Pathologic Characteristics and Pathogenesis.

Histopathologically, impetigo consists of superficial, intraepidermal, unilocular vesicopustules. In epidemiologic studies, group A streptococcal acquisition on normal skin antedates the appearance of impetigo by about 10 days.³ During that time, minor trauma (e.g., insect bite, abrasion) or primary dermatoses predispose to the development of infected lesions. Impetigo is most common during hot, humid summer weather. Two to 3 weeks after skin acquisition of streptococci, pharyngeal colonization by the same organism occurs in about 30% of children with skin lesions. (The sporadic cases of facial impetigo occurring in cooler climates probably result from contiguous spread from an initial nasopharyngeal infection, and the serotypes involved are those commonly causing pharyngeal disease.) In staphylococcal impetigo (in which S. aureus is the only pathogen), skin infection follows nasal colonization.^5,6 Among returning travelers, impetigo is commonly associated with antecedent insect bites.⁷

Nonbullous impetigo caused by group A streptococcus (Streptococcus pyogenes) begins when the corneal layer of the epidermis is disrupted and the bacteria gain access to highly differentiated subcorneal keratinocytes. Impetigo strains, but not pharyngeal strains, of S. pyogenes preferentially bind to differentiated keratinocytes,⁸ mediated by S. pyogenes M protein.⁹ A second streptococcal surface protein (protein F, fibronectin-binding protein), mediates adherence to antigen-presenting Langerhans’ cells located along the basal layer of the epidermis. Staphylococcal infection usually develops after nasal or skin colonization. Bacteriocin production may inhibit competing commensal flora, and several virulence factors have been proposed to enhance adhesion to epithelial cells and to underlying matrix proteins.¹⁰ Surprisingly, the production of exfoliative toxins A and B has been associated with both nonbullous and bullous impetigo; Panton-Valentine leukocidin is generally absent among staphylococcal impetigo isolates.⁵ Impetigo is a highly communicable infection. Spread in families (particularly among preschool-aged children) is facilitated by crowding and poor hygiene.

Clinical Manifestations.

Streptococcal impetigo begins on exposed areas as small vesicles, sometimes with narrow inflammatory halos, that rapidly pustulate and readily rupture. The purulent discharge dries and forms the characteristic thick, golden-yellow, “stuck-on” crusts. Pruritus is common, and scratching of lesions can spread infection. Occasionally, large crusts are produced by coalescence of smaller pustules. The lesions remain superficial and do not ulcerate or infiltrate the dermis; mild regional lymphadenopathy is common. Healing generally occurs without scarring. The lesions are painless, and constitutional manifestations are minimal.

Laboratory Findings.

Gram-stained smears of vesicles show gram-positive cocci. Culture of exudate beneath an unroofed crust reveals S. aureus, group A streptococci, or a mixture of streptococci and S. aureus. The anti–streptolysin O titer after streptococcal impetigo is scant, probably related to inhibition of streptolysin O by skin lipids at the infection site. In contrast, the anti–DNase B response readily occurs after streptococcal impetigo (with elevated titers in 90% of patients with nephritis complicating streptococcal skin infections).¹¹

Etiologic Agents.

The group A streptococci responsible for impetigo usually belong to different M serotypes from those of strains that produce pharyngitis. M surface proteins, which are key virulence factors, are encoded in emm genes. Five major emm chromosomal patterns (groups A through E) have been described based on nucleotide sequences encoding part of the peptidoglycan-spanning M protein domain.¹² Almost all group A streptococcal impetigo isolates belong to emm chromosomal patterns D and, to a lesser extent, E, whereas most isolates from patients with uncomplicated pharyngitis or acute rheumatic fever belong to emm chromosomal pattern group A, B, or C. Groups C and G streptococci may rarely cause impetigo; group B streptococci have been associated with impetigo in neonates. The rising incidence of MRSA impetigo has been associated with both hospital- and community-acquired strains.⁵

Differential Diagnosis.

Although the initial vesicular lesions may resemble early varicella, the crusts of impetigo are darker brown and harder. The central clearing of a confluent cluster of lesions of impetigo may suggest tinea circinata but can be distinguished by the thick crusts, which are not formed in the fungus infection. When the vesicles of herpes simplex become turbid, they may resemble those of impetigo. Distinguishing between herpes simplex and impetigo is important because irritation from topical therapy may exacerbate primary herpes simplex lesions. Acute palmoplantar pustulosis, a sterile, idiopathic, self-limited pustular eruption on the palms and soles that sometimes occurs after pharyngitis, may initially resemble impetigo.¹³ Localized acute pustular psoriasis may also be mistaken for impetigo. Primary cutaneous listeriosis, an occupational disease of veterinarians and farmers involved in calving, is characterized by papulovesicular and pustular lesions on the forearms that may resemble those of impetigo.¹⁴ Atopic or contact dermatitis, discoid lupus erythematosus, and infestations such as scabies may mimic impetigo or develop secondary impetiginization.¹⁵

Presumptive Therapy.

Penicillin was the classic drug of choice for the treatment of impetigo, because of the predominant role of group A streptococci and the subsequent risk for acute glomerulonephritis. Because mixed streptococcal-staphylococcal or staphylococcal impetigo is clinically indistinguishable from streptococcal impetigo, and S. aureus, either alone or in concert with S. pyogenes, currently is the predominant cause of impetigo, primary therapy must be revised accordingly. Penicillinase-resistant oral penicillins (e.g., dicloxacillin or amoxicillin-clavulanate) or cephalosporins (e.g., cephalexin, cefa­droxil) are generally effective for treating methicillin-sensitive strains of S. aureus as well as S. pyogenes. The relative incidence of MRSA (vs. methicillin-susceptible S. aureus [MSSA]) causing impetigo is not well established. Erythromycin or newer macrolides generally are reserved for β-lactam–allergic patients. The efficacy of macrolides may be reduced in areas in which erythromycin-resistant staphylococci and streptococci are prevalent. Local care (removal of crusts by soaking with soap and water) is helpful. Patients with extensive disease should undergo wound culture and reevaluation after an initial trial of oral therapy. The presence of MRSA must be strongly considered if there is a poor initial response to therapy, even if no culture data are available, and empirical therapy must be broadened (see later). Co-trimoxazole has excellent activity against community-acquired MRSA, and in vitro data support its possible use against S. pyogenes as well, although clinical data are lacking.¹⁶ Clindamycin and macrolides have variable efficacy against many community-acquired MRSA isolates. Topical antibiotic therapy may be considered when treating limited impetigo, including that caused by MRSA.

Topical mupirocin ointment in a polyethylene glycol base is as effective as oral erythromycin for the treatment of impetigo¹⁷ and is more effective when treating erythromycin-resistant S. aureus.¹⁸ In the past decade, the incidence of mupirocin resistance among S. aureus isolates has been rising slowly but steadily. A second topical antibiotic, retapamulin ointment, is approved for the treatment of impetigo. This is the first of a novel class of bacterial protein synthesis inhibitors (pleuromutilins) and is effective against S. aureus and Streptococcus pyogenes independent of other antibiotic susceptibilities.¹⁹ Fusidic acid cream is available in Europe and is effective in treating childhood impetigo (primarily S. aureus), but rising resistance rates² and policies to restrict its applicability for systemic infection have limited its use. Gentle application of topical agents is important to minimize tissue maceration and spread of infection. Systemic therapy is preferred when treating widespread impetigo. Close follow-up of patients is important because of rising rates of resistance to these topical and systemic agents.

Mupirocin has also been used topically to eradicate MRSA from secondarily infected skin lesions and from colonized patients. However, because resistance in S. aureus strains has emerged sooner than anticipated after the introduction of mupirocin,¹⁸ particularly when long-term therapy was used, prolonged administration should probably be avoided.