A Rare Pediatric Case of Cefixime Induced Toxic Epidermal Necrolysis

Abstract

Cefixime is a third-generation cephalosporin that has been used for the treatment of a wide range of infections in children and adults. The incidence of cefixime induced toxic epidermal necrolysis (TEN) is less than 2% in adults, but it is infrequent among pediatric patients. We report a rare case of cefixime induced TEN in a 7-year-old boy. In this case, the child presented with symptoms of TEN after 2 days of administration of cefixime. This case highlights the need to select structurally different antibiotics in case of antibiotic-induced severe cutaneous adverse reaction (SCAR) to avoid recurrence of SCAR. Furthermore, concluded that irrational use of antibiotics could be disastrous as it can result in TEN as the incidence of antibiotics induced TEN ranges from 29% to 42%.

Introduction

Toxic epidermal necrolysis (TEN) is a life-threatening severe cutaneous adverse reaction (SCAR), with an acute onset and rapid progression of painful lesions of the skin and mucous membranes that advance to blisters and erosions along with severe constitutional symptoms and extensive detachment of the epidermis.^1,2 TEN is distinguished from other SCARs by skin detachment of more than 30% of the body surface area. ³ Although TEN is a rare disease, it can result in disability or death, with a mortality rate of 10% to 40%. ¹ There is a need for prompt diagnosis and early management initiation because of the high risk of mortality in this case. ⁴

Drugs are identified as the leading cause of TEN in 80 % of cases. ⁵ Antibiotics, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), and allopurinol are the principal causative drugs associated with the development of TEN. ² Cefixime (third-generation cephalosporin) has been used for the treatment of a wide range of infections in children and adults. ⁶ The incidence of cefixime induced TEN is less than 2% in adults, but it is infrequent among pediatric patients. Herein, we present a case of cefixime-induced TEN in a pediatric patient. ⁶

Case Report

A 7-year-old boy was admitted to the hospital’s pediatric department with complaints of fluid-filled lesions over the trunk, bilateral upper and lower limbs for 1 day. In addition to the above symptoms, the child had conjunctival congestion, swelling of the face, crusting of lips, altered sensorium and high-grade fever (Figure 1). Two days before the onset of the above symptoms, the child had been taken to a local clinic for fever and was prescribed syrup cefixime (100 mg, 2 times a day) and syrup paracetamol (250 mg 3 times a day). He had taken 2 doses of each medication. The papules started to appear over the abdomen, progressively increased in size and became fluid-filled lesions after 24 hours.

Figure 1.

Swelling of the face, crusting of lips, and fluid-filled lesions over the trunk, bilateral upper and lower limbs.

General examination revealed: temperature of 38.9 degree Celsius, heart rate of 190 beats per minute, respiratory rate of 66 breaths per minute, blood pressure of 100/60 mmHg and SpO₂ of 77% in room air. The child was lethargic with a Glasgow coma scale score of 8. Bilateral crepitations were present. The skin lesions were multiple erythematous macules with darker purpuric centers and flaccid vesicles over the trunk and legs. There was peeling of the skin over the neck and chest areas, erosions over buccal mucosa and cheilitis. Genital examination revealed preputial edema and phimosis with erythema over the glans. Eye examination showed bilateral conjunctival congestion and chemosis with matting of eyelashes and corneal haziness. Nikolsky’s sign was positive, and the bullous detachment of the skin involved about 80 % of the body surface area.

Laboratory examination revealed leukopenia, thrombocytopenia, elevated C-reactive protein and blood urea nitrogen (66 mg/dl). Anti-HIV serology was negative. Chest X-ray showed patchy consolidation. The provisional diagnosis made was pneumonia with cefixime induced TEN. The child was intubated and shifted to pediatric ICU for further management. As cefixime was suspected to be the cause of TEN, the child was treated with a non-beta lactam class of antibiotics. He was managed conservatively with maintenance fluids, multivitamin supplements, antibiotics (clindamycin 120 mg IV 3 times a day, linezolid 180 mg IV 3 times a day, and amikacin 150 mg IV 2 times a day), systemic steroid (dexamethasone 3 mg IV 3 times a day) with appropriate eye and wound care (tobramycin ointment, lubricating eye drops, fluorometholone eye drops, and fusidic acid cream). Because of the corneal epithelial defect, bandage contact lenses were also applied.

On day 3 of admission, the child had low urine output, blood pressure of 70/50 mmHg and was given with IV fluid bolus (20 ml/kg). But the child continued to have hypotension and low urine output; hence dopamine infusion (5 mcg/kg/minute) was started. Dobutamine infusion (0.5 mcg/kg/minute) was also added to the therapy as the 2D ECHO showed global hypokinesia with an ejection fraction of 30%. Gradually, the urine output improved, and blood pressure was normalized by day 5; therefore, Dopamine and Dobutamine were tapered and stopped. On day 7 of admission, the child was extubated as he was maintaining saturation with minimal ventilator settings and the repeat chest X-ray showed clearance.

The oral and cutaneous skin lesions were gradually healing, and the child was started on oral feeds (protein and calorie-rich foods). Based on the medication history, subjective, and objective evidence, the final diagnosis was pneumonia, sepsis with cardiogenic shock, and TEN induced by cefixime.

The child improved clinically and symptomatically during the hospital and was discharged after 3 weeks. A drug alert card of cefixime was provided to the parents with appropriate drug counselling. On follow up, he was asymptomatic, and the skin lesions were healing well (Figure 2).

Figure 2.

Follow up image showing healing of skin lesions.

Discussion

Alan Lyell first termed TEN in 1956. It remains one of the dermatological emergencies characterized by extensive destruction of the epidermis and mucosal epithelia, which often can be caused by drugs. ⁴ The latency period between the drug administration and the beginning of symptoms can range from few hours to 45 days in the case of TEN. ⁷ Early skin findings consist of red-purple, dusky, flat spots known as macules that start on the trunk and spread out from there. These skin lesions then change into large blisters. The affected skin can then become necrotic from the body and peel off in great swaths. Almost all people with TEN have oral, eye and genital involvement as well. The key players in the pathogenesis of TEN are CD8 T-cells, cytolytic molecules FasL and granulysin. However, a culprit drug in a given patient who will develop TEN regulates the function of these key players. ⁴

Several factors favor cefixime as the cause of TEN in this case. First, fever, sore throat, and reduced state of health shortly before the appearance of cutaneous and mucosal lesions considered as the prodromal symptom and sometimes the drugs used to treat these early symptoms of SJS/TEN considered as the culprit. This error called protopathic bias. However, in this case, the patient had only a mild fever; hence it cannot be regarded as a protopathic bias. Second, the chest x-ray revealed patchy consolidation, and the provisional diagnosis made as pneumonia with cefixime induced TEN. Thus, the child treated with a non-beta lactum class of antibiotics (clindamycin, linezolid, and amikacin), and he improved both clinically and symptomatically in the hospital. So, the probability of viral infection-induced TEN is ruled out. Third, the patient had no previous adverse reaction to paracetamol syrup. Forth, the time temporal relationship between cefixime administration and the development of TEN. Finally, the drug causality algorithm for epidermal necrolysis (ALDEN) revealed a score of 4 for cefixime induced TEN. It was a probable cause for TEN due to cefixime by Naranjo and World Health Organization (WHO) causality assessment system.

Cefixime induced TEN was categorized as serious Adverse Drug Reaction (ADR) according to the Hartwig ADR severity assessment scale with a score of 5. At the time of admission, the severity-of-illness score for TEN (SCORTEN) was 3 with a mortality rate of 33%, and by day 5 of admission, the score decreased to 2 with a mortality rate of 13.8%. In this case, the SCAR subsided after the culprit drug’s withdrawal, followed by the supportive therapy for skin lesions.

There are published reports available in the literature for TEN correlated to antibiotics in adults. But this is a rare case of TEN due to cefixime in a child. Cefixime is commonly used in children, which highlights the fact that it can cause serious adverse reactions.

Learning Points

1. The incidence of cefixime induced TEN is less than 2% in adults, but it is very rare among pediatric patients.

2. The incidence of TEN induced by antibiotics ranges from 29% to 42%. So, the irrational use of antibiotics can be disastrous as it can result in TEN.

3. Complicated underlying disease conditions and infections may increase mortality in patients with antibiotic-related SCARs. So, the selection of structurally different alternative drugs is essential to avoid recurrence of SCAR.