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 (CL_cr) 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 (CL_me 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V₁ 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 (CL_me 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V₁ 13.7 ± 2.0 vs 14.0 ± 5.1 L, t_1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CL_cr and Cockroft-Gault CL_cr were stable in time and comparable. The correlation with CL_me was weak to moderate (CL_cr, 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 CL_me and creatinine clearance.

Keywords: Critically ill patients; Fluid therapy; Meropenem; Pharmacodynamics; Pharmacokinetics; Sepsis.