Highlight
- MARS therapy leads to a considerable reduction (34%) in plasma piperacillin concentrations per treatment session in critically ill patients with acute or acute-on-chronic liver failure.
- Higher creatinine clearance correlates with increased piperacillin loss during MARS, while elevated bilirubin is associated with reduced drug clearance.
- Approximately one-third of post-MARS piperacillin concentrations fell below the therapeutic target, potentially risking suboptimal antimicrobial exposure.
- Findings advocate for systematic therapeutic drug monitoring (TDM) and tailored antibiotic dosing during MARS therapy to ensure efficacy.
Study Background
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are critical syndromes associated with high morbidity and mortality, often complicated by sepsis requiring antibiotic treatment. The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal liver support therapy designed to remove albumin-bound toxins and assist patients with severe liver dysfunction. However, MARS may unintentionally clear important drugs such as antibiotics, compromising their effectiveness. Piperacillin, a broad-spectrum β-lactam antibiotic commonly used in critically ill patients, is typically administered with tazobactam. Its pharmacokinetics in liver failure remains complex, and the impact of MARS on piperacillin plasma concentration is poorly characterized. Understanding this interaction is critical to optimize antimicrobial therapy and improve patient outcomes in ICU settings.
Study Design
This investigation was a retrospective, single-center observational cohort study conducted in a university intensive care unit. The study included 30 consecutive adult patients who received MARS therapy alongside continuous infusion piperacillin-tazobactam treatment between March 2023 and June 2025. MARS sessions lasted 8 hours, administered for up to three consecutive days. Blood samples were drawn immediately before and after each MARS session, with piperacillin concentrations quantified via ultrahigh-performance liquid chromatography. The primary endpoint was the relative reduction in total plasma piperacillin concentration attributable to each MARS session. Secondary analyses evaluated factors influencing drug concentration changes, such as renal function and liver disease severity.
Key Findings
The cohort primarily consisted of patients with cirrhosis (73%), with a median Model for End-Stage Liver Disease (MELD) score of 31, indicating severe hepatic impairment. A total of 121 piperacillin measurements over 77 MARS sessions were analyzed. The principal finding was a mean intra-session piperacillin concentration reduction of 34% (±7.9%). Statistical analysis identified two significant predictors of intra-session piperacillin loss: creatinine clearance and bilirubin levels. Higher creatinine clearance was independently associated with greater antibiotic clearance during MARS (p<0.001), reflecting the influence of renal function on drug elimination. Conversely, elevated serum bilirubin was linked to reduced piperacillin removal (p=0.01), possibly reflecting competitive binding effects or altered protein binding dynamics during MARS.
Notably, 31.6% of post-MARS piperacillin concentrations were below 80 mg/L, the predefined lower target threshold for effective therapy, with 38% of patients exhibiting at least one value outside therapeutic range, highlighting potential subtherapeutic dosing risks. The data underscore that MARS substantially impacts piperacillin pharmacokinetics, raising concerns about antibiotic underdosing and treatment failure during extracorporeal liver support.
Expert Commentary
These findings provide pivotal clinical evidence about the drug-clearing capacity of MARS therapy for piperacillin, signaling a need for vigilant antimicrobial stewardship in this vulnerable population. The magnitude of reduction across MARS sessions signifies that standard dosing regimens, without monitoring, may result in inadequate plasma concentrations, predisposing to ineffective infection control and resistance development.
From a mechanistic perspective, MARS employs albumin dialysis, which adsorbs protein-bound toxins—and likely protein-bound drugs like piperacillin—leading to drug loss. The interplay between renal function and bilirubin levels influencing piperacillin clearance also aligns with expected pharmacokinetic alterations in critical illness and liver dysfunction. These insights emphasize the necessity of individualized dosing strategies tailored to dynamic patient parameters.
Study limitations include its retrospective and single-center nature, relatively small sample size, and the focus on total rather than unbound piperacillin concentrations, which might better reflect pharmacologically active drug. Prospective studies should explore optimized dosing algorithms and the role of real-time therapeutic drug monitoring during MARS.
Conclusion
This observational cohort study robustly demonstrates that MARS therapy significantly reduces total plasma piperacillin concentrations in critically ill patients with acute or acute-on-chronic liver failure. The observed one-third reduction per session presents a clinically relevant challenge for maintaining effective antimicrobial therapy. Systematic measurement of piperacillin levels and individualized dose adjustments—accounting for renal function and liver disease severity—should be integral to MARS treatment protocols. This approach may enhance therapeutic outcomes and mitigate risks associated with subtherapeutic antibiotic exposure in this high-risk ICU population.
Future research should focus on prospective validation of dosing strategies, exploration of other antibiotics affected by MARS, and the clinical impact of optimized drug management on infection resolution and survival.
Funding and Clinical Trial Registration
Details regarding funding sources and trial registration were not provided in the original study abstract.
References
- Monet C, Allegre L, Kozoriz A, et al. Impact of Molecular Adsorbent Recirculating System Therapy on Piperacillin Concentration in Critically Ill Patients: An Observational Cohort Study. Crit Care Med. 2026 Jun 16. PMID: 42301229.
- Wendon J, Mitzner SR, Jalan R. Extracorporeal Liver Support in Acute and Acute-on-chronic Liver Failure. Hepatology. 2023;68(1):370-381.
- Kara E, Blaschke AJ, Bennett CL. Impact of Renal Replacement Techniques on Antibiotic Pharmacokinetics in Critically Ill Patients. Clin Pharmacokinet. 2025;64(2):191-204.
- Roberts JA, Abdul-Aziz MH, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: enhanced pharmacokinetic/pharmacodynamic efficacy and safety. J Antimicrob Chemother. 2016;71(12):3592-3600.
