Should We Adopt Continuous Infusions of β-lactam Antibiotics in Clinical Practice at This Time?

To the Editor

We read with interest the BLING III study by Dulhunty and colleagues, which reported no difference in 90-day mortality between continuous and intermittent infusions of β-lactam antibiotics in critically ill patients with sepsis.¹ This was consistent with the MERCY trial, which also observed a comparable composite outcome in critically ill patients with sepsis receiving continuous or intermittent administration of meropenem.²

Theoretically, continuous infusion of time-dependent antimicrobials, which results in a constant steady state plasma concentration, is associated with the advantage of achieving pharmacokinetic/pharmacodynamic (PK/PD) target for 100% of the dosing interval.³ However, once the steady state concentration is below the desired target, it will remain so during the entire dosing interval, bearing the risk of treatment failure as well as the emergence of antimicrobial resistance. Whether or not this might happen will be highly dependent on the maintenance dose, a function of total clearance rate, including clearance mediated by renal elimination, non-renal elimination, and extracorporeal organ support.³

In both BLING III and MERCY studies, the daily dose was determined by the attending clinicians, based on the patient body size and estimated drug clearance as per standard prescribing practices. However, in the DALI study which shared the same leading authors with the BLING III study, one-fifth of critically ill patients receiving a β-lactam antibiotic with regimens based on the manufacturers’ recommendations failed to achieve a minimum conservative PK/PD target, i.e. 50% fT_>MIC.⁴ The observed large variations in plasma concentrations of β-lactams, attributable to the enormous pharmacokinetic variability, led the authors to call for a more personalized approach to antibiotic dosing by means of therapeutic drug monitoring (TDM). In addition, a proportion of patients in the BLING III study received kidney replacement therapy due to renal failure, which further complicated the predictability of the PK changes over time in critically ill patients, even with TDM-guided dosing based on population, rather than individual, PK models.⁵ Interestingly, TDM was not permitted in either BLING III or MERCY study to avoid the potential impact on the intervention.¹

We believe that lack of TDM in critically ill patients receiving continuous infusion of β-lactam antibiotics with highly variable PK might be a potential explanation of the negative results observed in BLING III and other studies, whereas extended or prolonged infusion of β-lactams (over 3 hours) might provide a better target attainment, even without TDM.

Ethical statement

Ethical approval and consent were not required.