What is the differential diagnosis and management approach for a 39-year-old female, post right lung decortication, with a maculopapular rash and eosinophilia, unresponsive to oral steroids, with a history of using Augmentin (amoxicillin/clavulanate), Voltaren (diclofenac), Vancomycin, Meropenem, and currently on Levofloxacin?

DRESS Syndrome with Steroid Resistance: Immediate Escalation Required

This patient has progressed from maculopapular rash to targetoid lesions with worsening eosinophilia despite oral steroids—this represents severe DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) that is steroid-resistant and requires immediate escalation to high-dose intravenous corticosteroids and discontinuation of levofloxacin. 1

Differential Diagnosis

Your patient meets criteria for severe DRESS syndrome based on the following:

• Maculopapular rash progressing to targetoid lesions involving >50% body surface area 1
• Marked eosinophilia (initially 1.23, now 3.02—a 2.5-fold increase) 1
• Leukocytosis with neutrophilia suggesting systemic involvement 1
• Temporal relationship: Rash developed 2-3 weeks after Augmentin/Voltaren exposure, classic timing for DRESS 2
• Progression despite treatment: Worsening on oral steroids indicates severe disease 2

Key Differential Considerations:

1. DRESS Syndrome (Most Likely): The combination of maculopapular rash, eosinophilia >1.5, organ involvement (leukocytosis), and progression to targetoid lesions meets criteria for severe cutaneous adverse reaction 1, 2

2. Stevens-Johnson Syndrome/TEN overlap: The targetoid lesions raise concern for SJS/TEN, though the marked eosinophilia and systemic symptoms favor DRESS 1

3. Acute Generalized Exanthematous Pustulosis (AGEP): Less likely given absence of pustules, but facial edema and fever >38.5°C would support this 1

Most Likely Culprit Drugs

Augmentin (amoxicillin-clavulanate) is the primary suspect, with vancomycin and levofloxacin as additional concerns:

• Amoxicillin-clavulanate: Well-documented DRESS trigger with median onset 24 days, can cause severe reactions even without prior sulfasalazine allergy 3, 4, 2
• Vancomycin: Known DRESS trigger, particularly concerning given prior exposure and potential for delayed hypersensitivity 5, 4
• Levofloxacin (current): Can cause severe dermatologic reactions including TEN and SJS, and may be perpetuating the reaction 6
• Diclofenac (Voltaren): NSAIDs are implicated in DRESS but less commonly than antibiotics 2

Why Oral Steroids Failed

Oral prednisone 40 mg is insufficient for severe DRESS syndrome—the progression indicates:

• Inadequate dosing: Severe DRESS requires 1-2 mg/kg/day (approximately 60-120 mg for a 60 kg patient) 3, 5
• Ongoing drug exposure: Levofloxacin may be perpetuating the hypersensitivity reaction 6, 2
• Severe systemic involvement: Targetoid lesions and rising eosinophilia indicate progression requiring IV therapy 1, 5

Immediate Management Algorithm

Step 1: Drug Discontinuation (Within Hours)

• Stop levofloxacin immediately—fluoroquinolones can cause severe cutaneous reactions and may be cross-reacting 6
• Avoid all beta-lactams permanently—flag Augmentin as severe allergy 4, 7
• Document vancomycin allergy given prior exposure and current presentation 5

Step 2: Escalate Corticosteroid Therapy (Immediately)

• Switch to IV methylprednisolone 1-2 mg/kg/day (60-120 mg daily in divided doses) 3, 5
• Continue for minimum 2-3 weeks before attempting taper 5, 2
• Monitor for steroid-related complications: hyperglycemia, infection risk, GI bleeding 3

Step 3: Comprehensive Organ Assessment (Within 24 Hours)

• Liver function tests: AST, ALT, alkaline phosphatase, bilirubin—hepatitis is the main organ manifestation 1, 5
• Renal function: Creatinine, urinalysis for hematuria/proteinuria—acute kidney injury common 5
• Complete blood count with differential: Monitor for atypical lymphocytes, thrombocytopenia, anemia 1, 5
• Chest imaging: Given continuous air leak, assess for eosinophilic infiltration 3

Step 4: Skin Biopsy (Within 48 Hours)

• Punch biopsy of targetoid lesion: Look for interface dermatitis with eosinophilic infiltrates to confirm DRESS vs SJS/TEN 4
• RegiSCAR scoring: Calculate definitive score (≥5 = definite DRESS) 5, 4, 2

Step 5: Alternative Antibiotic Selection

For the continuous air leak requiring ongoing coverage:

• Aztreonam (monobactam)—no cross-reactivity with beta-lactams 1
• Linezolid—if MRSA coverage needed, avoid vancomycin 1
• Avoid fluoroquinolones given current levofloxacin exposure 6

Critical Pitfalls to Avoid

1. Do not continue levofloxacin "because the patient needs antibiotics"—the drug reaction carries 9% mortality risk and must be stopped 2

2. Do not rely on oral steroids for severe DRESS—progression to targetoid lesions with rising eosinophilia demands IV therapy 3, 5

3. Do not assume improvement means resolution—DRESS can have prolonged course with flares during steroid taper requiring 3-6 months treatment 2

4. Do not miss organ involvement—check liver/kidney function even without symptoms, as hepatitis represents main organ manifestation 1, 5

5. Do not rechallenge with any beta-lactam—amoxicillin can trigger DRESS even without prior sulfasalazine allergy, and cross-reactivity is high 3, 7

Monitoring During Treatment

• Daily clinical assessment: Rash extent, new targetoid lesions, mucosal involvement 1
• Eosinophil count every 2-3 days: Should decrease within 1 week of appropriate therapy 3, 5
• Liver enzymes twice weekly: Peak typically occurs 2-4 weeks after onset 5, 2
• Renal function every 2-3 days: Acute kidney injury can develop or worsen 5

When to Consider Additional Immunosuppression

If no improvement after 3-5 days of high-dose IV steroids:

• IVIG 2 g/kg over 3-5 days—reported benefit in steroid-refractory DRESS 2
• Cyclosporine—consider for severe cases with extensive skin involvement 2
• Dermatology and allergy consultation—mandatory for refractory cases 1

Prognosis and Long-Term Management

• Mortality risk 9% overall, higher with allopurinol (23% of deaths), but antibiotics also carry significant risk 2
• Steroid taper over 3-6 months—rapid taper causes flares 2
• Permanent drug allergy documentation: Augmentin, vancomycin, potentially all beta-lactams and levofloxacin 4, 7
• Genetic testing not routinely indicated for antibiotic-induced DRESS (unlike abacavir) 1