Cellulitis

Etiology

The skin is a protective barrier that prevents normal skin flora and other microbial pathogens from reaching the subcutaneous tissue and lymphatic system. When a break in the skin occurs, normal skin flora and other bacteria enter the dermis and subcutaneous tissue. Introducing these bacteria below the skin surface can lead to an acute superficial infection affecting the deep dermis and subcutaneous tissue, causing cellulitis. Cellulitis most commonly results from infection with group A beta-hemolytic streptococcus (ie, Streptococcus pyogenes).[4]

Risk factors for cellulitis include any cause of skin barrier breakdown, such as skin injuries, surgical incisions, intravenous site punctures, fissures between toes, insect bites, animal bites, and other skin infections.[5] Patients with comorbidities such as diabetes mellitus, venous insufficiency, peripheral arterial disease, and lymphedema are at higher risk of developing cellulitis.[6] See Image. Venous Insufficiency and Lipodermatosclerosis.

Epidemiology

Cellulitis is relatively common and most often occurs in middle-aged and older adults. When comparing men and women, there is no statistically significant difference in the incidence of cellulitis. There are approximately 50 cases per 1000 patient-years.[7] 

Pathophysiology

Cellulitis is characterized by erythema, warmth, edema, and tenderness to palpation resulting from cytokine and neutrophil response from bacteria breaching the epidermis.[8] The cytokines and neutrophils are recruited to the affected area after bacteria have penetrated the skin, leading to an epidermal response. This response includes the production of antimicrobial peptides and keratinocyte proliferation and is postulated to produce the characteristic exam findings in cellulitis.[9] Group A Streptococci, the most common bacteria to cause cellulitis, can also produce virulence factors such as pyrogenic exotoxins (A, B, C, and F) and streptococcal superantigen that can lead to a more pronounced and invasive disease.[10]

History and Physical

Patients with cellulitis typically present with a poorly demarcated area of erythema that is warm, swollen, and tender to the touch. Constitutional symptoms, including fever, malaise, and fatigue, may also be present, reflecting systemic involvement in moderate to severe cases.[11] When evaluating patients with cellulitis, clinicians should obtain a comprehensive history of the presenting illness, focusing on the circumstances surrounding the onset of skin changes. Key questions include recent travel, trauma or injuries, history of intravenous drug use, and any insect or animal bites to the affected area. A thorough medical history should also be reviewed to identify chronic conditions that increase the risk of cellulitis, such as diabetes mellitus, venous insufficiency, peripheral vascular disease, chronic tinea pedis, and lymphedema.

The affected area should be thoroughly inspected for skin breakdown and outlined with a marker to monitor progression. The area should be palpated to assess for fluctuance, which may indicate a developing abscess. Clinicians should also note any warmth, tenderness, or purulent drainage during gentle palpation. Cellulitis can occur in any area of the body, but most commonly affects the lower extremities (see Image. Cellulitis of the Extremity). This condition is rarely bilateral; in cases of lower extremity cellulitis, careful examination between the interspaces of the toes is recommended.[12] Clinicians should also assess sensation and verify pulses in the affected extremities to monitor for potential compartment syndrome. Additionally, it is important to document the presence of vesicles, bullae, peau d’orange, or lymphadenopathy.

Evaluation

Cellulitis is diagnosed clinically based on spreading erythematous inflammation of the deep dermis and subcutaneous tissue. This condition presents with worsening erythema, edema, warmth, and tenderness. Two of the 4 criteria (warmth, erythema, edema, or tenderness) are required to make the diagnosis. Cellulitis's most common presentation is on the lower extremities, but it can affect any body area; it is most often unilateral and rarely (if ever) presents bilaterally. The patient's skin should be thoroughly evaluated to find the potential source for the cellulitis by looking for microabrasions of the skin secondary to injuries, insect bites, pressure ulcers, or injection sites. If cellulitis affects the patient's lower extremities, careful evaluation should be made to look between the patient's toes for fissuring or tinea pedis. 

Additionally, cellulitis can affect the lymphatic system and cause underlying lymphadenopathy. The associated edema with cellulitis can lead to the formation of vesicles, bullae, and edema surrounding hair follicles, leading to peau d'orange.[13] The Infectious Disease Society of America practice guidelines recommend against imaging the infected area except in patients with febrile neutropenia. Consider blood cultures only in patients who are immunocompromised, have experienced an immersion injury, or have had animal bites.[12] Blood cultures are also necessary when a patient has signs of systemic infection.[10]

Treatment / Management

Patients presenting with mild cellulitis and no systemic signs of infection should receive antibiotics effective against streptococcal species. Although a less common cause, MSSA should also be considered in the choice of therapy. The oral antibiotic therapy duration should be at least 5 days. In nonpurulent cellulitis, patients should receive cephalexin 500 mg every 6 hours. If they have a severe allergic reaction to beta-lactamase inhibitors, they should receive clindamycin 300 mg to 450 mg every 6 hours.[14](B3)

In patients with purulent cellulitis, MRSA colonization, cellulitis associated with an abscess or extensive puncture wounds, or a history of intravenous drug use, patients should receive antibiotics that treat MRSA as well. Cellulitis with MRSA risk factors should be treated with trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily for 5 days, and cephalexin 500 mg every 6 hours. If a patient is allergic to trimethoprim-sulfamethoxazole, treat with clindamycin 300 mg to 450 mg every 6 hours. A longer duration of antibiotic treatment may be a consideration in patients who show minimal improvement with antibiotic therapy within 48 hours. 

Hospitalization with the initiation of systemic antibiotics may be necessary for patients who present with systemic signs of infection (defined as 2 or more systemic inflammatory response criteria, such as fever above 38° C, heart rate greater than 90 beats/min, respiratory rate over 20 breaths/min, leukocytosis with white blood cell count above 12,000/mm³, leukopenia with white blood cell count below 4000/mm³, or bandemia ≥10%).[12] Admission should also be considered for those who have failed outpatient treatment, are immunocompromised, exhibit rapidly progressing erythema, are unable to tolerate oral medications, or have cellulitis overlying or near an indwelling medical device.(A1)

Patients requiring intravenous antibiotics should first receive treatment targeting group A strep. If there are no risk factors for MRSA, begin with intravenous cefazolin, then switch to oral cephalexin when possible, for a total of 5 days of therapy. If MRSA risk factors are present, start with intravenous vancomycin and later transition to oral trimethoprim-sulfamethoxazole. For immunocompromised individuals who need hospital-level intravenous therapy, broader treatment may be required, such as combining vancomycin with piperacillin-tazobactam or using a carbapenem. The clinician should obtain blood cultures if a patient is exhibiting signs of systemic toxicity, has persistent cellulitis despite adequate treatment, or has unique exposures such as animal bites or water-associated injuries.[15]

Atypical organisms can cause cellulitis in particular situations. If exposed to a dog or cat bite, patients risk developing cellulitis secondary to Pasteurella multocida. Cellulitis can also be caused by Vibrio vulnificus if secondary to an injury involving exposure to water, such as a cut from an oyster shell. Diabetic individuals and patients with diabetic foot ulcers are at risk for Pseudomonas aeruginosa. Those who are immunocompromised are at risk for Pseudomonas aeruginosa and Cryptococcus. Suppose patients have significant edema with a known cause for the edema. In that case, the underlying condition should receive proper treatment to decrease the edema and prevent future episodes of cellulitis. Patients should be instructed to keep the affected area elevated.[12](A1)

Differential Diagnosis

Cellulitis is a common infection of the deep dermis and subcutaneous tissue, often affecting the lower extremities. Still, it can be difficult to distinguish because many other conditions can appear similar.[16] Erysipelas is sometimes considered a form of cellulitis (see Image. Erysipelas). However, it is a more superficial infection affecting the upper dermis and superficial lymphatic system. Bright red erythema, elevation of the affected skin, and well-demarcated borders can help to diagnose erysipelas and distinguish it from cellulitis, which tends to be more mildly erythematous (pink) and flat with less distinct boundaries. Erysipelas may also have streaking when superficial lymphatics are involved. This condition most commonly results from the exotoxins released from group A strep (Streptococcus pyogenes). The first-line treatment for erysipelas is amoxicillin or cephalexin.[17]

Chronic venous stasis dermatitis is a long-standing, bilateral, inflammatory dermatosis secondary to chronic venous insufficiency and typically involves the medial malleoli. This appears on the lower extremities and manifests as erythema with scaling, peripheral edema, and hyperpigmentation. Treatment focuses on treating the underlying chronic venous insufficiency and its sequelae, such as lower extremity edema.[1]

Necrotizing fasciitis is a rare infection of the fascia that leads to necrosis of the subcutaneous tissue. The characteristic presentation includes fevers, erythema, edema, pain out of proportion to the exam, and crepitus. This qualifies as a surgical emergency and requires surgical debridement immediately. Imaging may be obtained to help confirm the diagnosis of necrotizing fasciitis, but it should not delay surgical intervention. Computed tomography imaging revealing subcutaneous gas in the soft tissue is highly specific for necrotizing fasciitis. Septic arthritis, or an infected joint, can involve any joint but typically occurs at the knee. Patients present with swelling, warmth, pain, and decreased joint mobility. Treatment is joint aspiration and antibiotics directed at the most common pathogens.

Deep vein thrombosis is typically unilateral and presents with tenderness, erythema, warmth, and edema.  This often affects the lower extremities. Patients commonly have the presence of risk factors for deep vein thrombosis, such as a history of immobility, active cancer, or a family history of venous thromboembolism. Deep vein thrombosis rarely manifests with fevers or leukocytosis, but they can be present. Ultrasound imaging is used to confirm the diagnosis.[5]

Prognosis

If the clinician promptly identifies cellulitis and initiates treatment with the correct antibiotic, patients can expect to notice an improvement in signs and symptoms within 48 hours. Annual recurrence of cellulitis occurs in about 8% to 20% of patients, with overall recurrence rates reaching as high as 49%.[1][9] Recurrence is preventable with prompt treatment of cuts or abrasions, proper hand hygiene, and effective treatment of any underlying comorbidities. There is approximately an 18% failure rate with initial antibiotic treatment. Overall, cellulitis has a good prognosis.[18]

Complications

Without prompt diagnosis and treatment, cellulitis could lead to several complications. If the bacterial infection reaches the bloodstream, it could lead to bacteremia. Bacteremia is diagnosable by obtaining blood cultures in patients who exhibit systemic symptoms. The clinician should obtain identification and susceptibilities from the blood cultures and tailor antibiotics accordingly.[19] Failure to identify and treat bacteremia from cellulitis can lead to endocarditis, an infection of the heart's inner lining (endocardium). 

Patients with cellulitis and 2 or more systemic inflammatory response syndrome criteria (fever over 100.4° F, tachypnea, tachycardia, or abnormal white cell count) are diagnosed with sepsis. If cellulitis moves from the deep dermis and subcutaneous tissue to the bone, it can lead to osteomyelitis. Cellulitis that leads to bacteremia, endocarditis, or osteomyelitis requires longer antibiotics and possibly surgery.[1]