Case report on Fluconazole Induced stevens - Johnson Syndrome

 

Remya Antony¹, Ashly Fernandez¹, Sandhya Lekshmi¹, Sreedevan Velayudhan², Sruthy Jose¹,

Meenu Vijayan^1*

¹Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.

²Department of Dermatology, Amrita Institute of Medical Sciences, Amrita Vishwa  Vidyapeetham, Kochi, Kerala, India

 

ABSTRACT:

Stevens-Johnson syndrome (SJS) is a rare cutaneous reaction characterised by mucosal erosions and epidermal detachment of about less than 10% of the total area of body skin. The incidence of SJS is approximately 1-6 cases per million person-years. The incidence of fluconazole induced SJS is less than 1%. Here the patient came with complaints of scaly lesions over chest and axilla following which he was started on topical antifungals (Lulliconazole) and antihistamines with the suspicion of Tinea versicolor. Though few lesions resolved on treatment, the patient later developed a small scaly macule over the left upper arm. Thus the patient upon further evaluation was given a stat dose of Tablet Fluconazole 400mg. Following this, the patient developed swelling of lower lips and tip of the glans and erythema over palms. This was later confirmed as Stevens-Johnson syndrome. The reaction was suspected to have occurred in association with Fluconazole. Fluconazole had a probable causal relationship with Stevens Johnson Syndrome as per ALDEN Algorithm in the EuroSCAR study. As per the Naranjo ADR probability scale, the causality assessment score for this reaction was found to be 5 which indicates a probable causal relationship. Clinicians must be more vigilant while prescribing Fluconazole by conducting regular monitoring of such patients and carrying out early diagnosis of such reactions.

 

 

 

INTRODUCTION:

Stevens-Johnson syndrome (SJS) is a cutaneous reaction which is acute, severe and self-limiting in nature but milder than toxic epidermal necrolysis (TEN) characterised by mucosal erosions and epidermal detachment. In SJS, the epidermal detachment is less than 10% of the total area of body skin unlike TEN and SJS/TEN overlap, where the epidermal detachment is over 30% and 10-30% respectively.¹ SJS is associated with a high morbidity and mortality rate of 5%.

 

 

 

The incidence of SJS is approximately 1-6 cases per million person-years, indicating that it is a rare syndrome.² The etiology of SJS is not clearly known but the most common cause of SJS is attributed to medications by an immunological mechanism.³ Other etiologies include infection and genetic factors. The common medications implicated in causing SJS are Carbamazepine, Phenytoin, Phenobarbitone, Paracetamol, Nimesulide, Diclofenac, Co-trimoxazole, Allopurinol and Sulphonamides.⁴Only few isolated cases of SJS have been reported secondary to drugs and drug classes other than those mentioned above. The incidence of fluconazole induced SJS is less than 1%. This case report throws light on fluconazole associated Stevens Johnson Syndrome after a single (stat) dose of 400mg of the drug.

 

 

CASE REPORT:

A 23 year old gentleman, came to the Department of Dermatology in the month of February, 2017 with multiple erythematous scaly lesions over the chest and axilla, associated with itching. The patient also reported increased itching while sweating. The patient was apparently asymptomatic 1 month ago after which he noticed these lesions. The patient also gave a history of similar lesions occurring on and off for the past 11years which subsided temporarily with the treatment. Thus treatment was started with topical antifungals (Lulliconazole) and antihistamines with the suspicion of Tinea versicolor. On treatment few of the lesions subsided but as the patient began to develop a small hypopigmented scaly macule on the left upper arm, upon evaluation he was given a stat dose of tablet Fluconazole 400mg. At night, the patient began to develop swelling of the lower lip and the tip of the glans along with pain. The patient also began to develop erythema and redness over the palms. Swelling over the lips further developed into small blisters over the lower lip and swelling over the glans developed into an erosion. The patient then gave a history of developing Stevens-Johnson syndrome 3 years back following intake of Ketoconazole, for which he was admitted in a local hospital and treated, which introduced a suspicion of the same. On clinical examination, the patient was found to be well built and nourished, oriented to time and place with absence of pallor, icterus, clubbing, cyanosis, lymphadenopathy and edema. The pulse rate was 86 beats/minute and the remaining vitals were within the normal limits. The dermatological examination revealed multiple well defined hyper and hypopigmented scaly macules over the upper back (interscapular region) and over the left upper arm. Post inflammatory hyperpigmentation (PIH) was present over the upper back. Erosions and crusting were present over the lower lip, and the scalp was found to be normal. On examining the oral cavity, there were whitish plaques present over the surface of the tongue and on the buccal mucosa along with a few erosions over the buccal mucosa. Palms and soles were normal with preserved dermatoglyphics. In the genital area, the erosions on the tip of the glans were still persisting. Systemic examination results were found to be within the normal limits.

 

The patient details were obtained using the hospital information system. Laboratory evaluation revealed a slightly raised WBC count (10.4K/µL) which reduced to 8.2K/µL, liver enzymes within the normal range (ALT 37.2 IU/L, AST 22.4 IU/L, ALP 61.5 IU/L) and elevated bilirubin levels (Total Bilirubin–2.79mg/dl and Direct bilirubin – 0.44mg/dl).

 

The above clinical picture, laboratory investigations and history of similar reaction 3 years back established the diagnosis of Steven-Johnson Syndrome. The patient was admitted and started on injection Hydrocortisone 100mg thrice daily along with tablet Azithromycin and topicals for the erosions following which the oral erosions had improved but were still persisting. The patient was given an injection of Tramadol and Ondansetron because of complaints of severe pain in the oral cavity and genital region.

 

As the patient wanted to get discharged at the earliest, injection Hydrocortisone dose was tapered after 3 days and the patient was started on oral steroids and was discharged at his request. He was discharged with tablet Ranitidine 150mg twice daily, tablet Prednisolone 50mg (30-20-0) once daily, tablet Levocetirizine 5mg at bedtime and capsule Bifilac twice daily for 2 days, and Triamcinolone acetonide buccal paste for local application over the erosions, Benzocaine gel mixed with water for the oral lesions, saline gargles thrice daily, Calosoft (Calamine + Aloe vera gel + Light liquid Paraffin) lotion for local application over the itchy sites twice daily and was advised to review after 2 days. On review, the patient was found to be improving with healing erosions and without the appearance of new lesions.

 

DISCUSSION:

Fluconazole is a triazole antifungal indicated for the treatment of candidiasis, treatment and prophylaxis of coccidioidomycosis and cryptococcosis, and for empiric treatment of critically ill patients. It is also used in bone marrow transplant recipients as a prophylaxis against fungal infections. It acts by inhibiting the fungal cytochrome P450 enzymes thereby reducing ergosterol synthesis. It also inhibits human cytochrome P450 enzymes. It is a strong inhibitor of CYP2C19 and 2C9, weak inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4. It was believed that SJS and TEN occur as a result of imbalance in activation and detoxification mechanisms which may be the result of inherited or acquired deficiency in phase 2 metabolising enzymes and an increase in the cytochrome P450 isozymes responsible for the conversion of the drug to its reactive metabolites. This can lead to high levels of compounds serving as potential immunogens or exhibiting a direct cytotoxic effect.⁵ Diseases which lead to an immunocompromised state can also induce or make the patients vulnerable to SJS or TEN.

 

Reduction of morbidity and prevention of complications are the goals of the treatment in SJS and TEN. There was no specific treatment modality that has been proven effective, but agents such as crystalloids, antibiotics, antihistamines,anticoagulants, analgesics, corticosteroids and antiseptic agents are important and required for supportive care⁶

In this case, the patient was not immunocompromised or having any comorbidities predisposing the patient to SJS and was treated with systemic corticosteroids followed by oral corticosteroids, which act by exerting suppressive effects on cytotoxic T lymphocytes and also by inhibiting interferon gamma mediated apoptosis. It also inhibits chemokines and numerous cytokines thus exerting a pleomorphic effect on the immune system.⁷ The patient was also prescribed oral antihistamines and topical cortisosteroids.

 

In the EuroSCAR (Severe cutaneous adverse reactions) study, Fluconazole had a probable causal relationship with Stevens Johnson Syndrome when assessed by the ALDEN Algorithm (Algorithm of drug causality for Epidermal Necrolysis).⁸ Causality assessment was done using the Naranjo Adverse Drug Reaction probability scale. The Naranjo score was found to be 5 indicating a probable causal relationship which is consistent with the result of EuroSCAR study.⁹

On reviewing the medical literature, Fluconazole has been stated as a cause of SJS or TEN for a few studies which has been enlisted in Table 1. The below mentioned reports including this study demonstrates the occurrence of this reaction at varying doses of fluconazole ranging from 150-400mg/day, indicating that the reaction is dose-independent. On analysing of these reports, the reaction occurred at a duration ranging from 2-3 hours to 1 week after drug administration. Thus the clinicians prescribing Fluconazole is required to monitor the patients for SJS for at least a week or more in order to facilitate early detection of such fatal reactions. The reaction resolved within a duration of 3-4 weeks of appropriate therapy with intravenous or oral steroids, antihistamines, antibiotics, soothing agents and adequate hydration. This indicates that a complete resolution can be achieved with intensive treatment and monitoring with the above mentioned classes of medications.

 

 

Table 1: Description of other case reports on Fluconazole induced Stevens Johnson Syndrome

Author, year	Number of patients	Dose of Fluconazole	Day of reaction	Treatment	Recovered	Day of resolution
Alexandra Monastirli et al.10	1	200mg/day	After 1 week of drug administration	Intravenous methylprednisolone 120 mg/day for 3 days - gradually tapered over a period of 3 weeks.	Yes–complete recovery	4 weeks
Uchenna R Ofoma et al.5	1	150mg/day	After 5 days of drug administration	pain control, skin, mouth and eye care, intravenous hydration and withdrawal of fluconazole	Yes	-
Efi Pasmatzi MD et al.11	3	100 -200mg/day	After 1-4 days of drug administration	Intravenous methylprednisolone (80-160 mg/day for 3-6 days), oral and skin washings, and antiseptic eye drops	Yes - complete recovery	3-4 weeks
Jacob George et al.12	1	150mg/day	On 2nd day	local soothing agents, analgesics, azithromycin, antihistamines, and eye care with adequate parenteral hydration	Yes	3 weeks
Umashanker P. Keshri et al.13	1	150mg/day	After 2-3 hours of drug administration	Tablet Amoxicillin clavulinic acid , tablet prednisolone, tablet ranitidine, tablet cetirizine, and local application of glycerin and gentian violet	Yes	Improved in 2 weeks
Present study	1	400mg stat dose	On 1st day	Tablet prednisolone 50mg, calamine lotion, triamcinolone acetonide buccal paste, tablet levocetirizine, saline gargles, tablet ranitidine, benzocaine gel	Yes – partial recovery	Improved with no new lesions appearing in 1 week

 

CONCLUSION:

The incidence of fluconazole induced SJS is less than 1%. Clinicians must be vigilant while prescribing Fluconazole. The patients must be monitored regularly. Early diagnosis and treatment of such reactions are necessary.

 

 

ACKNOWLEDGEMENT:

We would like to thank our department of pharmacy practice for their valuable suggestions in bringing the case report to completion. We would also like to thank the hospital authority, patient and his bystanders for their cooperation.

 

CONFLICT OF INTEREST:

There is no conflict of interest.

 

REFERENCES:

1        Bastuji-Garin S, Rzany B, Stern RS et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Archives of dermatology. 1993; 129 (1): 92-6.

2        Jahirul Islam Laskar, Pinaki Chakravarty and Babul Dewan. Toxic Epidermal Necrolysis induced by Carbamazepine: a case study. Asian Journal of Pharmaceutical and Clinical Research. 2017; 10 (7): 78-81.

3        Pavithran K and Thomas M. Imatinib induced Stevens-Johnson syndrome: lack of recurrence following re-challenge with a lower dose. Indian Journal of Dermatology, Venereology, Leprology. 2005; 71(4): 288.

4        Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenetics and genomics. 2008; 18 (2): 99-107.

5        Ofoma UR and Chapnick EK. Fluconazole induced toxic epidermal necrolysis: a case report. Cases journal. 2009; 2(1): 9071.

6        Das AR, Saikeerthana PC, Raj K, Anila KN. Carbamazepine induced toxic epidermal necrolysis – A rare case report. International Journal of Pharmaceutical Sciences Review and Research. 2016; 40 (2): 18-19.

7        Jagadeesan S, Sobhanakumari K, Sadanandan SM et al. Low dose intravenous immunoglobulins and steroids in toxic epidermal necrolysis: a prospective comparative open-labelled study of 36 cases. Indian Journal of Dermatology, Venereology, and Leprology. 2013; 79(4): 506.

8        Sassolas B, Haddad C, Mockenhaupt M et al. ALDEN, an algorithm for assessment of drug causality in Stevens–Johnson syndrome and toxic epidermal necrolysis: comparison with case–control analysis. Clinical Pharmacology & Therapeutics. 2010; 88(1): 60-8.

9        Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clinical Pharmacology & Therapeutics. 1981; 30 (2): 239-45.

10      Monastirli A, Pasmatzi E, Vryzaki E et al. Fluconazole-induced Stevens-Johnson syndrome in a HIV-negative patient. Acta dermato-venereologica. 2008; 88(5):521-2.

11      Pasmatzi E, Monastirli A, Georgiou S et al. Short-term and low-dose oral fluconazole treatment can cause Stevens-Johnson syndrome in HIV-negative patients. Journal of drugs in dermatology. 2009; 10(12): 1360.

12      George J, Sharma A, Dixit R et al. Toxic epidermal necrolysis caused by fluconazole in a patient with human immunodeficiency virus infection. Journal of Pharmacology and Pharmacotherapeutics. 2012; 3(3): 276-278.

13      Keshri UP, Kumar N, Kumar R et al. Fluconazole-induced Stevens-Jonson syndrome. International Journal of Basic and Clinical Pharmacology. 2014; 3 (3): 566-568.

 

 

 

 

 

Accepted on 18.05.2019          © RJPT All right reserved

Research J. Pharm. and Tech 2019; 12(8):3735-3738.