Ecthyma Gangrenosum

Background

Ecthyma gangrenosum (EG) is a well-recognized but uncommon cutaneous infection classically associated with Pseudomonas aeruginosa bacteremia.^[1]  EG usually occurs in patients who are critically ill and immunocompromised; it is almost always a sign of pseudomonal sepsis. Rarely, other bacteria, including Proteus species, Escherichia coli, and methicillin-resistant Staphylococcus epidermidis, have been implicated in similar lesions.^{[2, 3, 4]}  The characteristic lesions of EG are hemorrhagic vesicles or pustules that evolve into necrotic ulcers with a tender erythematous border. EG was first described in association with Pseudomonas septicemia by Barker in 1897 and was later given the name "ecthyma gangrenosum" by Hitschmann and Kreibich. Not all cases have been associated with sepsis.^[5]  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.

Related Medscape articles include Pseudomonas aeruginosa Infections and Pseudomonas Infection.

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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 ecthyma gangrenosum (EG) result from perivascular bacterial invasion of arteries and veins in the dermis and subcutaneous tissues, producing a necrotizing vasculitis.^[6] Perivascular involvement can occur by hematogenous seeding of the skin in bacteremic patients or by direct inoculation through the skin in non-bacteremic 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

Ecthyma gangrenosum (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.^[7] Organisms that cause ecthyma and EG-like lesions include the following:

Gram-positive bacteria are as follows:

• Staphylococcus aureus
• Streptococcus pyogenes

Gram-negative bacteria are as follows:

• Aeromonas hydrophila
• Burkholderia cepacia ^[8]
• Chromobacterium violaceum ^[9]
• Citrobacter freundii
• Corynebacterium diphtheriae
• Escherichia coli
• Klebsiella pneumoniae
• Morganella morganii ^[10]
• Neisseria gonorrhea
• Pseudomonas aeruginosa
• Pseudomonas stutzeri
• Serratia marcescens
• Vibrio vulnificus
• Yersinia pestis
• Xanthomonas maltophilia

Fungi are as follows:

• Aspergillus fumigatus
• Candida albicans ^[11]
• Curvularia species^[12]
• Exserohilum species
• Fusarium solani ^[13]
• Mucor and Rhizopus species
• Pseudallescheria boydii ^[12]
• Scytalidium dimidiatum

Viral causes include herpes simplex virus.^[14]

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Epidemiology

Frequency

Ecthyma gangrenosum (EG) develops in 1.3-13% patients with P aeruginosa sepsis and, to a lesser extent, in patients who are not bacteremic.

Sex

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.

Age

EG may affect patients of any age, although it is commonly reported in infants and elderly patients due to underdeveloped and/or compromised immune systems, including chronic granulomatous disease.^[15]

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Prognosis

A high mortality rate is reported with delayed diagnosis and therapy. Mortality rates of Pseudomonas sepsis in immunocompromised persons range from 18-96%, whereas the mortality rate of ecthyma gangrenosum (EG) in nonbacteremic patients is 15.4%. Coexisting conditions in patients prone to Pseudomonas sepsis may contribute to the morbidity and mortality rates.

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

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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. While a few case reports describe the development of EG in previously healthy children, most of these patients had unrecognized risk factors for the development of EG, including intra-abdominal or appendiceal abscesses, recent viral illness such as influenza B leading to a transient severe neutropenia,^[16] or antibiotic treatment for underlying medical conditions such as hypogammaglobulinemia and neutropenia.

Two reports describe toxic epidermal necrolysis followed by EG, one in a 62-year-old woman and the other in a 3-year-old boy.^{[17, 18]}

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 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 promoted Pseudomonas overgrowth.

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

Patients often present with fever a few days prior to developing EG.

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Physical Examination

Primary lesions

Primary cutaneous lesions of ecthyma gangrenosum (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/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.^{[19, 20]}

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Laboratory Studies

See the list below:

• Gram stain: 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.
• Blood cultures: Two specimens should be collected prior to initiating antibiotic therapy. The optimal time of collection is during temperature spikes. Sensitivity studies should be performed on isolated organisms.
• Urine culture
• Skin biopsy: One 4- to 5-mm deep skin biopsy specimen should be obtained and placed in formalin fixative. Specimens should be stained with tissue Gram stain in addition to standard hematoxylin and eosin. Staining with special stains (eg, periodic acid-Schiff, methamine silver, Fite stains) should be performed to rule out other organisms that may cause ecthyma gangrenosum (EG)–like lesions.
• Tissue cultures: 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 confirmed diagnosis of ecthyma gangrenosum (EG) of the plantar foot, magnetic resonance imaging (MRI) showed edema of the skin, subcutaneous fat, deep and superficial fascia, and plantar muscles. The postcontrast fat-suppressed images showed a geographic pattern of absent enhancement, which was consistent with muscle ischemia and/or necrosis. Deep fascial enhancement was absent; this is in contrast to necrotizing fasciitis, which on MRI demonstrates fascial enhancement after contrast administration.^[21]

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Histologic Findings

Skin biopsy specimens of ecthyma gangrenosum (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.^[22] 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 appropriately selected antibiotics for the underlying etiology. If the lesion fails to respond to antimicrobials, surgical debridement of the spreading, necrotic lesion may be required.^{[23, 24]} The presence of EG should alert the physician to the likelihood of pseudomonal bacteremia, and the early implementation of antimicrobial agents is necessary to reduce the high mortality associated with pseudomonal sepsis.

Treatment of EG requires the use of antipseudomonal penicillins, aminoglycosides, fluoroquinolones, third-generation cephalosporins, or aztreonam. While awaiting results, an antipseudomonal penicillin (piperacillin) should be used in conjunction with an aminoglycoside (gentamicin). Further adjustment of antibiotics may be required after sensitivity results are known. Granulocyte-macrophage colony-stimulating factor may also be administered to patients with severe leukopenia and ecthyma gangrenosum to aid in recovery.^[25]

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

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

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Consultations

See the list below:

• 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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Medication Summary

Treatment of ecthyma gangrenosum (EG) requires the use of antipseudomonal penicillins, aminoglycosides, fluoroquinolones, third-generation cephalosporins, or aztreonam. Initially, antipseudomonal penicillin (piperacillin) is used in conjunction with an aminoglycoside (gentamicin). Further adjustment of antibiotics may be required after sensitivity results are known.

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Piperacillin (Pipracil)

• Dosing, Interactions, etc.

Clinical Context:  Piperacillin is a broad-spectrum penicillin. It inhibits the biosynthesis of cell wall mucopeptides and the stage of active multiplication. It has antipseudomonal activity.

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Gentamicin (Gentacidin, Garamycin)

• Dosing, Interactions, etc.

Clinical Context:  Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Gentamicin is not the drug of choice. Consider it if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous; adjust the dose based on CrCl and changes in the volume of distribution. Gentamicin may be given IV/IM.

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Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth. It is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.

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Ceftazidime (Fortaz, Ceptaz)

• Dosing, Interactions, etc.

Clinical Context:  Ceftazidime is a third-generation cephalosporin with broad-spectrum, gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftazidime arrests bacterial growth by binding to one or more penicillin-binding proteins.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

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