Comparative pharmacokinetics of polymyxin B in critically ill elderly patients with extensively drug-resistant gram-negative bacteria infections

Abstract

Introduction: Elderly patients are more prone to develop acute kidney injury during infections and polymyxin B (PMB)-associated nephrotoxicity than young patients. The differential response to PMB between the elderly and young critically ill patients is unknown. We aimed to assess PMB exposure in elderly patients compared with young critically ill patients, and to determine the covariates of PMB pharmacokinetics in critically ill patients. Methods: Seventeen elderly patients (age ≥ 65 years) and six young critically ill patients (age < 65 years) were enrolled. Six to eight blood samples were collected during the 12 h intervals after at least six doses of intravenous PMB in each patient. PMB plasma concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was PMB exposure as assessed by the area under the concentration-time curve over 24 h at steady state (AUC_{ss, 0-24 h}). Results and Discussion: The elderly group had lower total body weight (TBW) and higher Charlson comorbidity scores than young group. Neither AUC_{ss, 0-24 h} nor normalized AUC_{ss, 0-24 h} (adjusting AUC for the daily dose in mg/kg of TBW) was significantly different between the elderly group and young group. The half-life time was longer in the elderly patients than in young patients (11.21 vs 6.56 h respectively, p = 0.003). Age and TBW were the covariates of half-life time (r = 0.415, p = 0.049 and r = -0.489, p = 0.018, respectively). TBW was the covariate of clearance (r = 0.527, p = 0.010) and AUC_{ss, 0-24 h} (r = -0.414, p = 0.049). Patients with AUC_{ss, 0-24 h} ≥ 100 mg·h/L had higher baseline serum creatinine levels and lower TBW than patients with AUC_{ss, 0-24 h} < 50 mg·h/L or patients with AUC_{ss, 0-24 h} 50-100 mg·h/L. The PMB exposures were comparable in elderly and young critically ill patients. High baseline serum creatinine levels and low TBW was associated with PMB overdose. Trial registration: ChiCTR2300073896 retrospectively registered on 25 July 2023.

Keywords: critical care; elderly; pharmacokinetics; polymyxin B; renal function; total body weight.

FIGURE 1

Plasma concentration-time profile of polymyxin B at steady state. Circles represent multiple time point sampling. (A) the elderly patients; (B) the young patients.

FIGURE 2

Potential factors of polymyxin B overdose in critically ill patients. (A) serum creatinine levels (µmmol/L); (B) age (years); (C) total body weight (TBW) (Kg); (D) CrCl (creatinine clearance) (ml/min). AUC_{ss, 0–24 h}: the area under the concentration-time curve over 24 h at steady state.