Beta-lactams are a category of antibiotics that are most effective when their plasma concentrations persistently exceed the minimum inhibitory concentration (MIC), thus classifying them as time-dependent antibiotics. In this context, the critical pharmacodynamic parameter simplifies to the time period where serum concentrations surpass the MIC within the dosing interval, labeled as t>MIC.
Standard intermittent infusions, administered over 30-60 minutes, lead to fluctuating drug concentrations with characteristic peaks and troughs. Conversely, prolonged infusions, either extended over 2-4 hours or given continuously, may deliver more stable serum levels that consistently exceed the minimum inhibitory concentration required for the targeted pathogen [Figure 1].
Prolonged infusions are particularly beneficial when addressing infections from gram-negative organisms with higher susceptibility-range MICs, and in critically ill patients, where pharmacokinetics are frequently variable due to changes in drug clearance and distribution, fluid balance, and protein binding.
Do you administer prolonged beta-lactam infusions (i.e. meropenem) in the treatment of sepsis caused by gram-negative organisms in your ICU?
0%Yes
0%No
0%Never heard of it!
Meta-analyses
A systematic review and meta-analysis aimed to evaluate the effectiveness of prolonged versus short-term infusion of antipseudomonal β-lactams in sepsis patients. The study included 22 randomized controlled trials (RCTs) involving 1876 patients and was published in 2017. Various β-lactams were studied (including carbapenems, penicillins, and cephalosporins) in patients of differing ages, sepsis severity, and renal function. The meta-analysis found that prolonged infusion was associated with significantly lower all-cause mortality than short-term infusion (RR 0.70, 95% CI 0.56-0.87), with high-quality evidence and no observed heterogeneity or publication bias [1].
A separate systematic review and meta-analysis that synthesized data from 3401 critically ill patients across 18 retrospective and prospective studies found a correlation between prolonged infusion of piperacillin-tazobactam and a reduced risk of mortality, with an odds ratio of 0.69 (95% CI, 0.56-0.84) [2]. Crucially, these systematic reviews and meta-analyses found no indications of heightened toxicity or other adverse effects resulting from extended infusions.
Protocols & Guidelines
Numerous medical institutions worldwide have instituted policies and clinical protocols that aim to optimize the antibacterial killing effects of beta-lactam agents through extended infusion. However, despite these widespread practices, there is a notable absence of support from large randomized clinical trials.
In addition, the Surviving Sepsis Campaign introduced a cautious recommendation for the extended infusion of β-lactam antibiotics in its 2021 updated guidelines. This recommendation, which suggests administering an initial loading dose to swiftly achieve effective drug concentrations, prefers extended infusion over the traditional intermittent administration. The endorsement is classified as "weak," with its basis grounded on evidence deemed to be of "moderate quality" [4].
The BLING II and III Trials
A phase II randomized control trial (BLING II) was conducted in 25 intensive care units (ICUs) across Australia and New Zealand and included 432 patients with severe sepsis. The investigators found that the continuous infusion of β-lactam antibiotics did not result in significant clinical improvement compared to intermittent β-lactam antibiotic infusion. There was no difference in ICU-free days, 90-day survival, clinical cure rate, organ failure-free days, or duration of bacteremia between the two treatment groups [3].
As we anticipate the 90-day mortality results of the BLING III trial, involving 7000 critically ill patients randomized to receive either piperacillin-tazobactam or meropenem via continuous or intermittent infusion, we note the recent publication of the MERCY trial in JAMA [5,6].
The MERCY Trial
Monti et al. present a multinational, double-blind randomized controlled trial investigating the efficacy of continuous versus intermittent administration of meropenem in 607 septic ICU patients. The respiratory tract was the most common infection site, and almost 70% of patients had identifiable gram-negative pathogens, including Klebsiella and Pseudomonas species. There was no significant differences in 28-day all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria between the two groups. Similarly, 90-day mortality and emergence of drug-resistant bacteria were not different between the two groups [6].
The study included severely ill patients with expected altered, including those with high minimum inhibitory concentrations to carbapenem antibiotics or intrinsically resistant pathogens, populations expected to benefit most from prolonged infusions. The study has several limitations to consider. Firstly, the majority of patients were already admitted to the hospital and receiving other antibiotics prior to enrollment, which may have influenced the trial's outcomes and makes it challenging to solely attribute prognoses to the antibiotics given at randomization. Secondly, while approximately 70% of patients had identifiable organisms, most were isolated from respiratory specimens with limited predictive value, and confirmed bacteremia was only present in 10% of patients. Lastly, it's important to note that the study focused specifically on meropenem, and caution should be exercised when extrapolating the results to other beta-lactam agents like piperacillin/tazobactam.
Insights
Considering the factors at hand, the impact of the MERCY trial on clinical guidelines remains uncertain. The trial did not show any evidence of harm associated with prolonged infusion, which makes it difficult for clinicians and guideline authors to disregard the potential mortality reductions reported in previous meta-analyses. In fact, the absolute 28-day mortality rate in the continuous administration group was lower than in the intermittent administration group 47% versus 49%), which suggests that incorporating the MERCY trial into an updated meta-analysis is likely to strengthen the previously reported mortality benefits.
Furthermore, the logistical barriers to prolonged infusions, such as limited intravenous access or nursing resources, are generally less concerning in the intensive care unit setting. However, it is important to note that the MERCY trial is unlikely to be the definitive trial on prolonged versus intermittent infusion of β-lactam antibiotics. The ongoing β-Lactam Infusion Group (BLING III) study, with its larger sample size and inclusion of piperacillin-tazobactam, aims to provide more conclusive evidence by comparing continuous and intermittent infusion on 90-day all-cause mortality in critically ill patients with sepsis.
Conclusion
Despite the negative results of the MERCY trial, the current inclination towards prolonged dosing of β-lactam antibiotics may still endure in clinical guidelines and practice. This is due to the potential benefits and lack of harm associated with this approach, as well as the anticipation of the forthcoming results from the BLING III trial.
REFERENCES:
Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018 Jan;18(1):108-120. doi: 10.1016/S1473-3099(17)30615-1. Epub 2017 Nov 5. PMID: 29102324. [PubMed]
Rhodes NJ, Liu J, O’Donnell JN, et al. Prolonged infusion piperacillin-tazobactam decreases mortality and improves outcomes in severely ill patients: results of a systematic review and meta-analysis.  Crit Care Med. 2018;46(2):236-243. doi:10.1097/CCM.0000000000002836 [PubMed]
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 *. A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. Am J Respir Crit Care Med. 2015 Dec 1;192(11):1298-305. doi: 10.1164/rccm.201505-0857OC. PMID: 26200166. [PubMed]
Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021.  Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337 [PubMed]
Lipman J, Brett SJ, De Waele JJ, Cotta MO, Davis JS, Finfer S, Glass P, Knowles S, McGuinness S, Myburgh J, Paterson DL, Peake S, Rajbhandari D, Rhodes A, Roberts JA, Shirwadkar C, Starr T, Taylor C, Billot L, Dulhunty JM. A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis: BLING III. Crit Care Resusc. 2019 Mar;21(1):63-68. PMID: 30857514. [PubMed]
Monti G, Bradić N, Marzaroli M, et al. Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial. JAMA. 2023;330(2):141–151. doi:10.1001/jama.2023.10598 [Article]