Continuous-Infusion β-Lactam Antibiotics During Continuous Venovenous Hemofiltration for the Treatment of Resistant Gram-Negative Bacteria

Abstract

Objective: To describe the rationale, principles, and dosage calculations for continuous-infusion β-lactam antibiotics to treat multidrug-resistant bacteria in patients undergoing continuous venovenous hemofiltration (CVVH). Data Sources: A MEDLINE search (1968–November 2008) of the English-language literature was performed using the terms continuous infusion and Pseudomonas or Acinetobacter, hemofiltration or CVVH or hemodiafiltration or CVVHDF or continuous renal replacement therapy or pharmacokinetics; and terms describing different β-lactam antibiotics. Study Selection and Data Extraction: In vitro, in vivo, and human studies were evaluated that used continuous-infusion β-lactam antibiotics to treat Pseudomonas aeruginosa and Acinetobacter baumannii infections. Studies were reviewed that described the pharmacokinetics of β-lactam antibiotics during CVVH as well as other modalities of continuous renal replacement therapy. Data Synthesis: Continuous infusion of β-lactam antibiotics, maintaining drug concentrations 4–5 times higher than the minimum inhibitory concentration, is a promising approach for managing infections caused by P. aeruginosa and A. baumannii. Safe yet effective continuous infusion therapy is made difficult by the occurrence of acute renal failure and the need for renal replacement therapy. Case series and pharmacokinetic properties indicate that several β-lactam antimicrobials that have been studied for continuous infusion, such as cefepime, ceftazidime, piperacillin, ticarcillin, clavulanic acid, and tazobactam, are significantly cleared by hemofiltralion. Methodology and formulas are provided that allow practitioners to calculate dosage regimens and reach target drug concentrations for continuous β-lactam antibiotic infusions during CVVH based on a literature review, pharmacokinetic principles, and our experience at the National Institutes of Health Clinical Center. Conclusions: Continuous infusion of β-lactam antibiotics may be a useful treatment strategy for multidrug-resistant gram-negative infections in the intensive care unit. Well-established pharmacokinetic and pharmacodynamic principles can be used to safely reach and maintain steady-state target concentrations of β-lactam antibiotics in critical illness complicated by acute renal failure requiring CVVH.