Pharmacogenomic Predictors of Antibiotic-Associated Drug-Induced Liver Injury in Critically Ill Children: Observational Study Results

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.

АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.

MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).

RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6; 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14; 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 ge­notype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous ge­notype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions ­associated with meropenem and tigecycline (r=9.8, p=0.002).

CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.

The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

1. Yu Y, Nie X, Song Z, Xie Y, Zhang X, Du Z, et al. Signal detection of potentially drug-induced liver injury in children using electronic health records. Front Pediatr. 2020;8:171. https://doi.org/10.3389/fped.2020.00171

2. Yu Z, Zhao Y, Jin J, Zhu J, Yu L, Han G. Prevalence and risk factors of tigecycline-induced liver injury: a multicenter retrospective study. Int J Infect Dis. 2022;120:59–64. https://doi.org/10.1016/j.ijid.2022.04.024

3. Baietto L, Corcione S, Pacini G, Perri GD, D’Avolio A, De Rosa FG. A 30-years review on pharmacokinetics of antibiotics: is the right time for pharmacogenetics? Curr Drug Metab. 2014;15(6):581–98. https://doi.org/10.2174/1389200215666140605130935

4. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009;29(4):400–11. https://doi.org/10.1055/s-0029-1240009

5. Zed PJ, Haughn C, Black KJL, Fitzpatrick EA, Ackroyd-Stolarz S, Murphy NG, et al. Medication-related emergency department visits and hospital admissions in pediatric patients: a qualitative systematic review. J Pediatr. 2013;163(2):477–83. https://doi.org/10.1016/j.jpeds.2013.01.042

6. Ersulo TA, Yizengaw MA, Tesfaye BT. Incidence of adverse drug events in patients hospitalized in the medical wards of a teaching referral hospital in Ethiopia: a prospective observational study. BMC Pharmacol Toxicol. 2022;23(1):30. https://doi.org/10.1186/s40360-022-00570-w

7. Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47. https://doi.org/10.1053/j.gastro.2011.04.001

8. Alshabeeb M, Alomar FA, Khan A. Impact of ­SLCO1B1*5 on flucloxacillin and co-amoxiclav-related liver injury. Front Pharmacol. 2022;13:882962. https://doi.org/10.3389/fphar.2022.882962

9. Vlasova AV, Shubina YuF, Sychev DA. Antibiotic-associated drug-induced liver injury in critically ill child­ren: a prospective observational study. Safety and Risk of Pharmacotherapy. 2024 (In Russ.). https://doi.org/10.30895/2312-7821-2023-389

10. Manolis E, Musuamba FT, Karlsson KE. The European Medicines Agency experience with pediatric dose selection. J Clin Pharmacol. 2021;61:S22–S27. https://doi.org/10.1002/jcph.1863

11. Ivashchenko DV, Buromskaya NI, Savchenko LM, Shevchenko YuS, Sychev DA. Global trigger tool va­lue for revealing of unwanted events related to medi­cal care in pediatrics. Medical Council. 2018;(17):56–65 (In Russ.). https://doi.org/10.21518/2079-701X-2018-17-56-65

12. Vlasova AV, Smirnova EV, Gorev VV, Sychev DA. Adverse reactions in children to antimicrobials: ­limitations of the spontaneous reporting method and the possibilities of the global trigger method for drug-induced conditions. Farmateka. 2023;30(1/2):18–31 (In Russ.). https://doi.org/10.18565/pharmateca.2023.1-2.18-31

13. Classen DC, Resar R, Griffin F, Federico F, Frankel T, Kimmel N, et al. “Global Trigger Tool” shows that adverse events in hospitals may be ten times greater than previously measured. Health Aff (Millwood). 2011;30(4):581–9. https://doi.org/10.1377/hlthaff.2011.0190

14. Katarey D, Verma S. Drug-induced liver injury. Clin Med. 2016;16(Suppl 6):S104–S109. https://doi.org/10.7861/clinmedicine.16-6-s104

15. Yu Y, Mao YM, Chen CW, Chen JJ, Chen J, Cong WM, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int. 2017;11(3):221–41. https://doi.org/10.1007/s12072-017-9793-2

16. Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y. Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology. 2014;60(3):1015–22. https://doi.org/10.1002/hep.27206

17. Darwish MH, Farah RA, Farhat GN, Torbey PH, Ghandour FA, Bejjani-Doueihy NA, Dhaini HR. Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma. Mol Med Rep. 2015;11(2):1462–8. https://doi.org/10.3892/mmr.2014.2835

18. Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K. Functional characterization of ­SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics. 2005;15(7):513–22. https://doi.org/10.1097/01.fpc.0000170913.73780.5f

19. Jindal C, Kumar S, Choudhari G, Goel H, Mittal B. Organic anion transporter protein (OATP1B1) encoded by SLCO1B1 gene polymorphism (388A>G) and susceptibility in gallstone disease. Indian J Med Res. 2009;129(2):170–5. PMID: 19293444

20. Alshabeeb M, Alomar FA, Khan A. Impact of ­SLCO1B1*5 on flucloxacillin and co-amoxiclav-related liver injury. Front Pharmacol. 2022;13:882962. https://doi.org/10.3389/fphar.2022.882962