Multiple drugs

Abstract

Stevens-Johnson syndrome/toxic epidermal necrolysis, increased INR and liver injury: case report A 61-year-old man developed Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) during treatment with cefalotin, rabeprazole, vancomycin and warfarin. Additionally, he developed liver injury and increased INR during treatment with warfarin [routes not stated; not all dosages stated]. The man presented to the Cardiac Surgery Department of a hospital with a 3-year history of severe aortic stenosis. The results of preoperative examinations were found to be normal, and he underwent aortic valve replacement. Postoperatively, he was treated with several drugs including cefalotin [cephalothin], warfarin 2–4mg once daily and rabeprazole 20mg once daily. He was also receiving various medications concomitantly. On postoperative day 10, he developed fever; therefore, vancomycin 500mg every 6 hours was added as an anti-infective treatment. On postoperative day 15, his INR exceeded to 4.0. Due to increased INR, warfarin was withdrawn. On postoperative day 18, the man developed a maculopapular facial rash, which subsequently spread to his arms and trunk. Two days afterwards, the rash progressed into erythema multiforme. He was then transferred to the Dermatology Department. At the Dermatology Department, physical examination showed fever and atypical target lesions on the trunk, extremities and face accompanied by oral mucosal erosion. Skin biopsy showed epidermal apoptotic keratinocytes and basilar vacuolar changes with perivascular dermal lymphocytic inflammation. He was diagnosed with SJS/TEN. Initially, vancomycin was suspected as the culprit drug, and it was immediately discontinued. He received methylprednisolone, immune globulin [immunoglobulin] and supportive therapy, including lubricating eye drops and mouthwash for mucositis. Five days later, his skin lesions gradually resolved, his transaminase value decreased, and his temperature normalised. Consequently, methylprednisolone dose was reduced. On postoperative day 28, the man’s INR decreased to less than 2.0; therefore, he was commenced on warfarin again. Thereafter, a sudden increase of atypical target lesions was noted, some of which rapidly developed into blisters within 2 days, with a concomitant increase in transaminase levels. Thus, warfarin was suspected as a culprit drug, and it was changed to enoxaparin sodium as the anticoagulant therapy. Additionally, the dose of methylprednisolone was increased. No resurgence of new lesions was observed, and there was apparent amelioration of the existing lesions within 1 week. Moreover, the results of liver function tests ameliorated, and methylprednisolone dose was gradually tapered. He progressively experienced full re-epithelialisation of skin lesions, and he was discharged on postoperative day 50. To identify the causative drug, algorithm of drug causality for epidermal necrolysis (ALDEN) was first applied to assess all drugs. The ALDEN score of warfarin was 6, indicating very probable causality, whereas the scores of cefalotin, vancomycin and rabeprazole were 3, 4, and 1, indicating possible, probable, and unlikely causality, respectively. To confirm the culprit drug, an interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay was conducted. A remarkably high number of IFN-γ spot-forming cells were noted in the positive control and upon incubation with warfarin. Nevertheless, IFN-γ–secreting cells were not observed in the negative control or upon stimulation with vancomycin. Therefore, warfarin was confirmed as the culprit drug for SJS/TEN. Routine laboratory test results were remarkable for hepatic injury since the onset of SJS. Serological tests were found to be negative for hepatitis A, B, C and E and for cytomegalovirus. Thus, Therefore, Roussel Uclaf Causality Assessment Method (RUCAM) was conducted to confirm the diagnosis of drug-induced liver injury (DILI). The score for warfarin was 9, indicating a strong relationship between warfarin and liver injury. Additionally, the Model of End-stage Liver Disease (MELD) was used to evaluate the degree of liver injury. The MELD score of was 22, which suggested seriously deteriorated liver function.