Abstract
Background:
Fixed drug reaction (FDE) is characterized by the development of well-circumscribed, round, erythematous macules and plaques on cutaneous or mucosal surface following ingestion of the offending drug.
Aim and Objectives:
To study the etiological agents responsible for FDE and to study the clinical patterns of FDE due to different drugs.
Materials and Methods:
It was a hospital-based observational cross-sectional clinical study. The study period was 24 months. Fifty patients were included. The study was done after a literature search, hypothesis generation, protocol write-up, ethical submission, ethical clearance, patient enrollment, data collection, data analysis, and research. The patients were selected on the basis of the Naranjo scoring system. The patients with a history of combination drug intake were not included in the study.
Results:
A total of 0.11% patients presented with FDE in the study period. Out of them, 52% of the patients belonged to 20–39 years age group, having sex ratio of 1.6:1. About 64% of the patients presented with multiple lesions, whereas 36% had a single lesion. A total of 46% patients presented with first episode and 54% had recurrent episodes. The mean time intervals of first and subsequent episodes were 6.5 days and 4.3 hours, respectively. Also, 16% patients had a history of herpes infection. Extremities were more affected followed by trunk and mucosa. Fluoroquinolones were the most common etiological agent found in 56% patients having cutaneous (48%) and mucosal lesions (14%). The most common drug was norfloxacin (36%) followed by both paracetamol (12%) and metronidazole (12%). Fluoroquinolones were the most common drugs implicated in bullous lesions and generalized bullous FDE.
Limitations:
The study population was small and the study was for a limited period of time.
Conclusion:
The patient should be aware of the offending drug and opt for any alternative agent after visiting the physician.
Keywords: Bullous FDE, drug rash, FDE, fixed drug eruption
Introduction
Fixed drug eruption (FDE) is a type of drug-induced cutaneous disorder that characteristically presents with a recurrence of a similar lesion at the same skin or mucosal site because of systemic exposure to a drug. It is characterized by the development of well-circumscribed, round, erythematous macules and plaques on cutaneous or mucosal surfaces.[1,2]
It typically occurs within 30 minutes to 8 hours of the intake of the offending agent, and it usually resolves after withdrawal of the offending drug.[3] It may leave residual hyperpigmentation.[4]
Though there had been many studies in different parts of India and the world citing the clinical pattern and offending agents, we found there is a paucity of literature when it comes to the eastern part of India. So, here in a tertiary center in Kolkata, we conducted a clinico-epidemiological study over 2 years to find out the clinical pattern and common offending agents in our part of the world.
Materials and Methods
A cross-sectional study was conducted on all the suspected patients of FDE in the dermatology department of a tertiary care hospital in eastern India. The period of the study was 24 months, from March 2020 to February 2022. The aim of this study was to assess the clinico-epidemiological correlation between the cases of FDE and drugs responsible for causing it. The primary objective of this study was to record the drugs responsible for FDE and to establish the causal relationships. The Naranjo score was done to check the probability of the drug association. The patients with a history of combination drug intake were not included in the study.
Results
In this study period, a total of 60 cases of FDE were screened among 51,215 patients attending dermatology outpatient department (OPD). Some 10 patients were excluded from the study due to the exclusion criteria. Incidence of FDE was 0.11 per 100 patients (60/51215) among all patients attending dermatology OPD during our study period.
About 62% of our study population were males and 38% of the study population were females. The ratio of male and female in our study was 1.6:1. The incidence of FDE was higher in males than in females. About 58% of the study population came from rural areas and the rest 42% from urban areas. In our study, the age group ranged from 5 years to 78 years. Most of the study population (52%) belonged to the age group of 20–39 years [Table 1].
Table 1.
Demographic profile of the study population
| Number of patients (%) | |
|---|---|
| Gender | |
| 1. Male | 31 (62%) |
| 2. Female | 19 (38%) |
| Age group | |
| 1. 0-19 years | 5 (10%) |
| 2. 20-39 years | 26 (52%) |
| 3. >40 years | 19 (38%) |
| Number of lesions | |
| 1. Single | 18 (36%) |
| 2. Multiple | 32 (64%) |
| Number of episodes | |
| 1. First | 23 (46%) |
| 2. Recurrent | 27 (54%) |
| Sites of involvement | |
| 1. Extremities | 17 (34%) |
| 2. Trunk | 13 (26%) |
| 3. Face | 4 (8%) |
| 4. Mucosa | 14 (28%) |
| 5. Palms and soles | 4 (8%) |
Most of the patients (62%) were asymptomatic. About 64% of the patients presenting with FDE had multiple lesions, whereas only 36% of the patients had a single lesion. About 36% of patients had a single plaque, 30% had two to five plaques, and 34% had more than five plaques on initial presentation. About 46% of patients presented with single episode and 54% of patients presented with recurrent episodes. The mean time intervals of first and subsequent episodes were 6.5 days and 4.3 hours, respectively.
Anti-bacterial group of drugs caused FDE in 50% of patients in less than 1 day and in 12% of patients after 1 day. About 12% of patients had FDE in less than 1 day by the anti-amoebic drugs, which also caused FDE in 6% of patients after 1 day of drug intake. About 16% of patients developed FDE in less than 1 day after having nonsteroidal anti-inflammatory drugs (NSAIDS) and only 4% of patients developed FDE after 1 day. The FDE was induced by trauma in some cases. About 16% of the patients had a prior history of healed herpes simplex infection, 8% had a history of burns, and 2% had a bite history.
About 16% of patients had oral mucosal lesions, 12% had genital mucosal lesions [Figure 1], 8% had face involvement, 26% had trunk involvement [Figure 2], and 34% had lesions on extremities [Figure 3]. Antibacterial group of drugs had more cutaneous involvement than mucosal involvement. Anti-amoebic drugs also had more cutaneous distribution. NSAIDS had equal involvement of skin and mucosa. In our study, extremities (34%) were found to be more affected than trunk, genitals, palms, and soles.
Figure 1.
FDE due to fluroquinolone (levofloxacin) on scrotum
Figure 2.
Classical lesion of bullous FDE due to norfloxacin on abdomen
Figure 3.
FDE due to metronidazole on lower limbs
Most commonly involved drugs causing FDE were norfloxacin (36%) followed by metronidazole (12%) and paracetamol (12%). Ciprofloxacin, ofloxacin, and ibuprofen had 8% of incidence each. Levofloxacin and ampicillin both had 4% incidence, whereas trimethoprim-sulfamethoxazole had only 2% incidence. In our study, 56% of FDE were due to fluoroquinolones. [Table 2]
Table 2.
Agents responsible for fixed drug eruption
| Drugs | No. of patients |
|---|---|
| Anti-bacterial | |
| 1. Norfloxacin | 18 (36%) |
| 2. Ciprofloxacin | 4 (8%) |
| 3. Levofloxacin | 2 (4%) |
| 4. Ofloxacin | 4 (8%) |
| 5. Trimethoprim sulfamethoxazole | 1 (2%) |
| 6. Ampicillin | 2 (4%) |
| Anti-amoebic | |
| 1. Tinidazole | 3 (6%) |
| 2. Metronidazole | 6 (12%) |
| NSAIDS | |
| 1. Ibuprofen | 4 (8%) |
| 2. Paracetamol | 6 (12%) |
About 28% of patients had only mucosal FDE, 62% had classical FDE, 8% had bullous FDE, and only 2% had generalized bullous FDE. Antibacterial drugs contributed more to classic FDE and mucosal FDE. Fluoroquinolones were the most common drugs implicated in generalized bullous FDE. Bullous FDE was found to be caused by antibacterials and NSAIDS. In this study, bullous FDE was caused by both norfloxacin [Figure 2] and paracetamol.
All of the patients had a history of oral route of drug intake. They were advised to discontinue the offending drug. They were treated with topical corticosteroids and antihistamines. The patients recovered with persistent hyperpigmentation of the affected area.
Discussion
Many drugs are associated with FDE, with continuous evolving documentation of the responsible agents and clinical presentations. In our study, the age group ranged from 5 years to 78 years. Most of the study population (52%) belonged to the age group of 20–39 years which is almost similar according to Tripathy et al. and Kornmehl et al.[5,6] According to studies done by Mahboob et al. and others, 16% of patients had a single plaque, 36% had two to five plaques, and 47% had more than five plaques on initial presentation.[7,8,9,10] About 46% of patients presented with single episode and 54% of patients presented with recurrent episodes. This is in accordance to the studies done by Mahboob et al. and Nnoruka et al.[7,9] About 16% of the patients had a prior history of healed herpes simplex infection, 8% had a history of burns, and 2% had a bite history. The rest 74% of patients had no history of any trauma which is also in accordance to Ahmed et al.[3] In our study, extremities (34%) were found to be more affected than trunk, genitals, palms, and soles. In the study conducted by Dhar et al.,[11] extremities were the most common sites affected. In a study conducted by Ozkaya-Bayazit et al., genitalia was the most common affected site.[12]
Most commonly involved drug causing FDE was norfloxacin (36%), followed by metronidazole (12%) and paracetamol (12%). This correlates with studies done by Byrd et al. and Dharamsi et al.[4,13] According to the study conducted by Brahimi et al., paracetamol was the most common offending drug.[14] Tetracyclines were found to be the main offenders in a study conducted in Singapore by Chan.[15]
In this study, bullous FDE was caused by both norfloxacin and paracetamol. Bullous FDE to paracetamol have already been reported across the world.[16,17,18] Other morphological variants were not found in our study.
Limitations
The study population was small and a larger population would have generated variety of presentations of FDE and different causes, which would be statistically significant. The study was for a limited period of time. Longer study duration would have benefited the study greatly by adding more variety of causes of FDE. As it is a cross-sectional study, larger sample size is required to properly calculate the most common causes of FDE.
Conclusion
Fixed drug eruption subsides with residual hyperpigmentation which may persist for a prolonged period of time. With recurrent intake of the offending drug, the patient may develop generalized bullous FDE. Hence the patient should be aware of the offending drug and opt for any alternative agent after visiting the physician.
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.
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