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Risk of Hepatic Events in Patients Treated with Vancomycin in Clinical Studies

A Systematic Review and Meta-Analysis

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Abstract

Background: Routine surveillance of spontaneous reporting data and subsequent disproportionality analyses have indicated that the use of vancomycin might be associated with an increased risk of hepatic events.

Objective: To conduct a meta-analysis of published randomized controlled clinical trials (RCTs) to better understand if the use of vancomycin is potentially associated with an increased risk of hepatic events.

Data Sources: A comprehensive search and review of published clinical studies indexed in MEDLINE, PubMed, International Pharmaceutical Abstracts and the Cochrane Library from 1950 to June 2010 was conducted.

Study Selection: The inclusion criteria consisted of (i) published RCTs comparing vancomycin with/without other additional treatments to other comparators; and (ii) studies that reported hepatic events.

Data Extraction: The data related to any hepatic events reported in RCTs were extracted and examined. The quality of selected studies was assessed based on the Jadad scale. The effect size was presented as a risk ratio (RR) with a 95% CI and number needed to harm. The pooled RRs were calculated by using both fixed-effects and random-effects models. The impact of publication bias was assessed by funnel plot and the Egger’s test.

Data Synthesis: A total of 20 RCTs, including 7419 patients, met the study inclusion criteria and were selected. An increased incidence of hepatic events, specifically elevated serum aminotransferase levels, was observed in patients receiving vancomycin, when compared with other comparators (pooled RR= 1.95; 95% CI 1.62, 2.36; ps< 0.001), but the majority of the events were mild to moderate in nature. No evidence is currently available suggesting that the use of vancomcycin confers a risk of progressive or severe drug-induced liver injury.

Conclusions: Continuous monitoring of hepatic events on a routine basis among patients with the use of vancomycin is suggested.

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References

  1. Griffith RS. Introduction to vancomycin. Rev Infect Dis 1981; 3: 200–4

    Article  CAS  Google Scholar 

  2. Anderson RCGR, Higgins Jr HM, Pettinga CD. Symposium: how a drug is born. Cincinnati J Med 1961; 42: 49–60

    Google Scholar 

  3. Moellering RC. Vancomycin: a 50-year reassessment. Clin Infec Dis 2006; 42 Suppl. 1: 3–4

    Article  Google Scholar 

  4. Farber BF, Moellering Jr RC. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983; 23: 138–41

    Article  PubMed  CAS  Google Scholar 

  5. Elting LS, Rubenstein EB, Kurtin D, et al. Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998; 83: 2597–607

    Article  PubMed  CAS  Google Scholar 

  6. Chen Y, Guo JJ, Steinbuch M, et al. Comparisons of data mining algorithms for signal detection: an empirical study based on the Adverse Event Reporting System of the Food and Drug Administration. Pharmaceut Med 2008; 22(6): 359–69

    Article  Google Scholar 

  7. Chen Y, Guo JJ, Healy DP, et al. The risk of hepatotoxicity associated with the use of Ketek: signal detection based upon FDA Spontaneous Reporting System. Ann Pharmacother 2008;42(12): 1791–6

    Article  PubMed  CAS  Google Scholar 

  8. Cadle RM, Mansouri MD, Darouiche RO. Vancomycin-induced elevation of liver enzyme levels. Ann Pharma-cother 2006; 40: 1186–9

    Article  Google Scholar 

  9. Sikuler E, Guetta V, Keynan A, et al. Abnormalities in bilirubin and liver enzyme levels in adult patients with bacteremia: a prospective study. Arch Intern Med 1989; 149: 2246–8

    Article  PubMed  CAS  Google Scholar 

  10. Jaded AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12

    Article  Google Scholar 

  11. Sierra F. Evidence-based medicine (EBM) in practice: applying number needed to treat and number needed to harm. Am J Gastroenterol 2005; 100: 1661–3

    Article  PubMed  Google Scholar 

  12. RevMan 4.2 user guide. Oxford: The Cochrane Collaboration, 2004; 82–4

  13. Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 10: 101–29

    Article  Google Scholar 

  14. Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–34

    Article  PubMed  CAS  Google Scholar 

  15. Shenep JL, Hughes WT, Roberson PK, et al. Vancomycin, ticarcillin, and amikacin compared with ticarcillin-clavulanate and amikacin in the empirical treatment of febrile, neutropenic children with cancer. N Engl J Med 1988; 319(16): 1053–8

    Article  PubMed  CAS  Google Scholar 

  16. Calandra T, Zinner SH, Glauser MP, et al. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. European Organization for Research and Treatment of Cancer (EORTC). J Infect Dis 1991; 163(5): 951–8

    Article  Google Scholar 

  17. Wilson AP, Gruneberg RN, Neu H. A critical review of the dosage of teicoplanin in Europe and the USA. Int J Anti-microb Agents 1994; 4 Suppl. 1: 1–40

    Article  Google Scholar 

  18. Breedt J, Teras J, Gardovskis J, et al. Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase III comparison study with vancomycin-aztreonam. Tigecycline 305 cSSSI Study Group. Antimicrob Agents Chemother 2005; 49(11): 4658–66

    Article  PubMed  CAS  Google Scholar 

  19. Sacchidanand S, Penn RL, Embil JM, et al. Efficacy and safety of tigecycline monotherapy compared with vancomycin plus aztreonam in patients with complicated skin and skin structure infections: results from a phase III, randomized, double-blind trial. Int J Infect Dis 2005; 9(5): 251–61

    Article  PubMed  CAS  Google Scholar 

  20. Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis 2008; 46: 1683–93

    Article  PubMed  CAS  Google Scholar 

  21. Stryjewski ME, Chu VH, O’Riordan WD, et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006; 50(3): 862–7

    Article  PubMed  CAS  Google Scholar 

  22. Stryjewski ME, O’Riordan WD, Lau WK, et al. Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria. Clin Infect Dis 2005; 40(11): 1601–7

    Article  PubMed  CAS  Google Scholar 

  23. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004; 38(12): 1673–81

    Article  PubMed  CAS  Google Scholar 

  24. Lin DF, Zhang YY, Wu JF, et al. Linezolid for the treatment of infections caused by Gram-positive pathogens in China. Int J Antimicrob Agents 2008; 32(3): 241–9

    Article  PubMed  CAS  Google Scholar 

  25. Jantausch BA, Deville J, Adler S, et al. Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens. Pediatr Infect Dis J 2003; 22 (9 Suppl.): 164–71

    Google Scholar 

  26. Deville JG, Adler S, Azimi PH, et al. Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates. Pediatr Infect Dis J 2003; 22 (9 Suppl.): 158–63

    Article  Google Scholar 

  27. Kaplan SL, Deville JG, Yogev R, et al. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children. Linezolid Pediatric Study Group. Pediatr Infect Dis J 2003; 22(8): 677–86

    Article  PubMed  Google Scholar 

  28. Talbot GH, Thye D, Das A, et al. Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 2007; 51(10): 3612–6

    Article  PubMed  CAS  Google Scholar 

  29. Vazquez L, Encinas MP, Morin LS, et al. Randomized prospective study comparing cost-effectiveness of teicoplanin and vancomycin as second-line empiric therapy for infection in neutropenic patients. Haematologica 1999; 84(3): 231–6

    PubMed  CAS  Google Scholar 

  30. Rubinstein E, Cammarata S, Oliphant T, et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Linezolid Nosocomial Pneumonia Study Group. Clin Infect Dis 2001; 32(3): 402–12

    Article  PubMed  CAS  Google Scholar 

  31. Florescu I, Beuran M, Dimov R, et al. Efficacy and safety of tigecycline compared with vancomyin or linezolid for treatments of serious infections with methicillin-resistant staphylococcus aureus or vancomycin-resistant enterococci: a phase 3, multicentre, double-blind, randomized study. J Antimicrob Chemother 2008; 62 Suppl.: i17–28

    Article  PubMed  CAS  Google Scholar 

  32. Lv YH, Zhou QY, Li XH, et al. Clinical evaluation of vancomycin in treatment of neonatal infection pneumonia in NICU. Chin J Birth Health Hered 2004; 12: 95–6

    Google Scholar 

  33. Neville LO, Brumfitt W, Hamilton-Miller JMT, et al. Teicoplanin vs. vancomycin for the treatment of serious infections: a randomized trial. Int J Antimicrob Agents 1995; 5: 187–93

    Article  PubMed  CAS  Google Scholar 

  34. Kohno S, Yamaguchi K, Aikawa N, et al. Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus aureus in Japan. J Antimicrob Chemother 2007; 60: 1361–9

    Article  PubMed  CAS  Google Scholar 

  35. FDA. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf [Accessed 2009 Aug 7]

  36. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002; 22: 145–55

    Article  PubMed  CAS  Google Scholar 

  37. Holt MP, Ju C. Mechanisms of drug-induced liver injury. AAPS J 2006; 8: E48–54

    Article  PubMed  CAS  Google Scholar 

  38. Blazka ME, Wilmer JL, Holladay SD, et al. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995; 133: 43–52

    Article  PubMed  CAS  Google Scholar 

  39. Naisbitt DJ, Farrell J, Wong G, et al. Characterization of drug specific T cells in lamotrigine hypersensitivity. J Allergy Clin Immunol 2003; 111: 1393–403

    Article  PubMed  CAS  Google Scholar 

  40. Hamilton JR, Sass-Kortsak A. Jaundice associated with severe bacterial infection in young infacts. J Pediatr 1963; 63: 121–32

    Article  PubMed  CAS  Google Scholar 

  41. Rosner B. The binomial distribution. In: Rosner B. Fundamentals of biostatistics. Belmont (CA): Duxbury Press, 1995: 82–5

    Google Scholar 

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Acknowledgements

The authors give special thanks to Indiana Strombom, PhD, for her insightful comments on the manuscript, and to Alice Russell, MPH, Eileen White, MPH, and Jill Layton, MPH, for their great assistance with the literature search.

The study was conducted as part of routine surveillance by Eli Lilly and Company. All authors are full-time employees of Eli Lilly and Company. The opinions and conclusions expressed in this manuscript are solely those of the authors. This study was presented at the International Conference on Pharmacoepidemiology & Therapeutic Risk Management, Providence, RI, USA, 16–19 September 2009.

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Authors and Affiliations

  1. Global Patient Safety, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Yan Chen, Xiao Yan Yang, Michael Zeckel, Chris Killian, Kenneth Hornbuckle, Arie Regev & Simon Voss

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  1. Yan Chen
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Correspondence to Yan Chen.

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Chen, Y., Yang, X.Y., Zeckel, M. et al. Risk of Hepatic Events in Patients Treated with Vancomycin in Clinical Studies. Drug-Safety 34, 73–82 (2011). https://doi.org/10.2165/11539560-000000000-00000

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