What is the next step in treating cellulitis (inflammation of the skin and subcutaneous tissues) that is resistant to Keflex (Cephalexin) and Vancomycin?

Management of Cellulitis Resistant to Cephalexin and Vancomycin

For cellulitis that has failed both cephalexin and vancomycin, immediately obtain blood cultures and tissue biopsy/aspirate for culture and susceptibility testing, then initiate empiric therapy with linezolid 600 mg IV/PO every 12 hours or daptomycin 4 mg/kg IV every 24 hours while awaiting culture results. 1

Immediate Diagnostic Steps

When cellulitis fails standard therapy, cultures become essential rather than optional:

• Obtain blood cultures immediately - these are strongly recommended for patients with severe infection or treatment failure 1
• Perform tissue biopsy, aspiration, or deep swab for culture and susceptibility testing to identify the causative organism and resistance patterns 1
• Consider imaging if necrotizing fasciitis is a concern, as rapid progression despite antibiotics is a red flag 1

Empiric Antibiotic Selection While Awaiting Cultures

The failure of both a beta-lactam (cephalexin) and vancomycin suggests either:

1. An unusual or resistant organism
2. MRSA with reduced vancomycin susceptibility (hVISA)
3. A non-infectious mimic of cellulitis
4. Inadequate source control

First-line alternatives for vancomycin-resistant cases:

• Linezolid 600 mg IV or PO every 12 hours - bacteriostatic but no cross-resistance with other antibiotic classes, making it ideal for resistant organisms 1
• Daptomycin 4 mg/kg IV every 24 hours - bactericidal alternative with different mechanism of action 1
• Ceftaroline 600 mg IV every 12 hours - active against MRSA including some vancomycin-intermediate strains 1

Broadening Coverage for Severe or Immunocompromised Patients

If the patient is severely compromised (malignancy on chemotherapy, neutropenia, severe immunodeficiency, immersion injuries, or animal bites):

• Vancomycin plus piperacillin-tazobactam provides broad gram-positive, gram-negative, and anaerobic coverage 1
• Vancomycin plus imipenem or meropenem as an alternative broad-spectrum regimen 1

These combinations cover atypical organisms including Pseudomonas, Aeromonas (water exposure), and Pasteurella (animal bites) 1

Critical Reassessment

Rule out cellulitis mimics - many conditions appear similar to cellulitis but won't respond to antibiotics:

• Stasis dermatitis
• Contact dermatitis
• Deep vein thrombosis
• Lipodermatosclerosis
• Panniculitis 2

Evaluate for complications requiring surgical intervention:

• Abscess formation requiring drainage 1
• Necrotizing fasciitis requiring emergent debridement 1
• Retained foreign body 1

Duration and Monitoring

• Continue antibiotics for 7-14 days for severe infections, individualized based on clinical response 3
• Reevaluate within 24-48 hours after changing therapy to verify clinical response 1
• If no improvement after 5 days on appropriate antibiotics, extend duration and reconsider diagnosis 1, 3

Common Pitfalls to Avoid

• Don't assume all treatment failures are due to MRSA - only 15% of cellulitis cases have identifiable organisms, and beta-hemolytic streptococci remain the most common cause 2
• Don't overlook predisposing factors - examine interdigital toe spaces for tinea pedis or fissuring that may serve as portals of entry 3
• Don't forget elevation - failure to elevate the affected limb delays improvement regardless of antibiotic choice 3
• Avoid using clindamycin empirically for vancomycin failures - 50% of MRSA strains have inducible or constitutive clindamycin resistance 1

Adjusting Therapy Based on Culture Results

Once susceptibility data return:

• De-escalate to narrower spectrum agents when possible based on sensitivities 1
• For confirmed MRSA with vancomycin MIC >1.5 mcg/mL, switch to linezolid or daptomycin 4
• Consider combination therapy with rifampicin plus fusidic acid for multi-resistant MRSA, as resistance develops rapidly with single agents 4