Continuous Infusion Versus Intermittent Bolus of Beta-Lactams in Critically Ill Patients with Respiratory Infections: A Systematic Review and Meta-analysis
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.
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.
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.
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).
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.
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.
Compliance with Ethical Standards
Conflict of interest
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.
No funding was received for this review.
- 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.
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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).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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefGoogle 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.CrossRefPubMedGoogle 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.
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.
- 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.Google Scholar
- 51.Zosyn [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2005. Google Scholar
- 52.Timentin [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007. Google Scholar
- 53.Maxipime [package insert]. Lake Forest, IL: Hospira, Inc.; 2012. Google Scholar
- 54.Fortaz [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007. Google Scholar
- 55.Merrem I.V. [package insert]. Lake Forest, IL: Hospira, Inc.; 2013.Google Scholar
- 56.Primaxin I.V. [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2016.Google Scholar
- 57.Negaban [package insert]. Brussels, Belgium: Eumedica S.A.; 2011.Google Scholar
- 58.Rocephin [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2015. Google Scholar