Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01

Abstract

Background: Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury.

Objective: To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury.

Methods: Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples.

Results: Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n = 5) to fatal (n = 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations.

Conclusions: Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

Keywords: DRESS syndrome; Drug-induced liver injury; HLA testing; HLA-A∗32:01; Vancomycin.

Figure 1:

A Clinical course of a 60-year-old man with hepatocellular liver injury after vancomycin therapy of aortic valve endocarditis (Case #1). He developed rash, facial edema, and eosinophilia (16% eosinophils) 20 days after starting iv vancomycin. Liver tests results showed marked elevations in serum alanine aminotransferase (ALT: peak value 2018 U/L) but modest increases in alkaline phosphatase levels (Alk P: peak 300 U/L) and total bilirubin (peak 3.0 mg/dL). He was started on prednisone 1 week after liver injury onset and all clinical symptoms and laboratory abnormalities resolved within the next few weeks. B Clinical course of a 57-year-old male with cholestatic liver injury after treatment with vancomycin, ceftriaxone and metronidazole for osteomyelitis (Case #5). After 27 days of iv vancomycin therapy, he developed rash, fever, and jaundice. Liver test results 7 days later showed marked elevations in alkaline phosphatase levels (Alk P: peak 968 U/L) and total bilirubin (peak 19.4 mg/dL), with moderate elevations in alanine aminotransferase levels (ALT: peak 561 U/L). Liver biopsy showed portal, lobular, and granulomatous hepatitis with evidence of bile duct injury and portal fibrosis. All antimicrobials were stopped, and he was treated with prednisone. At follow up 3 and 8 months later, all clinical symptoms and liver test abnormalities had resolved.

Figure 1:

A Clinical course of a 60-year-old man with hepatocellular liver injury after vancomycin therapy of aortic valve endocarditis (Case #1). He developed rash, facial edema, and eosinophilia (16% eosinophils) 20 days after starting iv vancomycin. Liver tests results showed marked elevations in serum alanine aminotransferase (ALT: peak value 2018 U/L) but modest increases in alkaline phosphatase levels (Alk P: peak 300 U/L) and total bilirubin (peak 3.0 mg/dL). He was started on prednisone 1 week after liver injury onset and all clinical symptoms and laboratory abnormalities resolved within the next few weeks. B Clinical course of a 57-year-old male with cholestatic liver injury after treatment with vancomycin, ceftriaxone and metronidazole for osteomyelitis (Case #5). After 27 days of iv vancomycin therapy, he developed rash, fever, and jaundice. Liver test results 7 days later showed marked elevations in alkaline phosphatase levels (Alk P: peak 968 U/L) and total bilirubin (peak 19.4 mg/dL), with moderate elevations in alanine aminotransferase levels (ALT: peak 561 U/L). Liver biopsy showed portal, lobular, and granulomatous hepatitis with evidence of bile duct injury and portal fibrosis. All antimicrobials were stopped, and he was treated with prednisone. At follow up 3 and 8 months later, all clinical symptoms and liver test abnormalities had resolved.