Cellulitis is a common infection in the skin and subcutaneous tissues. The most common cause of cellulitis is beta-hemolytic Streptococci and Staphyloccocus aureus. It is usually located in the lower limbs in association with decreased lymphatic circulation.
Erythema, edema, pain, and increased local temperature are the classic clinical features of cellulitis. Though in most cases the diagnosis is clinical, in the context of certain risk factors or disease severity, further diagnostic measurements are taken, including laboratory studies, blood cultures, or imaging studies.
Treatment consists of empirical antibiotic therapy, with targeted antibiotic management when necessary.
Introduction to Cellulitis Diagnosis and Management
Cellulitis (cellula: derivative of cella, meaning “cell” + itis: suffix indicating inflammation) is a frequent infection affecting the skin and subcutaneous tissues. (1) It is caused by bacterial infection leading to inflammation of the dermis and subcutaneous tissue. Mostly, beta-hemolytic streptococci, such as group A streptococci (i.e., Streptococcus pyogenes), are involved in this, followed by methicillin-sensitive Staphylococcus aureus (MSSA). (2, 3) The organism enters the body through various sites such as cuts, varicose eczema/ulcers, tinea pedis, or ear infections. Old age, diabetes, and immunosuppressed conditions are the major predisposing factors. (3)
Cellulitis is a bacterial infection involving soft tissues and occurs when the skin barrier is disrupted, or circulation is impaired. Bacteria present on the skin surface may not prove to be harmful, but when they cross the skin to reach deeper structures, an infection can result. Cuts, bites, and wounds provide the passage for bacterial entry.
Cellulitis should be differentiated from erysipelas and impetigo, which may mimic the presentation. Another entity called “cellulite” is not the same as cellulitis, as it may be mistaken due to look-alike names. Cellulite is dimpled skin caused by the deposition of fat and is harmless. (4)
This article will discuss the epidemiology, causative factors, pathophysiology, diagnostic strategies, and treatment plan of cellulitis.
Epidemiology of Cellulitis
Fourteen million people across the United States are affected by cellulitis annually. Out of these, 650,000 patients need hospitalization. In terms of financial burden, 3.7 billion dollars are being spent each year on ambulatory care for patients with cellulitis. (2) A study was conducted in Olmsted County on the prevalence of lower-extremity cellulitis, which shows that the incidence is 199 per 100,000 persons annually (5).
In England, the number of patients treated for cellulitis reached 114,190 in 2014-15. The average hospital stay of these patients was three days (6). The chances of recurrence in these patients are also seen due to possible damage to the lymphatic system and other risk factors.
There is no difference in prevalence between male and female patients. However, it is affected by the age group. The prevalence usually increases with advancing age (2, 5).
Etiology of Cellulitis
Cellulitis is mainly caused by bacterial species. These include Gram-positive cocci such as Streptococcus (S.pyogenes and S. saprophyticus) and Staphylococcus aureus. Tissue culture is done in most cases but is negative in 70% of them. Group A streptococci and S. aureus are the most common organisms found. Skin infection with pus draining wound is strongly indicative of S. aureus infection, while a negative culture is usually associated with streptococcal infection. Group A streptococci are also the causative agent in necrotizing fasciitis, especially in immunocompromised and elderly patients, although other organisms may also be involved. (6)
Animal bites can also cause cellulitis due to organisms such as Pasteurella and Capnocytophaga. While Vibrio vulnificus and Aeromonas species are found in water sources and cause cellulitis when a skin cut is exposed to fresh or salty water. (6)
Although bacteria are the main culprits of cellulitis, in some patients who are elderly or immunocompromised, opportunistic infections by fungi can also cause cellulitis. These include Fusarium solani and Purpureocillium lilacinum. Fungal cellulitis should be suspected when atypical features are present and the patient is not responding to antibiotics. (7)
Anatomy of skin lesions:
Before discussing the pathophysiology of cellulitis, let us look at the skin’s basic anatomy to have a better understanding. The skin consists of three layers, the epidermis, dermis, and hypodermis. All of these have different anatomical and physiological functions. (8)
- The epidermis is the most superficial layer. It is further divided into five layers, stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. It acts as a barrier to the external environment and gives the sensations of warmth, cold, and touch. (3)
- The dermis is the second layer that gives support to the epidermis both nutritionally and structurally. It has a thickness of 1-4 mm, depending on the part of the body. It contains fibroelastic tissue, including collagen bundles and other connective tissue. (3, 9)
- The hypodermis, also called subcutaneous tissue, is present beneath the dermis and contains adipose tissue, skin appendages like hair follicles, and the neurovascular bundle. Below this layer lies the fascia and muscular structures. (8)
Skin infections are defined according to these layers and structures. Impetigo is defined as the infection of the superficial keratin layer, while erysipelas is the infection of the superficial epidermal layer. Cellulitis involves the dermis and subcutaneous tissue, while the underlying fascia and muscle infection are called fasciitis and myositis, respectively. This understanding of basic anatomy and involved structures is essential for the better management of each disease. (10, 11, 12)
Pathophysiology of Cellulitis
Cellulitis is caused by Group A streptococci and Staphylococcus aureus mostly. In response to these bacteria, cytokines, and neutrophils are recruited to the site of infection, producing antimicrobial peptides and inducing keratinocyte proliferation. This leads to the appearance of characteristic findings which are used to diagnose cellulitis, such as erythema, edema of the involved area, warmth, and tenderness upon palpation. These bacteria, especially Group A streptococci, are also believed to produce other virulence factors, such as pyrogenic exotoxins and superantigens, which lead to further tissue destruction and invasive disease. (2, 13)
History and Clinical Features:
- The history of signs and symptoms of cellulitis is critical as these are primarily used to establish the diagnosis. When evaluating a patient for cellulitis, a complete history is compulsory. This should include the time of onset, pattern of spread, and any associated diseases if present.
- How the patient noticed the skin changes for the first time is also relevant in this context. Further, it includes any recent travel history, history of intravenous drug abuse, any trauma or skin injury, and/or any history of animal or insect bite.
- Complete investigations for comorbidities such as diabetes, tinea pedis, chronic lymphedema, venous stasis, or peripheral vascular disease should also be done.
Cellulitis presents as an affected skin area with a pinkish hue and poorly demarcated margins (in contrast to erysipelas, which have well-defined margins). The affected area is tender when palpated, warm to the touch compared to normal skin, and is associated with edema. The skin may also look pitted, and blisters may sometimes develop. Fever and chills may be present. (2, 3)
- The next step is the examination of the affected area.
- It should be inspected thoroughly for any breach, cuts, pitting of the skin, bullae, developing vesicles, or discharge.
- The skin is palpated to check fluctuance, warmth, and tenderness.
- The area is usually demarcated with a marker to monitor the increases in size if present.
- The peripheral pulses and sensations are also checked as intact pulses, and sensations rule out the possibility of compartment syndrome. (3, 10, 14)
Cellulitis is primarily unilateral but can also be bilateral in rare cases. It can affect any part of the body, but in adults, it is usually present in the lower extremities, while children tend to develop it on the neck or the face. It can also be further classified depending on its location. Some types are:
- Orbital cellulitis.
- Periorbital cellulitis.
- Breast cellulitis.
- Facial cellulitis.
- Perianal cellulitis. (4)
Differential Diagnosis of Cellulitis
Many skin lesions and other diseases can mimic cellulitis, and a thorough evaluation should be done. The diseases which should be considered in the differential diagnosis are as follows:
- Impetigo is the infection of superficial layers of the epidermis and commonly presents as erythematous plaques with yellow crust. It is mostly painful, itchy, and highly contagious.
- Erysipelas is the infection of the upper dermis layer presenting as erythema and elevation of the skin. It has well-demarcated borders which are used to differentiate from less distinct borders of cellulitis.
- Necrotizing fasciitis is the infection of fascia leading to necrosis of subcutaneous tissue presenting as fever, erythema, crepitus, and severe pain. It is a surgical emergency, and immediate debridement should be done.
- Chronic deep venous stasis dermatitis is usually bilateral with inflammatory dermatosis and results from chronic venous insufficiency. It affects the lower extremities and presents as peripheral edema and hyperpigmentation.
- Deep venous thrombosis presents with edema, warmth, erythema, and pain in the limb. It is mainly unilateral but can also be bilateral. Usually, there is a history of immobility, coagulation disorders, or a family history of venous thromboembolism.
- Septic arthritis usually presents with joint swelling, decreased joint mobility, warmth, and tenderness. The knee joint is most commonly affected.
- Cellulitis is usually diagnosed clinically. Investigations are not needed in most cases, but they prove to be helpful in checking the patient’s systemic status.
- Baseline liver and renal investigations are done for assessment of end-organ damage in patients with sepsis.
- Blood cultures and biopsies are not routinely done. However, they may be recommended in case of severe skin infection, systemic signs, immunocompromised patients, underlying diseases such as carcinoma, any animal or insect bite, or poor response to antibiotic treatment.
Treatment of Cellulitis
The management of cellulitis depends upon the severity and resistance of the causative organism. Antibiotics are the mainstay of treatment, including non-antibiotic treatments for symptom relief. Moreover, patients treated with no or inadequate antibiotics are associated with prolonged hospital stays and treatment durations. (1) Both of the treatment strategies are discussed here.
Antibiotic Therapy for Cellulitis:
- In cases of mild cellulitis with no systemic involvement, cephalexin and flucloxacillin are considered effective against beta-hemolytic streptococci and methicillin-susceptible Staphylococcus aureus. Cephalexin 500 mg or flucloxacillin 500 mg every 6 hours is recommended. The duration of therapy should be at least five days, with improvement seen within the first two days of therapy. Proper intake timing is advised in flucloxacillin oral therapy before meals or long after. It is also important to note that in obese patients, beta-lactams have low serum concentrations and bioavailability. A higher oral dose may prove to be beneficial in such cases.
- In case of allergy to beta-lactam drugs, clindamycin is the alternative option. Clindamycin, 300 mg to 450 mg, is given after every 6 hours for at least five days. (1, 2)Clindamycin is considered to have more tissue penetration than cephalexin and flucloxacillin, but more evidence is required for this. Some of the S. aureus strains also have the ability to inducible resistance against clindamycin. (2, 15)
- Patients having purulent cellulitis, any abscess or punctured wound associated, a history of intravenous drug abuse, or infection by methicillin-resistant Staphylococcus aureus (MRSA) should be given trimethoprim-sulfamethoxazole 800 mg/160 mg two times a day in addition to the cephalexin or flucloxacillin regimen. Clindamycin can also be used as an alternative, especially if there is an allergy to trimethoprim-sulfamethoxazole. A longer duration of therapy is also required in these cases. (2)
- Severe cases may need hospitalization and intravenous antibiotics. These include patients who are immunocompromised, have failed the initial treatment or cannot tolerate oral medications, have rapidly increasing erythema, or show systemic signs of infection. In severe cases, intravenous antibiotics are recommended. In patients with an absent risk for MRSA, intravenous cefazoline is started initially, and when the patient gets better, then shifted to oral cephalexin for five days.
- If MRSA infection is suspected and risk factors for MRSA are present, intravenous therapy with vancomycin should be initiated with de-escalation to trimethoprim/sulfamethoxazole according to the patient’s response. In the immunocompromised patient, broad-spectrum antibiotics such as vancomycin plus carbapenem or piperacillin-tazobactam are necessary.
- In addition to these drugs, European Medicines Agency has recently approved three novel antibiotics for the treatment of skin infections. These are oritavancin, dalbavancin, and tedizolid, all showing efficacy against MRSA similar to linezolid and vancomycin. Oritavancin and dalbavancin also have the advantage of longer half-lives of over two weeks. This makes one single dose of these antibiotics equal to a 2-week-long course of vancomycin. However, these results still need to be backed up by more studies, and whether it actually decreases the number of admissions remains to be evaluated. (16)
- Cellulitis can also be caused by atypical organisms such as Pseudomonas aeruginosa, Vibrio vulnificus, Cryptococcus, or Pastuerella multocida. Any injury involving water exposure can cause cellulitis by Vibrio vulnificus. Pseudomonas aeruginosa is most common in diabetic foot ulcers and cellulitis in diabetic patients. Pasteurella multocida is the cause of cellulitis in the case of a dog or cat bite. Infection by Cryptococcus is also prevalent in immunocompromised patients.
- Some patients having comorbidities are at increased risk of complications. Delayed antibiotic treatment and smoking are associated with abscess formation. Local complications such as hemorrhagic lesions, necrosis, and bullae formation may occur in obese patients. Similarly, patients with liver cirrhosis, congestive heart failure, and neutropenia may experience local or systemic complications. In patients with significant edema, the underlying cause of edema should be treated as it may cause recurrent cellulitis. Leg elevation and compression stockings can also be used for this purpose.
The non-antibiotic treatment includes compression stockings, leg elevation, and non-steroidal anti-inflammatory drugs (NSAIDs). These are believed to shorten the hospital stay and treatment duration. However, the role of these alternatives in the absence of antibiotic agents is not supported by any study.
Compression stockings are used to reduce edema, which in turn shortens the time to cure. However, patients may complain of pain, itching, dry skin, and constriction. Compression stockings are indicated in cases of persistent lymphedema after several weeks of antibiotic treatment. Before applying compression stockings, the patient’s peripheral arterial status should also be considered. (17) Passive leg elevation is considered another approach to reducing edema.
Many studies support the use of NSAIDs as it helps in faster recovery of patients in adjunct therapy with antibiotics. Similarly, patients receiving steroids such as adjunctive oral prednisolone show earlier resolution of symptoms. However, the effect of these drugs on microbial eradication is still unknown. (18)
Cellulitis can lead to different complications if not treated properly. The most common complication is bacteremia, a condition where the bacterial infection reaches the bloodstream. The clinician should suspect bacteremia when the patient shows systemic signs of infection. A blood culture is required to identify the organism, and appropriate antibiotics should be given immediately.
Bacteremia, if left untreated, can further lead to endocarditis and sepsis (19). Almost 10% of hospitalized cellulitis patients are estimated to develop sepsis during the course of the disease. (20) Diabetes and immunocompromised conditions are also considered risk factors for bacteremia and sepsis. Cellulitis can also lead to osteomyelitis if the infection passes from the dermis and subcutaneous tissue to bone. All these complicated cases need appropriate treatment for a longer duration than uncomplicated cases and may also need surgery.
Cellulitis has an overall good prognosis. If diagnosed and treated with appropriate antibiotics, the patient usually shows signs of recovery in the first 2 days of treatment. The two-year recurrence rate of cellulitis is almost 17%. (2) It can be prevented with proper management, good hand hygiene, proper handling of cuts and abrasions, compression stockings, and leg elevation to relieve edema and treatment of underlying diseases. (2, 17)
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Dr. Muhammad Daniyal Haider is a general physician who continuously seeks for platforms to serve the community and utilize his knowledge and abilities to improve the health
system. Dedication to the cure of diseases and, more importantly, prevention and
awareness of people about these diseases is the goal. He is a general physician, author
and a calligrapher. He is passionate about research projects, latest guidelines and
techniques which can lead to a better approach to the patient’s condition.