According to 2024 Infectious Diseases Society of America (IDSA) guidance on the treatment of antimicrobial-resistant gram-negative infections outside of the urinary tract caused by extended-spectrum beta-lactamase-E.coli (ESBL-E), meropenem or imipenem-cilastatin are the preferred carbapenems for patients who are critically ill and/or experiencing hypoalbuminemia, including those who are treated for sepsis. Unlike meropenem and imipenem, ertapenem is highly protein bound, leading to increased ertapenem clearance in patients with hypoalbuminemia and potentially resulting in a significant decrease in the serum half-life of this agent. One 2015 prospective cohort study evaluated the effectiveness of ertapenem in the setting of hypoalbuminemia (serum albumin <2.5 g/dL) in 279 patients with Enterobacterales infections (see Table 1). Among 173 individuals treated with ertapenem and 106 with meropenem or imipenem (I/M), odds ratio (OR) for 30-day mortality with hypoalbuminemia was 4.6 (95% confidence interval [CI] 2.1 to 10.1) among ertapenem-recipients versus 1.2 (95% CI 0.5 to 2.70) with I/M (p= 0.02). Additional analyses using regression models confirmed the significant interaction between lower albumin levels and increased 30-day mortality associated with ertapenem (OR 2.45; 95% CI 1.19 to 5.05) but not with I/M. Overall, given the known pharmacokinetic (PK) alterations in critically ill patients and limited and conflicting evidence regarding the use of ertapenem, the panel suggests using meropenem or imipenem-cilastatin rather than ertapenem as initial therapy in critically ill patients. Higher doses or more frequent dosing of ertapenem may circumvent target attainment issues in critically ill patients with hypoalbuminemia, but data to support this are limited. [1], [2]
A 2009 single-center, prospective, open-label study was conducted on a cohort of eight critically ill patients with severe sepsis with normal renal function who were treated with 1 gram of ertapenem once daily. Samples of venous blood and urine were collected before infusion and at specific time points in the 24-hour post-infusion period. This study revealed differences in PK parameters when compared to young healthy volunteers, in which critically ill patients demonstrated a lower maximum plasma concentration (Cmax; 52.30 mg/L vs. 253 mg/L) and area under the concentration-time curve from 0 h to infinity (AUC0–∞; 188 mg h/L vs. 817 mg h/L), but a higher volume of distribution at steady state (Vss; 26.8 L vs. 5.7 L). Regarding unbound ertapenem, the geometric means of Cmax and AUC0–∞ were 29.5 mg/L and 103.5 mg*h/L, respectively, with a negative correlation observed with hypoalbuminemia. Notably, unbound levels failed to exceed a minimum inhibitory concentration (MIC) of 1 mg/L for more than 7.1 hours (30% of the dosing interval) in two patients. The highly variable and unpredictable intersubject PK parameters identified in this study resulted in suboptimal unbound concentrations in some patients. This prompts the question of whether ertapenem is a suitable choice for initial treatment in critically ill patients with severe sepsis. It should be noted that the study involved a highly diverse group, potentially leading to small sample sizes that may not accurately represent the drug’s characteristics. Additionally, patients with hepatic or renal dysfunction were intentionally excluded, making it challenging to apply these results to all severe sepsis patients. [3]
A 2011 editorial assessed if ertapenem is an appropriate first-line agent to treat critically ill patients, particularly those with sepsis. The largest area of concern raised is the lack of consensus data on the pharmacodynamics and pharmacokinetics of ertapenem in ICU patients. Some data shows ertapenem has a lower Cmax and higher Vd in critically ill patients compared to healthy volunteers. A negative correlation is seen with unbound ertapenem in patients with hypoalbuminemia, with many levels failing to exceed the MIC of offending organisms. This is especially important because ertapenem exhibits time-dependent killing of microorganisms when higher than the MIC. Besides the variable pharmacokinetics, other intrinsic properties of ertapenem, such as no Pseudomonas or Acinetobacter coverage, may limit its use in critically ill patients. However, the authors propose future studies may be able to identify specific infections for which ertapenem can be safe. [4]
Ertapenem is highly protein-bound (85-95%), which may make it difficult to dose correctly in certain critically ill patients. This protein binding gives it a longer half-life compared to other carbapenems. However, these pharmacokinetic and pharmacodynamic properties may be altered in critically ill patients with hypoalbuminemia. A 2007 PK study found that the AUC of unbound ertapenem significantly increased in patients with hypoalbuminemia, with the unbound drug failing to reach the minimum concentrations to exert its antibacterial properties in some patients. These results were confirmed in a second study of critically ill patients, where unbound ertapenem did not achieve concentrations needed to meet the required MICs. An additional concern is the short stability of ertapenem, meaning continuous infusions would likely need to be changed every 6 hours. [5], [6], [7], [8]