Norfloxacin-Tinidazole Induced Stevens-Johnson Syndrome in Elderly Diabetic Patient: A Case Report

Stevens-Johnson Syndrome (SJS) is an acute severe, uncommon, and potentially life-threatening condition involving skin and mucous membrane. Stevens Johnson Syndrome incidence is estimated to occur in 0.05 to 2 individuals per million people in a year globally. SJS is a very serious hypersensitivity reaction that can occurs due to infections or as a side effect of drugs (Anticonvulsants, Antibiotics, NSAIDS). Fluoroquinolones are broad spectrum antibiotics with wide range of activity used to treat respiratory tract infections, gastrointestinal and genitourinary infections. Fluoroquinolones such as Norfloxacin is reported to rarely associated in inducing SJS (0.01% to 0.1%). Nitroimidazole such as Tinidazole could exacerbate SJS when used in conjunction with fluoroquinolones (FQs). In this case, a 66year old diabetic, hypertensive female of Indian nationality was presented with complaints of rashes, multiple blisters over legs, hands and swelling of her lips for the past 3 days. Patient was prescribed with antibiotic Norflox-TZ for her previous conditions which included loose stools and fever. After 48 hours of Norflox-TZ twice a day consumption she developed rashes, associated with blisters. Therefore, it was suspected that fluoroquinolone along with nitroimidazole could be the possible causative agent in our case. The causality assessment was done based on the Naranjo’s causality scale and it was scored as ‘probable’ fluoroquinolone along with nitroimidazole induced SJS. The patient recovered after withdrawal of suspected drug and treatment with both systemic corticosteroids, topical applications and medications for her comorbid conditions. After full recovery, the patient was discharged in a stable condition. Pharmacist role is emphasized in identifying, preventing and managing adverse drug reactions considering their intensive knowledge in medications.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) are acute severe, uncommon, but potentially life-threatening skin conditions characterized by skin loss and, in some instances, mucosal membrane is also involved. Systemic manifestations are also reported in few cases. Stevens-Johnson Syndrome (SJS) is an inflammatory vesiculobullous reaction of the skin, the mucosa of the ocular surface, the oral cavity, and of the genitals; whereas its severe type is called Toxic Epidermal Necrolysis (TEN) [1].

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis is estimated to occur in 0.05 to 2 individuals per million people in a year globally [2,3]. Mortality rates range from 4.8-9% to 14.8-48%, with females being more commonly affected than males. SJS is considered as delayed type hypersensitivity reactions to medications. Over 80% of cases are caused by medications like anticonvulsants (Phenytoin), Allopurinol, sulfonamides, antibiotics (penicillins, cephalosporins), nonsteroidal anti-inflammatory drugs derived from propionic acid (e.g., ibuprofen) etc. Genetic factors, such as specific human leukocyte antigen (HLA) allotypes, can increase the risk of developing Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis when exposed to aromatic anticonvulsants and allopurinol [4].

Fluoroquinolones (FQ’s) are classified as broad-spectrum antibiotics, commonly prescribed for treating infections in the genitourinary, respiratory, gastrointestinal, skin, and soft tissue areas [5]. Tinidazole is a nitroimidazole class of drug. It is commonly used as an antibiotic and antiprotozoal medication to treat various infections, caused by bacteria and protozoa. These antibiotics are typically well tolerated, with fewer than 5% of patients requiring to discontinue treatment due to side effects. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been associated with fluoroquinolones and nitroimidazole, although these occurrences are very rare. Fixed drug combination eruptions are localized skin reactions that appear at the same site upon repeated exposure to the drug, and they may occur in some individuals. These types of reactions are consistent with usage of fluoroquinolones along with nitroimidazole [6].

A 66-year-old post-menopausal female was presented with chief complaints of rashes, multiple blisters over legs, hands and swelling of her lips for 3 days. Patient had history of abdominal pain associated with multiple episodes of loose stools, fever, body aches for the past 5 days. The patient was prescribed with Tab. Paracetamol for body pains, Tab. Lomotil for loose stools and antibiotic Tab. Norflox-TZ in other medical facility, after 48 hours of Norflox-TZ twice a day consumption she developed rashes, associated with blisters. During present admission, she was conscious, oriented, cooperative. Her temperature was 98F, pulse was 79beats/minute, respiratory rate was 20breaths/minute, blood pressure was 110/80 mmHg and her random blood sugar level was 250mg/dl. Her medical history revealed that she had type 2 diabetes mellitus, hypertension, choriocarcinoma, status post chemotherapy. Patient is on medication for comorbid conditions, includes Pantoprazole (PAN) 40mg, Glimepiride in combination with Metformin (Zoryl M2) for diabetes, Cilnidipine in combination with Telmisartan (Cinod-T) for hypertension, Rosuvastatin for dyslipidemia (Rozavel) 10mg, Pregabalin and Methyl Cobalamin (Pregator-M) 75mg, Inj Apidra (Insulin glulisine) 10units to control blood glucose levels. On evaluation investigations showed TSH within normal limits, RFT (Renal function test) within normal limits, serum electrolytes within normal limits sodium: 140, pota-ssium: 4.2, Hb-12.2, ALP-139, ALT-54, HbA1c- 6.7%, CRP-9.63, ESR-70.93, Albumin-globulin ratio: 0.9.

2DECHO with colour doppler demonstrated normal sized cardiac chambers with no LV Regional wall motion abnormality, LVEF: 60%, Urine culture showed no growth. Gastrointestinal panel detected presence of E. coli. The patient had history of rash in the past but not associated with blisters subsided with antihistamines. Present reaction occurred after introduction of Norflox-TZ but not due to usage of long-term medications. The final diagnosis concluded by clinician was Norflox-TZ induced Stevens Johnson Syndrome. After diagnosis of SJS, Tab. Norflox-TZ was stopped and treated with steroids, antihistamines.

Adverse Drug Reactions (ADRs) are a major cause of illness and death. In India, approximately 2.9% to 5.6% of hospital admissions are attributed to ADRs [7]. SJS is a rare and severe cutaneous ADR which requires hospitalization. According to the involvement of body surface area (BSA), the disease can be classified into SJS (30% BSA) and SJS-TEN overlaps (10%-30% BSA) [8]. Approximately 40% of drug-induced Stevens-Johnson Syndrome (SJS) cases are associated with antibiotics. Fluoroquinolones (FQ), such as Ciprofloxacin (less than 0.01%) and Norfloxacin (0.01% to 0.1%) rarely cause drug-induced SJS [9,10]. Norfloxacin, a Fluoroquinolone derivative, is a broad-spectrum antibiotic commonly used to treat urinary and respiratory tract infections. It has an extensive antimicrobial spectrum, covering a wide range of gram negative and gram-positive organisms. To date, there have been no confirmed cases of Stevens-Johnson Syndrome (SJS) linked to Tinidazole. In such case, it's possible that inidazole could exacerbate SJS when used in conjunction with fluoroquinolones (FQs) [11].

In this condition, blisters begin to form on the skin, which then spread, causing the skin to peel or shed, eventually leading to the death of the affected skin. This occurs due to an overly active immune response, which triggers severe inflammation. This process involves various components of the immune system, including MHC-1, T-helper cells, cytokines, neutrophils, macrophages, CD-8+ T cells, and other elements of the innate immune system. Variations in the HLA-B gene can cause abnormal immune reactions to certain medications that are likely to trigger Stevens-Johnson syndrome (SJS). Drug-induced cytotoxic T cells and natural killer cells produce granulysin, which destroys skin and mucosal cells due to the body's inability to eliminate reactive metabolites. Diagnosis is primarily based on clinical symptoms and the histopathological examination of skin lesions. This condition typically begins with flu-like symptoms followed by red or purple rashes that spread to form blisters and also leads to high fever, tiredness, fatigue, sore throat, mouth ulcers. This requires immediate medical attention. A skin specialist typically diagnoses it by evaluating a combination of the patient's symptoms, medical history (both past and present), and physical examination [12].

Naranjo’s Algorithm

In this case, Naranjo’s algorithm was applied to assess the likelihood of a reaction caused by Norfloxacin-Tinidazole [13]. Based on total score of 8 (Table 1), this Stevens-Johnson Syndrome (SJS) was classified as a "probable" reaction to Norfloxacin-Tinidazole administration. Such adverse event has been previously reported which provides evidence that this is a probable reaction and with further dermatologist consultation reconfirmed it as Norfloxacin TZ induced Stevens-Johnson Syndrome.

Table 1: Naranjo’s Algorithm.

In India, guidelines are available for management of SJS which recommend immediate withdrawal of all suspected drugs along with adequate supportive treatment. If patients of SJS have been identified at a primary or secondary healthcare facility, the treatment should be initialized prior to their referral to a tertiary care center [14]. Preventive measures against infection include maintaining hygiene, caring for wounds, replenishing lost fluids and nutrients, and providing eye care. The approach also focuses on symptomatic management and improvement through the use of general pain relievers, antibiotics, and other medications tailored to the patient's needs, which helps prevent potential complications.

Patient was given with intravenous fluids (IV NS 70ml/hr) for hydration, systemic administration of corticosteroids (Solumedrol), Empirical antibiotic (Zostum 1.5g), antihypertensives (Cilnidipine 10mg twice a day, Telmisartan 40mg was later added for breakthrough spikes in BP), pain management (Pregabalin 75mg). SJS symptoms treated with Inj.Avil 22.75mg, Inj.Hydrocort 100mg, topical application of Fusidic acid cream for rashes.

In hospital patient developed rashes all over the face upon administration of Inj.Zostum 1.5g, no new blisters found and the drug was withdrawn. This shows patient is hypersensitive to other drugs also apart from Norflox-TZ. Further, Mupirocin Ointment was prescribed for rashes. The patient recovered and was discharged after 4 days of treatment. Since the gastrointestinal panel confirmed presence of E. coli, Inflammatory bowel disease is also suspected which needs further evaluation. The discharge medications included Rabeprazole 20mg OD, Prednisolone 20mg OD for 7 days, Fusidic acid over the rash OD, Telmisartan 40mg OD, Pregaba M 75mg OD, Rosuvastatin 10mg OD, Mupirocin ointment as a topical applicant BD, Inj Apidra (Insulin glulisine)10units TID for diabetes mellitus type-2 and adjust the dosage management according to blood glucose levels. Patient was educated to avoid any quinolone group of antibiotics, Tinidazole, Metronidazole and Ornidazole. Follow up was scheduled after 7 days.

Role of Clinical Pharmacist in Identifying, Preventing and Managing Adverse Reactions

Pharmacists play an important role in identification, and prevention as well as management of ADRs [15]. The role of pharmacists is crucial due to their extensive knowledge of medications. Pharmacists are responsible for promoting the maintenance, development, and continuous evaluation of programs aimed at minimizing the risks of adverse drug reactions (ADRs) [16]. Reporting ADRs is an essential component in monitoring and evaluating the activities performed in hospitals. A hospital-based reporting program provides valuable insights into medication-related issues within the healthcare facility. By identifying and addressing these problems, patient care can be enhanced. Pharmacists play an important role in educating patients about medications and their potential adverse effects is crucial for preventing such reactions. Patient medicals records should be properly flagged for proven allergies to avoid further adverse reactions.

The incidence of SJS associated with Norfloxacin and Tinidazole is very uncommon. We encountered a patient who was diagnosed with Norfloxacin-Tinidazole induced SJS. The patient was having comorbid conditions such as diabetes mellitus, hypertension. She recovered completely after withdrawing the drug in addition to treatment with other symptomatic measures. Generally, use of medications that can potentially cause SJS requires careful monitoring. Patients should be educated to observe and report any adverse reactions (ADR’s) encountered with the use of such medications. SJS is very rare and early identification, management is necessary to prevent detrimental outcomes.