Sepsis is a life-threatening condition that continues to pose significant challenges to clinicians worldwide. Meropenem, a potent broad-spectrum β-lactam antibiotic, is commonly prescribed to combat severe bacterial infections in critically ill patients. The optimisation of antibiotic dosing strategies, such as continuous infusion, has been an area of interest to maximise the drug’s efficacy in treating infections and potentially improve patient outcomes.
In light of this, the MERCY Randomised Clinical Trial set out to investigate whether continuous administration of meropenem offers superior outcomes compared to intermittent administration in critically ill patients with sepsis.
In this article, we report on a critical appraisal of the study during the Pharmacy Infection Journal Club held in July 2023.
Beta-lactam antibiotics
Beta-lactam antibiotics, including meropenem, are time-dependent antimicrobial agents, where the time that drug concentrations remain above the minimum inhibitory concentration (MIC) is crucial for their bactericidal activity. Continuous or extended infusion of beta-lactams is hypothesised to optimise the pharmacokinetic/pharmacodynamic (PK/PD) parameters of these antibiotics, potentially leading to improved clinical outcomes through optimising time above MIC (T > MIC).
Continuous infusion provides a constant, sustained drug concentration in the bloodstream, resulting in a longer duration during which the drug concentration remains above the MIC. This prolonged T > MIC allows for more prolonged exposure of bacteria to effective drug levels, maximising the time during which bacterial growth is inhibited or killed. Increased T > MIC is associated with enhanced bactericidal activity and has been shown to be positively correlated with treatment success in beta-lactam therapy.
Bacterial resistance suppression
Continuous infusion may also play a role in suppressing the emergence of bacterial resistance. Prolonged exposure of bacteria to sub-inhibitory concentrations has been shown to inhibit the expression of resistance mechanisms. By maintaining drug levels above the MIC over an extended period, continuous infusion may reduce the selection pressure for resistant bacterial mutants, thus delaying or preventing the development of resistance.
How this PK/PD model translates into clinical practice is less clear. The advantages of serum beta-lactam levels may be negated by lower tissue levels of beta-lactam. For urinary tract infections where high concentrations of beta-lactams are expected, for low MIC bacteria where T > MIC parameters are achieved irrespective of administration and for non-severe infections, dosing administration is not expected to impact significantly on patient infection outcomes.
The MERCY trial
The MERCY trial – conducted as a prospective, double-blind, randomised clinical trial – sought to assess the impact of beta-lactam administration on patient outcomes.
The study enrolled 607 critically ill patients with sepsis or septic shock across 31 intensive care units in four countries. Patients were randomised into two groups: one receiving meropenem through continuous infusion and the other through intermittent administration. The primary outcome measured was a composite of all-cause mortality and the emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.
The results of the MERCY trial found continuous administration of meropenem did not lead to significant differences in the composite outcome compared to intermittent administration. Both groups had similar rates of all-cause mortality and the emergence of resistant bacteria at day 28, with no statistically significant distinction. Additionally, secondary outcomes, including days alive and free from antibiotics, days alive and free from the intensive care unit, and all-cause mortality at day 90, did not show significant differences between the two groups.
Critical analysis
The MERCY trial’s findings were met with interest and scrutiny during the journal club review, where the study’s design, limitations and implications for clinical practice were thoroughly discussed.
The journal club review highlighted the study’s underpowered nature, potentially limiting its ability to detect clinically significant changes in patient mortality. A study of >3,000 participants in each arm would be needed to detect the expect differences in mortality between two groups.
The high rates of carbapenem resistance observed in both study groups (>30%) raised concerns about the potential impact on study outcomes. The exclusion of immunocompromised patients may also have implications for the generalisability of the findings to this patient population. Concurrent therapy with other antimicrobial agents, as observed in some patients, could have introduced confounding variables that might have influenced the results. It is unclear why such a high proportion of patients were treated with concurrent beta-lactams; it is possible these were combination agents for KPC resistance and therefore these would negate any benefit of meropenem usage and skew the study findings.
Implications for clinical practice
The MERCY trial’s outcomes raise important considerations for clinical practice, particularly in the management of critically ill patients with sepsis. The theoretical benefits of continuous infusion on PK/PD parameters of beta-lactam antibiotics have been supported by in vitro and animal studies.
However, the clinical evidence in critically ill patients has been less definitive, as demonstrated by the MERCY trial. While continuous infusion may optimise PK/PD parameters and theoretically improve clinical outcomes, the study’s findings highlight the complexity of applying these principles in real-world settings.
Pharmacists and clinicians should carefully evaluate individual patient characteristics, antimicrobial resistance patterns, and regional differences when deciding on the optimal administration method of meropenem.
Future directions
As a narrative review of the MERCY trial and its journal club discussion, it becomes evident that further research is necessary to fully understand the role of continuous infusions in antibacterial therapy. Large-scale studies, such as BLING-3, may provide more robust evidence on the potential benefits of continuous meropenem administration in specific patient subgroups. Future studies should also consider including immunocompromised patients and address regional variations in carbapenem resistance rates.
Conclusion
The MERCY trial adds to the body of knowledge regarding the optimal administration of meropenem in critically ill patients with sepsis. Although prior pharmacodynamic principles suggested potential benefits of continuous infusion, the study’s results did not show significant improvements in clinically relevant outcomes compared to intermittent administration.
As pharmacists with specialist knowledge of antibacterials, it is essential to recognise the study’s limitations and consider individual patient characteristics when making therapeutic decisions. Future research efforts should be directed towards conducting larger, more inclusive studies to elucidate the potential benefits of continuous infusions and guide evidence-based practice in the treatment of sepsis.
The opinions expressed in this article are those of the author. They do not purport to reflect the opinions or views of the UKCPA or its members. We encourage readers to follow links and references to primary research papers and guidance.
Competing interest statement:
The author declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. The authors has consulted for/received speaker fees from the following companies: Shionogi (2021–22); BowMed (2021); Eumedica (2022-23); Kent Pharma (2021); Gilead (2021–22); Baxter (2022) and Pfizer (2020–2023), and received research grants from the CW + Charity (2021–2023).
