Intensive Care Medicine

, Volume 42, Issue 10, pp 1535–1545 | Cite as

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

  • Mohd H. Abdul-AzizEmail author
  • Helmi Sulaiman
  • Mohd-Basri Mat-Nor
  • Vineya Rai
  • Kang K. Wong
  • Mohd S. Hasan
  • Azrin N. Abd Rahman
  • Janattul A. Jamal
  • Steven C. Wallis
  • Jeffrey Lipman
  • Christine E. Staatz
  • Jason A. RobertsEmail author



This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis.


This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation.


A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p < 0.043) than IB participants. PK/PD target attainment rates were higher in the CI arm at 100 % fT >MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms.


In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT.

Malaysian National Medical Research Register ID: NMRR-12-1013-14017.


Antibiotics Critically ill Intermittent bolus Pharmacokinetics Pharmacodynamics Prolonged infusion 



We would like to thank ICU research coordinators Nurhafizah Zarudin and Siti Nabilah Mohd Zanidin (Tengku Ampuan Afzan Hospital) and Nurul Syazwani Muhtar and Kay Shannu Stanislaus Asirvatham (University Malaya Medical Centre); ICU pharmacists Aida Roziana Ramlan (Tengku Ampuan Afzan Hospital) and Yeap Li Ling and Lim Ka Yin (University Malaya Medical Centre); Suzanne Parker-Scott and Jenny Lisette Ordonez Mejia at The Burns, Trauma and Critical Care Research Centre, The University of Queensland for laboratory analysis; and Dr Joel Dulhunty at The Royal Brisbane and Women’s Hospital, Brisbane for statistical analysis advice. Mohd H. Abdul-Aziz and Azrin N. Abd Rahman would like to acknowledge the support of the Ministry of Education, Malaysia in the form of scholarships. Jason A. Roberts is funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652). We wish to acknowledge funding from the Australian National Health and Medical Research Council for Centre of Research Excellence (APP1099452).

Compliance with ethical standards

Conflicts of interest

All of the other authors declare that there are no conflicts of interest.


This project has received funding from the International Islamic University of Malaysia (IIUM) Research Endowment Grant (Grant Number EDW B 11-148-0626). IIUM had no role in study design, analysis or drafting of the manuscript.

Supplementary material

134_2015_4188_MOESM1_ESM.doc (1.3 mb)
Supplementary material 1 (DOC 1287 kb)


  1. 1.
    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580–637CrossRefPubMedGoogle Scholar
  2. 2.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL (2014) Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14:498–509CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10 (quiz 11–12)CrossRefPubMedGoogle Scholar
  4. 4.
    Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA (2012) Continuous beta-lactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care 2:37CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Abdul-Aziz MH, Lipman J, Mouton JW, Hope WW, Roberts JA (2015) Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med 36:136–153CrossRefPubMedGoogle Scholar
  6. 6.
    van Zanten AR, Oudijk M, Nohlmans-Paulssen MK, van der Meer YG, Girbes AR, Polderman KH (2007) Continuous vs. intermittent cefotaxime administration in patients with chronic obstructive pulmonary disease and respiratory tract infections: pharmacokinetics/pharmacodynamics, bacterial susceptibility and clinical efficacy. Br J Clin Pharmacol 63:100–109CrossRefPubMedGoogle Scholar
  7. 7.
    Rafati MR, Rouini MR, Mojtahedzadeh M, Najafi A, Tavakoli H, Gholami K, Fazeli MR (2006) Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents 28:122–127CrossRefPubMedGoogle Scholar
  8. 8.
    Lau WK, Mercer D, Itani KM, Nicolau DP, Kuti JL, Mansfield D, Dana A (2006) Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother 50:3556–3561CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Georges B, Conil JM, Cougot P, Decun JF, Archambaud M, Seguin T, Chabanon G, Virenque C, Houin G, Saivin S (2005) Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen. Int J Clin Pharmacol Ther 43:360–369CrossRefPubMedGoogle Scholar
  10. 10.
    Lubasch A, Luck S, Lode H, Mauch H, Lorenz J, Bolcskei P, Welte T (2003) Optimizing ceftazidime pharmacodynamics in patients with acute exacerbation of severe chronic bronchitis. J Antimicrob Chemother 51:659–664CrossRefPubMedGoogle Scholar
  11. 11.
    Nicolau DP, McNabb J, Lacy MK, Quintiliani R, Nightingale CH (2001) Continuous versus intermittent administration of ceftazidime in intensive care unit patients with nosocomial pneumonia. Int J Antimicrob Agents 17:497–504CrossRefPubMedGoogle Scholar
  12. 12.
    Angus BJ, Smith MD, Suputtamongkol Y, Mattie H, Walsh AL, Wuthiekanun V, Chaowagul W, White NJ (2000) Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. Br J Clin Pharmacol 50:184–191CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hanes SD, Wood GC, Herring V, Croce MA, Fabian TC, Pritchard E, Boucher BA (2000) Intermittent and continuous ceftazidime infusion for critically ill trauma patients. Am J Surg 179:436–440CrossRefPubMedGoogle Scholar
  14. 14.
    Shiu J, Wang E, Tejani AM, Wasdell M (2013) Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev 3:CD008481PubMedGoogle Scholar
  15. 15.
    Roberts JA, Webb S, Paterson D, Ho KM, Lipman J (2009) A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med 37:2071–2078CrossRefPubMedGoogle Scholar
  16. 16.
    Kasiakou SK, Sermaides GJ, Michalopoulos A, Soteriades ES, Falagas ME (2005) Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials. Lancet Infect Dis 5:581–589CrossRefPubMedGoogle Scholar
  17. 17.
    Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL, Lipman J (2013) Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 56:236–244CrossRefPubMedGoogle Scholar
  18. 18.
    Chytra I, Stepan M, Benes J, Pelnar P, Zidkova A, Bergerova T, Pradl R, Kasal E (2012) Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care 16:R113CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, Richards B, Lipman J (2007) Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother 59:285–291CrossRefPubMedGoogle Scholar
  20. 20.
    Kiratisin P, Chongthaleong A, Tan TY, Lagamayo E, Roberts S, Garcia J, Davies T (2012) Comparative in vitro activity of carbapenems against major Gram-negative pathogens: results of Asia–Pacific surveillance from the COMPACT II study. Int J Antimicrob Agents 39:311–316CrossRefPubMedGoogle Scholar
  21. 21.
    Abdul-Aziz M, Sulaiman H, Mat-Nor M, Rai V, Wong K, Hasan M, Wallis S, Lipman J, Staatz C, Roberts J (2015) The BLISS Study: beta-lactam infusion in severe sepsis-randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis in a Malaysian ICU setting. In: 55th interscience conference of antimicrobial agents and chemotherapy (ICAAC), San Diego, 18–21 September 2015Google Scholar
  22. 22.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefPubMedGoogle Scholar
  23. 23.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829CrossRefPubMedGoogle Scholar
  24. 24.
    Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286:1754–1758CrossRefPubMedGoogle Scholar
  25. 25.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383CrossRefPubMedGoogle Scholar
  26. 26.
    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239–245CrossRefPubMedGoogle Scholar
  27. 27.
    McWhinney BC, Wallis SC, Hillister T, Roberts JA, Lipman J, Ungerer JP (2010) Analysis of 12 beta-lactam antibiotics in human plasma by HPLC with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci 878:2039–2043CrossRefPubMedGoogle Scholar
  28. 28.
    Food and Drug Administration (2001) Guidance for industry: bioanalytical method validation. FDA, RockvilleGoogle Scholar
  29. 29.
    Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, Roberts JA (2013) Protein binding of beta-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother 57:6165–6170CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL, Starr T, Paul SK, Lipman J, BLING II Investigators for the ANZICS Clinical Trials Group (2015) A multicenter randomized trial of continuous versus intermittent beta-lactam infusion in severe sepsis. Am J Respir Crit Care Med 192:1298–1305Google Scholar
  31. 31.
    Abdul-Aziz MH, Lipman J, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Dulhunty J, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Roberts JA, DALI Study Group (2016) Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 71(1):196–207Google Scholar
  32. 32.
    McKinnon PS, Paladino JA, Schentag JJ (2008) 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 31:345–351CrossRefPubMedGoogle Scholar
  33. 33.
    De Waele JJ, Lipman J, Akova M, Bassetti M, Dimopoulos G, Kaukonen M, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Udy AA, Starr T, Wallis SC, Roberts JA (2014) Risk factors for target non-attainment during empirical treatment with beta-lactam antibiotics in critically ill patients. Intensive Care Med 40:1340–1351CrossRefPubMedGoogle Scholar
  34. 34.
    Jamal JA, Roberts DM, Udy AA, Mat-Nor MB, Mohamad-Nor FS, Wallis SC, Lipman J, Roberts JA (2015) Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents 46:39–44CrossRefPubMedGoogle Scholar
  35. 35.
    Jamal JA, Mat-Nor MB, Mohamad-Nor FS, Udy AA, Wallis SC, Lipman J, Roberts JA (2015) Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents 45:41–45CrossRefPubMedGoogle Scholar
  36. 36.
    Hsaiky L, Murray KP, Kokoska L, Desai N, Cha R (2013) Standard versus prolonged doripenem infusion for treatment of gram-negative infections. Ann Pharmacother 47:999–1006CrossRefPubMedGoogle Scholar
  37. 37.
    Bauer KA, West JE, O’Brien JM, Goff DA (2013) Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother 57:2907–2912CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mustafa M, Chan WM, Lee C, Harijanto E, Loo CM, Van Kinh N, Anh ND, Garcia J (2014) A PROspective study on the usage patterns of doripenem in the Asia–Pacific region (PROUD study). Int J Antimicrob Agents 43:353–360CrossRefPubMedGoogle Scholar
  39. 39.
    Carlier M, Dumoulin A, Janssen A, Picavet S, Vanthuyne S, Van Eynde R, Vanholder R, Delanghe J, De Schoenmakere G, De Waele JJ, Hoste EA (2015) Comparison of different equations to assess glomerular filtration in critically ill patients. Intensive Care Med 41:427–435CrossRefPubMedGoogle Scholar
  40. 40.
    Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J (2014) DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58:1072–1083CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • Mohd H. Abdul-Aziz
    • 1
    • 2
    Email author
  • Helmi Sulaiman
    • 3
  • Mohd-Basri Mat-Nor
    • 4
  • Vineya Rai
    • 5
  • Kang K. Wong
    • 5
  • Mohd S. Hasan
    • 5
  • Azrin N. Abd Rahman
    • 2
    • 6
  • Janattul A. Jamal
    • 7
  • Steven C. Wallis
    • 1
  • Jeffrey Lipman
    • 1
    • 8
  • Christine E. Staatz
    • 6
    • 9
  • Jason A. Roberts
    • 1
    • 6
    • 8
    Email author
  1. 1.Burns, Trauma and Critical Care Research Centre, Level 3, Ned Hanlon Building, Royal Brisbane and Women’s HospitalThe University of QueenslandHerstonAustralia
  2. 2.School of PharmacyInternational Islamic University of MalaysiaKuantanMalaysia
  3. 3.Infectious Diseases Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  4. 4.Department of Anaesthesiology and Intensive Care, School of MedicineInternational Islamic University of MalaysiaKuantanMalaysia
  5. 5.Department of Anaesthesiology, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  6. 6.School of PharmacyThe University of QueenslandBrisbaneAustralia
  7. 7.Department of PharmacyHospital Tengku Ampuan AfzanKuantanMalaysia
  8. 8.Department of Intensive Care MedicineRoyal Brisbane and Women’s HospitalBrisbaneAustralia
  9. 9.Australian Centre of PharmacometricsBrisbaneAustralia

Personalised recommendations