Ecthyma Gangrenosum

Background

Ecthyma gangrenosum (EG) is a well-recognized but uncommon cutaneous infection classically associated with Pseudomonas aeruginosa.^[1] It was first described in association with Pseudomonas septicemia by Barker in 1897 and was later given the name ecthyma gangrenosum by Hitschmann and Kreibich.

EG usually occurs in patients who are critically ill and immunocompromised. Although it is almost always a sign of pseudomonal sepsis, there have been instances in which other bacteria (eg, including Proteus species, Escherichia coli, and methicillin-resistant Staphylococcus epidermidis, have been implicated in similar lesions.^{[2, 3, 4]} Fungi have been implicated as well in some cases.^[5] Not all cases have been associated with sepsis.^{[6, 7, 8, 9]}

The characteristic lesions of EG are hemorrhagic vesicles or pustules that evolve into necrotic ulcers with a tender erythematous border (see the image below).

View Image

Violaceous plaques and necrotic ulcers on the abdomen of a renal transplant patient. Tissue cultures were positive for Pseudomonas aeruginosa.

EG requires prompt diagnosis and treatment with antibiotics that are appropriately selected for the underlying etiology. If the lesion fails to respond to antimicrobials, surgical debridement of the spreading necrotic lesion may be required. (See Treatment.)

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Pathophysiology

Impaired humoral or cellular immunity leads to increased susceptibility to infections with P aeruginosa or other pathogens. In addition, breakdown of mechanical defensive barriers, such as the skin and mucosa, may allow infectious organisms to disseminate.

The lesions of EG result from perivascular bacterial invasion of arteries and veins in the dermis and subcutaneous tissues, which produces a necrotizing vasculitis.^[10] Perivascular involvement can occur via hematogenous seeding of the skin in bacteremic patients or via direct inoculation through the skin in nonbacteremic patients. Extravasation of blood, edema, and necrosis around the vessel interrupt the blood supply to these tissues, resulting in secondary ischemic necrosis of the epidermis and dermis, which manifests as nodular lesions that rapidly evolve through stages of central hemorrhage, ulceration, and necrosis.

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Etiology

EG is typically and most commonly caused by P aeruginosa; however, EG-like lesions have been observed in patients with other bacterial and fungal infections.^[11]

Gram-positive bacteria that cause ecthyma and EG-like lesions include the following:

• Staphylococcus aureus^[12]
• Streptococcus pyogenes

Gram-negative bacteria that cause ecthyma and EG-like lesions include the following:

• Aeromonas hydrophila
• Burkholderia cepacia^[13]
• Chromobacterium violaceum^[14]
• Citrobacter freundii
• Corynebacterium diphtheriae
• E coli
• Klebsiella pneumoniae
• Morganella morganii^[15]
• Neisseria gonorrhoeae
• P aeruginosa
• Pseudomonas stutzeri
• Serratia marcescens
• Vibrio vulnificus
• Yersinia pestis
• Xanthomonas maltophilia

Fungi that cause ecthyma and EG-like lesions include the following:

• Aspergillus fumigatus
• Candida albicans^[16]
• Curvularia species^[17]
• Exserohilum species
• Fusarium solani^[18]
• Mucor and Rhizopus species
• Pseudallescheria boydii^[17]
• Neoscytalidium dimidiatum

Viral causes include herpes simplex virus (HSV).^[19]

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Epidemiology

EG develops in 1.3-13% of patients with P aeruginosa sepsis and in a smaller percentage of patients who are not bacteremic.

EG may affect patients of any age, though it is more commonly reported in infants and elderly patients, whose immune systems may be underdeveloped or compromised (eg, by chronic granulomatous disease^[20] ).

No sexual predilection is evident in the overall prevalence of EG; however, a slight predominance of bacteremic EG in males (male-to-female ratio, 1.3-5:1) and nonbacteremic EG in females (female-to-male ratio, 2.3:1) has been observed.

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Prognosis

Delays in diagnosis and treatment have been associated with a high mortality. Rates of death from Pseudomonas sepsis in immunocompromised persons have ranged from 18% to 96%, whereas the mortality of EG in nonbacteremic patients has been reported to be 15.4%. In a study (N = 82) from a single integrated health system, the overall mortality was approximately 34%.^[21]  Mortality was higher in patients with sepsis or immunocompromise than in those without. 

Factors associated with a poor prognosis include the following:

• Multiple lesions
• Delayed diagnosis and institution of appropriate antibiotics
• Persistent neutropenia
• High bacteremic load
• Repeated catheterization and instrumentation

Coexisting conditions in patients prone to Pseudomonas sepsis may contribute to morbidity and mortality.

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History

Ecthyma gangrenosum (EG) typically occurs in patients who are immunocompromised, including patients with hematologic malignancies, immunodeficiency syndromes, severe burns, malnutrition, recent chemotherapy, immunosuppressive therapy, and diabetes mellitus. Some case reports have described EG developing in previously healthy children; however, most of these patients had unrecognized risk factors for the development of EG, including intra-abdominal or appendiceal abscesses, recent viral illness (eg, influenza B leading to a transient severe neutropenia^[22] ), or antibiotic treatment for an underlying medical condition (eg, hypogammaglobulinemia or neutropenia).

Two reports described toxic epidermal necrolysis followed by EG, one in a 62-year-old woman and the other in a 3-year-old boy.^{[23, 24]}

Breakdown of mechanical defense barriers increases susceptibility to pseudomonal or fungal infections. Pseudomonas sepsis frequently occurs after surgical procedures, especially urologic procedures. Long-term indwelling urinary catheters, long-term intravenous (IV) placements, and tracheostomies have been associated with EG.

In several reported cases, patients with EG were on prolonged antibiotic therapy targeting non-Pseudomonas organisms. This may have led to elimination of normal flora and thereby to promotion of Pseudomonas overgrowth.

Children with EG may develop diarrhea (30%) before the onset of cutaneous lesions.

Patients often present with fever a few days before developing EG.

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Physical Examination

Primary lesions

Primary cutaneous lesions of EG initially appear as painless round erythematous macules that rapidly become pustular with surrounding erythema. A hemorrhagic focus appears in the center, forming a bulla. As the hemorrhagic bulla spreads peripherally, it evolves into a gangrenous ulcer with a central black or gray eschar surrounded by an erythematous halo. The transformation of an early lesion to a necrotic ulcer may occur in as little as 12 hours.

Distribution of lesions

The patient may have a single lesion or multiple lesions. EG may appear at any location on the body; however, it predominately affects the anogenital and axillary areas. Distribution occurs at the following frequencies: gluteal or perineal region (57%), extremities (30%), trunk (6%), and face (6%); bilateral periorbital manifestations are rare but have been reported.^{[25, 26]}

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Laboratory Studies

A Gram stain of fluid from the central hemorrhagic pustule or bulla can rapidly indicate the diagnosis. If no fluid is present, the eschar should be elevated and the underlying tissue swabbed for a Gram stain.

Two specimens should be collected for blood culture before initiation of antibiotic therapy. The optimal collection time is during temperature spikes. Sensitivity studies should be performed on isolated organisms.

Urine culture should be obtained.

Early skin biopsy is useful for diagnosis.^[27] One 4- to 5-mm-deep skin biopsy specimen should be obtained and placed in formalin fixative. Specimens should be stained with Gram stain in addition to standard hematoxylin and eosin (H&E). Staining with special stains (eg, periodic acid–Schiff [PAF], methamine silver, Fite stains) should be performed to rule out other organisms that may cause ecthyma gangrenosum (EG)-like lesions.

A second skin biopsy specimen should be placed in a sterile container for tissue culture. Specimens should be tested for bacteria, fungus, yeast, and mycobacteria. Preservative-free anesthetics and saline should be used for the procedure. Sensitivity studies should be performed on isolated organisms.

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Imaging Studies

In a case report involving a child with a confirmed diagnosis of EG of the plantar foot, magnetic resonance imaging (MRI) showed edema of the skin, subcutaneous fat, deep and superficial fascia, and plantar muscles.^[28] The postcontrast fat-suppressed images showed a geographic pattern of absent enhancement, which was consistent with muscle ischemia or necrosis. Deep fascial enhancement was absent; this finding differentiates EG from necrotizing fasciitis, which on MRI demonstrates fascial enhancement after contrast administration.

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Histologic Findings

Skin biopsy specimens of EG lesions show a necrotizing hemorrhagic vasculitis with few inflammatory cells but many surrounding bacilli. In sections stained with Gram stain, gram-negative rods are numerous in the media and adventitia of the necrotic vessels but typically spare the intima.^[29] Extravasation of blood, edema, and necrosis are seen around the involved vessels.

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Medical Care

Ecthyma gangrenosum (EG) requires prompt diagnosis and treatment with antibiotics that are appropriately selected for the underlying etiology. If the lesion fails to respond to antimicrobials, surgical debridement of the spreading, necrotic lesion may be required.^{[30, 31]} The presence of EG should alert the physician to the likelihood of pseudomonal bacteremia, and early implementation of antimicrobial therapy is necessary to reduce the high mortality associated with pseudomonal sepsis.

Treatment of EG may involve the use of antipseudomonal penicillins, aminoglycosides, fluoroquinolones, third-generation cephalosporins, or aztreonam. While sensitivity results are being awaited, an antipseudomonal penicillin (piperacillin) should be administered in conjunction with an aminoglycoside (gentamicin). Further adjustment of antibiotics may be required after sensitivity results are known. Granulocyte-macrophage colony-stimulating factor (GM-CSF) may also be administered to patients with severe leukopenia and ecthyma gangrenosum to aid in recovery.^[32]

Systemic antifungal coverage should be considered if fungemia is suspected, including coverage against Aspergillus, Candida, and Mucor species with an azole (eg, voriconazole or fluconazole), amphotericin B, or both, if appropriate.

If empiric antibiotic and antifungal therapy is used, it must be comprehensive and must cover all likely pathogens in the context of the clinical setting. Antimicrobial selection should be guided by blood culture sensitivity results whenever feasible.

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Consultations

The following consultations may be considered:

• Dermatologist - For evaluation of cutaneous lesions
• Infectious disease specialist - For evaluation and treatment of infection
• Internist or pediatrician - For evaluation of possible immunocompromised states
• General surgeon - For evaluation of possible surgical excision of lesions that failed to respond to antibiotics

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Piperacillin (Pipracil)

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Gentamicin

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Ciprofloxacin (Cipro, Cipro XR, ProQuin XR)

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Ceftazidime (Fortaz, Tazicef, Tazidime)

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Aztreonam (Azactam)

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Amphotericin B deoxycholate (Amphotericin B (conventional))

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Fluconazole (Diflucan)

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Voriconazole (Vfend)

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