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: NNT of 26 for 90-day mortality (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 with NNT=26 (RR 0.86, 95% CrI 0.72-0.98) – 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

• LITFL – Antimicrobial dosing and kill characteristics

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

• Deranged Physiology – Antibiotic dosing as continuous infusions
• The Bottom Line – Bling III