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
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.
KeywordsAntibiotics Critically ill Intermittent bolus Pharmacokinetics Pharmacodynamics Prolonged infusion
- 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.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
- 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
- 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
- 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
- 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.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
- 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
- 28.Food and Drug Administration (2001) Guidance for industry: bioanalytical method validation. FDA, RockvilleGoogle Scholar
- 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.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.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.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.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.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
- 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