs after uses of whirlpools, hot tubs and swimming pools. The characteristic lesions are erythematous papules and pustules on the trunk, buttocks and extremities. Lesions develop 8 hours to 48 hours after exposure and resolve in 7 day to 10 days. P. aeruginosa is a rare cause of toe-web infections and “green nails.” Decubitus ulcers and thermal burns may be secondarily infected by P. aeruginosa. Pasteurella multocida is a gram-negative coccobacillus that is present in the nasopharynx of dogs and cats.35 Bites from these animals lead to a local cellulitis with lymphadenitis. Complications include septic arthritis, tenosynovitis, and osteomyelitis. Capnocytophaga canimorsus, a gram-negative rod present in the oral flora of cats and dogs, causes infection after animal bites. The most common presentation is overwhelming sepsis in a patient with a predisposing condition such as splenectomy, trauma or Hodgkin’s disease.36 Bartonella are aerobic, fastidious, gram-negative rods that lead to multiple diseases.37 Cat-scratch disease, caused by Bartonella henselae, is transmitted by the bite or scratch of a cat. A papule develops at the site of trauma, usually on the head and neck, with lymphadenopathy occurring an average of 2 weeks later. Bacillary angiomatosis (BA) occurs in immunosuppressed patients. B. henselae and B. quintana are the etiologic agents. BA presents with pyogenic granuloma-like papules and nodules and lymphadenopathy. A low CD4 count is typical in BA patients. Helping Patients While the skin typically acts as a barrier to most bacterial infections, it’s important to note that infections do happen. Knowing how the skin is compromised and what signs to look for to diagnose infection helps us know how to best treat our patients.
