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Joseph et al
alkaline phosphatase (Alk P), to more standard definitions calculating the degree above the upper limit of normal (ULN) of
AST, ALT, Alk P, and/or total serum bilirubin.4-8 The DILIN
has since developed a standardized definition to identify cases
of drug-related liver injury and has been using this tool to
identify cases of suspected drug-induced liver injury.
Therefore, we chose this tool to identify cases of
fluconazole-associated liver injury with the standardized
DILIN definition in this intensive care unit (ICU) population.
While there is a variety of definitions studies have used to
identify liver toxicity, the categorization of hepatotoxicity as
hepatocellular, cholestatic, or mixed is fairly consistent.
Fluconazole liver injury is usually hepatocellular but may
present as cholestatic or mixed.9,10 While fluconazole has
been implicated in drug-induced liver injury, no specific risk
factor, including weight-based dosing, in the fluconazole
regimen has been linked to drug-induced liver injury.11
We evaluated the incidence of patients meeting DILIN criteria with fluconazole dosing of <6 mg/kg vs ⩾6 mg/kg in an
ICU population. This fluconazole dose is based on the Infectious
Diseases Society of America (IDSA) recommendation for fluconazole (loading dose of 800 mg [12 mg/kg], then 400 mg [6
mg/kg] daily) for empiric therapy for suspected candidiasis and
candidiasis treatment in nonneutropenic patients.12 Our secondary objectives were to evaluate the incidence of fluconazole
patients meeting DILIN criteria in patients with renal dysfunction (creatinine clearance [CrCl] < 50 mL/min), cirrhosis, septic shock, or those receiving a loading dose of fluconazole.

Methods

were reviewed for alternate etiologies of liver toxicity,
including the presence of hepatitis A, B, or C, cirrhosis, or
nonalcoholic steatohepatitis. To evaluate the development
of drug-induced liver injury, AST, ALT, Alk P, total serum
bilirubin, and international normalized ratio (INR) were
collected on days 0, 3, 7, and weekly thereafter during fluconazole therapy. Index date was the start date of fluconazole. Peak values were recorded during therapy and for up
to 14 days after fluconazole discontinuation.

Baseline Characteristic Definitions
Patients were considered to have received a loading dose if the
first fluconazole dose was higher than the average maintenance dose. Vitals at ICU admission were recorded, and
patients were considered to have sepsis if they met 2 of the 4
systemic inflammatory response syndrome (SIRS) criteria and
had evidence of infection. SIRS criteria include temperature
>100.4°F or <96.8°F, heart rate >90 beats per minute, respiratory rate >20 breaths per minute or Paco₂ <32 mm Hg, and
white blood cell >12 000/mm³ or <4000/mm³. Patients were
considered to have septic shock if they met sepsis criteria at
ICU admission and received norepinephrine or vasopressin at
any time during fluconazole treatment. CrCl was calculated by
the Cockcroft-Gault method on the index date. Ideal body
weight (IBW) was calculated and used for CrCl calculations
unless actual body weight (ABW) was less than IBW or if
ABW was >30% of IBW. In the former case, ABW was used.
In the latter case, an adjusted body weight (AjBW) was calculated and used: AjBW = IBW + 0.4(ABW - IBW).

Study Design

Indications

We performed a dual-center, retrospective cohort study
involving patients admitted to any ICU at two academic
medical centers in San Antonio, Texas, from January 1, 2009,
to December 31, 2012. Eligible patients received fluconazole
for 3 or more days with at least 1 dose administered in the
ICU. Patients were excluded if they were pregnant, had concomitant acetaminophen toxicity, received fluconazole
within 1 week of liver transplantation, missed 2 or more
doses of fluconazole during the treatment period, received
fluconazole for candiduria, or had missing baseline or follow-up liver function tests. Patients with candiduria were
excluded as asymptomatic candiduria rarely requires treatment. This study was approved by the institutional review
boards of the University of Texas Health Science Center at
San Antonio, the University of the Incarnate Word, and the
research and development offices of University Health
System and the South Texas Veterans Health Care System.

Treatment indications were divided into 5 different categories: (1) empiric therapy if treatment started without a known
cause, (2) oropharyngeal or esophageal candidiasis, (3) superficial fungal infections for vaginitis or tinea, (4) prophylaxis
for chemotherapy treatment, or (5) documented invasive systemic infection for treatment of fungemia, fungal pneumonia,
meningitis, pyelonephritis, coccidioidomycosis, positive
intra-abdominal culture, and spontaneous fungal peritonitis.

Data Collected
We collected data on baseline patient demographics, fluconazole indication, dose, and duration. All patient charts

Drug-Induced Liver Injury Definitions
Patients were considered to have met DILIN criteria if they met
one of the following criteria: (1) AST or ALT > 5× ULN or >
5× baseline abnormal value, or, (2) alkaline phosphatase >
2× ULN (or pretreatment baseline if baseline level is abnormal), or (3) total serum bilirubin level > 2.5 mg/dL along with
elevated AST or ALT or alkaline phosphatase, or (4) INR > 1.5
with elevated AST or ALT or alkaline phosphatase.
DILI was further characterized by injury type or "R." "R"
is equal to the ratio of serum ALT (as a multiple of its ULN)
to serum Alk P (as a multiple of its ULN). The following
normal values were used: AST ⩽ 42 units/L, ALT ⩽ 30
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