Severe cutaneous adverse reaction to amoxicillin-clavulanate: Pediatric toxic epidermal necrolysis in the Gulf: A case report and literature review

Abstract

Introduction and importance

Toxic epidermal necrolysis (TEN) is a severe form of Stevens-Johnson syndrome (SJS), and both are rare blistering skin reactions triggered by drugs and illnesses.

Case presentation

We have reported a case of a previously healthy five-year-old boy who presented with a maculopapular rash covering more than 90 % of the total body surface area (TBSA), bilateral conjunctivitis, and oral thrush five days after receiving amoxicillin-clavulanate for upper respiratory infection. On assessment, dehydrated, hemodynamically unstable with extensive, dark maculopapular rash covering approximately 90 % of the total body surface area, skin biopsy confirmed full-thickness epidermal necrosis with lymphocytic dermal infiltration consistent with TEN. The patient was managed in the pediatric intensive care unit with rehydration, immediate cessation of the culprit drugs, surgical debridement, and aggressive wound care, as well as Intravenous immunoglobulin, systemic steroids, and meropenem for sepsis prophylaxis. Despite the patient developing complications (respiratory distress syndrome necessitating 9-day mechanical ventilation), the reepithelialization began by day ten, and the patient was extubated after 80 % wound healing.

Clinical discussion

This case discusses Toxic epidermal necrolysis (TEN), a rare and severe skin response caused by amoxicillin-clavulanate exposure in a pediatric patient. Early clinical diagnosis confirmed by skin biopsy and immediate management with supportive care, corticosteroids, and intensive wound care contributed to full recovery despite involvement of more than 90 % of the body.

Conclusion

Though TEN remains a medical emergency, even in severe cases, the timely and multidisciplinary approach can have a good outcome. It is a clinical reminder for clinicians to maintain a high index of suspicion of drug-induced severe cutaneous reactions, especially in children.

Highlights

• •A rare case of TEN with severe skin eruption
• •A multidisciplinary approach is vital for TEN management.
• •Emphasizes Amoxicillin-Clavulanic acid as a high trigger
• •Early intervention in TEN has good outcomes.

1. Background

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two rare and severe blistering skin responses caused by illnesses or drugs. SJS and TEN are considered to be within the spectrum of the same condition with different severities, characterized by the skin surface affected [1]. SJS is characterized by skin detachment of less than 10 % of the total body surface area (TBSA). In contrast, TEN is diagnosed by skin detachment of more than 30 % of the BSA, and skin detachment between 10 and 30 % is categorized as SJS-TEN overlap. [2]. Stevens-Johnson syndrome was first outlined in 1922 by two American paediatricians- Albert Mason Stevens and Frank Chambliss Johnson. [3]. The physicians identified this syndrome when they encountered cases of two boys, aged 7 and 8, exhibiting symptoms of a widespread skin eruption, unrelenting fever, inflammation of the mouth's mucous membrane, and severe pus-filled conjunctivitis, initially misdiagnosed as hemorrhagic measles by the boys' primary care physicians. Herein, we describe the case of a pediatric patient in Saudi Arabia with toxic epidermal necrolysis after the use of Augmentin. This case report has been reported in line with the SCARE checklist. [4].

2. Case presentation

A five-year-old boy was referred to our institution with a maculopapular rash over the trunk, bilateral conjunctival infection, and oral thrush. Five days before his presentation, the rash developed, and the patient had an upper respiratory tract infection, including a productive cough, managed with Augmentin (amoxicillin-clavulanate) and supportive therapy. The child is up to date with his vaccinations and has reached developmental milestones pertinent to his age, and no family history of the same condition. The child presented in an unstable condition with dehydration. The referral was to investigate the possibility of toxic epidermal necrolysis syndrome or severe infectious diseases, such as Staphylococcal Scalded Skin Syndrome (SSSS). A thorough examination of the patient's history, as reported by the parents through testimonials, revealed the rapid expansion of the rash without any contact with sick individuals or a history of past travel. The patient was admitted to a negative-pressure room and underwent a physical examination, which revealed an extensive, dark maculopapular rash covering approximately 90 % of the total body surface area (TBSA), scaling of the mucous membranes, and oral thrush. No lymphadenopathy was detected (Fig. 1). All other vital signs were stable. A multidisciplinary team approach, including plastic surgeons, dermatologists, pediatric infectious disease specialists, and pediatric ICU specialists, was adopted, and the diagnosis of toxic epidermolysis was made. The lab investigation showed leukopenia with anaemia and neutropenia, normal platelets and elevated CRP. Moreover, it showed low albumin, calcium, creatinine, phosphorus, and potassium, and slightly high lipase. The patient was stabilized and was urgently referred for surgical debridement. The surgical debridement was performed under general anaesthesia. The debridement involved gently removing the blisters and the superficial necrotic tissue from 90 % of the body surface, preserving the underlying dermis to enable self-healing. Then, the exposed wound bed was covered with protective Vaseline gauze and MEBO ointment to promote regeneration. A wound swab was taken for microbiological examination, which proved negative. A skin biopsy was taken and sent for histopathological examination. The histopathology report revealed full-thickness epidermal necrosis with moderate lymphocytic dermal infiltration. No evidence of fungal infection was detected via PAS stain, and no dysplastic changes or malignancy were identified. Upon diagnosis of toxic epidermal necrolysis syndrome, the dermatologist started a steroid regimen for two days, and intravenous immunoglobulin (IVIG)for three days with a dose of 3 g/kg. Additionally, meropenem (250 mg intravenously every 8 h) was administered for the first three days. All medications were stopped except for sedatives (midazolam) and paracetamol. Postoperatively, the patient was kept on mechanical ventilation and a dressing consisting of Vaseline gauze and MEBO. The ophthalmology department consultation revealed no secondary bacterial infection. The patient's clinical status deteriorated with a drop in blood pressure and development of respiratory distress syndrome (on the second day after admission), which required mechanical ventilation (for nine days). The dressings were changed every other day in wet areas, such as the proximal thighs and buttocks, and every five days in other affected areas. Ten days after the initial presentation, the wound began to heal, and the patient's general condition improved. The child was exhausted at 10 (Fig. 1). After successful extubation, the patient's condition continued to improve gradually. Enteral feeding was steadily introduced through an NG tube, followed by oral administration, and wound dressing was continued with two weekly dressings until complete re-epithelialization was achieved. The Duration of admission to the PICU was 23 days, and then kept 5 days in the ward, and then discharged on hospital day 28. The patient was followed up for 18 months, and he developed widespread hypopigmented and hyperpigmented areas in his body with no ocular complications(Fig. 1). The clinical course of the patient was summarized in Table 1.

Fig. 1.

The Overall images of the patient before and immediately after initiating management (A), day 11 after extubation (B) and 12 months after discharge (C).

Table 1.

Timeline summarizing the clinical course.

Day	Key Clinical Events	Management & Outcomes
Day −5	Onset of upper respiratory infection with productive cough.	Started Augmentin and supportive care.
Day 0 (Admission)	Rapidly spreading rash (~90 % TBSA), mucosal involvement, oral thrush, dehydration	Admitted to PICU, Diagnosed with TEN.
Day 0 (Surgery)	Extensive epidermal detachment.	Urgent surgical debridement, Biopsy confirmed the diagnosis
Day 1–3	Postoperative critical care.	Steroids, meropenem, Sedation and analgesia started. Mechanical ventilation initiated.
Day 2	Clinical deterioration: hypotension, respiratory distress.	Required mechanical ventilation for a total of 9 days.
Day 2–9	Supportive care during the critical phase.	Regular wound dressing, ongoing PICU monitoring.
Day 10	Signs of wound healing and improving general condition.	Extubated; started enteral then oral feeding; continued dressings.
Day 10–23	Recovery in PICU.	Steady improvement; continued wound dressing and monitoring.
Day 23	Stable condition	Transferred from PICU to the general ward.
Day 28	Discharge from hospital.	Fully stable; follow-up plan arranged.
18 months follow-up	Long-term outcome: skin healing completed.	Residual hypo/hyperpigmentation; no ocular or systemic complications.

3. Discussion

Fever, erosions of the conjunctiva and oral mucosa, skin rash, and detachment of more than 30 % of the body surface area (BSA) are the primary presenting clinical features of suspected cases of TEN. However, symptoms of other connective tissue diseases, such as scleroderma and SLE, may mimic the clinical presentation of TEN, hence requiring additional laboratory tests, including antinuclear (ANA), antihistone, and anti-dsDNA autoantibody tests, to avoid misdiagnosis in such cases [5].In this case report, the patient presented with a maculopapular rash covering more than 90 % of the total body surface area (TBSA), bilateral conjunctival infection, and oral thrush five days after receiving amoxicillin-clavulanate. A drug challenge test is another approach that involves the recurrence of skin manifestations after reintroducing a specific drug. Skin biopsy can also confirm TEN cases and exclude other diseases with similar rashes, such as S [6]. In this case study, we performed a skin biopsy, which revealed full-thickness epidermal necrosis with a moderate lymphocytic dermal infiltrate, consistent with a diagnosis of TEN. Infection and sepsis are the leading causes of death in TEN cases, making invasive procedures such as biopsies risky and clinical diagnosis a safer option [7]. Generally, TEN develops after exposure to drugs, usually within two weeks [5,8,9]. Sometimes, it is associated with infections of the Epstein-Barr virus and the influenza virus, Mycoplasma pneumoniae [10,11], and with vaccinations for smallpox, COVID-19, and combined MMR vaccines [12,13]. Therefore, it is crucial to obtain a detailed history of drug exposure and vaccination, as well as to perform PCR, blood culture, and CBC to diagnose the etiology of TEN and prevent recurrent episodes. In the Gulf countries, TEN and SJS cases were reported to be caused by antiepileptics (phenytoin, carbamazepine, and lamotrigine), analgesics (ibuprofen, acetaminophen, diclofenac sodium, and piroxicam), vaccination (COVID-19, Pfizer), vasodilators (hydralazine, captopril, and sildenafil), and antibiotics (amoxicillin, cotrimoxazole, amoxicillin/clavulanate, azithromycin, levetiracetam, ciprofloxacin, cefixime, and vancomycin) (Table 1). In our case, TEN symptoms were reported five days after receiving Augmentin. Seven cases of TEN related to amoxicillin-clavulanate administration have been reported [14]. There was an urgent need for antibiotic therapy in the present case to combat URTI with a productive cough; however, antibiotic prescribing patterns in Gulf countries have been reported to be highly inappropriate, with amoxicillin and co-amoxiclav being the most frequently prescribed drugs [15]. Therefore, improving antibiotic prescription patterns in Gulf countries is essential to prevent an escalation of cases of TEN and SJS.

TEN is a severe condition that requires hospitalization, ICU admission, the discontinuation of the causative drugs, and supportive care such as IV fluids and nutritional support, along with IVIG and systemic corticosteroids, and cyclosporin as an addition. However, no consistency has been found in the previous studies regarding the doses and the drugs for additional treatment. In addition to the standard care, our case involved skin debridement and a two-day steroid regimen, three days of IVIG at a total dose of 3 g/kg, and meropenem for the first three days. The case showed improvement after one week. However, other regimens have been employed in the Gulf countries, whose inhabitants share a similar genetic makeup and environmental conditions to our patients (Table 2). There are several prescribed treatment regimens used for TEN, such as two doses of etanercept (50 mg/mL) with a tumour necrosis factor (TNF)-alpha antagonist for two days(16)An oral dose of cyclosporine at 5 mg/kg/day for 15 days [8], administered prednisolone (30 mg/day) [12] IVIG 0.5 g/kg for five days [3], and IVIG 1 g/kg daily for five days, IV dexamethasone, followed by oral prednisolone, and cyclosporin 3 mg/kg daily [9] resulting in full recovery, whereas only supportive care leading to full recovery was reported in five cases [5,[16], [17], [18], [19], [20]]. However, due to insufficient evidence, the superiority of one over the other in terms of safety and healing time cannot be confirmed, necessitating additional research using randomized clinical trials.

Table 2.

Summary of cases of TEN and SJS reported in the Gulf countries.

Study ID	Country	Age (years)	Gender	Type of the syndrome	TBSA	Management	Response
Al-Shouli et al. 2005 [17]	Saudi Arabia	67	Male	TEN	40 % to 50 %	systemic corticosteroids and antibiotics	Recovered
Elkharaz et al. 2006 [25]	Saudi Arabia	5 to 11	NA	TEN [5]	30 to 85 %	systemic corticosteroids and antibiotics	Recovered
Jan et al. 2007 [20]	Saudi Arabia	4 to 9	Males [3], and Females [2]	TEN [1] and SJS [4]	NA	systemic corticosteroids and antibiotics	Recovery (80 %), death (20 %)
AlQuliti et al. 2014 [26]	Saudi Arabia	45	Female	TEN	More than 80 %	Supportive and systemic corticosteroids	Death
Suliman et al. 2006 [18]	Saudi Arabia	30	Female	TEN	NA	systemic corticosteroids and antibiotics	Recovered
Alkurtass et al. 2003 [19]	Saudi Arabia	11	Male	TEN	NA	systemic corticosteroids and antibiotics	Recovered
Wani et al. 2009 [27]	Saudi Arabia	46	Female	TEN	70 %	Supportive and systemic corticosteroids	Recovered
Nassar et al. 2010 [22]	Saudi Arabia	15 to 75	Males [7] and Females [6]	TEN [8], SJS [1], SJS-TEN overlap [4]	(Range: 8–90 %)	Supportive and systemic corticosteroids	Recovery (85 %), death (15 %)
Alajaji et al. 2020 [23]	Saudi Arabia	16 to 74	Males [4] and Females [6]	TEN [6] and SJS [4]	One patient showed >90 %	Supportive and systemic corticosteroids	Recovery (90 %), death (10 %)
Amal et al. 2022 [24]	Saudi Arabia	3 to 74	Males [3], and Females [9]	TEN [6], SJS [5], SJS-TEN overlap [1]	NA	Supportive and systemic corticosteroids	Recovery (75 %), death (25 %)
Elboraey et al. 2021 [12]	Saudi Arabia	40	Female	SJS	NA	Supportive and systemic corticosteroids	Recovery
Bakir et al. 2021 [16]	Saudi Arabia	49	Female	TEN	More than 30 %	Supportive and systemic corticosteroids.	Recovery
Alnofaiey et al. 2022 [20]	Saudi Arabia	102	Female	SJS	NA	Supportive and systemic corticosteroids.	Recovery
El-Naggari et al. 2013 [7]	Oman	9 months	Male	TEN	Around 60 %	Supportive and systemic corticosteroids.	Recovery
Rajaibi et al. 2021 [23]	Oman	38	Female	SJS-TEN overlap	50 %	Supportive and systemic corticosteroids.	Recovery
Mahfouz et al. 2014 [5]	Qatar	75	Female	TEN	NA	Supportive and systemic corticosteroids.	Recovery
Jouhar et al. 2022 [9]	Qatar	6	Male	TEN	NA	Supportive and systemic corticosteroids.	Recovery

The mortality rate of TEN in Saudi Arabia ranged from 10 % to 25 % [[21], [22], [23], [24]]. Our review showed eight cases died out of 54 cases in Saudi Arabia, with a mortality rate of 15 % (Table 2).

A notable observation in this case was that, despite 90 % of the TBSA involvement, the patient fully recovered, corroborating other findings in Saudi Arabia (Table 3). Similarly, there were also reported cases of TEN with more than 90 % skin involvement due to amoxicillin and clavulanic acid [23] and trimethoprim/sulfamethoxazole administration [22], leading to death in one and healing after nine days treated with 1 g/kg/day IVIG with systemic steroids and antibiotics, coincident with the present study, with healing in seven days. Therefore, considering the severity of TEN, rapid intervention is the most probable measure in achieving full recovery.

Table 3.

Summary of cases with TEN involving≥90 % of TBSA.

Variables	Our case	Nassar et al. 2010 [21]	Alajaji et al. 2020 [22]
Age	5	59	35
Gender	Male	Male	Female
Culprit medications	Amoxicillin-clavulanic acid	Trimethoprim-sulfamethoxazole	Amoxicillin-clavulanic acid
Duration before admission	3 days	4 days	10 days
Management	IVIG at 1 g/kg/day for three days With a total dose of 3 g/kg + systemic corticosteroids and antibiotics (meropenem 250 mg intravenously every 8 h) for the first three days	IVIG at 1 g/kg/day for 5 days + systemic corticosteroids and antibiotics before and after starting IVIG	Supportive care only
			The patient's transfer from a private hospital, where only supportive care was given, was delayed.
Outcome	After 10 days, the wound started to heal, and the general condition began to improve after the first week.	Blister formation was stopped after 4 days, and complete healing occurred after 9 days from IVIG	Died because of sepsis

4. Conclusion

This case highlights the severity of TEN in pediatric patients triggered by amoxicillin-clavulanate. Involving more than 90 % of the TBSA and raising the risk of serious complications, such as sepsis. Prompt intervention with IVIG, systemic steroids, and antibiotics, combined with a multidisciplinary team approach, resulted in complete recovery in this case. Though TEN remains a medical emergency, even in severe cases, the timely and multidisciplinary approach can have a good outcome. It is a clinical reminder for clinicians to maintain a high index of suspicion of drug-induced severe cutaneous reactions, especially in children.

Consent

Written informed consent was obtained from the patient's parents/legal guardians for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

This case report was approved by the Ethics Committee in the Institutional Review Board and was performed following the Declaration of Helsinki. Informed consent to participate was obtained from all the participants.

Funding

The authors of this study have no financial relationships relevant to this article to disclose.

Author contribution

Mohammed Nasser Asiri perform study concept or design, data collection, data analysis or interpretation, and writing the paper.

Guarantor

Mohammed Nasser Asiri.

Research registration number

NA

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Available on request from the author.