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Clinical factors predicting drug-induced liver injury due to flucloxacillin

Authors Lindh M, Hallberg P, Yue QY, Wadelius M

Received 27 June 2018

Accepted for publication 29 September 2018

Published 21 November 2018 Volume 2018:10 Pages 95—101

DOI https://doi.org/10.2147/DHPS.S178394

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Professor Siew-Siang Chua


Mikaela Lindh,1 Pär Hallberg,1 Qun-Ying Yue,2 Mia Wadelius1

1Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 2Swedish Medical Products Agency, Uppsala, Sweden

Objectives:
Drug-induced liver injury (DILI) is a serious adverse reaction due to flucloxacillin. The pathogenesis is not fully understood. Female sex, age over 60 years, and a longer treatment duration have been suggested to be predisposing factors. Carriers of HLA-B*57:01 have an 80-fold increased risk, but due to the rarity of the reaction, testing of all patients is not cost-effective. We aimed to validate and detect clinical risk factors for flucloxacillin DILI. 
Methods: Clinical characteristics of flucloxacillin-treated patients with (n=50) and without DILI (n=2,330) were compared in a retrospective case control study. Cases were recruited from the Swedish database of spontaneously reported adverse drug reactions. Treated controls were selected from the Swedish Twin Registry. Statistical comparisons were made using chi-squared test and logistic regression. The significance threshold was set to P<0.00357 to correct for multiple comparisons. Reliable variables were tested in a multiple regression model.
Results: DILI was associated with female sex, OR 2.79, 95% CI 1.50–5.17, P=0.0011, and with a history of kidney stones, OR 5.51, 95% CI 2.21–13.72, P=0.0003. Cases were younger than controls, OR per increase in years 0.91, 95% CI 0.88–0.94, P<0.0001, probably due to selection bias. No difference in treatment duration was detected, OR 1.03, 95% CI 0.98–1.08, P=0.1790.
Conclusion: We established female sex as a risk factor for flucloxacillin-induced DILI, and a history of kidney stones was identified as a potential risk factor. Clinical risk factors for flucloxacillin-induced DILI could be used to indicate whom to test for HLA-B*57:01 before treatment.

Keywords:
floxacillin, chemical and drug induced liver injury, drug-related side effects and adverse reactions, alanine transaminase, bilirubin

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