What is Erythema Multiforme?
Erythema multiforme (EM) is an acute, immune-mediated skin condition characterized by the sudden appearance of distinctive target-like lesions [1.3.5]. These lesions are often symmetrical and have a predilection for the palms, soles, and extensor surfaces of the limbs [1.10.4]. While the majority of cases are triggered by infections, particularly the herpes simplex virus (HSV), a significant portion are caused by adverse reactions to medications [1.7.4]. Antibiotics are among the most frequently cited drug culprits [1.5.1].
EM is categorized into minor and major forms. EM minor involves the skin with little to no mucous membrane involvement, while EM major features more extensive rash and affects at least two mucosal surfaces, such as the mouth, eyes, or genitals [1.4.4, 1.10.4]. It's important to distinguish EM from more severe conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which were once considered part of the same spectrum but are now understood to be distinct disorders [1.6.4, 1.7.4].
The Link Between Antibiotics and Erythema Multiforme
The reaction is a type of delayed-hypersensitivity response where the immune system reacts to a drug [1.3.1]. In drug-induced EM (DIEM), the mechanism is thought to be mediated by tumor necrosis factor-alpha (TNF-α), which leads to inflammation and damage to keratinocytes (skin cells) [1.3.2]. The onset of symptoms typically occurs within one to four weeks after starting a new medication [1.7.3].
Which Antibiotics Are Most Commonly Implicated?
Several classes of antibiotics are frequently associated with erythema multiforme. While many antibiotics have been linked to EM, some pose a higher risk than others [1.2.3, 1.8.2].
Sulfonamides
This class, particularly trimethoprim-sulfamethoxazole, is one of the most common pharmacologic triggers for EM and more severe reactions like SJS [1.8.2, 1.10.1]. Their widespread use and known potential for causing cutaneous adverse reactions place them at the top of the list [1.8.1].
Penicillins
Penicillins, including amoxicillin and ampicillin, are also frequently implicated in causing EM [1.2.2, 1.11.1]. The aminopenicillins have one of the highest rates of reaction among all recipients [1.8.1]. Concurrent viral infections, like Epstein-Barr virus, can increase the likelihood of a rash when taking amoxicillin [1.8.1].
Cephalosporins
This class of beta-lactam antibiotics, which includes drugs like cefaclor and cephalexin, is also associated with EM [1.2.3, 1.8.2]. As they are structurally related to penicillins, there can be a risk of cross-reactivity.
Other Implicated Antibiotics
While less frequent than the classes above, other antibiotics have also been reported to cause EM:
- Tetracyclines: Includes minocycline and doxycycline [1.2.2].
- Macrolides: Such as erythromycin and azithromycin [1.2.2, 1.2.3].
- Quinolones: For example, ciprofloxacin and levofloxacin [1.2.4, 1.2.5].
Comparison of Common Antibiotics and EM Risk
| Antibiotic Class | Common Examples | Associated Risk Level | Notes |
|---|---|---|---|
| Sulfonamides | Trimethoprim-sulfamethoxazole | High | Frequently implicated in EM and more severe reactions like SJS/TEN [1.8.2, 1.10.1]. |
| Penicillins | Amoxicillin, Ampicillin | High | Aminopenicillins have a high incidence rate of cutaneous reactions [1.8.1, 1.11.1]. |
| Cephalosporins | Cefaclor, Cephalexin, Ceftriaxone | Moderate | Known triggers for EM [1.2.3, 1.5.3, 1.8.2]. |
| Quinolones | Ciprofloxacin, Levofloxacin | Low to Moderate | Reports exist linking these to EM, though less common than penicillins or sulfa drugs [1.2.4, 1.2.5]. |
| Tetracyclines | Minocycline, Doxycycline | Low | Associated with EM, but reported less frequently than other classes [1.2.2]. |
| Macrolides | Azithromycin, Erythromycin | Low | Have been linked to EM, but are considered lower-risk triggers [1.2.2, 1.2.3]. |
Diagnosis and Management
Diagnosis of drug-induced EM is primarily clinical, based on the characteristic target lesions and a temporal relationship with the initiation of a new drug [1.3.2]. A skin biopsy may be performed to confirm the diagnosis and rule out other conditions [1.4.3].
The most critical first step in management is to identify and discontinue the suspected causative antibiotic [1.9.1].
Treatment is largely supportive and focuses on symptom relief [1.9.1]:
- Topical corticosteroids and oral antihistamines can help relieve itching and inflammation [1.9.1].
- For painful oral lesions, anesthetic mouthwashes (like viscous lidocaine) and antiseptic rinses can be used [1.9.3].
- In severe cases, especially EM major with significant mucosal involvement, a short course of systemic corticosteroids like prednisone may be prescribed [1.9.4].
- If oral intake is compromised due to painful mouth sores, hospitalization for intravenous fluids may be necessary [1.9.3].
It is crucial to seek urgent medical attention if the rash is widespread, painful, involves the eyes or genitals, or is accompanied by fever or blistering, as these could be signs of the more dangerous SJS or TEN [1.4.5].
Differentiating EM from SJS/TEN
Distinguishing EM from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) is critical because the latter are medical emergencies with higher mortality rates [1.6.1].
- Etiology: EM is most often caused by infections (~90%), while SJS/TEN are predominantly caused by drugs [1.6.2].
- Lesions: EM features classic, well-defined "typical" target lesions. SJS/TEN lesions are often flat, atypical targets or purpuric macules [1.6.2].
- Distribution: EM lesions are typically acral (hands, feet) and spread centripetally. SJS/TEN often starts on the trunk and spreads outward [1.6.2].
- Skin Detachment: Epidermal detachment in EM, if present, is less than 10% of the body surface area. SJS involves <10%, SJS/TEN overlap is 10-30%, and TEN is >30% [1.6.2].
Conclusion
While antibiotics are essential for treating bacterial infections, they are also a leading drug-related cause of erythema multiforme. Sulfonamides and penicillins are the most frequent culprits, but several other classes can also trigger this hypersensitivity reaction. Recognizing the characteristic target rash and its timing in relation to starting a new antibiotic is key. The cornerstone of management is immediate discontinuation of the offending drug and supportive care to alleviate symptoms. Patients should always report any new, unexplained rash to their healthcare provider, especially after starting a new medication.
For further reading, an authoritative resource on this topic is the National Center for Biotechnology Information (NCBI): https://www.ncbi.nlm.nih.gov/books/NBK470259/
