Hospital Pharmacy - December 2019 - 378

802583
research-article2018

HPXXXX10.1177/0018578718802583Hospital PharmacyJoseph et al

Original Article

Critically Ill Recipients of Weight-Based
Fluconazole Meeting Drug-Induced Liver
Injury Network Criteria

Hospital Pharmacy
2019, Vol. 54(6) 378-384
© The Author(s) 2018
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https://doi.org/10.1177/0018578718802583
DOI: 10.1177/0018578718802583
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Merlyn Joseph1,2 , Rebecca Brady3, Russell Attridge2,4,
Jason Cota4, Cheryl Horlen4 , Kathleen Lusk4,5,
and Rebecca L. Attridge4,5

Abstract
Background: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, effect of weight-based
fluconazole dosing on liver injury is unknown. Furthermore, no studies have systematically applied the Drug-Induced Liver Injury
Network (DILIN) Criteria to identify patients who may have drug-induced liver injury in an intensive care unit (ICU) setting.
Objective: This study evaluated how often patients met DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus
⩾6 mg/kg. Methods: This dual-center, retrospective cohort study was performed in hospitalized critically ill fluconazole recipients.
We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after discontinuation using
DILIN criteria. The primary objective was to evaluate the number of patients meeting DILIN criteria when receiving fluconazole
daily doses of <6 mg/kg versus ⩾6 mg/kg. Secondary objectives were to evaluate incidence of patients meeting DILIN criteria in
patients with renal dysfunction, cirrhosis, septic shock, or those receiving a loading dose. Results: Of 248 patients included, 90%
had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. In patients receiving <6 mg/kg
of fluconazole, 55% (110/199) met DILIN criteria versus 46.9% (23/49) in the ⩾6 mg/kg cohort (P = .20). Only 14.5% of patients
meeting DILIN criteria also met the definition for hepatocellular damage. Weight-based fluconazole dose and creatinine clearance
<50 mL/min were not independent risk factors for meeting DILIN criteria. However, 77.3% of patients with cirrhosis met DILIN
criteria (OR 4.84 [95% confidence interval, CI, 2.61-9.28]) and 76.3% with septic shock met DILIN criteria (OR 4.56 [95% CI, 2.448.88]). Conclusion: 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.
Keywords
adverse drug reactions reporting/monitoring, critical care, medication safety, fluconazole, drug-induced liver toxicity,
hepatotoxicity

Background
In the United States, drug-induced liver injury is the leading cause of acute liver failure, which has a mortality rate
of 30% without transplantation.1 The Drug-Induced Liver
Injury Network (DILIN) developed standardized definitions to identify cases of suspected drug-induced liver
injury. Currently, inpatients and outpatients who meet
DILIN criteria are referred to investigators and followed
prospectively to determine the likely causality of hepatotoxicity of the implicated drug.2 In a study published by
DILIN investigators, of the 899 patients enrolled with
likely drug-induced liver injury, the most common implicated agents were herbal and dietary supplements
(n = 145), amoxicillin/clavulanate (n = 91), isoniazid
(n = 48), nitrofurantoin (n = 42), and trimethoprim-sulfamethoxazole (n = 31). While fluconazole was implicated

as a possible causative agent, only 4 patients were determined to have possible fluconazole hepatotoxicity.3
The definition of hepatotoxicity has varied widely in published studies from undefined elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
1

Irma Lerma Rangel College of Pharmacy, Texas A&M University,
Houston, TX, USA
2
South Texas Veterans Health Care System, Audie L. Murphy VA
Hospital, San Antonio, TX, USA
3
University Hospital, San Antonio, TX, USA
4
Feik School of Pharmacy, University of the Incarnate Word, San Antonio,
TX, USA
5
University of Texas Health San Antonio, San Antonio, TX USA
Corresponding Author:
Merlyn Joseph, Texas A&M University, Irma Lerma Rangel College of
Pharmacy, 2121 W. Holcombe Blvd #1107A, Houston, TX 77030, USA.
Email: joseph@pharmacy.tamhsc.edu
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