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] Cross-sensitivity 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 micro-organisms 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.

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 (NEIGRIHMS), 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 (NEIGRIHMS), 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 21-30 years and male:female incidence is generally equal, although any age/sex may be affected. Genetic predisposition to FDE 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 cross-reactions 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.