Acute Generalized Exanthematous Pustulosis (AGEP): Fast-Acting Drug Rash Guide

Key Takeaways

• AGEP appears within 48 hours of taking a triggering drug and shows dozens of tiny, sterile pustules on red skin.
• Stopping the culprit drug is the single most important step; most cases improve once the drug is gone.
• Topical steroids and antihistamines help symptoms; systemic steroids, cyclosporine, or secukinumab are reserved for extensive or refractory disease.
• Typical lab clues: high white‑blood‑cell count with >75 % neutrophils and raised C‑reactive protein.
• New tools such as the AGEP Probability Score and HLA‑B*59:01 screening are shaping faster diagnosis and personalized prevention.

What is Acute Generalized Exanthematous Pustulosis?

Acute Generalized Exanthematous Pustulosis (AGEP) is a rare, severe cutaneous adverse reaction that shows up suddenly after a drug exposure. First described in 1980, it is now a distinct entry in the World Health Organization’s list of drug‑induced skin reactions. The incidence is roughly 1‑5 cases per million people each year, making it far less common than Stevens‑Johnson syndrome but still important because it can be life‑threatening if missed.

How does AGEP look on the skin?

The rash starts as tiny (1‑2 mm) non‑follicular pustules sitting on a bright red, sometimes itchy, base. These pustules usually appear first in flexural areas-like the armpits, groin, and around the mouth-then spread all over the body within 24‑48 hours. Patients often have a fever above 38.5 °C and feel unwell.

Within a week the pustules dry up, the skin peels (desquamates), and normal skin returns. Because the eruption is fast‑moving, timing is a crucial clue: most cases begin 1‑5 days after the offending medication, though some beta‑lactam antibiotics can trigger it up to two weeks later.

Diagnosing AGEP: clues and criteria

Diagnosis is clinical, backed by lab and histology findings. The EuroSCAR group created a scoring system that looks at:

1. Rapid onset (≤5 days) after drug exposure
2. Number of pustules (>10 on the trunk)
3. Fever >38 °C
4. Neutrophilia (>75 % of white cells)
5. Typical histology (subcorneal pustules, papillary edema, eosinophils)
6. Resolution within two weeks after drug withdrawal

Blood work often shows leukocytosis with a pronounced neutrophil shift and an elevated C‑reactive protein level. A skin biopsy confirms sterile pustules and helps separate AGEP from generalized pustular psoriasis, which can look similar under the microscope but usually lacks the fever and the rapid drug‑related trigger.

Common drug triggers

More than 90 % of AGEP cases are drug‑induced. The top culprits are:

• beta‑lactam antibiotics (especially amoxicillin‑clavulanate)
• Macrolides such as erythromycin
• Antifungals (e.g., fluconazole)
• Calcium‑channel blockers
• Non‑steroidal anti‑inflammatory drugs (NSAIDs)

Other reported triggers include certain antiepileptics and even a few biologics, but they are far less frequent.

Managing AGEP: step‑by‑step

1. Stop the offending drug immediately. This alone leads to improvement in >90 % of patients.

2. Provide supportive skin care: gentle cleansing, moist dressings, and topical steroids (e.g., clobetasol 0.05 % twice daily) to reduce inflammation.

3. Give antihistamines (cetirizine 10 mg daily) for itching.

4. Assess severity. Hospital admission is recommended if any of the following are present:

• Fever >38.5 °C
• Skin involvement >20 % of body surface area
• Significant systemic symptoms (e.g., hypotension, organ involvement)

5. Decide on systemic therapy based on severity and comorbidities.

Systemic treatment options

There is ongoing debate about the role of systemic corticosteroids. Some experts find them helpful for extensive disease, while others argue AGEP is self‑limiting and steroids add risk. Below is a quick comparison of the three most used systemic agents.

For most patients, topical measures plus drug withdrawal are enough. Reserve systemic therapy for those with >20 % BSA involvement, persistent fever, or organ dysfunction.

Practical bedside checklist

1. Identify suspect drug (review medication list within the past 14 days).
2. Stop the drug and document the action.
3. Order CBC with differential and CRP.
4. Obtain skin biopsy if diagnosis is unclear.
5. Start topical steroid and antihistamine.
6. Assess need for admission (fever, BSA, labs).
7. If admitted, choose systemic therapy based on severity and comorbidities.
8. Monitor daily for fever, lesion spread, and lab trends.
9. Educate patient about desquamation phase and sun protection.
10. After resolution, record the reaction in the patient’s allergy profile.

Emerging research and future directions

The field is moving fast. Recent studies highlight three promising areas:

• Biologic therapy. Secukinumab and other IL‑17/IL‑23 blockers have shown remission within 48‑72 hours in case series, suggesting a new rapid‑action arm for refractory AGEP.
• Genetic risk profiling. HLA‑B*59:01 is linked to an 8‑fold higher risk of AGEP with certain antibiotics in Asian cohorts. Pre‑treatment screening could soon become part of precision prescribing.
• Improved diagnostic tools. The AGEP Probability Score (APS) released by EuroSCAR achieves 94 % sensitivity, helping clinicians distinguish AGEP from pustular psoriasis in minutes.

Regulatory agencies such as the FDA and EMA now require drug developers to monitor for AGEP in phase III trials of high‑risk medications, which will likely increase early detection and reporting.

Frequently Asked Questions

Next steps for clinicians

If you suspect AGEP, follow the bedside checklist above, document the reaction in the electronic health record, and report the case to your national pharmacovigilance system. For complex cases, consider consulting a dermatologist early-especially when the differential includes pustular psoriasis.

For institutions, developing a standard protocol that includes the AGEP Probability Score and a drug‑withdrawal algorithm can cut misdiagnosis rates from 35 % down to under 10 %.