ABSTRACT
Antibacterial and antifungal agents are among the most frequently prescribed medications, yet
clinically significant liver injury is a relatively rare event. In addition, the assessment of
the hepatotoxicity of antibacterial and antifungal agents is confounded by the effects and the
severity of the underlying infection being treated. A cholestatic liver injury pattern is a well-
described feature of sepsis, in part, reflecting adaptive responses in bile acid transport proteins
that serve to protect the liver from the effects of bile acid retention and facilitate extrahepatic
routes of bile acid excretion (1,2). Nevertheless, there are well-described hepatic reactions to
antibacterial and antifungal agents, and the incidence of clinically significant liver injury
associated with the use of these agents has been estimated from several different surveys.
UsingMedicaid billing data fromMichigan and Florida from the years 1980 to 1987, the number
of patients developing acute symptomatic liverdisease resulting inhospitalization froma10-day
course of sulfonamides, erythromycin, and tetracycline was determined to be 4.8, 2.28, and 1.56
cases for each million patients treated, respectively (3). In a French study of 81,301 patients who
could not go elsewhere for medical care, 6 out of 34 cases of reported drug-induced liver injury
over a three-year periodwere attributed to antibiotics (four to amoxicillin-clavulanic acid, one to
cloxacillin, and one to amoxicillin) (4). In a population-based case-control study using the U.K.-
based General Practice Research Database as the source of information that examined 1,636,792
persons aged 5 to 75 years old registered in the database from 1 January, 1994, to 31 December,
1999, and followed up for a total of 5,404,705 person-years, strong associations with acute and
clinically relevant drug-induced liver injury were found for amoxicillin-clavulanic acid
[adjusted odds ratio (AOR); 95% confidence interval (CI)Z94.8; 27.8, 323], flucloxacillin
(AORZ17.7; 4.4, 71.0), macrolides (AORZ6.9; 2.3, 21.0), and tetracyclines (AORZ6.2; 2.4,
15.8), exceeded only by chlorpromazine (5). In a review of 4039 outpatients referred to a
community-based hepatology practice in the United States, antibiotics (amoxicillin-clavulanic
acid, minocycline, nitrofurantoin, telithromycin, trimethoprim-sulfamethoxazole (TMP/SMX),
and trovafloxacin) were the class of drugsmost frequently implicated in self-limited acute drug-
induced liver injury (6). The incidence of liver injury associated with antibacterial and
antimycotic use in a hospitalized patient populationwas found to be 1.5% and 1.1%, respectively
(7). Antimicrobial agentswere themost frequently implicated drugs in an analysis fromSpain of
reports of drug-induced liver injury; amoxicillin-clavulanic acid accounted for 12.8% of the
reports (8). Finally, flucloxacillin and TMP/SMX were among the five most common drugs
associated with a fatal outcome in a Swedish analysis of drug-induced liver injury (9,10).
