Identification and Characterization of Cefazolin-Induced Liver Injury

Abstract

Background & aims: Cephalosporin antibiotics are popular because they have a broad spectrum of activity and are generally well tolerated; however, cephalosporin-induced liver injury is considered rare. We describe a new syndrome associated with a single intravenous dose of cefazolin and the clinical features of cephalosporin-induced liver injury.

Methods: The Drug-Induced Liver Injury (DILI) Network collected detailed clinical data on 1212 patients with DILI between 2004 and 2012. We analyzed data from 41 patients in whom cephalosporins were implicated as primary agents of liver disease; 33 formally were adjudicated as having cephalosporin-induced DILI.

Results: Nineteen patients developed clinically apparent DILI after a single intravenous dose of cefazolin. All patients developed self-limited liver injury 3 to 23 days after receiving cefazolin during surgery-often during a minor outpatient procedure. The latency period was 20 days. Clinical features included itching, jaundice, nausea, fever, and rash. Laboratory abnormalities included a mixed or cholestatic pattern of serum enzyme increases. We identified 14 more patients with DILI attributed to other cephalosporins (5 first-generation, 2 second-generation, 6 third-generation, and 1 fourth-generation agent). Although latency and injury patterns were similar for cefazolin and other cephalosporins, the other cephalosporins were associated with more severe courses of injury, including 2 deaths from liver failure.

Conclusions: DILI can develop after a single dose of cefazolin. It is characterized by a latency period of 1 to 3 weeks after exposure, a cholestatic biochemical pattern, and a self-limited moderate to severe clinical course. Other cephalosporins can cause a similar but more severe injury.

Keywords: Antibiotic; Cephalosporin; DILIN; Hepatotoxicity.

Figure 1. Liver test abnormalities

The liver test abnormalities in 19 patients with cefazolin induced DILI are depicted. In (A) are shown patients falling into the early peak abnormality group, and in (B), the later peak group. Values on the X axis include bilirubin (mg/dL) or fold elevations over the upper limit of normal (ULN) in international units.

Figure 1. Liver test abnormalities

The liver test abnormalities in 19 patients with cefazolin induced DILI are depicted. In (A) are shown patients falling into the early peak abnormality group, and in (B), the later peak group. Values on the X axis include bilirubin (mg/dL) or fold elevations over the upper limit of normal (ULN) in international units.

Figure 2. Cefazolin induced DILI - histology

In (A) is shown the liver test profile of a patient with typical cholestasis from cefazolin induced DILI. Values on the X-axis include bilirubin (mg/dL) or fold elevations over the upper limit of normal (ULN) in international units (IU). In (B-C) are shown photomicrographs of the liver biopsy specimen taken 30 days after exposure to cefazolin in a representative patient. In (B), the image depicts cholestatic hepatitis with mild portal and lobular inflammation (H&E, 200x). In (C), high magnification of zone 3 revealed prominent canalicular cholestasis (arrowheads), which was demonstrated more clearly on the iron stain (inset) (H&E, 600x). In (D), is depicted prominent canalicular cholestasis (arrowhead) in a different patient with cefazolin induced DILI (H&E, 400x) in a different patient.