Impact of cumulative fluid balance on the pharmacokinetics of extended infusion meropenem in critically ill patients with sepsis

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 < 0.05). Over three days, the CFB of the FO patients decreased (11.7 +/- 3.3 vs 6.7 +/- 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 +/- 3.8 vs 11.5 +/- 2.0 L/h, V-1 13.7 +/- 2.0 vs 14.0 +/- 5.1 L, t(1/2) 0.81 +/- 0.23 vs 0.87 +/- 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCL(cr)) or absent (day 1 and 2 CGCL(cr)). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f C-min > MIC: 67 vs 27%, p < 0.001; day 1%f T > 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.

Automated summary

This study showed that fluid overload in infected patients can significantly affect the pharmacokinetic/pharmacodynamic parameters of meropenem, but these effects can be mitigated over time with appropriate monitoring and dosing adjustments.