Levofloxacin and furazolidone induced toxic epidermal necrosis.

Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a severe cutaneous drug reaction with a high mortality. Immune response is the possible cause in its pathogenesis. Levofloxacin is one of the most commonly used quinolones and has been reported to cause of TEN. On the other hand, furazolidone was proposed to augment the action of immediate hypersensitivity of levofloxacin by its cytotoxic effect and by the generation of free radicals. Here, we present a case of TEN where, levofloxacin and furazolidone were the probable cause of these adverse drug reactions.

Introduction

Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN, Lyell's syndrome) are severe life-threatening cutaneous adverse drug reactions (ADR). TEN is characterized by the involvement of more than 30% skin detachment and causes mortality in 25-35% cases.[1] Fluoroquinolones are the most widely used drugs which have broad coverage and low adverse effect profile. Levofloxacin has a high incidence of this ADR among all the drugs in this class.[2] Furazolidone is a synthetic nitrofuran widely used in the treatment of gastrointestinal infections. Levofloxacin has been implicated as an offending agent in TEN in literature,[3] whereas furazolidone induces the skin condition by affecting the immune system. We present a case of TEN probably caused by levofloxacin and furazolidone.

Case Report

A 69-year-old male patient with the complaints of fever of mild to moderate grade and loose motions, 4-6 times a day consulted a private practitioner and was prescribed tablet levofloxacin 500 mg twice daily, tablet furazolidone 100 mg thrice a day and tablet rabeprazole 20 mg once a day. After taking medications for 2 days, he complained of rashes all over his body associated with pain, which later developed into erosions and peeling of the skin. He also complained the difficulty in swallowing food due to oral ulcers.

On examination, the patient was alert and his pulse and blood pressure were within normal limits. He had no pallor, icterus, lymphadenopathy, clubbing and pedal edema. His respiratory, cardiovascular and central nervous systems were within normal limits. On examination, oral erosions, dusky red skin over the chest, abdomen, back, face, upper and lower limbs with epidermal peeling involving more than 40% of the total body surface area was observed. The Nikolsky's sign was positive. Ocular inflammation was also present [Figure 1].

Figure 1

Toxic epidermal necrolysis before treatment Access

On the day of admission, his serum urea and serum creatinine was 78 mg/dl and 1.4 mg/dl, respectively. The red blood cell counter was 19.7 cell/μl (mcL) and peripheral blood smear showed neutrophils with toxic granules and band form. Nuclei and platelets were adequate. His erythrocyte sedimentation rate was 60 mm/h. The liver function tests were within the normal limit. Blood culture report done at the time of admission was negative after 24 h incubation. His Scorten Score was 2. Following the abnormal reports, levofloxacin and furazolidone were stopped and he was prescribed injection dexamethasone 8 mg intravenous (i.v.) 4 times a day for 5 days, later tapered for the next 4 days. Injection of combination of amoxicillin with clavulunic acid 1.2 g i.v. thrice a day for 15 days, calamine lotion locally twice a day, betadine gargles 4 times a day for oral ulcers and injection pantoprazole 40 mg i.v once a day were also prescribed. At 10 days later, the symptoms improved, he was able to take food orally and the epidermal peeling also subsided. Laboratory investigations were repeated after 10 days were normal.

Discussion

TEN is a rare disease that usually follows drug-exposure. It is predominantly induced by medications such as allopurinol, anticonvulsants, quinolones and non-steroidal anti-inflammatory drugs.[1] The pathogenesis of TEN is complicated but believed to be immune-mediated. TEN is a specific drug hypersensitivity reaction in which T lymphocytes play a role in the pathogenesis of the disease. In literature, it was found that in early stage of the disease, the blister fluid contains cytotoxic CD8+ T lymphocytes, which may suggest a major histocompatibility class-I restricted drug presentation, which may lead to clonal expansion of CD8 and cytotoxic lymphocytes.[4] The increase in the leucocytes counts in the case may correlate with finding in the literature. The cytotoxic proteins and cells implicated in the pathogenesis of TEN are not fully understood and is a key subject of ongoing research. There is a cross-link which suggest that disseminated keratinocyte apoptosis in TEN is mostly due to cytotoxic molecules FasL and granulysin.[5]

Furazolidone is an antimicrobial used in Gram negative bacterial infections, giardiasis and trichomoniasis. It up-regulates the production of intracellular reactive oxygen species which bind with mitochondrial deoxyribonucleic acid and causes oxidation of the cell. Due to oxidative stress, it may cause abnormal progression of cell cycle, which may result in cell cytotoxicity and cell death. Thus, it has been known to cause agranulocytosis, hemolysis and rash.[6] On the other hand, levofloxacin has already been reported as an offending agent in TEN.[3] The probable cause of the ADR in this case may be immediate hypersensitivity reaction due to levofloxacin which is a rare adverse reaction of this drug. The mechanism of underlying immediate reaction is not clearly defined. However, it may be postulated that the drug may bind with basal keratinocytes and stimulate the inflammatory process by causing the release of lymphokines, mast cell and antibodies, which in turn causes damage to basal cell. CD8+ on activation causes the release of interferon and cytotoxic granules which may add to further damage to basal cell.[7] This may up-regulate the immune response and cause TEN. Thus, we can assume that the combination of levofloxacin induces immediate hypersensitivity reaction and furazolidone induced oxidative stress and cell toxicity may be the contributing factor in the pathogenesis of TEN.

In this case, patient had improved gradually after offending drugs were withdrawn. Causality assessment using Naranjo algorithm shows that a probable relationship exists between levofloxacin and furazolidine and TEN.[8] Hence, caution is advised while co-administering these drugs, particularly in patients with a known history of hypersensitivity to these drugs.