Cellulitis and erysipelas

INTRODUCTION  —

 Cellulitis and erysipelas are skin infections that develop as a result of bacterial entry via breaches in the skin barrier. The incidence is about 200 cases per 100,000 patient-years. Cellulitis is observed most frequently among middle-aged and elderly individuals, while erysipelas occurs in young children and the elderly .

CLINICAL MANIFESTATIONS  —

 Cellulitis and erysipelas manifest as areas of skin erythema, edema, and warmth. They differ in that erysipelas involves the upper dermis and superficial lymphatics, whereas cellulitis involves the deeper dermis and subcutaneous fat. As a result, erysipelas has more distinctive anatomic features than cellulitis; erysipelas lesions are raised above the level of surrounding skin, and there is a clear line of demarcation between involved and uninvolved tissue . Classic descriptions of erysipelas note "butterfly" involvement of the face. Involvement of the ear (Milian's ear sign) is a distinguishing feature for erysipelas, since this region does not contain deeper dermis tissue. In addition, patients with erysipelas tend to have acute onset of symptoms with systemic manifestations including fever and chills; patients with cellulitis tend to have a more indolent course with development of localized symptoms over a few days' time. Cellulitis may present with or without purulent drainage or exudate .

The lower extremities are the most common site of infection for both erysipelas and cellulitis . Other forms of cellulitis include periorbital cellulitis, abdominal wall cellulitis (in morbidly obese individuals), buccal cellulitis (due to Streptococcus pneumoniae and, prior to the conjugate vaccine era, Haemophilus influenzae type b) and perianal cellulitis (due to group A beta-hemolytic streptococcus) .

Rarely, infections involving the medial third of the face (ie, the areas around the eyes and nose) can be complicated by septic cavernous thrombosis, since the veins in this region are valveless . 

Additional manifestations of cellulitis and erysipelas include lymphangitis and inflammation of regional lymph nodes. Edema surrounding the hair follicles may lead to dimpling in the skin, creating an appearance reminiscent of an orange peel texture ("peau d'orange"). Vesicles, bullae, and ecchymoses or petechiae may be observed. Crepitant and gangrenous cellulitis are unusual manifestations of cellulitis due to clostridia and other anaerobes. Severe manifestations with systemic toxicity should prompt investigation for additional underlying sources of infection. 

Predisposing factors include disruption to the skin barrier as a result of trauma (such as insect bites, abrasions, penetrating wounds, or injection drug use), inflammation (such as eczema or radiation therapy), preexisting skin infection (such as impetigo or tinea pedis), varicella, and edema (due to venous insufficiency). Lymphatic obstruction following surgical procedures also predisposes to cellulitis. Such procedures include saphenous venectomy, breast cancer axillary node dissection, and lymph node dissection for pelvic malignancy. Breaks in the skin between the toes ("toe web intertrigo") are perhaps the most important potential sites for pathogen entry . However, breaches in the skin may be small and clinically inapparent. 

DIFFERENTIAL DIAGNOSIS  —

 In adults, cellulitis must be distinguished from other infections including necrotizing fasciitis, gas gangrene, toxic shock syndrome, bursitis, osteomyelitis, herpes zoster, and erythema migrans. Rapidly progressive erythema with signs of systemic toxicity should prompt consideration of more severe infection. 

In children, cellulitis must be distinguished from erythema migrans, nummular eczema, insect bite hypersensitivity, necrotizing fasciitis, and toxic shock syndrome. 

It is important to distinguish between cellulitis and skin abscess. Skin abscess may present with surrounding cellulitic findings that may delay diagnosis and appropriate management (eg, surgical incision and drainage). Management of skin abscess is discussed further separately. 

Noninfectious masqueraders of cellulitis include contact dermatitis, deep venous thrombosis, acute gout, drug reactions, insect stings, and malignancy. Contact dermatitis may be distinguished from cellulitis and erysipelas in that the contact dermatitis lesions are pruritic but not painful. 

DIAGNOSIS  — 

The diagnosis of cellulitis and erysipelas is based upon clinical manifestations. Cultures of blood, needle aspirations, or punch biopsies are usually not useful in the setting of mild infection . Blood cultures are positive in less than 5 percent of cases . Culture results from needle aspiration vary from ≤5 to 40 percent, while culture of punch biopsy specimens yields a pathogen in 20 to 30 percent of cases .

Cultures of blood, pus, or bullae are more useful and should be performed in patients with systemic toxicity, extensive skin involvement, underlying comorbidities (lymphedema, malignancy, neutropenia, immunodeficiency, splenectomy, diabetes), special exposures (animal bite, water-associated injury) or recurrent or persistent cellulitis . Cultures of swabs from intact skin are not helpful and should not be performed.

Cultures obtained from patients with lower extremity cellulitis and toe web intertrigo due to tinea pedis may be useful for identification of pathogenic bacteria . This was illustrated in a study of 24 patients with cellulitis; 83 percent had tinea pedis. Cultures of the interdigital spaces yielded beta-hemolytic streptococci, S. aureus, and gram-negative bacilli (85, 45, and 35 percent of cases, respectively). In addition, molecular typing of isolates from paired blood and toe web cultures in two cases demonstrated identical streptococcal strains .

Radiographic examination can be a useful tool for excluding occult abscess and for distinguishing cellulitis from osteomyelitis . Radiographic examination cannot reliably distinguish cellulitis from necrotizing fasciitis or gas gangrene; if there is clinical suspicion for these entities, radiographic imaging should not delay surgical intervention . 

Serology may have a useful diagnostic role in patients with recurrent cellulitis. 

MICROBIOLOGY  —

 The vast majority of cases of erysipelas are caused by beta-hemolytic streptococci .

The most common cellulitis pathogens are beta-hemolytic streptococci (groups A, B, C, G, and F) and S. aureus, including methicillin-resistant strains (MRSA); gram-negative aerobic bacilli are identified in a minority of cases. A prospective study of nonpurulent (eg, nonculturable) cellulitis among 179 hospitalized patients found that beta-hemolytic streptococci accounted for 73 percent of cases (diagnosed by positive blood culture results or serologic testing for anti-streptolysin-O and anti-DNase-B antibodies); despite the lack of an identifiable etiology in 27 percent of cases, the overall clinical response rate to beta-lactam therapy was 96 percent .

Less common pathogens include H. influenzae (buccal cellulitis), clostridia and non-spore-forming anaerobes (crepitant cellulitis), pneumococcus, and meningococcus . Cellulitis pathogens implicated in special clinical circumstances discussed in detail separately include:

• Pasteurella multocida and Capnocytophaga canimorsus 
• Aeromonas hydrophila and Vibrio vulnificus
• S. aureus 
• S. pneumoniae
• Streptococcus agalactiae 
• Streptococcus iniae 
• Clostridium species 
• Erysipelothrix rhusiopathiae
• Cryptococcus neoformans
• Helicobacter cinaedi
• Pseudomonas aeruginosa
• Group B streptococcus

TREATMENT

Nonantibiotic therapy  —

 Management of cellulitis and erysipelas should include elevation of the affected area and treatment of underlying conditions. Elevation facilitates gravity drainage of edema and inflammatory substances. The skin should be sufficiently hydrated to avoid dryness and cracking without interdigital maceration.

Many patients with cellulitis have underlying conditions that predispose them to developing recurrent cellulitis (these include tinea pedis, lymphedema, and chronic venous insufficiency). In such patients, treatment should be directed at both the cellulitis and the predisposing condition. Patients with edema may benefit from treatment with compressive stockings and diuretic therapy. 

Antibiotics  — 

The following guidelines for empiric antimicrobial therapy should be modified as indicated in the setting of known pathogens, underlying conditions, such as diabetes, and special circumstances, such as animal bites and water exposure. Management of patients in these settings is discussed in detail separately. 

Cellulitis  —

 The approach to antibiotic selection for treatment of cellulitis depends on whether the clinical presentation consists of purulent or nonpurulent cellulitis. These terms, which previously have not been used routinely to categorize cellulitis, are designations within the 2011 Infectious Disease Society of America clinical practice guidelines for methicillin-resistant S. aureus (MRSA). The use of these terms in the guidelines suggests that an infection involving purulence – whether the process began as an abscess (with secondary cellulitis) or as a cellulitis (with secondary purulence) – is potentially attributable to S. aureus, which should be reflected in the choice of empiric antimicrobial therapy.

Most patients develop mild cellulitis and can be treated with oral antibiotics; patients with signs of systemic toxicity or erythema that has progressed rapidly should be treated initially with parenteral antibiotics. Attention to dosing is important, particularly in obese individuals .

Treatment of cellulitis for neonates usually requires hospitalization and initial parenteral therapy, except for the mildest of cases. Empiric therapy must include coverage for group B streptococcus in addition to methicillin-resistant Staphylococcus aureus and other beta-hemolytic streptococci. Empiric parenteral therapy options include vancomycin plus either cefotaxime or gentamicin . Antibiotics that should be avoided in this age group include tetracyclines, trimethoprim-sulfamethoxazole , and ceftriaxone (cefotaxime is preferred over ceftriaxone). Dosing is weight- and age-based . Therapy is usually administered for 7 to 10 days.

Purulent  —

 Patients with purulent cellulitis (eg, cellulitis associated with purulent drainage or exudate, in the absence of a drainable abscess) should be managed with empiric therapy for infection due to MRSA, pending culture results . Empiric therapy for infection due to beta-hemolytic streptococci is likely not necessary. In a study including 422 patients with purulent soft tissue infection, MRSA was the dominant organism, isolated from 59 percent of patients, followed by methicillin-susceptible S. aureus (MSSA) (17 percent); beta-hemolytic streptococci accounted for a much smaller proportion of these infections (2.6 percent) .

Options for empiric oral therapy for treatment of MRSA include :

• Clindamycin
• Trimethoprim-sulfamethoxazole
• Tetracycline ( doxycycline or minocycline )
• Linezolid or tedizolid

The duration of therapy should be individualized depending on clinical response; 5 to 10 days is usually appropriate (7 to 10 days in neonates); longer duration of therapy may be warranted in patients with severe disease .

The approach to parenteral therapy is discussed separately . 

Nonpurulent  —

 Patients with nonpurulent cellulitis (eg, cellulitis with no purulent drainage or exudate and no associated abscess) should be managed with empiric therapy for infection due to beta-hemolytic streptococci and MSSA; antibiotic therapy options are summarized in the Table .

Additional empiric coverage for MRSA is warranted in patients who do not respond to initial therapy, patients with signs of systemic illness, patients with recurrent infection in the setting of underlying predisposing conditions, and patients with a previous episode of MRSA infection. In addition, empiric coverage for MRSA should be considered in patients with risk factors for MRSA infection and in communities where the prevalence of MRSA is greater than 30 percent .

Options for empiric oral therapy for treatment of both beta-hemolytic streptococci and MRSA include :

• Clindamycin
• Amoxicillin combined with trimethoprim-sulfamethoxazole
• Amoxicillin combined with a tetracycline ( doxycycline or minocycline )
• Linezolid or tedizolid

The duration of therapy should be individualized depending on clinical response; 5 to 10 days is usually appropriate (7 to 10 days for neonates); longer duration of therapy may be warranted in patients with severe disease.

The approach to parenteral therapy for MRSA is discussed separately.

Erysipelas  —

 Patients with classic manifestations of erysipelas and systemic manifestations, such as fever and chills, should be treated with parenteral therapy. Appropriate choices include ceftriaxone or cefazolin. Ceftriaxone has activity against beta-hemolytic streptococci, the cause of erysipelas in the majority of cases. In addition, once-daily dosing allows for convenient outpatient administration. Cefazolin provides coverage against streptococci as well as MSSA, which can be useful in settings where erysipelas cannot be reliably distinguished from cellulitis.

Patients with mild infection or those who have improved following initial treatment with parenteral antibiotic therapy may be treated with oral penicillin or amoxicillin . Macrolides (particularly erythromycin ) have also traditionally been used but may not be adequate therapy in areas with relatively high resistance rates among beta-hemolytic streptococci . In the setting of beta-lactam allergy, cephalexin (if the patient can tolerate cephalosporins), clindamycin , or linezolid may be used .

The duration of therapy should be individualized depending on clinical response; 5 to 10 days is usually appropriate.

Follow-up  — Patients with cellulitis typically report symptomatic improvement within 24 to 48 hours of beginning antimicrobial therapy, although visible improvement of clinical manifestations may take up to 72 hours. Continuing extension of erythema or worsening systemic symptoms after this period of time should prompt consideration of resistant pathogens or alternative diagnoses. 

Some patients may observe a deepening of erythema after initiating antimicrobial therapy, particularly in the setting of erysipelas. This may be due to destruction of pathogens that release enzymes, increasing local inflammation. This should not be mistaken for a failure to respond to therapy. In one study, treatment with corticosteroids (in addition to antimicrobials) did not alter the risk of relapse or recurrence, but slightly reduced healing time and antibiotic duration in patients with erysipelas.

RECURRENT CELLULITIS  —

 Management of recurrent infection can be a challenging problem. 

Preventive measures for reducing the spread of staphylococci may be helpful for reducing risk for recurrent skin infection and are discussed in detail separately. 

The efficacy of prophylactic antibiotics for management of recurrent cellulitis is unclear . Prophylaxis is warranted in some circumstances of frequently recurrent cellulitis in patients with predisposing factors that cannot be alleviated (eg, abnormal anatomy due to lymph node dissection, large hemangioma, or congenital malformations, such as lymphangioma or cystic hygroma). These patients tend to have lymphatic obstruction following surgical procedures, such as saphenous venectomy, breast cancer axillary node dissection, and lymph node dissection for pelvic malignancy.

Some clinicians favor serologic testing for beta-hemolytic streptococci to help guide the choice of suppressive antibiotic therapy. Assays include the anti-streptolysin O (ASO) reaction, the anti-deoxyribonuclease B test (anti-DNAse B), the anti-hyaluronidase test (AHT), or the Streptozyme antibody assay . Anti-Dnase B and AHT responses are more reliable than the ASO response following GAS skin infections.

For known or presumed beta-hemolytic streptococcal infection, options for prophylactic antibiotics include monthly or bimonthly intramuscular benzathine penicillin injections (1.2 million units for patients who weigh >27 kg; 600,000 units for patients who weigh ≤27 kg) or oral therapy with penicillin V (250 to 500 mg orally twice daily). Staphylococcal infection prophylaxis may be attempted with clindamycin (150 mg orally once daily for adults) . Staphylococcal prophylaxis for recurrent cellulitis is rarely necessary in children. Suppressive therapy may be continued for several months with interval assessment for relapse. Alternatively, patients may self-initiate antibiotic therapy immediately when symptoms of infection begin and seek medical attention.