Fixed Drug Eruption Due to Tinidazole: 2 Case Reports and Review of Literature. K Sangma, J Wahlang, M Marak, M Sangma, M Lyngdoh, D Brahma

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1 ISPUB.COM The Internet Journal of Pharmacology Volume 10 Number 1 Fixed Drug Eruption Due to Tinidazole: 2 Case Reports and Review of Literature K Sangma, J Wahlang, M Marak, M Sangma, M Lyngdoh, D Brahma Citation K Sangma, J Wahlang, M Marak, M Sangma, M Lyngdoh, D Brahma. Fixed Drug Eruption Due to Tinidazole: 2 Case Reports and Review of Literature. The Internet Journal of Pharmacology Volume 10 Number 1. Abstract Fixed Drug Eruption (FDE) is a common type of drug eruption characterized by single or multiple skin lesions which occur at the same site each time the drug is administered. FDEs though usually not fatal, can cause cosmetic embarrassment if exposed parts are affected due to recurrence of the reaction on the previously affected site and residual hyperpigmentation. Genital fixed drug eruption in particular, is the cause for apprehension among the sufferers. FDE usually occurs within hours of administration of the offending agent. Nitroimidazoles including tinidazole have been used for anaerobic infections especially in intestinal amoebiasis, without much side effects, but may cause FDEs. We report 2 (two) cases of FDE due to tinidazole attending dermatology out patient clinic. The first one is a case of FDE on the glans penis and the second one is a case of FDE on the lips and trunk. In both the cases tinidazole was advised to stop. The cases were managed with steroid and anti histamines. Both the patient and famlily members were counseled for possible ADRs occurred due to tinidazole intake and advised to avoid tinidazole and any self medication and also to notify to physicians physicians regarding such reactions in future. INTRODUCTION Fixed Drug Eruption (FDE) is a common type of drug eruption seen in skin clinics. FDE is characterized by single or multiple skin lesions which occur at the same site each site each time the drug is administered. [1] Most commonly, the skin lesion is a dusky erythematous macule and is usually found on extremities, lips, genitalia and perianal areas, although any skin or mucosal surface may be involved. The skin lesions may be associated with a burning sensation and may be present in multiple numbers or progress to the development of central vesicles and bullae, particularly after the repeated use of an agent. [2] Crosssensitivity may occur with structurally similar drugs. The offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, thereby causing an inflammatory response. [3] Nitroimidazoles are low molecular weight antimicrobial compounds with excellent activity against anaerobic microorganisms and protozoa. They are indicated in trichomoniasis, amoebiasis, giardiasis, anaerobic and mixed bacterial infections, [4,5] and are the first line of drug in hepatic and intestinal amoebiasis. All nitroimidazoles, namely metronidazole, tinidazole, secnidazole and satrinidazole, have a similar nitroimidazole ring but different side chains. For example, metronidazole has ethanol, tinidazole has ethylsulphonyl ethyl, ornidazole has chloro propanol, secnidazole has propanol group and satrinidazole has methylsulphonyl imidazoline. [6] Although all these molecules have been used, including self medication for a long time without any side-effects, reports of FDEs caused by metronidazole [7,8,9,10,11] and tinidazole [12,13,14,15] are increasing. Reports of FDEs caused by ornidazole [16, 17, 5] are also available in recent times. However, FDEs due to tinidazole including on glans penis, occurs rarely so much so, not routinly included in books in the list of causative drugs. We report two cases of fixed drug eruption (FDE) due to tinidazole encountered within a period of two months in our outpatient clinic. The first case was a case of FDE on glans penis and the second one was in the lips and trunk. We also carried out the causality, severity and preventibility assessment as per Naranjo alogarithm [18], Hartwig scale [19] scales respectively. METHOD The cases were detected in the Dermatology outpatient clinic and diagnosis was confirmed by dermatologist. The cases were also informed to the Department of Pharmacology by a Senior Resident Doctor of Dermatology Department. 1 of 5

2 CASE REPORT 1 A 30 year old male attended the Dermatology Outpatient Clinic of North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, Meghalaya for generalized itching and lesion on genital region. He gives the history of intake of single tablet of Tinidazole one week before for diarrhoea with slight itching all over the body which disappeared on stopping the drug, but on subsequent intake of tinidazole tablet one week later for the same complain he started having itching in some parts of the body including glans penis with noticeable erosion over the glans penis from the next day onwards. On examination, vitals were stable. There was a single superficial non-tender ulceration with erythematous halo over the glans without lymphadenopathy. There was no pus or discharge. He was nondiabetic and denied history of any sexual exposure. The case was provisionally diagnosed as FDE due to tinidazole considering the temporal relation with the drug consumption. Our provisional diagnosis was supported by literature review which revealed the presence of fixed drug eruption due to tinidazole. Complete blood count, random blood sugar and serum electrolyte showed within normal limits. The FDE was managed with Tab. Deflazacort 12mg for 10 days, along with Tab. Ranitidine 150 mg, Tab. Cetirizine 10 mg 1 tablet HS and Fusidic acid+betamethasone cream. Follow up on the 4th day of treatment, there was no pruritus, erythematous ulceration was subsiding and on the the 11 th day no lesion was seen except a hyperpigmented area. The assessment showed probable (Score - 7) and moderate (level - 4) type of ADR as per Naranjo algorithm and [18] Hartwig scale [19] respectively. CASE REPORT 2 A 25 year old male patient gives a history of intake of Tinidazole 400 mg tablet twice daily prescribed for diarrhoea for a period of 7 days. On the fourth day the patient developed itching all over the body. By the 5 th day the patient noticed ulcerations on lips and trunk. He attended dermatology outpatient department of North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India. On examination, vitals were stable, slate grey pigmented macule on the trunk and lips were seen. There was no pus discharge. He was nondiabetic and did not give history of intake of any other medication. The case was also provisionally diagnosed as FDE due to tinidazole considering the temporal relation with the drug consumption. Complete blood count, random blood sugar and serum electrolyte showed within normal limits. He was treated with Deflazacort tablet 12 mg for 3 days and betamethasone ointment and tablet Cetrizine10 mg 1 tablet HS for 7 days. Follow up showed complete recovery after one week except a hyperpigmented area in the trunk. The assessment showed probable (Score - 7) and moderate (level - 4) type of ADR as per Naranjo algorithm and [18] Hartwig scale [19] respectively. DISCUSSION Different medications have been implicated, but the most commonly implicated are sulphonamides, salicylates, oxyphenbutazones, tetracycline, dapsone, chlordiazepoxide, barbiturates, phenolphtheline, morphine, codiene, quinine and derivatives, phenacetin, erythromycin, griseofulvin, mebendazole, meprobamate etc. [20,21] Certain medications also appear to have a predilection for certain anatomic locations, e.g. tetracyclines for genitalia. The exact pathogenesis of FDE is unknown, although the offending drug is thought to function as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response. [3] Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes may locally up-regulate expression of the intercellular adhesion molecule-1 (ICAM1). [22] The up-regulated ICAM1 has been shown to help T cells (CD4 and CD8) migrate to the site of an insult. [23] Migrated and residential CD8 cells likely perpetuate tissue damage by their production of the inflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. CD8 cells isolated from active lesions have also been shown to express alpha E beta 7, a ligand for E-cadherin, which may further contribute to the lymphocyte s ability to localize to the epidermis. Other cell surface molecules, such as CLA/alpha4beta1/CD4a, that bind E-selectin/vascular cellular adhesion molecule-2/icam1 help to further attract CD8 cells to the area. [24] The skin findings are usually associated with nonspecific constitutional symptoms, including fever, malaise, nausea, andvomiting. The peak incidence of FDE is years and male:female incidence is generally equal, although any age/sex may be affected. Genetic predisposition to FDE 2 of 5

3 appears to occur in individuals with a family history of diabetes mellitus, atopy, and drug allergies. [25] Histological findings of FDEs demonstrate mixed inflammatory infiltrate of lymphocytes, neutrophils and eosinophils at the dermal-epidermal junction. The epidermis contains necrotic keratiocytes. Melanin containing macrophages in the dermis and chronic epidermal changes including acanthosis, hypergranulosis and hyperkeratosis are seen in older lesions. [20] Differential diagnosis of FDE includes erythema multiforme (EM), as well as Steven-Johnson syndrome (SJS) and toxic epdermal necrolysis (TEN), in cases of disseminated or bullous FDE. In contrast to FDE, recurrent lesions in EM tend not to recur in the sites of previous involvement. [26] A careful history of previous drug exposure and skin lesions is important in identification of the causative drug. Oral rechallenge of smaller doses of suspected agent is a method to determine with certainity the source of a drug eruption. However, in severe cases like bullous or disseminated FDE, oral rechallenge is proved dangerous. Patch tests, scratch tests and intracutaneous testing are also helpful means of identifyig the offending agent, but are less reliable. FDEs resolve spontaneously without scarring, butpersistent hyperpigmentation at the site of the lesion is normally seen after healing. [2] FDE usually occurs within hours of administration of the offending agent. [6] Probably, Jafferany and Haroon, [12] first reported the FDE due to tinidazole in 1987, but available literature search gives very few reports of FDE directly involved due to tinidazole, although few reports of cross sensitivity with other nitroimidazoles [7,8,13,14] are available. In our cases, while the offending drug tinidazole alone caused FDE within 24 Hrs after oral administration in our first case, it occurred on the fourth day in the second case. The first case reported an ADR which occurred only after the intake of second dose that also after a gap of one week. The second case is reported as a delayed adverse reaction to tinidazole which is not commonly seen. In our case reports both the patients were male and aged between 21 and 30 years within the common age group of the peak incidence. FDEs have predilection for certain organs like glans Penis [27] and lips (2) in our case also it occurred in glans penis, trunk and lips. CONCLUSION Fixed drug eruption though usually not fatal, can cause enough cosmetic embarrassment if present on the exposed part due to recurrence of the reaction on the previously affected site and residual hyperpigmentation. Genital fixed drug eruption (FDE) in particular, is the cause for apprehension among the sufferers. Nitroimidazoles, not only commonly prescribed medications in India, but also available over the counter. Moreover, various combination preparations with other antimicrobials are readily available in Indian market and rampantly used by people. Patients are often unaware of the nature of the drugs which are consumed by them and do not relate their complaints to the use of the drugs. Therefore, whenever FDEs are encountered, patients should be counseled on medication avoidance and possible crossreactions of similar medications. Patients should be discouraged from self medication and alerted to notify their physicians of all drug allergies they have experienced. Clinicians should also be alerted that the most commonly used medications like nitroimidazoles have increasingly proved their potential to cause FDEs and cross-sensitivity may occur among the drugs from this group. Alertness of both, the patient and the physician is important towards promoting safe and rational use of medications. ACKNOWLEDGEMENT Authors thank the authorities of NEIGRIHMS for allowing ADR study in the Institute. 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4 S. Prabhu, M. Prabhu & P. Mishra: Metronidazole Induced Bullous Fixed Drug Eruptions: A Case Report And A Review Of Literature. The Internet Journal of Dermatology; 2007; Volume 5 Number Wahlang JB et al. FIXED DRUG ERUPTION DUE TO METRONIDAZOLE: REVIEW OF LITERATURE AND A CASE REPORT. International Journal of Pharma Sciences and Research (IJPSR);March 2012; 3(3): Jafferany M, Haroon TS. Tinidazole-induced fixed drug eruption. Int J Dermatol; 1988;27: Bansal A, Kumari R, Ramam M. Fixed drug eruption due to cross reaction between two azoles used for different indications. Indian J Dermatol Venereol Leprol; 2008;74: Mishra D, Mobashir M and Zaheer MS. Fixed Drug Eruption and Cross-reactivity Between Tinidazole and Metronidazole. International Journal of Dermatology;1990;29: Sengupta P, Sharma A, Bagchi C, Tripathi S. Nitroimidazole derivative-induced fixed drug eruptions. Not so uncommon.indian J Pharmacol; 2011 April; 43(2): Gupta S, Jain VK, Aggarwal K, Gupta S, Mahendra A. Fixed drug eruption caused by ornidazole. Contact Dermatitis; 2005;53: [PubMed]. 17. Davut Baltaci, Hikmet Akyazi, Hayati Kandis, Ayhan Saritas, Sevdegul Mungan, Ismail Hamdi Kara.Ornidazoleinduced fixed drug eruption: A case report. Slovenian Medical Journal;2012;Vol.81, No Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roborts EA. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther; 1991; 30: Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm; 1992; 49: Crowson AN and Magro CM. Recent advances in the pathology of cutaneousdrug eruptions. Dermatol Clin;1999; 17: Stern RS and Wintroub BU (1999) Cutaneous reactions to drugs, in Fitzpatrick sdermatology in General Medicine (Freedburg IM, Eisen AZ, Austen KF, Goldsmith LA, Katz SI, and Fitzpatrick TB eds) pp , McGraw-Hill, New York. 22. Smoller BR, Luster AD, Krane JF, et al. Fixed drug eruptions: evidence for a cytokine-mediated process. J Cutan Pathol; Feb 1991;18(1):13-9. [Medline]. 23. Hindsen M, Christensen OB, Gruic V, Lofberg H. Fixed drug eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol; Mar 1987;116(3): [Medline]. 24. Teraki Y, Shiohara T. IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption. J Allergy Clin Immunol; Sep 2003;112(3): [Medline]. 25. Hager JL, Mir MR,Hsu S. Fluoroquinolone-induced generalized fixed drug eruption. Dermatology Online Journal; 2009;15 (12): Sowden JM and Smith AG.Multifocal fixed drug eruption mimicking erythemamultiforme. Clin Exper Dermatol;1990;15: Bilimoria FE, Shah PP Drug reactions. In: IADVL Textbook and Atlas of Dermatology, Edited by Valia RG, Bhalani Publishing House, Bombay 1994; of 5

5 Author Information Kalkambe A. Sangma Department of Dermatology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences Julie Birdie Wahlang Maxilline D. Marak Marlina Ch. Sangma Department of Physiology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences Monalisa Lyngdoh Department of General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences Dhriti Kr. Brahma 5 of 5