Cellulitis: Causes, Treatment, and Key Investigations
Causes and Microbiology
Beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA) cause the vast majority of cellulitis cases. 1, 2 In the 15% of cases where organisms are identified, these two pathogens account for nearly all culturable infections. 2 The majority of cellulitis cases (approximately 85%) remain nonculturable, making empiric therapy essential. 2
Portal of Entry and Risk Factors
- Preceding skin trauma (minor abrasion, insect bite, injection site) serves as the portal of entry in most cases. 1
- Predisposing conditions include venous insufficiency, lymphedema, chronic edema, obesity, eczema, and tinea pedis with toe web abnormalities. 1
- Diabetes mellitus increases risk and requires special consideration for polymicrobial coverage. 1
- Immunocompromise or neutropenia elevates risk for severe infection. 1
First-Line Treatment for Uncomplicated Cellulitis
Beta-lactam monotherapy is the standard of care for typical nonpurulent cellulitis, achieving 96% clinical success. 1, 2 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary. 1, 3
Oral Antibiotic Options (Choose One)
- Cephalexin 500 mg orally every 6 hours for 5 days 1, 3
- Dicloxacillin 250–500 mg orally every 6 hours for 5 days 1, 3
- Amoxicillin 500 mg orally three times daily for 5 days 1
- Penicillin V 250–500 mg orally four times daily for 5 days 1
Intravenous Options for Hospitalized Patients
- Cefazolin 1–2 g IV every 8 hours (preferred IV beta-lactam) 1, 3
- Nafcillin 2 g IV every 6 hours (alternative) 1, 3
- Oxacillin 2 g IV every 6 hours (alternative) 1
Treatment Duration
Treat for exactly 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, no fever); extend only if symptoms have not improved. 1, 3 High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1 Traditional 7–14-day regimens are no longer necessary. 1
When to Add MRSA Coverage
Add MRSA-active antibiotics ONLY when specific risk factors are present. 1, 3, 2 Do not routinely add MRSA coverage for typical cellulitis, as this represents overtreatment in approximately 96% of cases. 1
MRSA Risk Factors (Any One Triggers Coverage)
- Penetrating trauma or injection drug use 1, 3
- Purulent drainage or exudate (visible at infection site) 1, 3
- Known MRSA colonization or prior MRSA infection 1, 3
- Systemic inflammatory response syndrome (SIRS): fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min 1, 3
- Failure to respond to beta-lactam therapy after 48–72 hours 1, 3
MRSA-Active Regimens (When Indicated)
For purulent cellulitis (monotherapy options):
- Clindamycin 300–450 mg orally every 6 hours for 5 days (provides single-agent coverage for both streptococci and MRSA; use only if local MRSA clindamycin resistance <10%) 1, 3
For nonpurulent cellulitis requiring MRSA coverage (combination therapy mandatory):
- Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS cephalexin 500 mg every 6 hours for 5 days 1, 3
- Doxycycline 100 mg orally twice daily PLUS cephalexin 500 mg every 6 hours for 5 days 1, 3
Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci. 1, 3
Severe Cellulitis Requiring Hospitalization
Hospitalization Criteria (Any One Mandates Admission)
- Systemic inflammatory response syndrome (SIRS): fever, tachycardia, hypotension, altered mental status 1, 3
- Signs of necrotizing infection: severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas in tissue, bullous changes 1
- Severe immunocompromise or neutropenia 1, 3
- Failure of outpatient treatment after 24–48 hours 1
IV Antibiotic Regimens for Severe Infection
For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis:
- Vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours 1, 3
- Alternative combinations: vancomycin PLUS meropenem 1 g IV every 8 hours, OR vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1
For complicated cellulitis without systemic toxicity (MRSA coverage needed):
- Vancomycin 15–20 mg/kg IV every 8–12 hours (first-line, A-I evidence) 1, 3
- Linezolid 600 mg IV twice daily (A-I evidence) 1, 3
- Daptomycin 4 mg/kg IV once daily (A-I evidence) 1, 3
- Clindamycin 600 mg IV every 8 hours (A-III evidence; only if local MRSA resistance <10%) 1, 3
Treatment duration for complicated infections is 7–14 days, individualized based on clinical response. 1
Key Investigations
When Laboratory Testing Is NOT Needed
For uncomplicated cellulitis without systemic signs, no laboratory studies are required. 3 Blood cultures are positive in only approximately 5% of typical cases and are therefore unnecessary. 1, 3
When to Obtain Laboratory Studies
Order the following ONLY when systemic toxicity is present (fever >38°C, tachycardia, hypotension, altered mental status): 3
- Blood cultures with susceptibility testing 3
- Complete blood count with differential 3
- Serum creatinine, bicarbonate, creatine phosphokinase (CPK), and C-reactive protein (CRP) 3
Laboratory Abnormalities Indicating Higher Risk
Consider hospitalization if any of the following are present: 3
- Hypotension or elevated serum creatinine 3
- Low serum bicarbonate 3
- CPK ≥2–3× upper limit of normal 3
- Marked left-shift on white-cell differential 3
- CRP >13 mg/L 3
Tissue Cultures and Biopsies
Gram stain and culture of needle-aspiration or punch-biopsy specimens are indicated ONLY in patients with: 3
- The laboratory abnormalities listed above 3
- Severe systemic features, malignancy, neutropenia, or unusual predisposing factors 1
Imaging Studies
Imaging is reserved for specific clinical scenarios: 1
- Plain radiographs or MRI when osteomyelitis is suspected (probing to bone, chronic non-healing wounds) 1
- Ultrasound to assess for abscess when clinical uncertainty exists (any fluctuance requires incision and drainage) 1
- MRI for suspected necrotizing fasciitis, deep abscess, or osteomyelitis 1
Do not delay antibiotics to obtain imaging when clinical presentation is straightforward. 1
Essential Adjunctive Measures
- Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and inflammatory substances. 1, 3
- Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection risk. 1, 3
- Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, obesity, eczema. 1, 3
- Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in nondiabetic adults, though evidence is limited. 1, 3 Avoid corticosteroids in diabetic patients. 1
Prevention of Recurrent Cellulitis
Annual recurrence rates are 8–20% in patients with previous cellulitis. 1 For patients with 3–4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: 1
- Penicillin V 250 mg orally twice daily for 4–52 weeks 1
- Erythromycin 250 mg orally twice daily for 4–52 weeks 1
- Intramuscular benzathine penicillin every 2–4 weeks 1
Common Pitfalls to Avoid
- Do not add MRSA coverage reflexively for typical nonpurulent cellulitis without specific risk factors—this overtreats 96% of cases and promotes resistance. 1, 3
- Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis—they lack reliable streptococcal coverage. 1, 3
- Do not automatically extend therapy to 7–10 days—extend only if warmth, tenderness, or erythema have not improved after 5 days. 1, 3
- Do not delay surgical consultation when signs of necrotizing infection (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue) are present. 1, 3
- Do not obtain blood cultures or extensive laboratory testing for typical uncomplicated cellulitis—this represents unnecessary resource utilization. 3
- Do not treat simple abscesses with antibiotics alone—incision and drainage is the primary treatment. 1, 3
Monitoring and Follow-Up
Reassess patients within 24–48 hours to verify clinical response. 1, 3 Treatment failure rates of approximately 21% have been reported with some oral regimens. 1 If no improvement after 48–72 hours of appropriate therapy, consider: 1