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Continuous Infusion Versus Intermittent Bolus of Beta-Lactams in Critically Ill Patients with Respiratory Infections: A Systematic Review and Meta-analysis

A Correction to this article was published on 07 November 2017

This article has been updated

Abstract

Background

Critically ill patients display altered pharmacokinetics and pharmacodynamics and are more likely to be infected with more resistant pathogens. Beta-lactam antibiotics exhibit time-dependent pharmacodynamics; therefore, it is postulated that continuous infusion (CI) may optimize these parameters.

Objective

To perform a systematic review and meta-analysis of the available literature comparing CI versus intermittent bolus (IB) of beta-lactam antibiotics in critically ill adult patients with respiratory infections to determine if clinical benefits exist.

Methods

PubMed, EMBASE, and Web of Science were searched. Thirteen randomized controlled trials were included in the meta-analyses of clinical cure and/or mortality. Four retrospective studies reporting clinical cure and/or mortality, and 11 studies that reported pharmacokinetic/pharmacodynamic parameters were included in the systematic review.

Results

The majority of patients in both groups maintained the percentage of time the free drug concentration exceeded the minimum inhibitory concentration (%fT > MIC) targets throughout the treatment, with differences favoring CI being more prevalent when the MIC of the offending pathogen increased. CI of beta-lactam antibiotics in critically ill adult patients with respiratory infections significantly improved clinical cure rates when compared to IB (risk ratio [RR] 1.177; 95% CI 1.065–1.300). No significant differences in mortality rates were seen when patients were treated with either dosing modality (RR 0.845; 95% CI 0.644–1.108).

Conclusions

CI of beta-lactam antibiotics is associated with better cure rates and higher %fT > MIC when administered to critically ill patients with respiratory infections, but may be most beneficial in severely ill patients with more resistant Gram-negative bacterial infections.

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Change history

  • 07 November 2017

    Unfortunately, ≥ was found missing between scores and 20 in conclusion section of the online published article. The original article was corrected.

References

  1. Antimicrobial Resistance Fact Sheet. World Health Organization Website. http://www.who.int/mediacentre/factsheets/fs194/en/. Updated September 2016. Accessed 8 March 2017.

  2. Antibiotic Resistance Solutions Initiative Providing Critical Support to Combat Antibiotic-Resistant Bacteria. Centers for Disease Control and Prevention Website. https://www.cdc.gov/drugresistance/solutions-initiative/index.html. Updated January 2017. Accessed 8 March 2016.

  3. Vasoo S, Barreto JN, Tosh PK. Emerging issues in gram-negative bacterial resistance: an update for the practicing clinician. Mayo Clin Proc. 2015;90(3):395–403.

    Article  PubMed  Google Scholar 

  4. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis. 2006;42(Suppl 2):S82–9. https://doi.org/10.1086/499406.

    Article  PubMed  Google Scholar 

  5. Khan HA, Ahmad A, Mehboob R. Nosocomial infections and their control strategies. Asian Pac J Trop Biomed. 2015;5(7):509–14. https://doi.org/10.1016/j.apjtb.2015.05.001.

    Article  Google Scholar 

  6. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5(1):4–11. https://doi.org/10.4161/viru.27372.

    Article  PubMed  Google Scholar 

  7. Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2011–2014. Infect Control Hosp Epidemiol. 2016;37(11):1288–301. https://doi.org/10.1017/ice.2016.174.

    Article  PubMed  Google Scholar 

  8. Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet. 2005;44(10):1009–34. https://doi.org/10.2165/00003088-200544100-00002.

    CAS  Article  PubMed  Google Scholar 

  9. Udy AA, Dulhunty JM, Roberts JA, Davis JS, Webb SAR, Bellomo R. Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomized, placebo-controlled, clinical trial. Int J Antimicrob Agents. 2017;49:624–30. https://doi.org/10.1016/j.ijantimicag.2016.12.022.

    CAS  Article  PubMed  Google Scholar 

  10. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1–10.

    CAS  Article  PubMed  Google Scholar 

  11. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol. 2004;2(4):289–300. https://doi.org/10.1038/nrmicro862.

    CAS  Article  PubMed  Google Scholar 

  12. Roberts JA, Lipman J, Blot S, Rello J. Better outcomes through continuous infusion of time-dependent antibiotics to critically ill patients? Curr Opin Crit Care. 2008;14(4):390–6. https://doi.org/10.1097/MCC.0b013e3283021b3a.

    Article  PubMed  Google Scholar 

  13. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    CAS  Article  PubMed  Google Scholar 

  14. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  15. Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol. 2009;9:80.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wallace BC, Dahabreh IJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Softw. 2012;049(i05).

  17. Hanes SD, Wood GC, Herring V, Croce MA, Fabian TC, Pritchard E, et al. Intermittent and continuous ceftazidime infusion for critically ill trauma patients. Am J Surg. 2000;179:436–40.

    CAS  Article  PubMed  Google Scholar 

  18. Nicolau DP, Mcnabb J, Lacy MK, Quintiliani R, Nightingale CH. Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia. Int J Antimicrob Agents. 2001;17(6):497–504.

    CAS  Article  PubMed  Google Scholar 

  19. Georges B, Conil JM, Cougot P, Decun JF, Archambaud M, Seguin T. Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen. Int J Clin Pharmacol Ther. 2005;43(8):360–9.

    CAS  Article  PubMed  Google Scholar 

  20. Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, Richards B, et al. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother. 2007;59:285–91.

    CAS  Article  PubMed  Google Scholar 

  21. Sakka SG, Glauner AK, Bulitta JB, Kinzig-Schippers Pfister W, Drusano GL, et al. Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial. Antimicrob Agents Chemother. 2007;51(9):3304–10. https://doi.org/10.1128/AAC.01318-06.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Chytra I, Stepan M, Benes J, Pelnar P, Zidkova A, Bergerova T, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16(3):1–13. https://doi.org/10.1186/cc11405.

    Article  Google Scholar 

  23. De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008;61:382–8. https://doi.org/10.1093/jac/dkm467.

    Article  PubMed  Google Scholar 

  24. Rafati MR, Rouini MR, Mojtahedzadeh M, Najafi A, Tavakoli H, Gholami K, Fazeli MR. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents. 2006;28(2):122–7. Epub 2006 Jul 3. doi:10.1016/j.ijantimicag.2006.02.020.

  25. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin penetration into tissue of critically ill patients with sepsis—Bolus versus continuous administration? Crit Care Med. 2009;37(3):926–33. https://doi.org/10.1097/CCM.0b013e3181968e44.

    Article  PubMed  Google Scholar 

  26. Roberts JA, Kirkpatrick CMJ, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010;35:156–63. https://doi.org/10.1016/j.ijantimicag.2009.10.008.

    CAS  Article  PubMed  Google Scholar 

  27. Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236–44. https://doi.org/10.1093/cid/cis856.

    CAS  Article  PubMed  Google Scholar 

  28. Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med. 2015;192(11):1298–305. https://doi.org/10.1164/rccm.201505-0857OC.

    CAS  Article  PubMed  Google Scholar 

  29. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, et al. Beta-lactam infusion in severe sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535–45. https://doi.org/10.1007/s00134-015-4188-0.

    CAS  Article  PubMed  Google Scholar 

  30. Lorente L, Lorenzo L, Martína MM, Jiménez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharrnacother. 2006;40:219–23. https://doi.org/10.1345/aph.1G467.

    CAS  Article  Google Scholar 

  31. Lorente L, Jiménez A, Palmero S, Jimenez JJ, Iribarren JL, Santana M, et al. Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther. 2007;29(11):2433–9. https://doi.org/10.1016/j.clinthera.2007.11.003.

    CAS  Article  PubMed  Google Scholar 

  32. Lorente L, Jiménez A, Martína MM, Iribarrena JL, Jiméneza JJ, Moraa ML. Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Int J Antimicrob Agents. 2009;33:464–8. https://doi.org/10.1016/j.ijantimicag.2008.10.025.

    CAS  Article  PubMed  Google Scholar 

  33. Gonçalves-pereira J, Oliveira BS, Janeiro S, Estilita J, Monteiro C, Salgueiro A, et al. Continuous infusion of piperacillin/tazobactam in septic critically ill patients—a multicenter propensity matched analysis. PLoS One. 2012;7(11):e49845. https://doi.org/10.1371/journal.pone.0049845.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Benko AS, Cappelletty DM, Kruse JA, Rybak MJ. Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram negative infections. Antimicrob Agents Chemother. 1996;40(3):691–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cousson J, Floch T, Guillard T, Vernet V, Raclot P, Wolak-Thierry A, et al. Lung concentrations of ceftazidime administered by continuous versus intermittent infusion in patients with ventilator-associated pneumonia. Antimicrob Agents Chemother. 2015;59:1905–9. https://doi.org/10.1128/AAC.04232-14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Thalhammer F, Traunmüller F, El Menyawi I, Frass M, Hollenstein UM, Locker GJ, et al. Continuous infusion versus intermittent administration of meropenem in critically ill patients. J Antimicrob Chemother. 1999;43:523–7.

    CAS  Article  PubMed  Google Scholar 

  37. Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin. 2011;27(1):19–34. https://doi.org/10.1016/j.ccc.2010.09.006.

    CAS  Article  PubMed  Google Scholar 

  38. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–9. https://doi.org/10.1001/jama.2009.1754.

    CAS  Article  PubMed  Google Scholar 

  39. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–51. https://doi.org/10.1097/CCM.0b013e3181961bff.

    CAS  Article  PubMed  Google Scholar 

  40. Bolt SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill. Adv Drug Deliv Rev. 2014;77:3–11. https://doi.org/10.1016/j.addr.2014.07.006.

    Article  Google Scholar 

  41. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care. 2013;17:1–9.

    Article  Google Scholar 

  42. Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care. 2011;47(1):1–7.

    Google Scholar 

  43. Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al. Continuous versus Intermittent β-lactam infusion in severe sepsis: a meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681–91. https://doi.org/10.1164/rccm.201601-0024OC.

    CAS  Article  PubMed  Google Scholar 

  44. Roger C, Cotta MO, Muller L, Wallis SC, Lipman J, Lefrant J-Y, Roberts JA. Impact of renal replacement modalities on clearance of piperacillin-tazobactam administered via continuous infusion in critically ill patients. Int J Antimicrob Agents. 2017;50(2):227–31. doi:10.1016/j.ijantimicag.2017.03.018.

  45. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, Lipman J. Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36:332–9. https://doi.org/10.1016/j.ijantimicag.2010.06.008.

    CAS  Article  PubMed  Google Scholar 

  46. Economou CJP, Wong G, McWhinney B, Ungerer J, Lipman J, Roberts JA. Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy. 2017;49:589–94. https://doi.org/10.1016/j.ijantimicag.2017.01.009.

    CAS  Google Scholar 

  47. Taeb AM, Hooper MH, Marik PE. Sepsis: current definition, pathophysiology, diagnosis, and management. Nutr Clin Pract. 2017;32(3):296–308. https://doi.org/10.1177/0884533617695243.

    CAS  Article  PubMed  Google Scholar 

  48. Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of β-lactam antibiotics. Crit Care Med. 2009;37(6):2071–8. https://doi.org/10.1097/CCM.0b013e3181a0054d.

    CAS  Article  PubMed  Google Scholar 

  49. McNabb JJ, Nightingale CH, Quintiliani R, Nicolau DP. Cost-effectiveness of ceftazidime by continuous infusion versus intermittent infusion for nosocomial pneumonia. Pharmacotherapy. 2001;21(3):549–55.

    CAS  Article  PubMed  Google Scholar 

  50. Florea NR, Kotapati S, Kuti JL, Geissler EC, Nightingale CH, Nicolau DP. Cost analysis of continuous versus intermittent infusion of piperacillin–tazobactam: a time–motion study. Am J Health Syst Pharm. 2003;60:2321–7.

    PubMed  Google Scholar 

  51. Zosyn [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2005. 

  52. Timentin [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007. 

  53. Maxipime [package insert]. Lake Forest, IL: Hospira, Inc.; 2012. 

  54. Fortaz [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007. 

  55. Merrem I.V. [package insert]. Lake Forest, IL: Hospira, Inc.; 2013.

  56. Primaxin I.V. [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2016.

  57. Negaban [package insert]. Brussels, Belgium: Eumedica S.A.; 2011.

  58. Rocephin [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2015.  

  59. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Authors would like to thank Peggy Edwards, Reference Librarian and Unit Manager at the Preston Smith Library at the Texas Tech University Health Sciences Center for her assistance with the literature search and search strategy information. Authors would also like to thank Dr. Irene La-Beck, Associate Professor at the Texas Tech University Health Sciences Center School of Pharmacy for her advice on the meta-analysis.

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Correspondence to Young R. Lee.

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Author Young Lee, author Pamela Miller, author Saeed Alzghari, author Delilah Blanco, author Kailey Kuntz, and author Jackson Hager declare that they have no conflict of interest.

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No funding was received for this review.

Additional information

The original version of this article was revised: ≥ was found missing between scores and 20 in the conclusion section of the online published article.

A correction to this article is available online at https://doi.org/10.1007/s13318-017-0446-6.

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Lee, Y.R., Miller, P.D., Alzghari, S.K. et al. Continuous Infusion Versus Intermittent Bolus of Beta-Lactams in Critically Ill Patients with Respiratory Infections: A Systematic Review and Meta-analysis. Eur J Drug Metab Pharmacokinet 43, 155–170 (2018). https://doi.org/10.1007/s13318-017-0439-5

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