Considerations and Concerns Regarding the Use of Ertapenem in Patients With Hypoalbuminemia: Is It Truly Inappropriate?

To the Editor—We read with great interest the Infectious Diseases Society of America (IDSA) 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. The guideline mentions that in patients with hypoalbuminemia and critical illness, the free fraction of ertapenem increases, leading to a significant decrease in the serum half-life. As it is widely known, ertapenem is a carbapenem antibiotic with time-dependent pharmacokinetics. It is administered once daily and is characterized by its high protein-binding affinity compared to its analogues. The binding to albumin is concentration-dependent: 85% at 300 μg/mL and 95% at <100 μg/mL. The approximate volume of distribution is 0.12 L/kg. To achieve maximum bactericidal effect, the unbound active fraction should exceed the minimum inhibitory concentration for >40% of the dosing interval. The primary metabolite of ertapenem is an open-ring derivative formed through hydrolysis of the β-lactam ring, mediated by dehydropeptidase I, predominantly renal. This metabolite is inactive. Hepatic metabolism is negligible [1]. However, we would like to draw attention to a study conducted by Liebchen et al [2], which compared serum levels of ertapenem between healthy subjects and intensive care unit (ICU) patients with hypoalbuminemia ranging from 2.5 to 3 mg/dL. The unbound concentrations of ertapenem exceeded 2 mg/L for a median of 72% (range, 39%–100%) of the 24-hour dosing interval and 0.25 mg/L for 100% (range, 79%–100%). The number of binding sites per albumin molecule was 1.22 (95% confidence interval [CI], 1.07–1.38) in plasma from healthy volunteers and 0.404 (95% CI, .158–.650) in samples from ICU patients. Although differences in serum levels were observed, it is important to note that the study included a small sample size and the patients had other baseline characteristics that may have influenced the outcomes. Therefore, it is uncertain whether these findings can be solely attributed to hypoalbuminemia. Furthermore, in a pharmacokinetic study [3], it was observed that critically ill patients had lower concentrations of ertapenem compared to healthy patients. The enhanced volume of distribution during the terminal phase (17 vs 8 L) and typical population value of clearance (43 vs 20 mL/minute) with resulting lower maximum concentration (Cmax) (90 vs 253 mg/L) and area under the curve (AUC0–1) (418 vs 817 mg × hour/L) values were mainly related to hypoalbuminemia (range, 9.2–25.6 g/L). However, this study was solely in vitro and lacks the level of evidence necessary to translate into clinical practice. Another study conducted by Brink et al [4] evaluated the concentrations of unbound ertapenem in a small group of 8 patients with hypoalbuminemia; geometric means of Cmax and AUC0–∞ were 29.5 mg/L and 103.5 mg hour/L, respectively. While it was a prospective study, the sample size was very limited, and the patients had discordant albumin levels and other baseline characteristics, making the group highly heterogeneous. Therefore, the decrease in ertapenem concentration cannot be solely attributed to hypoalbuminemia and remains a hypothesis. We are concerned that the recommendation to not use ertapenem alone in patients with hypoalbuminemia is based on a retrospective observational study [5] where the definition of hypoalbuminemia was assigned postanalysis. The study also found associations with mortality and baseline characteristics that could introduce significant bias, namely, Sequential Organ Failure Assessment score upon admission (P < .01), age (P < .04), and Charlson index (P < .07). Furthermore, it is important to consider that dosing and the types of infections being treated with ertapenem vary, with some infections falling outside the target coverage range for this antibiotic, such as meningitis or ventilator-associated pneumonia. To truly evaluate the appropriateness of ertapenem use in patients with hypoalbuminemia, randomized clinical trials should be conducted. Additionally, exploring alternative approaches such as dose adjustment or strategies to improve albumin levels in these patients may be worth considering. We sincerely appreciate your attention to this letter and commend the ongoing excellence of IDSA in promoting research and knowledge exchange in the field of infectious diseases.