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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 32-35

Generalized bullous fixed drug eruption due to fluconazole: A report of two cases


Department of Dermatology, Maulana Azad Medical College, Delhi, India

Date of Submission23-May-2020
Date of Decision10-Oct-2020
Date of Acceptance11-Jan-2021
Date of Web Publication25-Jun-2021

Correspondence Address:
Bijaylaxmi Sahoo
Flat no. 474, Kanungo Apartments, IP Extension, New Delhi - 110 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_32_20

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  Abstract 


Fixed drug eruption (FDE) is characterized by the development of well-demarcated erythematous to violaceous plaques, within minutes to hours of the intake of an offending drug. It is known as “fixed” because subsequent exposure to the implicated drug leads to the development of lesions at the same sites that were involved at the time of the previous drug exposure. Fluconazole, a widely used antifungal agent, has a good safety profile, and limited data exist on the development of bullous FDE due to fluconazole. Herein, we report a series of two cases presenting with a generalized bullous FDE (GBFDE), following the consumption of fluconazole. A temporal correlation, typical morphological features, symptoms, and a past history of FDE due to fluconazole were essential clues to the diagnosis. Furthermore, we utilized the Naranjo adverse drug reaction probability scale for causality assessment. Discontinuation of the drug was followed by the resolution of lesions in 7–10 days. GBFDE is an uncommon entity and requires immediate diagnosis as well as prompt discontinuation of the offending agent to minimize the complications.

Keywords: Bullous, fixed drug eruption, fluconazole, generalized, multifocal


How to cite this article:
Bansal A, Relhan V, Sahoo B. Generalized bullous fixed drug eruption due to fluconazole: A report of two cases. Indian J Drugs Dermatol 2021;7:32-5

How to cite this URL:
Bansal A, Relhan V, Sahoo B. Generalized bullous fixed drug eruption due to fluconazole: A report of two cases. Indian J Drugs Dermatol [serial online] 2021 [cited 2021 Dec 2];7:32-5. Available from: https://www.ijdd.in/text.asp?2021/7/1/32/319355




  Introduction Top


Fixed drug eruptions (FDEs) are a common cutaneous adverse drug reaction (ADR), characterized by the development of recurrent cutaneous lesions at the same site with repeated exposure to the offending drug.[1],[2] Fluconazole is a widely used antifungal agent and generalized bullous FDE (GBFDE) with it has been rarely described in the literature.[2],[3],[4] We report a series of two such cases with GBFDE due to fluconazole. A high index of suspicion, a temporal correlation, distinctive clinical features, and a detailed drug history, supported by causality assessment helped us to arrive at a diagnosis and a prompt discontinuation of the drug led to the clearance of the lesions.


  Case Report Top


Case 1

A 60-year-old female, presented to us with a history of multiple itchy, hyperpigmented macules, and bullae all over the body, which developed within 12 h, following the intake of tablet fluconazole 150 mg, prescribed to her for tinea cruris. On examination, multiple violaceous, oval, edematous macules, surrounded by an erythematous rim were present over the upper limbs, lower limbs, and trunk along with a few erosions in the various stages of healing, and some of the lesions were associated with central crusting [Figure 1]. A provisional diagnosis of FDE was made, and fluconazole was stopped. The patient was prescribed an anti-histaminic along with an emollient and the lesions resolved within a week, leaving behind slate-gray hyperpigmented macules. All routine investigations were found to be normal.
Figure 1: Multiple violaceous macules with an erythematous halo and few erosions with central crusting (black arrow) present over the lower back and buttock region

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Furthermore, a causality assessment for fluconazole was carried out using the Naranjo ADR probability (NADRP) scale, where the patient had a score of 7 (probable ADR).[5]

Considering the temporal correlation, location, morphology as well as the past history, a diagnosis of GBFDE due to fluconazole was made.

Case 2

A 33-year-old male presented to our outpatient department with pityriasis versicolor and was prescribed a single dose of tablet fluconazole 400 mg. The patient followed up with multiple fluid-filled lesions all over the body 8–10 h following the consumption of fluconazole.

On examination, the patient had multiple tense bullae present over the upper and lower limbs, lips, and penis, surrounded by a faint rim of erythema [Figure 2] and [Figure 3]. An FDE was suspected, fluconazole was discontinued, and the patient was prescribed tablet prednisolone 30 mg OD for 5 days. The lesions resolved over 5 days leaving behind grayish, hyperpigmented macules. All routine investigations were found to be normal. A detailed history revealed a similar episode of FDE due to fluconazole, 4 years back. The patient had a score of 7 on the NADRP scale, and a final diagnosis of GBFDE was made.
Figure 2: Resolving bullous fixed drug eruption over the lips – A common site for fixed drug eruption

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Figure 3: Bullous fixed drug eruption over the dorsum of both feet

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  Discussion Top


Fluconazole, a commonly prescribed antifungal drug, is rarely associated with significant side effects.[2],[6] Cutaneous side effects such as FDE are relatively uncommon, with only a limited number of case reports.[2],[6],[7] The most commonly implicated groups of drugs causing FDE are antibiotics and Non Steroidal Anti-inflammatory Drugs.[1] FDE occurs as a result of a CD8-T lymphocyte-mediated reaction in a genetically predisposed individual, where the culprit drug is believed to trigger a localized reactivation of memory T-cells.[8]

It occurs within 30 min to 24 h of consumption of the causative drug and presents as well-demarcated, round to oval, pruritic, erythematous macules which tend to become edematous, violaceous plaques, and resolve over days to weeks leaving behind slate gray hyperpigmented macules.[7],[9],[10] Although lesions can develop anywhere over the body, the most commonly implicated sites are the penis in males and extremities in females.[1],[7] Several morphological patterns have been described, including morbiliform, erythema multiforme like, scarlatiniform, pigmented, vesicular, and bullous.[10]

Recurrent FDE is associated with an increased amount of inflammation and the risk of development of bullae and vesicles.[11]

Vesicular FDE due to the fluconazole, occurring in the perioral region with mucosal involvement and mimicking herpes simplex has been previously described.[5],[12],[13],[14] However, generalized multifocal bullous FDE due to fluconazole is a rare entity. Bullous FDE presents as well demarcated erythematous macules with overlying blisters on a background of diffuse hyperpigmentation.[11] GBFDE is defined as, typical FDE lesions with bullae involving at least 10% of the body surface area or at least three of the following different anatomic sites: Head and neck (including the lips), anterior trunk, back, upper limbs, lower limbs, and genitalia.[15] Although GBFDE is rarely associated with systemic involvement, a surprisingly high risk of mortality, owing to the complications such as fluid loss, electrolyte derangement, or infection has been documented, especially among the elderly.[11],[16]

Histopathology of typical FDE shows basal cell vacuolation, pigment incontinence, and presence of apoptotic bodies in the epidermis.[17] In addition to these findings, a subepidermal blister is seen in case of bullous FDE.[4]

A diagnosis of FDE can be made, based upon morphology, temporal correlation with drug intake, previous history, and various diagnostic tests. Patch testing, lymphocyte transformation test, and histopathology may be used in certain cases; however, an oral provocation test is generally not recommended due to the potential risk of severe exacerbation.[2],[7],[9],[18] Causality assessment scales such as NADRP and the WHO-Uppsala Monitoring Center causality assessment system aid in the diagnosis.[7],[19]

GBFDE due to fluconazole is a rare entity, with only a few case reports in the literature [Table 1].[2],[3],[4] Both our patients developed violaceous itchy macules along with bullous lesions, within few hours of the intake of fluconazole. The lesions were generalized involving more than 3 out of the six classical sites and discontinuation of the drug was followed by a gradual resolution of lesions. Moreover, both the patients had a past history of fluconazole-induced FDE and using the NADRP scale, a score of + 7 (Probable ADR) was obtained. The limitations of our study included the lack of performing patch testing or skin biopsy, due to a paucity of time, resources, and adequate patient follow-up.
Table 1: Bullous fixed drug eruption: Review of the literature[2],[3],[4],[5],[12],[13],[14]

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Herein, we report an uncommon, potentially life-threatening side effect of a rather safe and commonly used drug. Prompt diagnosis, withdrawal of the offending drug, and symptomatic management are essential to minimize complications, and a more aggressive approach than conventional FDE including oral corticosteroids or cyclosporine may often be required.[4],[16]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Breathnach SM. Drug reactions. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook's Textbook of Dermatology. 8th ed. Oxford: Blackwell Science; 2010. p. 28-177.  Back to cited text no. 1
    
2.
Nath AK, Adityan B, Thappa DM. Multifocal bullous fixed drug eruption due to fluconazole. Indian J Dermatol 2008;53:156-7.  Back to cited text no. 2
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3.
Choudhury S, Loc BP, Debbarma RR, Das A. Fluconazole induced multifocal bullous eruptions: A case report. Int J Basic Clin Pharmacol 2016;5:1681-3.  Back to cited text no. 3
    
4.
Mithari HS, Gole PV, Kharkar VD, Mahajan SA. Generalized bullous fixed drug eruption to fluconazole; with cross-reactivity to tinidazole. Indian J Dermatol 2019;64:335-7.  Back to cited text no. 4
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5.
Benedix F, Schilling M, Schaller M, Röcken M, Biedermann T. A young woman with recurrent vesicles on the lower lip: Fixed drug eruption mimicking herpes simplex. Acta Derm Venereol 2008;88:491-4.  Back to cited text no. 5
    
6.
Amichai B, Grunwald MH. Adverse drug reactions of the new oral antifungal agents – Terbinafine, fluconazole, and itraconazole. Int J Dermatol 1998;37:410-5.  Back to cited text no. 6
    
7.
Pai VV, Bhandari P, Kikkeri NN, Athanikar SB, Sori T. Fixed drug eruption to fluconazole: A case report and review of literature. Indian J Pharmacol 2012;44:643-5.  Back to cited text no. 7
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8.
Shiohara T, Mizukawa Y. Fixed drug eruption: A disease mediated by self-inflicted responses of intraepidermal T cells. Eur J Dermatol 2007;17:201-8.  Back to cited text no. 8
    
9.
Fazeli SA, Abbasi M, Jalali H, Eskandari S, Shamshirgaran F, Dehghani Z, et al. Bullous fixed drug eruption following ibuprofen ingestion. J Res Pharm Pract 2018;7:51-6.  Back to cited text no. 9
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Sehgal VN, Srivastava G. Fixed drug eruption (FDE): Changing scenario of incriminating drugs. Int J Dermatol 2006;45:897-908.  Back to cited text no. 10
    
11.
Patel S, John AM, Handler MZ, Schwartz RA. Fixed drug eruptions: An update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol 2020;21:393-9.  Back to cited text no. 11
    
12.
Jensen ZN, Bygum A, Damkier P. Fluconazole-induced fixed drug eruption imitating herpes labialis with erythema multiforme. Eur J Dermatol 2012;22:693-4.  Back to cited text no. 12
    
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Sławińska M, Barańska-Rybak W, Wilkowska A, Nowicki R. Bullous fixed drug eruption due to fluconazole, imitating herpes simplex. Clin Exp Dermatol 2017;42:544-5.  Back to cited text no. 13
    
14.
Schneller-Pavelescu L, Ochando-Ibernón G, Vergara-de Caso E, Silvestre-Salvador JF. Herpes simplex-like fixed drug eruption induced by fluconazole without cross-reactivity to itraconazole. Dermatitis 2019;30:174-5.  Back to cited text no. 14
    
15.
Lee CH, Chen YC, Cho YT, Chang CY, Chu CY. Fixed-drug eruption: A retrospective study in a single referral center in northern Taiwan. DermatolSin 2012;30:11-5.  Back to cited text no. 15
    
16.
Daulatabadkar B, Pande S, Borkar M. Generalized bullous fixed drug reaction: A close similarity to Stevens–Johnson syndrome. Indian J Drugs Dermatol 2017;3:28-31.  Back to cited text no. 16
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17.
Hiatt KM, Horn TD. Cutaneous toxicities of drugs. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF, Xu X, editors. Levers Histopathology of the Skin. 10th ed. New Delhi: Lippincott Williams and Wilkins; 2009. p. 311-31.  Back to cited text no. 17
    
18.
Romano A, Viola M, Gaeta F, Rumi G, Maggioletti M. Patch testing in non-immediate drug eruptions. Allergy Asthma Clin Immunol 2008;4:66-74.  Back to cited text no. 18
    
19.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 19
    


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