Infections are prevalent among critically ill patients and significantly contribute to increased mortality rates and healthcare costs in ICUs. The administration of antibiotics, particularly β-lactam antibiotics, remains a cornerstone in the treatment of severe infections in these settings. However, optimising antibiotic therapy in critically ill patients is challenging due to altered drug pharmacokinetics (PKs), such as increased volume of distribution and variations in renal clearance, which can lead to suboptimal antibiotic concentrations and therapeutic failure.
A pro-con debate at the ISICEM Congress in Brussels examined the potential benefits and limitations of continuous infusion (CI) of β-lactam antibiotics compared to standard intermittent administration (IA) in critically ill patients.
β-lactam antibiotics exhibit time-dependent killing, meaning their efficacy is maximised when drug concentrations exceed the minimal inhibitory concentration (MIC) of the pathogen for an extended period between doses (T > MIC). In critically ill patients, standard IA may result in fluctuating drug levels due to altered PKs, potentially leading to periods where concentrations fall below the MIC. CI of β-lactams can maintain prolonged T > MIC, ensuring more consistent therapeutic levels, which is particularly beneficial against less susceptible pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii.
A study by Abdul-Aziz et al. investigated the effects of CI versus IA of β-lactams in patients with severe sepsis not requiring renal replacement therapy. The study included 140 patients and found that CI was associated with a higher clinical cure rate (56% vs. 34%) and more ventilator-free days compared to IA. Additionally, the target of 100% T > MIC between doses was achieved more frequently in the CI group on both day 1 (97% vs. 70%) and day 3. However, no significant difference in 14-day or 30-day survival rates was observed between the two groups.
While some studies have shown benefits of CI in specific subgroups, the overall evidence remains inconclusive. For instance, a study from the Defining Antibiotic Levels in Intensive Care Unit (DALI) database involving 182 patients reported that CI of piperacillin/tazobactam or meropenem resulted in a higher 30-day survival rate compared to IA, but this benefit was significant only in patients with respiratory infections (86% vs. 57%). Similarly, in cases of hospital-acquired pneumonia due to Pseudomonas aeruginosa, CI of piperacillin/tazobactam was associated with lower 14-day mortality than IA, particularly in patients with Acute Physiological and Chronic Health Evaluation (APACHE) II scores above 17 (12% vs. 32%).
The efficacy of CI may also depend on the susceptibility of the infecting pathogen. Standard IA may suffice for highly susceptible bacteria, but for strains with higher MICs—yet still within treatable ranges—CI could ensure adequate drug concentrations. A retrospective study demonstrated that CI of piperacillin/tazobactam led to a higher probability of clinical cure in ventilator-associated pneumonia (VAP) patients without renal failure when the pathogen's MIC was ≥8 mg/L (15/17 vs. 7/21).
Despite the theoretical advantages, CI of β-lactams is not without concerns. One major issue is the potential for drug accumulation, especially in patients with renal impairment or those undergoing renal replacement therapy (RRT), which could lead to toxic effects. A large cohort study involving 432 septic patients found no significant differences in 90-day survival (74% vs. 73%) or clinical cure rates (52% vs. 49%) between CI and IA groups.
While CI of β-lactam antibiotics offers a pharmacokinetic advantage by maintaining prolonged drug concentrations above the MIC, translating this benefit into improved clinical outcomes for all critically ill patients remains unproven. Evidence suggests that certain subgroups, such as patients with high disease severity, specific types of infections (e.g., respiratory infections), or infections caused by pathogens with higher MICs, may derive more benefit from CI. However, the potential risks, including drug accumulation and associated toxicities, necessitate careful patient selection and monitoring.
Source: Intensive Care Medicine
Image Credit: ISICEM Congresss 2025
