Editorial: Cephalosporin‐Induced Liver Injury—Interesting but Tricky

Despite their widespread use, cephalosporins have rarely been reported among DILI patients [1-4]. In the Spanish hepatotoxicity registry, only three cases of ceftriaxone and two of cefuroxime were identified, but no cases of liver injury associated with cefazolin [3] and no cephalosporin cases in the LATINDILI [4]. In a recent study from Korea, ceftriaxone was among the 10 most commonly observed antibiotics leading to DILI, but cefazolin was not mentioned [5]. A decade ago, the DILIN group described a novel syndrome of cholestatic liver disease occurring 1–3 weeks after a single dose of cefazolin [6]. This was met with some scepticism by many gastroenterologists and hepatologists probably for two reasons. Firstly, as it was reported after a single dose, and secondly as the latency was frequently 2–3 weeks [6]. In the current issue of the journal, the DILIN group reported 58 cases of suspected DILI associated with cephalosporins, mostly due to cefazolin (n = 40) [7]. Among DILI cases with a high likelihood score, 2004–2022, 3% of cases were attributed to cephalosporins [7]. Thus, cephalosporins made up an important proportion of cases in the total DILI cohort. The median treatment duration was 1 day (range 1–15 days). Interestingly, not only was cefazolin associated with a single instance leading to DILI but also other cephalosporins such as cefuroxime, cefepime, cefotetan and cefoxitin [7]. However, cefazolin accounted for around 70% of the cases, and most of the information in the study is related to liver injury due to cefazolin. Information that was not available in the previous study [6] was the comparison between a single intramuscular/intravenous dose or starting an oral therapy, with similar features and the comparison between multiple doses for infection and a single dose of surgical prophylaxis. Importantly, the latency and type of liver injury were similar in the doses given for infection and prophylactically, but the severity score and bilirubin elevation were more pronounced in the former indication [7]. Furthermore, novel genetic information was provided in the current study. In the entire cohort, HLA-A*02:01 was associated with the risk of liver injury, OR 2.5–2.7, p value < 0.0001. The relationship was strongest for cefazolin with a much higher carrier frequency than in those with DILI due to other drugs [7]. In a recent population-based study among patients with DILI due to antibiotics, seven cases with liver injury due to cefazolin were reported [8]. These patients had very similar clinical and biochemical features as previously reported [6, 7], with a latency of up to 32 days after two doses [8]. Why it has not been described in other DILI studies is not clear. However, it might be due to the delayed reaction. Only after careful review of those treated with cefazolin who developed elevated liver tests were the results of the DILIN group reproduced [8]. Cefazolin might therefore previously have been underappreciated as a cause of DILI [8]. Thus, the current study from DILIN and the recently published study [8] seem to convincingly demonstrate that cefazolin induced liver injury has a distinct clinical and genetic phenotype. Einar S. Björnsson: conceptualization, writing – original draft, writing – review and editing. The author declares no conflicts of interest. This article is linked to Vuppalanchi et al papers. To view these articles, visit https://doi.org/10.1111/apt.70284 and https://doi.org/10.1111/apt.70331. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.