Impact of cumulative fluid balance on the pharmacokinetics of extended infusion meropenem in critically ill patients with sepsis
Abstract
Background Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy.
Methods Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily.
Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. Results Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight.
Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 +/- 3.2 vs 11.5 +/- 3.5 L/h), higher volume of distribution (V-1 14.9 +/- 3.5 vs 13.5 +/- 4.1 L) and longer half-life (t(1/2) 1.4 +/- 0.63 vs 0.92 +/- 0.54 h) (p MIC: 67 vs 27%, p MIC: 79 +/- 17 vs 58 +/- 17, p < 0.05). Conclusions These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.