Molecular Adsorbent Recirculating System (MARS^®) removal of piperacillin/tazobactam in a patient with acetaminophen‐induced acute liver failure

Abstract

The objective of this study was to illustrate the pharmacokinetic removal of piperacillin/tazobactam in an anuric patient on Molecular Adsorbent Recirculating System (MARS(®)). The patient was a 32-year-old woman who presented to a medical intensive care unit with acute liver failure secondary to an acetaminophen overdose. While awaiting transplant, she was started on MARS therapy as a bridge to liver transplant and empirically started on piperacillin/tazobactam therapy. MARS is an extracorporeal hemofiltration device, which incorporates a continuous venovenous hemofiltration (CVVHD) machine linked to an albumin-enriched dialysate filter to normalize excess electrolytes, metabolic waste, and protein-bound toxins. In addition to protein-bound waste, MARS removes water-soluble, low molecular-weight molecules. The patient received piperacillin/tazobactam 4.5 g infused intravenously over 3 h. A steep decline in serum levels occurred between hours 4 and 6 while MARS continued and no antibiotic was infused. The elimination rate constant (k(e)) for the removal of piperacillin in this patent was 0.453 h(-1) and the half-life (λ) was 1.53 h. The k(e) was 2.9-fold higher than with CVVHD alone and the λ was 3.7-fold shorter. Low levels of piperacillin are achieved during MARS therapy, but in the treatment of more resistant organisms, such as Pseudomonas aeruginosa, these low levels may not be adequate to achieve bactericidal activity. Drug levels following a standard infusion of 30 min would likely be even lower. Formalized pharmacokinetic studies of piperacillin/tazobactam removal in patients on MARS therapy are necessary to make clear dosing recommendations.

Extracorporeal Elimination of Piperacillin/Tazobactam during Molecular Adsorbent Recirculating System Therapy

“…These properties suggest that elimination may be enhanced in the setting of MARS therapy. A previous case report suggested heightened total‐body piperacillin elimination in a patient receiving MARS therapy relative to historical controls receiving continuous venovenous hemodialysis (CVVHD) alone . Investigation also highlighted the importance of maintaining serum concentrations at the desired degree of elevation above the minimum inhibitory concentration (MIC) for the treatment of virulent and potentially resistant organisms.…”

“…Anticoagulation with intravenous heparin was titrated to maintain a goal activated partial thromboplastin time between 60 and 80 seconds. Based on the serum levels maintained in the previously published case report, piperacillin/tazobactam was administered using an extended infusion strategy of 3.375 g given over 4 hours at 8‐hour intervals. After the completion of the first extended infusion dose, piperacillin concentrates were measured at numerous points throughout the MARS circuit.…”

“…Total body elimination could not be calculated because the dosing interval of piperacillin/tazobactam prohibited sufficient time for redistribution after termination of the MARS session. It is notable, however, that serum concentrations were similar to the previously published case report, in which an extended interval infusion strategy of 4.5 g given over 3 hours at 8‐hour intervals was used . In that report, serum levels ranged between 110 and 175 μg/ml.…”

“…This indicates that 64 μg/ml, sustained for 4 hours, is the minimum acceptable trough concentration for adequate inhibition of microbial growth. Piperacillin concentrations in all three cases (including the previously published case) exceeded that which would be desired for treatment of these organisms. It is also notable that in each of the cases reported here, patients were considered to have achieved clinical cure while receiving piperacillin/tazobactam.…”

Management of Hepatic Encephalopathy in the Hospital

“…Also, MARS may reduce the bioavailability of certain antibiotics. 43 Cost is also a major concern with this modality. Nevertheless, MARS appears to be a viable option for patients with severe HE unresponsive to standard medical therapy.…”