Question 23

Regarding prolonged intravenous infusions of beta-lactam antibiotics in septic patients:

a)    Explain the pharmacological rationale for this method of drug delivery.    (30% marks)

b)    List the advantages and disadvantages of this method of drug delivery.    (40% marks)

c)    What is the available evidence for this method of drug delivery?    (30% marks)

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College answer

Not available.




  • Clinical efficacy of β-lactams depends on time spent above MIC
  • This may be difficult to achieve in septic patients (variable erratic pharmacokinetics)
  • Inadequate dosing may result in treatment failure and the development of resistance (Martinez et al, 2012)
  • High peaks seen with intermittent dosing can increase the risk of drug toxicity
  • Critically ill patients should benefit most  (clearance mechanisms are most erratic, organisms are most resistant, )



  • More rapid rates of clinical improvement and decreased morbidity/mortality
  • Continuous infusion should prevent drug-related adverse effects
  • Less nursing workload to set up on 24 hr infusion
  • Potential for treatment in the community (decrease healthcare costs)
  • The total dose of the drug may be lower, as clinical resolution may occur sooner
  • Less underdosing, thus less resistance development


  • Many drugs have clinically significant post-antibiotic concentration-dependent killing effects, including beta-lactams in gram positives
  • Boluses may achieve the higher concentration required to penetrate tissues
  • MIC targets are not consistently agreed upon
  • MIC is not always measured, nor are drug levels
  • Not all drugs are suitable for a 24-hour infusion because of their stability in room temperature solution
  • The 24 hour infusion usually takes out one whole lumen of a line



  • The evidence for mortality benefit is conflicting 
  • The larger trials with robust methodology (Dulhunty et al, 2013; BLING II; 2015BLISS, 2016)have not produced any mortality benefit or ICU length of stay improvement
  • The overall literature is heterogeneous, with everybody using different antibiotic regimens, infusion standards, MIC targets, patient populations and follow up strategies. 
  • One thing which has emerged is a consistent signal that there is no harm with continuous infusion
  • Of the (admittedly, low quality and largely observational) studies that report better outcomes with continuous infusions, the populations which seem to benefit the most are critically ill patients, i.e. low acuity patients do not seem to benefit.
  • BLING III should hopefully shed more light on this by enrolling 7,000 ICU patients


Nicolau, David P. "Pharmacodynamic optimization of β-lactams in the patient care setting." Critical Care 12.4 (2008): 1-5.

Martinez, Marilyn N., Mark G. Papich, and George L. Drusano. "Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target." Antimicrobial Agents and Chemotherapy 56.6 (2012): 2795-2805.

MacVane, Shawn H., Joseph L. Kuti, and David P. Nicolau. "Prolonging β-lactam infusion: a review of the rationale and evidence, and guidance for implementation." International journal of antimicrobial agents 43.2 (2014): 105-113.

Abdul-Aziz, Mohd H., et al. "Continuous beta-lactam infusion in critically ill patients: the clinical evidence." Annals of intensive care 2.1 (2012): 1-16.

Rodvold, Keith A. "Pharmacodynamics of antiinfective therapy: taking what we know to the patient's bedside." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 21.11P2 (2001): 319S-330S.

AA, Mohd Hafiz, et al. "Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics." Minerva anestesiologica 78.1 (2011): 94-104.

Craig, WA1, and S. C. Ebert. "Continuous infusion of beta-lactam antibiotics." Antimicrobial Agents and Chemotherapy 36.12 (1992): 2577-2583.

Kondo, Yutaka, et al. "Prolonged versus intermittent β-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials." Journal of intensive care 8.1 (2020): 1-11.

Abdul-Aziz, Mohd H., 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 medicine 42.10 (2016): 1535-1545.

Dulhunty, Joel M., et al. "A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis." American journal of respiratory and critical care medicine 192.11 (2015): 1298-1305.

Dulhunty, Joel M., et al. "Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.Clinical infectious diseases 56.2 (2013): 236-244.