Introduction
Cellulitis, a common yet clinically complex condition, presents a significant challenge in medical practice. The nuances of diagnosis, often obscured by conditions mimicking its presentation, frequently lead to both under and overtreatment with antimicrobials. This article aims to provide a comprehensive overview of cellulitis, focusing on typical presentations, underlying microbiology, and evidence-based management strategies to optimize patient outcomes.
Defining Cellulitis
Cellulitis is fundamentally an acute infection of the skin that extends into the dermis and subcutaneous tissues. It’s important to distinguish cellulitis from erysipelas, which is classically described as a more superficial infection, often involving the face or extremities, with notable lymphatic involvement and typically caused by streptococcal bacteria. While diabetic foot infections and wound infections share some characteristics with cellulitis, they are distinct clinical entities with different management approaches and will not be discussed in detail here. The primary focus of this article is cellulitis of the lower limb, the most frequently affected site.
The Clinical Burden of Cellulitis
The impact of cellulitis on healthcare systems is substantial. In the UK during 2014–15, cellulitis was the primary diagnosis in over 114,000 secondary care consultant episodes and accounted for nearly 76,000 inpatient admissions. The median hospital stay was 3 days, with a mean patient age of 63. These figures underscore the significant burden on secondary care, and it’s important to note that a considerably larger number of cases are managed in primary care settings, further highlighting the widespread prevalence of this condition.1
Understanding the Microbiology of Cellulitis
The predominant causative agents in cellulitis are Gram-positive cocci, primarily Streptococcus species and Staphylococcus aureus.2
Blood cultures are positive in less than 10% of cellulitis cases, limiting their diagnostic utility. Wound or tissue cultures are even less helpful, yielding negative results in up to 70% of cases.3 When cultures are positive, S. aureus, Group A streptococci, and Group G streptococci are the most frequently identified isolates from wound cultures.4 Serological studies suggest that Group A streptococcal infection is a significant contributor to culture-negative cellulitis.5 Notably, purulent skin infections are strongly correlated with S. aureus.6
Specific exposures can suggest less common pathogens. Animal bites raise suspicion for Gram-negative bacteria such as Pasteurella and Capnocytophaga. Exposure of skin breaks to saltwater or freshwater is associated with Vibrio vulnificus and Aeromonas species, respectively.2
It’s crucial to remember that while Group A streptococci are common in cellulitis, they are also implicated in necrotising fasciitis, a severe and rapidly progressing infection. Necrotising fasciitis can also arise from mixed infections involving Gram-negative and anaerobic organisms, particularly in vulnerable populations such as the elderly and immunosuppressed.2
Clinical Presentation: Recognizing Cellulitis
The cardinal signs of cellulitis are the classic inflammatory indicators: rubor (redness), dolor (pain), tumor (swelling), and calor (heat). The clinical severity spectrum ranges widely, from localized erythema in a patient who is otherwise systemically well to rapidly spreading erythema and the life-threatening sepsis seen in necrotising fasciitis. Disproportionate pain relative to the visible clinical signs, especially when coupled with a history of rapid progression, should raise immediate suspicion for necrotising fasciitis.7 The time course and evolution of skin findings can help differentiate cellulitis from conditions that mimic it but follow a more chronic clinical course. A history of recent antibiotic use or hospital contact should prompt consideration of antibiotic resistance in the potential causative organisms.
A thorough clinical examination is essential to identify a potential portal of entry, such as skin ulcers, trauma, eczema, or cutaneous mycosis.5 Bilateral lower limb erythema in an afebrile patient with normal inflammatory markers should prompt reconsideration of a cellulitis diagnosis.8 Systemic symptoms and groin pain are frequently observed and may even precede the onset of visible skin changes.5 In severe cases of cellulitis, skin breaks, bullae, or areas of necrotic tissue may be present. Box 1 outlines key elements in history taking to aid in accurate diagnosis.
Box 1. Key Points in History Taking for Cellulitis
| Aspect | Details to Elicit |
|---|---|
| Progression | Pattern and speed of progression of symptoms |
| Comorbidities | Age and underlying medical conditions (diabetes, chronic kidney disease, hepatic disease, vascular disease, immunosuppression) |
| Antibiotic History | Recent antimicrobial treatment |
| Inoculation Site | Possible site of inoculation – trauma, fungal infections |
| Recurrence | History of previous cellulitis episodes |
| Travel History | Recent travel, especially to areas with endemic infections |
| Atypical Organism Risk | Risk factors for atypical organisms: profound immunosuppression, animal or human bites, sea or freshwater exposure (to broken skin) including pools and spas, exposure to animals, fish, or reptiles, intravenous drug use (including skin-popping) |
aAdapted from reference 2
Risk Factors Predisposing to Cellulitis
Several factors increase the risk of developing lower limb cellulitis. Case-control studies have consistently identified skin breaks, lymphedema, venous insufficiency, tinea pedis (athlete’s foot), and obesity as significant risk factors.9–11 Addressing these modifiable risk factors is crucial in both preventing initial episodes and reducing the recurrence of cellulitis.
Initial Management and Diagnostic Considerations
Baseline assessment of liver and renal function can be valuable, particularly in patients with suspected sepsis, both for evaluating end-organ dysfunction and for guiding antimicrobial dosing. Routine cultures of blood, aspirates, or biopsies are generally not recommended in typical cellulitis cases. However, cultures should be considered in patients exhibiting systemic sepsis, those who are immunosuppressed, or in cases associated with immersion injuries or animal bites, where atypical pathogens are more likely.12
Differentiating Cellulitis from Mimics
Misdiagnosis of cellulitis is surprisingly common. Studies indicate that approximately 30% of patients initially diagnosed with cellulitis are ultimately found to have an alternate condition.13,14 Common conditions that mimic cellulitis include eczema, lymphoedema, and lipodermatosclerosis. Importantly, among misdiagnosed patients, a significant majority (85%) did not require hospital admission, and 92% received unnecessary antibiotics, highlighting the potential for antibiotic stewardship improvement and reduced healthcare costs through more accurate diagnosis.
Risk Stratification in Cellulitis
Accurate risk stratification is essential to guide appropriate management intensity. While the British Society for Antimicrobial Chemotherapy (BSAC) and the UK Clinical Resource Efficiency Support Team (CREST) guidelines recommend the Eron classification for grading cellulitis severity,15,16 its clinical utility has been limited by the lack of a clear sepsis definition and potentially overlapping categories.
Marwick and colleagues developed a modified version of the Eron classification, termed the Dundee classification, to better categorize patients based on the presence or absence of defined systemic sepsis features, significant comorbidities, and their Standardised Early Warning Score (SEWS).17 The sepsis markers used in the Dundee classification (Box 2) aligned with the Systemic Inflammatory Response Syndrome (SIRS) definition at the time of the study. The SEWS, a standardized early warning score derived from routine clinical observations, uses a threshold score of 4 to identify the most severely unwell patients (class IV) requiring immediate clinical review. Table 1 compares the Eron/CREST classification with the modified Dundee classification.
Box 2. Dundee Classification – Markers of Sepsis
| Criteria |
|---|
| Presence of infection with two or more of the following: white blood cell count >12/mm3, temperature >38°C, heart rate >90 beats/min, respiratory rate >20 breaths/min |
Table 1. Cellulitis Severity Classification
| Eron/CREST Classification | Modified ‘Dundee’ Classification |
|---|---|
| Class I | No or well-controlled comorbidities, systemically well |
| Class II | Systemically unwell with no uncontrolled comorbidities (e.g., obesity, peripheral vascular disease, or venous insufficiency) or systemically well with poorly controlled comorbidities that may delay recovery |
| Class III | Marked systemic inflammatory response (altered mental status, tachypnea, tachycardia, hypotension, etc.) or very poorly controlled comorbidities that may affect treatment response or limb-threatening infection due to vascular compromise |
| Class IV | Septic shock or life-threatening presentations such as necrotising fasciitis requiring urgent critical care and surgical input |
aLeft-hand column adapted from reference 16, right-hand column adapted from reference 17. CREST = Clinical Resource Efficiency Support Team; SEWS = Standardised Early Warning Score
Marwick and colleagues utilized the Dundee criteria to assess severity and then evaluated the appropriateness of prescribed antimicrobial regimens.17 Their findings revealed significant overtreatment of skin and soft tissue infections (SSTIs), particularly in the lowest severity group (Dundee class I), where 65% of patients were deemed overtreated, both in terms of antimicrobial spectrum and route of administration. Conversely, undertreatment and 30-day mortality increased with increasing disease severity class, ranging from 1% mortality and 14% undertreatment in class I to 33% mortality and 92% undertreatment in class IV. These results suggest that current severity scoring systems may not be sufficiently robust to guide empirical antimicrobial therapy. The study also found no significant difference in antimicrobial therapy or outcomes between class I and II patients, suggesting these groups could be combined to simplify the classification.
While other severity and prognostic scoring systems for SSTIs have been proposed, they require further validation.18 The National Institute for Health and Care Excellence (NICE) moderate- and high-risk criteria (high-risk criteria shown in Box 3) can assist clinicians in rapidly identifying patients with cellulitis-related sepsis who require urgent hospital admission and assessment.19
Box 3. Suspected Sepsis – High-Risk Criteriaa
| Criteria |
|---|
| Objective evidence of new altered mental state |
| Respiratory rate ≥25 breaths per minute or new need for oxygen (≥40% FiO2) to maintain saturation ≥92% (or ≥88% in known chronic obstructive pulmonary disease) |
| Heart rate ≥130 beats per minute |
| Systolic blood pressure ≤90 mmHg or ≥40 mmHg below normal |
| Not passed urine in previous 18 hours, or for catheterised patients passed minimal urine |
| Mottled or ashen appearance |
| Cyanosis of skin, lips, or tongue |
| Non-blanching rash of skin |
aAdapted from reference 19. © NICE [2016]. Available from www.nice.org.uk/guidance/ng51 All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication.
Evidence-Based Treatment Strategies for Cellulitis
For purulent skin and soft tissue infections, such as abscesses, furuncles, or carbuncles, incision and drainage of collections is the primary treatment. Bacterial cultures of drained material should be obtained, and systemic antibiotics should be considered in patients with systemic signs of infection.12
Non-purulent skin and soft tissue infections generally require systemic antimicrobial therapy. Oral antibiotics are typically sufficient for patients without systemic signs of infection and no significant comorbidities (Dundee class I). Some Dundee class II patients may also be suitable for oral therapy, while others may require an initial period of intravenous (IV) therapy, either in a hospital setting or via outpatient parenteral antimicrobial therapy (OPAT). IV agents are indicated for patients with systemic infection (Dundee class III and IV) or those who fail to respond to oral therapy. In cases where deep or necrotising infection is suspected, urgent surgical consultation for potential surgical exploration and debridement is crucial.12
Empirical antimicrobial regimens vary based on local practice and resistance patterns. However, in mild to moderate cellulitis, initial therapy should target streptococci. In patients with penetrating trauma or purulent infection, adding anti-staphylococcal coverage is strongly recommended.12 UK CREST guidelines suggest using an agent with activity against both streptococci and staphylococci, such as flucloxacillin.16 Given the increased risk of venous thromboembolism associated with acute inflammation and immobility, thromboprophylaxis with low-molecular-weight heparin should be considered according to local and national guidelines.
Table 2. Suggested Initial Oral and IV Antibiotic Recommendations for Cellulitis
| Penicillin Allergy Status | No Penicillin Allergy | Non-Severea Penicillin Allergy | Severea Penicillin Allergy |
|---|---|---|---|
| Initial Oral Therapy | Flucloxacillin 500 mg – 1 g four times daily (QDS) orally (PO) | Cephalexin 500 mg QDS PO or agents for severe penicillin allergy | Clarithromycin 500 mg twice daily (BD) PO or Doxycycline 100 mg BD PO |
| Initial IV Therapy | Flucloxacillin 1–2 g every 6 hours IV | Ceftriaxone 1–2 g once daily (OD) IV | Clindamycin 600 mg – 1.2 g QDS IV or IV vancomycin |
aSevere penicillin allergy: anaphylaxis, angioedema, stridor, immediate onset urticarial
Note: In patients colonised with MRSA, consider adding vancomycin and consult with local infectious diseases/microbiology team.
Antimicrobial selection in suspected necrotising fasciitis or cellulitis with systemic sepsis syndrome requires urgent discussion with local infectious diseases/microbiology specialists.
bd = twice daily; PO = oral; IV = intravenous; qds = four times daily
Specific clinical scenarios, such as infections following human or animal bites, may necessitate broader-spectrum antimicrobial coverage and should be discussed with an infectious disease specialist. Similarly, cellulitis involving atypical locations like the face, torso, and upper limb warrants expert consultation.
Patients with severe or necrotising infections require initial broad-spectrum antimicrobial therapy to cover staphylococci, streptococci, Gram-negative organisms, and to include agents with activity against toxin production in Group A streptococci, such as clindamycin or linezolid.12,15 Empirical MRSA coverage should be considered in patients with a history of or risk factors for MRSA colonisation, as well as in suspected necrotising fasciitis.12 However, recent prospective trials in the USA suggest that routine empiric MRSA coverage may not be necessary in non-purulent cellulitis.20
The historical practice of adding benzylpenicillin to flucloxacillin in cellulitis treatment lacks strong evidence.21 A randomised controlled trial comparing flucloxacillin and clindamycin versus flucloxacillin alone found no significant difference in clinical improvement or return to normal activities, but the clindamycin group experienced increased diarrhea.22 Brunn and colleagues found that early antimicrobial escalation within the first 3 days of therapy did not improve outcomes, emphasizing the importance of non-antibiotic measures like limb elevation and comorbidity management as integral components of cellulitis management.23
Outpatient parenteral antimicrobial therapy (OPAT) has become increasingly vital for ambulatory care delivery. Cellulitis was the most common primary infection diagnosis in the UK OPAT Outcomes registry in 2015.24 OPAT can be considered as initial management for suitable patients with moderate (Dundee grade II) cellulitis without necrotising infection or sepsis12,15 or to facilitate early discharge in improving patients. OPAT success rates are approximately 90%.25
The optimal duration of antimicrobial therapy for cellulitis remains debated. Traditionally, uncomplicated cellulitis has been treated with 1–2 weeks of antibiotics.15 However, emerging evidence suggests that shorter courses, such as 5 days, may be sufficient for uncomplicated cases.26 Provided there are no concerns about oral absorption and clinical improvement is evident, most patients with uncomplicated SSTIs can safely transition to oral antibiotics after 1–4 days of parenteral therapy.15,16 CREST guidelines recommend settling pyrexia, stable comorbidities, reduced erythema, and decreasing inflammatory markers as criteria for switching to oral antibiotics.16 Addressing any predisposing factors, such as tinea pedis or lymphedema, is essential to minimize the risk of recurrent cellulitis.
Prophylaxis for Recurrent Cellulitis
Patients with a history of cellulitis, particularly of the lower limbs, have a significant recurrence risk, estimated at 8–20%.12 Patients with recurrent cellulitis should be thoroughly evaluated for underlying predisposing factors like lower limb edema, lymphedema, dermatitis, and tinea pedis. Measures to address these factors should be implemented. For patients experiencing three to four episodes of cellulitis annually despite addressing predisposing factors, prophylactic antimicrobial therapy may be considered as long as these risk factors persist.12 A randomised controlled trial of phenoxymethylpenicillin prophylaxis demonstrated a reduced recurrence rate in the treatment group (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.35–0.86, p=0.001), with a number needed to treat (NNT) of five (95% CI 4–9).27
References
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