Fixed drug eruption induced by clarithromycin and paracetamol in a child

Fixed drug eruption (FDE) is a type of cutaneous adverse drug reaction characterized by recurrent lesions at the same site upon re-exposure to the culprit drug. Although paracetamol is a known trigger of FDE, clarithromycin-induced FDE is rarely reported, mostly in adults.1, 2 We present the first pediatric case of FDE in the literature, associated with both paracetamol and clarithromycin, in a child with an atopic background. A 13-year-old boy with a known history of asthma and allergic rhinitis, sensitized to house dust mites and cats, was referred to our allergy clinic for evaluation of recurrent cutaneous reactions after two unrelated drugs at different times. The patient reported that 2 years ago, 3–4 h after taking paracetamol, three livid red lesions, each approximately 1 cm in diameter, developed 1 cm above the right wrist. There was no itching, but pain accompanied the lesions. Six months later, the patient reported developing a few hyperemic lesions on his hand after taking oral clarithromycin. The lesion appeared 4 days after a 5-day course of clarithromycin treatment. Both eruptions turned purple in 10 days and persisted for several months without systemic symptoms. No photographs of the initial lesions were available. The patient denied any prior drug hypersensitivity reactions and had previously tolerated both medications. Informed consent was obtained for the intradermal test (IDT) and drug provocation test (DPT). Skin prick test (SPT) was performed using intravenous preparations: a 7 × 7 mm wheal was observed at 40 min with clarithromycin (Clarol®, Vem, Turkey), and a 4 × 4 mm wheal was noted at 20 min with paracetamol (Paracerol®, Polifarma, Turkey). Delayed readings were negative. The patch tests with paracetamol (10%) and clarithromycin (10%) (Chemotechnique Diagnostics, Vellinge, Sweden) were performed on the back using IQ Patch Test Chambers® (Chemotechnique Diagnostics, Vellinge, Sweden). The occlusion time was 48 h, and patch test results were evaluated at 48 h and 72 h. Both patch test results were negative. Considering the clinical history suggestive of delayed-type reactions, DPTs were planned. Two months later, a DPT with paracetamol (Parol®, Atabay, Turkey) was performed. Five hours after ingestion, a non-pruritic, asymptomatic, 3 × 3 cm oval livid-erythematous lesion developed at the same site on the arm where the previous lesion had occurred. The reaction was evaluated as a FDE to paracetamol. Another DPT was conducted 2 months later with oral clarithromycin (Klacid®, Abbott, Turkey). Approximately 4 h post-ingestion, two hyperemic lesions appeared on the dorsum of the hand, consistent with FDE (Figure 1). The clinical features, such as timing, lesion morphology, recurrence at the same sites, and resolution with residual hyperpigmentation, were consistent with FDE. The patient was thus diagnosed with FDE to both paracetamol and clarithromycin. Given that the two drugs have unrelated chemical structures, the possibility of a reaction to shared excipients was investigated. Both formulations contained povidone, which has been reported to cause anaphylaxis and contact dermatitis.3-5 Patch testing was performed on the hyperpigmented lesions and the patient's arm using povidone (Batticon® 10%, Adeka, Turkey). Two different concentrations were prepared for testing: 2% (aqueous) and 10% (aqueous).5 Patch testing was negative at both the lesional skin sites and the arm. FDE due to paracetamol has rarely been reported in children, with most cases presenting as the classic form and only a few involving bullous lesions.6 Clarithromycin-induced FDE is extremely uncommon even in adults; in one report, the diagnosis was made in a 14-year-old girl based solely on clinical history, without confirmation by oral provocation.7 To our knowledge, our case represents the first pediatric report of clarithromycin-induced FDE confirmed by DPT. It is also the first reported case of FDE triggered by both paracetamol and clarithromycin, which are chemically unrelated drugs. FDE is driven by intraepidermal CD8+ residual memory T cells that remain at the site of the initial lesion and become reactivated upon re-exposure to the causative agent. As a type IVc hypersensitivity reaction, it is characterized by the release of cytotoxic mediators such as perforin, granzyme B, and Fas ligand, which induce targeted keratinocyte apoptosis and localized tissue damage. Cross-reactivity among chemically related drugs has been reported.8 However, polysensitivity to chemically unrelated drugs is rarely observed, with an estimated prevalence of 0.2%.9 One proposed explanation is sensitization to common excipients. Moreover, the immunocompromised district hypothesis has been proposed to explain such presentations. According to this concept, specific cutaneous regions may exhibit increased vulnerability to external triggers as a result of localized immune dysregulation, which may be initiated by antecedent factors such as infection, trauma, or compromised lymphatic drainage.10 Furthermore, the occurrence of polysensitivity in combination with similar drug reactions among family members has been associated with genetic predisposition, such as specific HLA haplotypes.11 Such reactions may also be explained within the framework of broad ligand recognition, whereby T cells respond to structurally dissimilar agents through both promiscuous TCR recognition and MHC-independent activation by stress-induced ligands.12 It has been shown that with each repeated exposure to the culprit drug, FDE lesions may become more extensive and involve additional sites, emphasizing the importance of prompt identification and avoidance of the causative agent.13 However, DPT is contraindicated in cases of generalized FDE due to the risk of progression to generalized bullous fixed drug eruption. Patch testing may be utilized for diagnostic purposes. It has been reported that the sensitivity of patch tests performed on lesional skin is approximately 40%, whereas non-lesional testing shows significantly lower sensitivity.13 Because the lesion had occurred 2 years earlier and no residual pigmentation remained, patch testing was performed on non-lesional skin and yielded a negative result. Additionally, patch testing with povidone, a common excipient in both drugs that has been reported as a potential allergen, was also negative on both lesional and non-lesional skin.3 In this case, the immediate readings of SPTs performed with commercial preparations of paracetamol and clarithromycin were positive. However, skin testing for these drugs has not been standardized or validated in children.14, 15 The sensitivity of paracetamol skin testing is low, and a false-positive result has been reported.16 In a case series of children with a history of delayed-type reactions, approximately one-third had a positive immediate IDT reading with clarithromycin; however, the diagnosis was excluded by clarithromycin DPT.15 Consistent with prior reports, we considered the possibility of an irritant-related false-positive result. Therefore, as the clinical history was compatible with a delayed-type reaction, DPT, the diagnostic gold standard, was performed to confirm the diagnosis. This case highlights the unusual occurrence of FDE caused by two structurally unrelated drugs, paracetamol and clarithromycin, in a pediatric patient. DPT remains a valuable tool for confirming the diagnosis. Clinicians should be aware of the possibility of polysensitivity in suspected drug eruptions and manage the diagnostic process accordingly. Merve Karaca Şahin: Conceptualization; writing – original draft. Aslı Berivan Topçak: Investigation; data curation; visualization. Şefika İlknur Kökçü Karadağ: Investigation; data curation; visualization. Hasan Tunç Şarman: Investigation; data curation. Hilal Güngör: Investigation; data curation. Deniz Ozceker: Writing – review and editing; methodology; supervision. The authors declare no conflicts of interest. Ethical approval was not required for this case report. However, institutional approval was obtained from the University of Health Sciences of Prof. Dr. Cemil Tascioglu City Hospital (Decision No: 11, May 20, 2025). In addition, written informed consent for publication of clinical details and images was obtained from the patient's parents.