A novel analytical method to assess the effect of imipenem/cilastatin on liver function laboratory indexes in Chinese underage inpatients: Probability distribution curve

Autoři: Le Zou aff001;  Fanqi Meng aff002;  Weici Wang aff001;  Qianqian Ye aff001;  Lin Hu aff001;  Taoming Li aff005;  Tao Yin aff001
Působiště autorů: Pharmacy Department, Xiangya Hospital, Central South University, Changsha, Hunan Province, China aff001;  The Seventh Affiliated Hospital, Sun Yet-sun University, Shenzhen, Guangdong Province, China aff002;  Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan Province, China aff003;  Pharmacy Department, Hubei University of Science and Technology, Xianning, Hubei Province, China aff004;  Pharmacy Department, The Fourth Hospital of Changsha, Changsha, Hunan Province, China aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224352



The primary objective of this study was to establish a novel method to assess the effect of imipenem/cilastatin (IMP) on liver function laboratory indexes in Chinese underage inpatients (inpatients aged <18 year-old).


A retrospective study was conducted in 188 underage inpatients who received IMP in Xiangya Hospital from January 2016 to April 2018. Demographic data and clinical information of these inpatients were collected. As there was no reference interval of minors, the occurrence of abnormal liver function was estimated by that of adults, temporarily. A new concept (mean-variance induced by drug, MVID) was introduced to analyze the characteristics of total bilirubin (TBil), direct bilirubin (DBil), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Effect of MVID of TBil, DBil, ALT and AST in different patients (aged<1 year old and aged ≥ 1 year old) were compared by Mann-Whitney U test.


Estimating by reference intervals of adults, 57.4% underage inpatients (108/188) had abnormal liver function. According to the probability distribution curve of MVID, IMP can cause the increase of AST in 24% (0.62–0.38) Chinese underage inpatients, and the increase of ALT in 20% (0.60–0.40) Chinese underage inpatients. And liver protecting drugs can decrease MVID of ALT and AST. There were not statistically significant differences in MVID of TBil, DBil, ALT and AST in different patients (aged<1 year old and aged ≥ 1 year old); P value was 0.711, 0.734, 0.067 and 0.086, respectively.


IMP can affect the liver function of 20–24% Chinese underage inpatients mainly by increasing the AST and ALT. IMP may induce hepatocellular injury, but not cholestasis. And liver protecting drugs can reverse the side effects caused by IMP. Age may not affect the effect of IMP on liver function.

Klíčová slova:

Adverse reactions – Distribution curves – Drug administration – Drug therapy – Inpatients – Liver function tests – Probability distribution – Soft tissue infections


1. Cao J, Song W, Gu B, Mei YN, Tang JP, Meng L, et al. Correlation between carbapenem consumption and antimicrobial resistance rates of Acinetobacter baumannii in a university-affiliated hospital in China. J Clin Pharmacol. 2013; 53(1): 96–102. doi: 10.1177/0091270011435988 23400749

2. Li X, Chen Y, Gao W, Ye H, Shen Z, Wen A, et al. A 6-year study of complicated urinary tract infections in southern China: prevalence, antibiotic resistance, clinical and economic outcomes. Ther Clin Risk Manag. 2017; 13: 1479–1487. doi: 10.2147/TCRM.S143358 29184412

3. Pan K, Ma L, Xiang Q, Li X, Li H, Zhou Y, et al. Vancomycin-associated acute kidney injury: A cross-sectional study from a single center in China. PloS one. 2017; 12(4): e175688. doi: 10.1371/journal.pone.0175688 28426688

4. Wen ZP, Fan SS, Du C, Yin T, Zhou BT, Peng ZF, et al. Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients. J Clin Pharm Ther. 2017; 42(2): 221–227. doi: 10.1111/jcpt.12501 28145574

5. Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother. 2006; 58(5): 916–929. doi: 10.1093/jac/dkl354 16997845

6. Yoshizawa K, Ikawa K, Ikeda K, Ohge H, Morikawa N. Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children. Pediatr Infect Dis J. 2013; 32(11): 1208–1216. doi: 10.1097/INF.0b013e31829b5880 23676856

7. Balfour JA, Bryson HM, Brogden RN. Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs. 1996; 51(1): 99–136. doi: 10.2165/00003495-199651010-00008 8741235

8. Hornik CP, Herring AH, Benjamin DJ, Capparelli EV, Kearns GL, van den Anker J, et al. Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants. Pediatr Infect Dis J. 2013; 32(7): 748–753. doi: 10.1097/INF.0b013e31828be70b 23838776

9. RxList. Drug description of PRIMAXIN® I.V.. https://www.rxlist.com/primaxin-iv-drug.htm#description.

10. Nalin DR, Jacobsen CA. Imipenem/cilastatin therapy for serious infections in neonates and infants. Scand J Infect Dis Suppl. 1987; 52: 46–55. 3331042

11. Keller CA, Villavicencio J, Ramirez C. Intramuscular imipenem/cilastatin for treatment of mild and moderately severe bacterial infections. Scand J Infect Dis Suppl. 1987; 52: 26–31. 3483287

12. Nielsen DM, Meyer RD. Imipenem/cilastatin therapy for serious bacterial infections. Rev Infect Dis. 1985; 7 Suppl 3: S506. doi: 10.1093/clinids/7.supplement_3.s506 3901214

13. Calandra GB, Ricci FM, Wang C, Brown KR. Safety and tolerance comparison of imipenem-cilastatin to cephalothin and cefazolin. Journal of Antimicrobial Chemotherapy. 1983; 12 Suppl D: 125–1231. doi: 10.1093/jac/12.suppl_d.125 6583195

14. Zou L, Yin T, Huang SQ, and Zhu Y. Occurrence of hepatic dysfunction and influencing factors among preadult inpatients treated with imipenem-cilastatin sodium. Adverse Drug Reactions Journal. 2017; 19(5):353–358. doi: 10.3760/cma.j.issn.1008-5734.2017.05.007

15. National Health Commission of the People’s Republic of China. Reference intervals for common clinical biochemistry tests-Part 1: Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyltansferase (WS/T 404.1–2012). 2012; http://www.nhfpc.gov.cn/zwgkzt/s9492/201301/9b2e494990ce4825a48b4b476f6f928b.shtml.

16. Saruwatari H, Okamoto R, Takahashi Y, Shikano K. Blind Speech Extraction Combining Generalized MMSE STSA Estimator and ICA-Based Noise and Speech Probability Density Function Estimations. In: Vigneron V, Zarzoso V, Moreau E, Gribonval R, Vincent E, editors. Latent Variable Analysis and Signal Separation. LVA/ICA 2010. Proceedings of 9th International Conference on Latent Variable Analysis and Signal Separation; 2010 Sep 27–30; Malo, France. Berlin: Springer; 2010. p. 49–56.

17. US DEPARTMENT of Health and Human Services, National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 2009; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf

18. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30(2): 239–245. doi: 10.1038/clpt.1981.154 7249508

19. Wang C, Calandra GB, Aziz MA, Brown KR. Efficacy and safety of imipenem/cilastatin: a review of worldwide clinical experience. Rev Infect Dis. 1985; 7 Suppl 3: S528–S536. doi: 10.1093/clinids/7.supplement_3.s528 3901217

20. Edwards SJ, Emmas CE, Campbell HE. Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections. Curr Med Res Opin. 2005; 21(5): 785–94. doi: 10.1185/030079905X46223 15969878

21. Akaike H. On a successive transformation of probability distribution and its application to the analysis of the optimum gradient method. Annals of the Institute of Statistical Mathematics. 1959; 11(1): 1–16. https://doi.org/10.1007/BF01831719

22. Huang Z, Zwolski J. Effects of probability distribution choice on likelihood estimates in risk analysis. Reliability & Maintainability Symposium. 2017; 1–8. doi: 10.1109/RAM.2017.7889715

23. Wang YR, Zhang YB. Adverse reactions of tienam treatment for neonatal severe infections. J Ningxia Med Univ. 2010; 32(9), 1017–1018. doi: 10.3969/j.issn.1674-6309.2010.09.026

24. Ren B. Comparison of the effect of anti infection and bacterial clearance of biapenem and imipenem in patients with acute bacterial infection. Anti Infect Pharm. 2017; 14(3), 548–549. doi: 10.13493/j.issn.1672-7878.2017.03–024

25. Zajac BA, Fisher MA, Gibson GA, MacGregor RR. Safety and efficacy of high-dose treatment with imipenem-cilastatin in seriously ill patients. Antimicrob Agents Chemother. 1985; 27(5): 745–748. doi: 10.1128/aac.27.5.745 3860187

26. Sun T, Yang P, Zheng Y, Tang YJ, Zhang Y. Influence of Imipenem-cilastatin on 1372 Patients’ Liver Function. Chin J Pharmacoepidemiol. 2018; 27(1), 38–41. http://www.cnjpe.org/ch/reader/view_abstract.aspx?file_no=c1710356&flag=1

27. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285(13): 1711–1718. doi: 10.1001/jama.285.13.1711 11277825

28. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38(2): 518–526. doi: 10.1053/jhep.2003.50346 12883497

29. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999; 30(6): 1356–1362. doi: 10.1002/hep.510300604 10573511

30. Hennes HM, Smith DS, Schneider K, Hegenbarth MA, Duma MA, Jona JZ. Elevated liver transaminase levels in children with blunt abdominal trauma: a predictor of liver injury. Pediatrics. 1990; 86(1): 87–90. http://pediatrics.aappublications.org/content/86/1/87.long 2359686

31. Cotton A, Franklin BD, Brett S, Holmes A. Using imipenem and cilastatin during continuous renal replacement therapy. Pharm World Sci. 2005;27(5):371–375. doi: 10.1007/s11096-005-1636-x 16341743

32. Mori H, Takahashi K, Mizutani T. Interaction between valproic acid and carbapenem antibiotics. DRUG METAB REV. 2007;39(4):647–657. doi: 10.1080/03602530701690341 18058328

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden