Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 146 No. 4142 (2016)

Prolonged administration of β-lactam antibiotics – a comprehensive review and critical appraisal

  • Michael Osthoff
  • Martin Siegemund
  • Gianmarco Balestra
  • Mohd Hafiz Abdul-Aziz
  • Jason A Roberts
DOI
https://doi.org/10.4414/smw.2016.14368
Cite this as:
Swiss Med Wkly. 2016;146:w14368
Published
09.10.2016

Summary

Prolonged infusion of β-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates.

The pharmacokinetics of β-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance. This may lead to a significant decrease in plasma concentrations of β-lactam antibiotics. As a consequence, low pharmacokinetic/pharmacodynamic (PK/PD) target attainment, which is described as the percentage of time that the free drug concentration is maintained above the minimal inhibitory concentration (MIC) of the causative organism (fT>MIC), has been documented for β-lactam treatment in these patients when using standard intermittent bolus dosing, even for the most conservative target (50% fT>MIC).

Prolonged infusion of β-lactams has consistently been shown to improve PK/PD target attainment, particularly in patients with severe infections. However, evidence regarding relevant patient outcomes is still limited. Whereas previous observational studies have suggested a clinical benefit of prolonged infusion, results from two recent randomised controlled trials of continuous infusion versus intermittent bolus administration of β-lactams are conflicting. In particular, the larger, double-blind placebo-controlled randomised controlled trial including 443 patients did not demonstrate any difference in clinical outcomes.

We believe that a personalised approach is required to truly optimise β-lactam treatment in critically ill patients. This may include therapeutic drug monitoring with real-time adaptive feedback, rapid MIC determination and the use of antibiotic dosing software tools that incorporate patient parameters, dosing history, drug concentration and site of infection.

Universal administration of β-lactam antibiotics as prolonged infusion, even if supported by therapeutic drug monitoring, is not yet ready for “prime time”, as evidence for its clinical benefit is modest. There is a need for prospective randomised controlled trials that assess patient-centred outcomes (e.g. mortality) of a personalised approach in selected critically ill patients including prolonged infusion of β-lactams compared with the current standard of care.

References

  1. Keefer CS, Blake FG, Marshall EK, Jr, Lockwood JS, Wood BW. Penicillin and treatment of infections: a report of 500 cases. Statement by the Committee on Chemotherapeutic and Other Agents, Division of Medical Sciences, National Research Council. JAMA. 1943;122(18):1217–24.
  2. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013;13(9):785–96.
  3. Johnson AP, Woodford N. Global spread of antibiotic resistance: the example of New Delhi metallo-β-lactamase (NDM)-mediated carbapenem resistance. J Med Microbiol. 2013;62(Pt 4):499–513.
  4. Boucher HW, Talbot GH, Benjamin DK, Jr, Bradley J, Guidos RJ, Jones RN, et al.; Infectious Diseases Society of America. 10 x ’20 Progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685–94.
  5. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195–203.
  6. Huttner A, Von Dach E, Renzoni A, Huttner BD, Affaticati M, Pagani L, et al. Augmented renal clearance, low β-lactam concentrations and clinical outcomes in the critically ill: an observational prospective cohort study. Int J Antimicrob Agents. 2015;45(4):385–92.
  7. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al.; DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072–83.
  8. Kohanski MA, DePristo MA, Collins JJ. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell. 2010;37(3):311–20.
  9. Olofsson SK, Cars O. Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis. 2007;45(Suppl 2):S129–36.
  10. Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance – what’s dosing got to do with it? Crit Care Med. 2008;36(8):2433–40.
  11. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1–10, quiz 11–2.
  12. Eagle H, Fleischman R, Levy M. “Continuous” vs. “discontinuous” therapy with penicillin; the effect of the interval between injections on therapeutic efficacy. N Engl J Med. 1953;248(12):481–8.
  13. Flückiger U, Segessenmann C, Gerber AU. Integration of pharmacokinetics and pharmacodynamics of imipenem in a human-adapted mouse model. Antimicrob Agents Chemother. 1991;35(9):1905–10.
  14. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol. 2004;2(4):289–300.
  15. Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis Suppl. 1990;74:63–70.
  16. Abdul-Aziz MH, Lipman J, Mouton JW, Hope WW, Roberts JA. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med. 2015;36(1):136–53.
  17. Ariano RE, Nyhlén A, Donnelly JP, Sitar DS, Harding GK, Zelenitsky SA. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother. 2005;39(1):32–8.
  18. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345–51.
  19. Tam VH, McKinnon PS, Akins RL, Rybak MJ, Drusano GL. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother. 2002;50(3):425–8.
  20. Manduru M, Mihm LB, White RL, Friedrich LV, Flume PA, Bosso JA. In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother. 1997;41(9):2053–6.
  21. Li C, Du X, Kuti JL, Nicolau DP. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother. 2007;51(5):1725–30.
  22. Wong G, Brinkman A, Benefield RJ, Carlier M, De Waele JJ, El Helali N, et al. An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother. 2014;69(5):1416–23.
  23. Lodise TP, Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357–63.
  24. Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236–44.
  25. Muller AE, Punt N, Mouton JW. Exposure to ceftobiprole is associated with microbiological eradication and clinical cure in patients with nosocomial pneumonia. Antimicrob Agents Chemother. 2014;58(5):2512–9.
  26. Odenholt I, Holm SE, Cars O. Effect of antibiotic protein binding on the killing rate of Staphylococcus aureus and on the paradoxical phenomenon. Chemotherapy. 1987;33(5):331–9.
  27. Gonçalves-Pereira J, Póvoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams. Crit Care. 2011;15(5):R206.
  28. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al.; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509.
  29. van der Poll T. Immunotherapy of sepsis. Lancet Infect Dis. 2001;1(3):165–74.
  30. Hinshaw LB. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med. 1996;24(6):1072–8.
  31. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;77:3–11.
  32. Georges B, Conil JM, Seguin T, Ruiz S, Minville V, Cougot P, et al. Population pharmacokinetics of ceftazidime in intensive care unit patients: influence of glomerular filtration rate, mechanical ventilation, and reason for admission. Antimicrob Agents Chemother. 2009;53(10):4483–9.
  33. Finfer S, Bellomo R, McEvoy S, Lo SK, Myburgh J, Neal B, et al.; SAFE Study Investigators. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. 2006;333(7577):1044.
  34. Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011;50(2):99–110.
  35. Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong EL, Gin T. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother. 2001;47(4):421–9.
  36. Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. 2011;7(9):539–43.
  37. Udy AA, Baptista JP, Lim NL, Joynt GM, Jarrett P, Wockner L, et al. Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Crit Care Med. 2014;42(3):520–7.
  38. Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care. 2013;28(5):695–700.
  39. Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, et al. Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest. 2012;142(1):30–9.
  40. Udy AA, Lipman J, Jarrett P, Klein K, Wallis SC, Patel K, et al. Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance? Crit Care. 2015;19:28.
  41. Sunder S, Jayaraman R, Mahapatra HS, Sathi S, Ramanan V, Kanchi P, et al. Estimation of renal function in the intensive care unit: the covert concepts brought to light. J Intensive Care. 2014;2(1):31.
  42. De Waele JJ, Lipman J, Akova M, Bassetti M, Dimopoulos G, Kaukonen M, et al. Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients. Intensive Care Med. 2014;40(9):1340–51. Corrected in: Intensive Care Med. 2015 May;41(5):969. Dosage error in article test.
  43. Carlier M, Carrette S, Stove V, Verstraete AG, De Waele JJ. Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course. Int J Antimicrob Agents. 2014;43(5):470–3.
  44. Felton TW, McCalman K, Malagon I, Isalska B, Whalley S, Goodwin J, et al. Pulmonary penetration of piperacillin and tazobactam in critically ill patients. Clin Pharmacol Ther. 2014;96(4):438–48.
  45. Rodvold KA, George JM, Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin Pharmacokinet. 2011;50(10):637–64.
  46. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al.; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154–62.
  47. Boselli E, Breilh D, Rimmelé T, Poupelin JC, Saux MC, Chassard D, et al. Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia. Intensive Care Med. 2004;30(5):989–91.
  48. Rodvold KA, Nicolau DP, Lodise TP, Khashab M, Noel GJ, Kahn JB, et al. Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole. Antimicrob Agents Chemother. 2009;53(8):3294–301.
  49. Boselli E, Breilh D, Rimmelé T, Guillaume C, Xuereb F, Saux MC, et al. Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with ventilator-associated pneumonia. Crit Care Med. 2008;36(5):1500–6.
  50. Boselli E, Breilh D, Duflo F, Saux MC, Debon R, Chassard D, et al. Steady-state plasma and intrapulmonary concentrations of cefepime administered in continuous infusion in critically ill patients with severe nosocomial pneumonia. Crit Care Med. 2003;31(8):2102–6.
  51. Lodise TP, Sorgel F, Melnick D, Mason B, Kinzig M, Drusano GL. Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia. Antimicrob Agents Chemother. 2011;55(4):1606–10.
  52. Kuti JL, Dandekar PK, Nightingale CH, Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J Clin Pharmacol. 2003;43(10):1116–23.
  53. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64(1):142–50.
  54. Asín-Prieto E, Rodríguez-Gascón A, Trocóniz IF, Soraluce A, Maynar J, Sánchez-Izquierdo JA, et al. Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis. J Antimicrob Chemother. 2014;69(1):180–9.
  55. Cotta MO, Gowen B, Truloff N, Bursle E, McWhinney B, Ungerer JP, et al. Even high-dose extended infusions may not yield desired concentrations of β-lactams: the value of therapeutic drug monitoring. Infect Dis (Lond). 2015;47(10):739–42.
  56. Reese AM, Frei CR, Burgess DS. Pharmacodynamics of intermittent and continuous infusion piperacillin/tazobactam and cefepime against extended-spectrum beta-lactamase-producing organisms. Int J Antimicrob Agents. 2005;26(2):114–9.
  57. Carlier M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E, et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care. 2013;17(3):R84.
  58. Sime FB, Roberts MS, Tiong IS, Gardner JH, Lehman S, Peake SL, et al. Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial. J Antimicrob Chemother. 2015;70(8):2369–75.
  59. Roberts JA, Kirkpatrick CM, 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(2):156–63.
  60. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272–82.
  61. Felton TW, Goodwin J, O’Connor L, Sharp A, Gregson L, Livermore J, et al. Impact of Bolus dosing versus continuous infusion of Piperacillin and Tazobactam on the development of antimicrobial resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2013;57(12):5811–9.
  62. Teo J, Liew Y, Lee W, Kwa AL. Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis. Int J Antimicrob Agents. 2014;43(5):403–11.
  63. Shiu J, Wang E, Tejani AM, Wasdell M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev. 2013;3(3):CD008481.
  64. Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al.; BLING II Investigators for the ANZICS Clinical Trials Group *. 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.
  65. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36(4):332–9.
  66. Harris P, Paterson D, Rogers B. Facing the challenge of multidrug-resistant gram-negative bacilli in Australia. Med J Aust. 2015;202(5):243–7.
  67. 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 Jan 11. [Epub ahead of print].
  68. 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.
  69. Blot K, Bergs J, Vogelaers D, Blot S, Vandijck D. Prevention of central line-associated bloodstream infections through quality improvement interventions: a systematic review and meta-analysis. Clin Infect Dis. 2014;59(1):96–105.
  70. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. Reply to Rhodes et al. Clin Infect Dis. 2014;59(6):907–8.
  71. Ulldemolins M, Vaquer S, Llauradó-Serra M, Pontes C, Calvo G, Soy D, et al. Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy. Crit Care. 2014;18(3):227.
  72. Ulldemolins M, Rello J. The relevance of drug volume of distribution in antibiotic dosing. Curr Pharm Biotechnol. 2011;12(12):1996–2001.
  73. Nicasio AM, Eagye KJ, Nicolau DP, Shore E, Palter M, Pepe J, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care. 2010;25(1):69–77.
  74. Zelenitsky SA, Ariano RE, Zhanel GG. Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data. J Antimicrob Chemother. 2011;66(2):343–9.
  75. Roberts JA, Roberts DM. Antibiotic dosing in critically ill patients with septic shock and on continuous renal replacement therapy: can we resolve this problem with pharmacokinetic studies and dosing guidelines? Crit Care. 2014;18(3):156.
  76. Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, et al. Protein binding of β-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother. 2013;57(12):6165–70.
  77. Casu GS, Hites M, Jacobs F, Cotton F, Wolff F, Beumier M, et al. Can changes in renal function predict variations in β-lactam concentrations in septic patients? Int J Antimicrob Agents. 2013;42(5):422–8.
  78. Felton TW, Roberts JA, Lodise TP, Van Guilder M, Boselli E, Neely MN, et al. Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy. Antimicrob Agents Chemother. 2014;58(7):4094–102.
  79. Chapuis TM, Giannoni E, Majcherczyk PA, Chioléro R, Schaller MD, Berger MM, et al. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51.
  80. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264.
  81. George JM, Colton BJ, Rodvold KA. National survey on continuous and extended infusions of antibiotics. Am J Health Syst Pharm. 2012;69(21):1895–904.
  82. Buyle FM, Decruyenaere J, De Waele J, Tulkens PM, Van Audenrode T, Depuydt P, et al. A survey of beta-lactam antibiotics and vancomycin dosing strategies in intensive care units and general wards in Belgian hospitals. Eur J Clin Microbiol Infect Dis. 2013;32(6):763–8.
  83. Tabah A, De Waele J, Lipman J, Zahar JR, Cotta MO, Barton G, et al.; Working Group for Antimicrobial Use in the ICU within the Infection Section of the European Society of Intensive Care Medicine (ESICM). The ADMIN-ICU survey: a survey on antimicrobial dosing and monitoring in ICUs. J Antimicrob Chemother. 2015;70(9):2671–7.
  84. Hayashi Y, Lipman J, Udy AA, Ng M, McWhinney B, Ungerer J, et al. β-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. Int J Antimicrob Agents. 2013;41(2):162–6.
  85. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med. 2009;37(7):2268–82.

Most read articles by the same author(s)