In this episode, I’ll discuss how fluid overload affects the pharmacokinetics of extended infusion meropenem in critically ill patients with sepsis.
Therapeutic monitoring of beta-lactams has not yet reached everyday practice in most hospitals, owing both to a lack of data and a lack of in-house test results that would be available in a practical timeframe.
Researchers recently published in the journal Critical Care a prospective single-center study to assess whether fluid overload alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy.
The authors enrolled 25 septic ICU patients, 18 of which had perioperative intra-abdominal or respiratory infections with septic shock. Over 3 days of therapy with IV meropenem 2 grams over 3 hours every 8 hours, plasma levels, fluid balance, and urine creatinine clearance were measured.
Out of the 25 patients enrolled, 11 had fluid overload, and 9 of these were receiving meropenem for peritonitis. On average, the fluid overload patients had 26% lower meropenem clearance, 10% higher volume of distribution, and a 54% longer half-life.
Over the 3 day study period, as the fluid balance in the overloaded patients normalized, their pharmacokinetic parameters approached those of the non-fluid overload group.
The meropenem dosing regimen used ensured adequate concentrations to treat infections with pathogens that had a MIC of 2 mg/L or less. This is generally the breakpoint used to declare an organism ‘sensitive’ to meropenem. When a higher breakpoint of a MIC of 8 mg/L was applied to represent pathogens with reduced susceptibility, the fluid overload group performed much better. With the higher breakpoint fluid overload patients achieved the target concentration 67% of the time vs 27% for non-fluid overloaded patients, and achieved a fraction of the dosing interval above the MIC of 79% vs 58%.
The study is the first that I am aware of that highlights these differences in fluid overloaded patients. While the authors make good points like, “These findings emphasize the importance of therapeutic drug monitoring and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens,” until hospital laboratories are able to turn around meropenem levels in a clinically relevant timeframe, there will be no ability to monitor meropenem concentrations in practice. In the meantime, we can use this data to suggest the likelihood of achieving acceptable meropenem concentrations when treating fluid overloaded septic patients.
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