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units/L, and Alk P ⩽ 113 international units/L. The injury
was defined as hepatocellular if R ⩾ 5, cholestatic if R ⩽ 2,
or mixed if R > 2 and R < 5. Baseline values from date of
initiation or 1 day prior to initiation were compared with
peak values during fluconazole therapy and for up to 14 days
after fluconazole discontinuation.

Outcome Measures
Our primary objective was to evaluate the incidence of
patients meeting drug-induced liver injury criteria with
weight-based fluconazole dosing in an ICU population.
Weight-based fluconazole dosing was stratified based on
patients receiving <6 mg/kg vs ⩾6 mg/kg. Prespecified subgroup analyses were performed for patients with renal dysfunction (CrCl < 50 mL/min), cirrhosis, septic shock, and
patients receiving a loading dose of fluconazole to assess the
effects of these characteristics on meeting DILIN criteria.
Furthermore, we also stratified the patients into those receiving fluconazole < 400 mg or ⩾ 400 mg and compared the
rate of patients meeting DILIN criteria. We also collected
data on other antifungals patients received or were switched
to from fluconazole.

Statistical Analysis
Data were analyzed using JMP 10.0 (SAS Corporation, Cary,
North Carolina). All nominal data were analyzed using chisquared or Fisher exact, as appropriate. Continuous variables
were tested for normality using the Shapiro-Wilk W test. All
continuous data were determined to be nonparametric, analyzed using the Wilcoxon rank sum, and reported as median
and interquartile range (IQR). An a priori alpha level of
<0.05 was used to define statistical significance. Last, a
multivariable nominal logistic regression model was constructed with the following variables: weight-based fluconazole dose, cirrhosis, CrCl < 50 mL/min, and septic shock.
Variables that were significant in the nominal logistic regression model were considered independent predictors of meeting DILIN criteria.

Results
Study Participants
A total of 767 ICU patients were billed for 3 doses of fluconazole during the 4 study years, and 248 patients met inclusion criteria. Patients who were missing labs (n = 155), only
received two days of fluconazole (n = 25), missed two or
more fluconazole doses OR if patient was receiving fluconazole prior to hospital admission (n = 188), candiduria indication only (n = 70), liver transplant <1 week prior to index
date (n = 76), acetaminophen overdose (n = 5) were
excluded. Overall, there were 199 patients in the <6 mg/kg
group and 49 patients in the >6 mg/kg group

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Table 1 shows the baseline characteristics of the study participants. In the <6 mg/kg vs ⩾6 mg/kg groups, respectively,
there were more male patients (72% vs 55%), a higher median
(IQR) weight (80.3 [69.4-97.6] vs 59.1 [50.8-64.3] kg), and a
lower median CrCl (59.8 [30.7-92.8] vs 76.0 [46.8-121.0]
mL/min). In addition, the percentage of patients with cirrhosis was 39.7% and 18.3% in the <6 mg/kg group and ⩾6 mg/
kg group, respectively. The median (IQR) Model For EndStage Liver Disease (MELD) score for patients with cirrhosis
was 28 (20-36) and 19 (10-25.5) in the <6 mg/kg group and
⩾6 mg/kg group, respectively. The median of each patient's
average fluconazole dose was 222 mg (200-400 mg) and 400
mg (400-508 mg). Patients received a median of 3.44 mg/kg
of fluconazole in the <6 mg/kg dose group compared with
7.18 mg/kg in the ⩾6 mg/kg dose group (P < .0001).
There was no statistical difference in the primary end
point of incidence of patients meeting DILIN criteria while
receiving <6 mg/kg vs ⩾6 mg/kg of fluconazole (Table 2).
Overall, a total of 133 (53%) ICU patients met DILIN criteria and the majority of patients with DILIN were categorized
as having cholestatic liver injury (Table 2). Of those patients
who met DILIN criteria, 39 patients had elevations of greater
than 5 times in AST or ALT, 37 patients had elevations of
greater than 2 times in Alk P, 85 patients had an elevated total
serum bilirubin level, and 58 patients had an elevated INR.
Eighty-six patients met more than 1 component of the DILIN
criteria.
Of the secondary end points, only patients with septic
shock showed a statistically significant difference in meeting
DILIN criteria with <6 mg/kg vs ⩾6 mg/kg of fluconazole,
respectively (85% vs 50%, P = .0045) (Table 3). Interestingly,
those receiving lower mg/kg doses of fluconazole (<6 mg/
kg) had nonsignificant higher incidence of meeting DILIN
criteria. To account for the effect of these subgroups on the
incidence of meeting DILIN criteria, a nominal logistic
regression model was performed. Presence of cirrhosis and
presence of septic shock were both independent predictors of
meeting DILIN criteria (septic shock: OR 4.56 [95% confidence interval, CI, 2.44-8.88], cirrhosis: OR 4.84 [95% CI,
2.61-9.28]). However, neither weight-based fluconazole
dose nor CrCl < 50 mL/min increased the odds of meeting
DILIN criteria (Table 4).
We completed a separate analysis to see whether patients
were likely to meet DILIN criteria when grouped by fluconazole < 400 mg vs fluconazole ⩾ 400 mg. DILIN criteria
was met in 76 of 133 patients (57%) of patients receiving
<400 mg of fluconazole and 57 of 115 patients (50%) receiving ⩾ 400 mg of fluconazole (P = .25). In addition, we reran
a nominal logistic regression model with the patients grouped
by fluconazole dose of <400 mg vs fluconazole dose of
⩾400 mg or more. In the nominal regression model, presence of cirrhosis and presence of septic shock were still the
only independent predictors of meeting DILIN criteria (septic shock: OR 3.89 [95% CI, 2.02-7.73], cirrhosis: OR 8.10
[95% CI, 3.81-18.74]).
Hospital Pharmacy - December 2019

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