Fluconazole inducedoral mucosal lesions, mimicking herpes labialis.Adverse Drug Reactions (ADRs) like Fixed DoseEruption (FDE), Toxic Epidermal Necrolysis and StevensJohnson Syndrome following oral administration offluconazole,Bullous fixed drug eruption due to fluconazole, imitating herpes simplex

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Australasian Medical Journal 2009, 1, 14, 246-247246 CASE STUDY Please cite this paper as: Afonso N, Rane P, Dang A, RataboliP and Goel H. Fluconazole induced herpes labialis likelesions in an adult male. AMJ 2009, 1, 14, 246-247. Doi10.4066/AMJ.2009.182



Abstract Fluconazole is a bistriazole commonly prescribed for thetreatment of various fungal infections caused by yeasts anddermatophytes. However, there have been several reports of rare Adverse Drug Reactions (ADRs) like Fixed DoseEruption (FDE), Toxic Epidermal Necrolysis and StevensJohnson Syndrome following oral administration offluconazole. We report a rare case of fluconazole inducedoral mucosal lesions, mimicking herpes labialis, in a 34 yearold male patient receiving oral fluconazole for the treatment of allergic fungal sinusitis. Case report A 34 year old man presented with multiple, painless,shallow erosions, measuring about 1 cm in diameter, overthe mucosal surface of the upper lip and the outer surfaceof the lower lip along with burning, itching and crusting. Theerosions developed from painful vesicles characteristic oflocalised herpes simplex. Tzanck test for herpes simplexinfection was negative. The patient suffered from perennialallergic rhinosinusitis for one year which was treated withtopical steroids, antibiotics and antihistaminics leading tointermittent remission of symptoms. A CT scan of theparanasal sinuses showed opacification of both themaxillary and anterior ethmoid sinuses with diffuseintrasinus area of increased attenuation, suggesting fungalsinusitis. Hence, oral fluconazole 150mg once daily wasstarted presumptively for a week. History revealed thatfluconazole treatment was concomitantly associated withthe development of herpes labialis-like vesicles. The firstepisode of blistering started after the intake of the thirdtablet of fluconazole. There were no other constitutivesymptoms. Therefore, a Fixed Dose Eruption (FDE) tofluconazole was suspected. Oral provocation test withfluconazole 150mg was performed in the following weekwith the patient’s consent. The patient developed burningsensation and erythema on the mucosal aspect of both thelips, developing into herpes-like vesicles at the same site onthe very next day and painful erosions by the fourth day, mimicking the earlier episode. (Figure1)The erosions healed within a week of stopping fluconazoleand the patient continued receiving treatment for allergicrhinosinusitis. The ADR was reported to the peripheralpharmacovigilance centre of the state under the NationalPharmacovigilance Programme India. Figure 1. Pre and post provocative (left and right respectively)fluconazole induced lip lesions. Discussion Brocq in 1894 was the first to introduce the term FDE,although the phenomenon was described by Bourns 5 yearsearlier.1FDEs usually occur as a solitary pruritic,erythematous macule which evolves into an oedematousplaque. Vesicles and bullae with a prominent hemorrhagiccomponent may be present in the later stages.2 Bullous FDEsmimicking herpes simplex virus infection too has beendescribed in the past.3FDE is characterized by single or multiple skin lesions thatoccur at the same site each time a drug is administered.However, the number and size of sites may increase aftereach exposure. Lesions are usually round or oval and welldefined. Swelling and redness of skin are typically seenwithin 30 minutes to eight hours after exposure. The exactmechanism underlying FDEs is not known but immunologicalstudies strongly indicate a role of the immune system. Thedrug may act as a hapten and bind to the proteincomponent in melanocytes or dyskeratotic keratinocytesforming a drug-protein complex which is then detected,processed and presented to lymphocytes in the dermis orregional lymph nodes by Langhans’ cells as seen in allergiccontact dermatitis. There is subsequent activation of B and Tlymphocytes producing lymphokines and antibodies whichcause inflammation and damage to cells in the basal layer.The most common drug causing FDEs is cotrimoxazole(sulfamthoxazole/trimethoprim),othersincludetetracycline, metamizole, phenylbutazone, paracetamol, Fluconazole induced herpes labialis-like lesions in an adult male Dr. Nisha Afonso 1, Dr. Pawan Rane 2, Dr. Amit Dang 1, Dr. Padmanabh V. Rataboli 1, and Dr. Harish C. Goel 2 1 Department of Pharmacology, Goa Medical College2 Department of E.N.T, Goa Medical College Corresponding Author: Dr. Amit DangPost graduate studentDepartment of PharmacologyGoa Medical College+919764001983 dramit_gmc@rediffmail.com
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Australasian Medical Journal 2009, 1, 14, 246-247247 acetyl salicylic acid, mefenamic acid, metronidazole,tinidazole, chlormezanone, amoxicillin, ampicillin,erythromycin, griseofulvin, phenobarbitone, diclofenac,indomethacin, ibuprofen, diflunisal, pyrantel pamoate,clindamycin, allopurinol, and albendazole.4The first case of fluconazole induced FDE was reported inyear 1994 by Morgan and Carmichael, where theydescribed the reaction in a 27 year old man with an 18month history of 15 episodes of recurrent rash on theextensor surfaces of his elbows.5 In the second case, a localprovocation with 10% fluconazole test in petrolatumapplied at the site of a previous lesion of FDE reproducedthe eruption clinically and histopathologically in a 36 yearold woman.6Subsequently few more case reportsimplicated the causation of FDEs with fluconazole fromlimited skin involvement to extensive generalizedlesions.7,8,9,10 The most affected sites for eruptions werelimbs, palmar and plantar areas as well as the oral cavityand lips.11 A report of palatal FDE due to fluconazole hasalso been published in the past.12Most previous studies on FDE due to drugs demonstrated ahigher occurrence in men compared to women4 that is incongruence with our finding as well. However, majority ofthe FDEs due to fluconazole occurred in women ascompared to men.11 Only one case of fluconazole inducedrecurrent vesicles on the lower lip, mimicking herpessimplex virus infection, in a 23 year old woman, has beenreported so far. 13 In this case the lesions developed after 6months of recurrent fluconazole intake for ChronicRecurrent Vulvovaginal Candidiasis (CRVC). Oral provocationtest with increasing doses of fluconazole in the abovepatient produced herpes like vesicles within one day, at thesame site. Other antifungals implicated in causing FDEs areterbinafine14, griseofulvin15, ketokonazole16, itraconazole17and nystatin.18Fluconazole is generally well tolerated but the possibility ofit causing sensitization and allergic reactions should be bornin mind, especially in case of long term therapy in patientswith recurrent infections. Any new, localised skin lesion,during the course of such therapy, should be consideredpotentially drug induced unless proved otherwise. References 1. Brocq L. Éruption erythemato-pigmentée fixe due al’antipyrine. Ann Dermatol Vénéréol. 1894;5:308-13. 2. Korkji W, Soltani K. Fixed drug eruption. ArchDermatol. 1984; 120:520-4.3. Boyle J, Moul B. Fixed drug eruption masqueradingas herpes simplex labialis. BMJ 1984; 289:802.4. Mahboob A, Haroon TS. Drugs causing fixed drugeruption: a study of 450 cases. Int J Dermatol.1998; 37(11):833-8.5. Morgan JM, Carmichael AJ. Fixed drug eruptionswith fluconazole. BMJ 1994; 308:454.6. Heikkilä H, Timonen K, Stubb S. Fixed drug eruptiondue to fluconazole. J Am Acad Dermatol.2000;42:883-4.7. Ghislain PD, Ghislain E. Fixed drug eruption due tofluconazole: a third case. J Am Acad Dermatol.2002; 46(3):467.8. Lane JE, Buckthal J, Davis LS. Fixed drug eruptiondue to fluconazole. Oral Surg Oral Med Oral PatholOral Radiol Endod. 2003; 95(2):129-30.9. Goel A, Jain C. Fluconazole induced fixed drugeruption: a rare offender. J Dermatol. 2004;31(4):345-6.10. Nath AK, Adityan B, Thappa DM. Multifocal bullousfixed drug eruption due to fluconazole. Indian JDermatol. 2008; 53(3):156-7.11. Tavallaee M, Rad MM. Fixed drug eruptionresulting from fluconazole use: a case report. J MedCase Reports. 2009; 3:7368.12. Mahendra A, Gupta S, Gupta S, Sood S, Kumar P.Oral fixed drug eruption due to fluconazole. IndianJ Dermatol Venereol Leprol. 2006;72(5):391.13. Benedix F, Schilling M, Shaller M et al. A youngwoman with recurrent vesicles on the lower lip:fixed drug eruption mimicking herpes simplex. ActaDerm Venereol. 2008; 88:491-4.14. Dupin N, Gorin I, Djien V et al. Acute generalisedexanthematous pustulosis induced by terbinafine.Arch Dermatol. 1996; 132(10):1253-4.15. Boudghene-Stambouli O, Merad-Boudia A. Fixeddrug eruption induced by griseofulvin.Dermatologica. 1989; 179(2):92-3.16. Bharija SC, Belhaj MS. Ketoconazole-induced fixeddrug eruption. Int J Dermatol. 1988; 27(4):278-9.17. Gupta R, Thami GP. Fixed drug eruption caused byitraconazole: reactivity and cross reactivity. J AmAcad Dermatol. 2008; 58(3):521-2.18. Parek SS. Nystatin-induced fixed eruption. Br JDermatol. 1980; 103(6):679-80. PEER REVIEW Not commissioned; externally peer reviewed CONFLICTS OF INTEREST The authors declare that they have no conflict of interest.









Bullous fixed drug eruption due to fluconazole, imitating herpes simplex:



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