Critically-Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network (DILIN) criteria.
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Purpose: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, the effect of weight-based fluconazole dosing on liver injury has not been assessed. This study evaluated how often patients met Drug Induced Liver Injury Network (DILIN) criteria when receiving fluconazole daily doses of <6mg/kg versus ≥6mg/kg. Methods: This multi-center, retrospective cohort study was performed in critically-ill fluconazole recipients hospitalized from January 2009 to December 2012. It included patients who received ≥3 fluconazole doses with ≥1 dose administered in the intensive care unit. Patients were excluded if they were pregnant, presented with acetaminophen toxicity, received fluconazole within 1 week of liver transplantation, or missed >1 fluconazole dose during therapy. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after fluconazole discontinuation using DILIN criteria. The Fisher’s exact test was used to detect differences in the primary outcome of patients meeting DILIN criteria by weight-based dosing as well as in subgroups of patients with kidney dysfunction, liver disease, septic shock, and those receiving a loading dose. Results: Two-hundred and forty-eight of 767 patients met inclusion criteria; 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. Of the 199 patients receiving <6 mg/kg of fluconazole, 55% met DILIN criteria versus 46.9% of the 49 patients in the ≥6 mg/kg cohort (p=0.20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. In analysis of subgroups, 77.3% of patients with cirrhosis and 76.3% with septic shock met DILIN criteria (p<0.001 for both compared to those without these conditions). Conclusions: Weight-based fluconazole dosing did not affect the number of critically-ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically-ill patients.
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