Continuous beta-lactam infusions

Reviewed and revised 8 July 2025

OVERVIEW

Continuous infusion of beta-lactam antibiotics is an alternative to intermittent dosing in critically ill patients, especially those with sepsis.

  • Aims to optimise time-dependent killing by maintaining plasma concentrations above the MIC (minimum inhibitory concentration).
  • Commonly used antibiotics include: piperacillin-tazobactam, meropenem, cefepime, and flucloxacillin.

RATIONALE

Inadequate dosing of antibiotics is an issue in critical care

  • Up to 40% of patients treated with β-lactam antibiotics in the ICU may not achieve antibiotic concentrations above the MIC during >50% of dosing intervals (Wiersinga and van Agtmael, 2024)
  • predicts treatment failure
  • can lead to antibiotic resistance

Beta-lactams exhibit time-dependent killing

  • Most β-lactams have a half-life of 1 to 2 hours
  • Efficacy correlates with time above MIC (T>MIC), not peak concentration

Pharmacokinetics are less predictable in critically ill patients, due to factors such as:

  • Increased volume of distribution (Vd)
  • Altered renal clearance (augmented renal clearance or acute kidney injury)
  • Variable tissue penetration

Pharmacokinetic studies suggested that prolongation of administration time can:

  • provide constant serum levels
  • maximise time above MIC
  • potentially improve the efficacy of β-lactam antibiotics

Example regimen

  • Loading dose (e.g. meropenem 2 g IV over 30 min)
  • Followed by continuous infusion (e.g. meropenem 3–6 g/day over 24 h)
  • +/- check antibiotic levels (therapeutic drug monitoring)

ADVANTAGES

  • Improved pharmacokinetic/pharmacodynamic (PK/PD) target attainment
  • Potentially better efficacy in:
    • Septic shock
    • Nosocomial pneumonia
    • Infections with high MIC organisms (e.g. Pseudomonas)
  • May reduce emergence of resistance
  • Lower peak-related toxicity (e.g. neurotoxicity with cefepime)
  • Earlier clinical resolution may lead to decreased total antibiotic amount given, and associated costs
  • Potentially less time spent by nurses preparing and administering antibiotics
  • Less accessing of IV lines and decreased risk of line-associated bloodstream infections
  • Clinical benefit supported by systematic review (Abdul-Aziz et al, 2024)

DISADVANTAGES

  • Requires infusion pumps and line access
    • usually a dedicated lumen on a central venous catheter, rather than a peripheral IV line
  • Stability issues:
    • Meropenem stable for ~8 h at room temperature (may need 8h mini-bags)
    • Piperacillin-tazobactam stable for 24 h at room temperature
  • Compatibility concerns with other IV drugs
  • Not suitable for all patients (e.g. rapidly improving, short-course therapy)
  • Uncertain if clinical benefits from continuous infusion apply to all forms of prolonged infusion (e.g. extended infusions (>2h))
  • Uncertain if clinical benefits apply to all beta lactams (especially those with longer half-lives, e.g. 8h for ceftriaxone), or just those studied in detail (e.g. meropenem and piperacillin-tazobactam)
  • Intermittent doses with high peak levels may actually be advantageous in circumstances where tissue penetration is impaired (e.g. bone infections)
  • Some beta lactams (e.g. carbapenems) may have post-antibiotic effects that correlate better with peak concentrations rather than time above MIC 
  • Uncertainty about whether MIC is exceeded (and by how much) and what the MIC is in a given critically ill patient

EVIDENCE

Abdul-Aziz et al (2024) Systematic review and meta-analysis

  • Design: systematic review and meta-analysis including BLING III and prior RCTs
  • Studies included: 18 RCTs, 9,014 patients with sepsis or septic shock
  • Intervention: continuous vs intermittent infusions of  β-lactam antibiotics
  • Findings:
    • all-cause 90-day mortality benefit (RR 0.86, 95% CrI 0.72-0.98), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality
    • ICU mortality benefit RR 0.84, 95% CrI 0.70-0.97)
    • Improved clinical cure (RR 1.16, 95% CrI 1.07–1.31)
    • No distinction found between gram-negative and gram-positive infections.
  • Criticisms: Clinical heterogeneity, variable antibiotic regimens, inconsistent definitions of clinical cure

Dulhunty et al (2023) – BLING III Trial

  • Design: multicentre, open-label, phase 3 RCT
  • Population: 7,031 ICU patients with sepsis across 104 ICUs in 7 countries
  • Intervention: continuous (over 24h) vs intermittent (over 30 min) infusion of  β-lactam antibiotic (piperacillin-tazobactam or meropenem)
  • Findings:
    • No significant difference in 90-day mortality (24.9% vs 26.8%, p=0.57)
    • Improved clinical cure (55.7% vs 50.0%; ARR 5.7%, 95%CI 2.4% to 9.1%)
    • No differences found in subgroup analysis or secondary outcomes
    • No increase in toxicity or increase in development of resistance found
  • Criticisms: Heterogeneous population, open-label design, underpowered, no TDM, no antibiotic susceptibility testing

Monti et al (2023) – MERCY trial

  • Design: multicentre, open-label RCT in 31 ICUs (Croatia, Italy, Kazakhstan, Russia)
  • Population: 607 ICU patients with sepsis or septic shock
  • Intervention: continuous (2 g LD → 3 g/day) vs intermittent (1 g q8h) meropenem
  • Findings:
    •  No significant difference in composite outcome of 28-day mortality or emergence of resistance (47% vs 49%), RR 0.96 (95% CI, 0.81-1.13)
    • PK/PD: better target attainment in continuous group
  • Criticisms: No TDM, open-label, composite outcome driven by mortality, underpowered

CONCLUSION

  • Current evidence supports continuous infusion of beta-lactams for critically ill patients with sepsis or septic shock
  • If you want to “make antibiotics great again” this may be one way to do it!

REFERENCES

LITFL.com

Journal articles

  • Abdul-Aziz MH, Hammond NE, Brett SJ, et al Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. 2024 Aug 27;332(8):638-648. doi: 10.1001/jama.2024.9803. PMID: 38864162; PMCID: PMC11170459.
  • De Waele JJ, Lipman J, Carlier M, Roberts JA. Subtleties in practical application of prolonged infusion of β-lactam antibiotics. Int J Antimicrob Agents. 2015 May;45(5):461-3. doi: 10.1016/j.ijantimicag.2015.01.007. Epub 2015 Feb 16. PMID: 25749200.
  • Dulhunty JM, Brett SJ, De Waele JJ, et al. Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA. 2024;332(8):629–637. doi:10.1001/jama.2024.9779. PMID: 38864155; PMCID: PMC11170452.
  • MacVane SH, Kuti JL, Nicolau DP. Prolonging β-lactam infusion: a review of the rationale and evidence, and guidance for implementation. Int J Antimicrob Agents. 2014 Feb;43(2):105-13. doi: 10.1016/j.ijantimicag.2013.10.021. Epub 2013 Nov 24. PMID: 24359838.
  • Monti G, Bradic N, Marzaroli M, et al. Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial. JAMA. 2023 Jul 11;330(2):141-151. doi: 10.1001/jama.2023.10598. PMID: 37326473; PMCID: PMC10276329.
  • Wiersinga WJ, van Agtmael MA. Resolving the Dilemma on Continuous vs Intermittent β-Lactam Antibiotics in Sepsis. JAMA. 2024 Aug 27;332(8):623-625. doi: 10.1001/jama.2024.10168. PMID: 38864160.

FOAM and web resources

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at The Alfred ICU, where he is Deputy Director (Education). He is a Clinical Adjunct Associate Professor at Monash University, the Lead for the  Clinician Educator Incubator programme, and a CICM First Part Examiner.

He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives. He was one of the founders of the FOAM movement (Free Open-Access Medical education) has been recognised for his contributions to education with awards from ANZICS, ANZAHPE, and ACEM.

His one great achievement is being the father of three amazing children.

On Bluesky, he is @precordialthump.bsky.social and on the site that Elon has screwed up, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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