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CATEGORY	DETAILS
RISK FACTORS	Neonates and children under 2 years, warm and humid climates, crowded living conditions, poor hygiene, disrupted skin barrier (eczema, insect bites, minor trauma), daycare attendance
ETIOLOGY	Staphylococcus aureus (phage group II) producing exfoliative toxins A and B (ETA/ETB) that cause localized epidermal cleavage
PATIENT PRESENTATION	Parent brings a young child with "blisters that keep popping and spreading." The child is afebrile and nontoxic-appearing. Lesions started as small vesicles that rapidly enlarged into flaccid, fluid-filled blisters
CLASSIC PHYSICAL EXAM	Large (1 to 2 cm), flaccid bullae containing clear-to-yellow fluid on the trunk, extremities, or diaper area. Ruptured bullae leave a "varnished" or "collarette" erosion with a peripheral rim of scale. Nikolsky sign is negative. No mucosal involvement. No lymphadenopathy
KEY DIAGNOSTIC RESULTS	Gram stain and culture of blister fluid showing gram-positive cocci in clusters (S. aureus). Biopsy (rarely needed) shows subcorneal or intragranular cleavage with neutrophils
MANAGEMENT	Localized disease: topical mupirocin 2% three times daily for 5 to 7 days. Extensive or refractory disease: oral cephalexin or dicloxacillin for 7 days. If MRSA is suspected: oral TMP-SMX or clindamycin. Neonatal or systemic involvement: IV nafcillin/oxacillin (or vancomycin if MRSA)
KEYWORDS	"Flaccid bullae," "collarette of scale," "varnished erosion," "S. aureus," "exfoliative toxin," "neonate with blisters," "Nikolsky-negative," "subcorneal split"

1. Pathophysiology

Bullous impetigo is a localized, toxin-mediated infection of the superficial epidermis caused exclusively by Staphylococcus aureus. Unlike non-bullous impetigo, which can be caused by either S. aureus or Group A Streptococcus, the bullous form is always staphylococcal. This distinction is high-yield.

The pathogenic strains belong to phage group II (most commonly type 71) and produce exfoliative toxins A and B (ETA and ETB). These toxins function as serine proteases that selectively cleave desmoglein 1 (Dsg1), a desmosomal cadherin responsible for cell-to-cell adhesion in the granular layer of the epidermis. The cleavage of Dsg1 causes loss of keratinocyte adhesion (acantholysis) at the subcorneal or intragranular level, resulting in the formation of a superficial intraepidermal blister.

This mechanism directly explains the clinical presentation. Because the split occurs very superficially, the resulting bullae have thin, fragile roofs that rupture easily. After rupture, the base appears shiny and eroded, a finding described as a "varnished" or "lacquered" appearance surrounded by a collarette of residual scale from the collapsed blister roof. The Nikolsky sign is negative because the toxin acts locally at the site of bacterial colonization, not systemically. The surrounding normal skin has intact desmoglein and will not shear with lateral pressure.

This same exfoliative toxin mechanism underlies Staphylococcal Scalded Skin Syndrome (SSSS), but in SSSS, the toxin is produced at a distant site and reaches the skin hematogenously, causing widespread, generalized epidermal cleavage with a positive Nikolsky sign. Bullous impetigo, by contrast, represents the localized end of the exfoliative toxin disease spectrum. Understanding this spectrum is the key to distinguishing these two conditions on an exam.

The reason neonates and young children are disproportionately affected relates to two factors. First, they lack anti-exfoliative toxin antibodies that older children and adults develop over time. Second, their immature renal clearance means they are less efficient at clearing circulating toxin, increasing vulnerability if the disease begins to extend beyond localized infection.

2. Classification and Clinical Manifestation

Bullous impetigo falls within the broader classification of impetigo. The table below contrasts its two primary forms, which is a commonly tested comparison.

FEATURE	NON-BULLOUS IMPETIGO	BULLOUS IMPETIGO
FREQUENCY	~70% of cases	~30% of cases
CAUSATIVE ORGANISM	S. aureus or Group A Streptococcus (GAS)	S. aureus only (phage group II)
MECHANISM	Direct bacterial invasion of epidermis	Exfoliative toxin (ETA/ETB) cleaving desmoglein 1
TYPICAL AGE	2 to 5 years	Neonates and children under 2 years
PRIMARY LESION	Small vesicles/pustules on an erythematous base	Large (1 to 2 cm) flaccid bullae with clear-to-yellow fluid
CLASSIC APPEARANCE AFTER RUPTURE	"Honey-crusted" golden yellow lesions	"Varnished" erosion with collarette of scale
COMMON LOCATION	Face (perioral, perinasal), extremities	Trunk, extremities, intertriginous/diaper area
NIKOLSKY SIGN	Negative	Negative
LYMPHADENOPATHY	May be present (regional)	Usually absent
MUCOSAL INVOLVEMENT	No	No
SYSTEMIC SYMPTOMS	Rare	Rare (unless progressing toward SSSS in neonates)
RISK OF POST-STREPTOCOCCAL GLOMERULONEPHRITIS	Yes (if GAS etiology, nephritogenic strains)	No (S. aureus does not cause PSGN)

A critical pearl from this table: only non-bullous impetigo caused by nephritogenic strains of GAS carries a risk of post-streptococcal glomerulonephritis (PSGN). Bullous impetigo, being purely staphylococcal, never leads to PSGN. However, neither form of impetigo causes acute rheumatic fever, because impetigo-associated GAS strains are non-rheumatogenic. This is a frequently tested distinction.

3. Diagnostic Workup

TEST	ROLE	EXPECTED FINDINGS
CLINICAL DIAGNOSIS	Primary method; most cases diagnosed by appearance	Flaccid bullae or collarette erosions in a young child in typical distribution
GRAM STAIN OF BLISTER FLUID	Best initial confirmatory test	Gram-positive cocci in clusters
CULTURE OF BLISTER FLUID	Most accurate test / Gold standard	Growth of S. aureus; allows sensitivity testing
SKIN BIOPSY	Rarely indicated; used when diagnosis is uncertain	Subcorneal or intragranular split with neutrophilic infiltrate; acantholytic cells at cleavage plane
ANTI-STREPTOLYSIN O (ASO) / ANTI-DNASE B	Not indicated for bullous impetigo	Would be negative (no GAS involvement)

In the vast majority of clinical scenarios, bullous impetigo is a clinical diagnosis based on the characteristic morphology of flaccid bullae or post-rupture collarette erosions in a neonate or young child. The exam vignette will describe the lesion appearance, and you are expected to recognize it and initiate treatment without further testing.

When the question asks for the best initial test to confirm the organism, the answer is Gram stain and culture of fluid aspirated from an intact bulla. This is the ideal specimen because the blister fluid in bullous impetigo contains viable bacteria (unlike SSSS, where the bullae are sterile because the toxin arrives hematogenously). Gram stain will show gram-positive cocci in clusters, and culture will confirm S. aureus and provide antibiotic sensitivities.

If the question stem presents a diagnostically ambiguous case (for example, a child with blistering that could represent bullous impetigo, SSSS, pemphigus, or bullous pemphigoid), the most accurate test is a skin biopsy. Histopathology in bullous impetigo shows a subcorneal or intragranular split (cleavage within or just below the granular layer) with neutrophils and acantholytic keratinocytes. Direct immunofluorescence will be negative, which distinguishes it from autoimmune blistering diseases like pemphigus vulgaris (which shows intercellular IgG/"fishnet" pattern) or bullous pemphigoid (which shows linear IgG/C3 at the basement membrane zone).

A high-yield distinction for the workup: if you culture the blister fluid in bullous impetigo, it grows S. aureus. If you culture the blister fluid in SSSS, it is sterile. The reason is that in SSSS, the blistering is caused by toxin that has spread through the bloodstream from a remote focus (nasopharynx, umbilicus, or wound), not from local bacterial presence in the skin.

4. Management and Treatment

CLINICAL SCENARIO	TREATMENT	DOSE / REGIMEN	DURATION
LOCALIZED DISEASE (few lesions)	Topical mupirocin 2% ointment	Apply to lesions three times daily	5 to 7 days
LOCALIZED DISEASE (alternative)	Topical retapamulin 1% ointment	Apply to lesions twice daily	5 days
EXTENSIVE DISEASE (many lesions, spreading)	Oral cephalexin	25 to 50 mg/kg/day divided into 3 to 4 doses (pediatric); 250 to 500 mg four times daily (adult)	7 days
EXTENSIVE DISEASE (alternative)	Oral dicloxacillin	12.5 to 25 mg/kg/day divided into 4 doses (pediatric); 250 to 500 mg four times daily (adult)	7 days
SUSPECTED MRSA	Oral TMP-SMX or oral clindamycin	TMP-SMX: 8 to 12 mg/kg/day of TMP component divided twice daily; Clindamycin: 20 to 30 mg/kg/day divided 3 times daily	7 to 10 days
NEONATAL OR SYSTEMIC INVOLVEMENT	IV nafcillin or oxacillin	Nafcillin: 100 to 200 mg/kg/day IV divided every 6 hours	7 to 10 days (or per clinical response)
NEONATAL / SYSTEMIC WITH MRSA RISK	IV vancomycin	15 mg/kg/dose IV every 6 to 8 hours (adjusted to trough levels)	7 to 10 days

Acute management begins with gentle wound care. Parents should be instructed to wash affected areas with mild soap and water and remove crusts with warm compresses before applying topical antibiotics. This improves drug penetration and reduces bacterial burden.

For localized disease with only a few lesions, topical mupirocin 2% applied three times daily for 5 to 7 days is the first-line treatment. Mupirocin works by inhibiting bacterial isoleucyl-tRNA synthetase, which is a unique mechanism that avoids cross-resistance with systemic antibiotics. Retapamulin is an acceptable alternative but is less commonly tested. Topical fusidic acid is used in some regions but is not a standard answer in most licensing exam contexts.

When the disease is extensive (defined as numerous lesions, rapid spread, or involvement of multiple body areas), oral systemic antibiotics are required. The first-line choice is a beta-lactamase-resistant penicillin or first-generation cephalosporin: cephalexin or dicloxacillin. These cover methicillin-sensitive S. aureus (MSSA), which remains the most common cause. If the vignette provides risk factors for MRSA (recent hospitalization, prior MRSA infection, failure of initial therapy, high community MRSA prevalence), switch to TMP-SMX or clindamycin.

For neonates or any patient with signs of systemic toxicity (fever, irritability, poor feeding, widespread involvement), the next best step is hospitalization with IV antibiotics. The standard regimen is IV nafcillin or oxacillin for MSSA coverage. If MRSA is suspected or the patient is critically ill, IV vancomycin is used with dosing adjusted to trough levels (target 10 to 15 mcg/mL in standard infections).

An important contraindication: do not use topical therapy alone in neonates, even if the disease appears localized. Neonates are at higher risk of rapid progression to SSSS or bacteremia due to their immature immune system and poor renal toxin clearance. Any bullous impetigo in a neonate should prompt a lower threshold for systemic antibiotics and close monitoring.

Long-term management includes decolonization strategies for recurrent cases. This involves intranasal mupirocin twice daily for 5 days and chlorhexidine body washes to reduce S. aureus carriage. Household contacts may also require decolonization if recurrence is a problem.

5. Differential Diagnosis and Distractors

DIFFERENTIAL	WHY IT IS SIMILAR	KEY DISCRIMINATOR
Staphylococcal Scalded Skin Syndrome (SSSS)	Same toxin mechanism (exfoliative toxin cleaving Dsg1); same organism (S. aureus); occurs in neonates/young children	SSSS is generalized with diffuse erythema and positive Nikolsky sign. Blister fluid is sterile (toxin-mediated, not local infection). The child appears systemically ill. Bullous impetigo is localized with negative Nikolsky sign and culture-positive blister fluid
Non-bullous impetigo	Both are forms of impetigo in children with superficial skin infection	Non-bullous impetigo presents with honey-crusted lesions, not flaccid bullae. Can be caused by GAS (risk of PSGN), while bullous form is only S. aureus
Pemphigus vulgaris	Flaccid blisters with positive Nikolsky sign and acantholysis on histology	Pemphigus vulgaris affects middle-aged to older adults, involves oral mucosa (often first), has anti-desmoglein 3 antibodies, and shows intercellular IgG ("fishnet" pattern) on direct immunofluorescence
Bullous pemphigoid	Blistering disease; can occur in elderly patients	Bullae in pemphigoid are tense (not flaccid) because the split is at the dermal-epidermal junction (subepidermal). Direct immunofluorescence shows linear IgG and C3 at the basement membrane
Herpes simplex virus (HSV)	Vesicular skin lesions in children	HSV presents with grouped vesicles on an erythematous base that are painful, not flaccid bullae. Tzanck smear shows multinucleated giant cells. Distribution follows dermatomes or affects perioral/genital areas
Allergic contact dermatitis	Can cause vesicles or bullae with weeping	Contact dermatitis is intensely pruritic, follows the distribution of the contactant, and has spongiosis (intercellular edema) on histology rather than subcorneal split. No bacteria on culture
Burns or non-accidental trauma	Blistering in a young child may raise concern for burns or child abuse	Burn blisters have a clear traumatic history, follow patterns of thermal exposure, and lack surrounding collarette of scale. Non-accidental trauma may show blisters in unusual patterns (stocking-glove distribution from immersion burns). Always consider but distinguish from infectious etiology
Epidermolysis bullosa	Blistering in a neonate	Epidermolysis bullosa presents at or shortly after birth with blisters at sites of mechanical friction (hands, feet, knees). Family history is often present. Biopsy shows the level of cleavage varies by subtype but is often deeper than subcorneal

6. Traps and High-Yield Pearls

The single most common trap with bullous impetigo is confusing it with SSSS. Both are caused by S. aureus exfoliative toxins and both present with superficial blistering in young children. The discriminator the exam tests over and over is this: bullous impetigo is localized with a negative Nikolsky sign and culture-positive blister fluid, while SSSS is generalized with a positive Nikolsky sign and sterile blister fluid. If the vignette describes a well-appearing child with a few blisters on the trunk, think bullous impetigo. If it describes a toxic-appearing neonate with diffuse erythema, widespread skin peeling, and pain with gentle touch, think SSSS.

A second common error is assuming bullous impetigo can lead to post-streptococcal glomerulonephritis. Students sometimes apply the PSGN association from impetigo broadly without recognizing that this complication only follows infection with nephritogenic GAS strains. Bullous impetigo is caused exclusively by S. aureus and carries no PSGN risk. Similarly, neither form of impetigo leads to rheumatic fever, because skin strains of GAS are non-rheumatogenic.

The third pitfall involves treatment selection. When the vignette describes localized disease, the answer is topical mupirocin, not oral antibiotics. Students often over-treat. Conversely, when the patient is a neonate or has extensive or worsening disease, the answer shifts to systemic antibiotics, and topical therapy alone is insufficient. Recognizing the threshold for escalation is the core competency being tested.

Finally, remember that the Nikolsky sign is a frequent distractor across blistering diseases. It is positive in pemphigus vulgaris and SSSS (both involving disruption of intercellular adhesion broadly) but negative in bullous impetigo and bullous pemphigoid. If a question stem mentions Nikolsky sign, it is steering you toward one of these diagnoses, and your job is to match the sign with the correct clinical context.

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