Clinical and Genetic Associations in Cephalosporin-Induced Liver Injury: Insights From the Drug-Induced Liver Injury Network

Abstract

Introduction: Cephalosporins are widely prescribed antibiotics due to their efficacy and safety. Although rare, idiosyncratic drug-induced liver injury (DILI) has been reported with their use. Here, we characterise the clinical features and HLA associations of cephalosporin-related liver injury. Methods: Between Jan 1, 2004, and Nov 2, 2022, a total of 2347 cases of DILI were enrolled in the DILIN study, of which 1854 were adjudicated as probable, highly likely, or definite. HLA sequencing was performed, and association with the risk of DILI was examined. Results: 58 cases (3%) were attributed to different cephalosporins, including cefazolin (n = 40), cephalexin (n = 4), ceftriaxone (n = 3), cefdinir (n = 3), cefuroxime (n = 3), and five other individual agents. Clinical features included a self-limited course with a mixed or cholestatic biochemical pattern without hypersensitivity features occuring in 1 to 4 weeks. Most striking was the phenotype of cefazolin and other parenteral cephalosporins given as a single dose with the onset of jaundice, fatigue, and itching 1 to 3 weeks later. In the total cohort, HLA-A*02:01 was significantly associated with an increased risk of cephalosporin-induced liver injury (OR: ~2.5-2.7, P < 0.0001). The association was strongest with cefazolin, with carrier frequencies of 85% vs. 38% in those with DILI from other drugs. Conclusions: Cephalosporins can cause self-limited, mixed/cholestatic hepatitis that arises after a short course of therapy with a latency of up to 3 weeks with cefazolin. Cephalosporin-induced liver injury is associated with the HLA-A*02:01 allele, which is linked to more severe liver injury at the onset of illness.