Acute-on-chronic liver failure alters meropenem pharmacokinetics in critically ill patients with continuous hemodialysis: an observational study

Abstract

Background: Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Adequate dosing of antimicrobial therapy is of central importance to improve outcome. Liver failure may alter antibiotic drug concentrations via changes of drug distribution and elimination. We studied the pharmacokinetics of meropenem in critically ill patients with ACLF during continuous veno-venous hemodialysis (CVVHD) and compared it to critically ill patients without concomitant liver failure (NLF). Methods: In this prospective cohort study, patients received meropenem 1 g tid short-term infusion (SI). Meropenem serum samples were analyzed by high-performance liquid chromatography. A population pharmacokinetic analysis was performed followed by Monte Carlo simulations of (A) meropenem 1 g tid SI, (B) 2 g loading plus 1 g prolonged infusion tid (C) 2 g tid SI, and (D) 2 g loading and continuous infusion of 3 g/day on days 1 and 7. Probability of target attainment (PTA) was assessed for 4× the epidemiological cutoff values for Enterobacterales (4 × 0.25 mg/L) and Pseudomonas spp. (4 × 2 mg/L). Results: Nineteen patients were included in this study. Of these, 8 patients suffered from ACLF. A two-compartment model with linear clearance from the central compartment described meropenem pharmacokinetics. The peripheral volume of distribution (V 2) was significantly higher in ACLF compared to NLF (38.6L versus 19.7L, p = .05). PTA for Enterobacterales was achieved in 100% for all dosing regimens. PTA for Pseudomonas spp.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy

“…Flucloxacillin Ultrafiltration rate: 57 ± 9 ml/min 4.0 g q8h (Meyer et al, 2003) --1 g q8h 1h infusion (Onichimowski et al, 2020b) Dialysate rate: 20-35 ml/kg/h 2 g q12 h; or Loading dose:1 g, Maintenance dose:500 mg q8 h; or Loading dose:1 g LD, Maintenance dose:1 g q12 h (Shaw and Mueller, 2017) Dialysate rate:35 ml/kg/h 1 g q8h 1h infusion (Onichimowski et al, 2020b) Dialysate rate: 0.7-1 L/h 0.25 q24h for MIC ≤2 mg/L >0.5 g q8h for MIC = 16 mg/L (Kawano et al, 2015) Dialysate rate: 30 ml/kg/h 1 g q8h or 2 g q8h or 3 g continuous infusion q24h (Grensemann et al, 2020) Ultrafiltration rate: 22 ± 12 ml/kg/h Dialysate rate: 23 ± 9 ml/kg/h 1 g q12h (MIC ≤1 mg/L) (Seyler et al, 2011) Ultrafiltration rate: 2 L/h Dialysate rate: 1 L/h 500 mg q8h (MIC ≤4mg/L) (Varghese et al, 2015) Ultrafiltration rate: 1.5-2 L/h Dialysate rate: 1-1.5 L/h 1 g q8h Imipenem Ultrafiltration rate: 52 ± 14 ml/kg/h 1.0 g q6h Ultrafiltration rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Dialysate rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Combined flow rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Panipenan CLtot (ml/min) = (1.2 creatinine clearance + 66.5) +0.86 (dialysate rate+ ultrafiltration rate) CLtot <80 ml/min, 0.5 q12h or 1.0 g q15h; 80 ≤ CLtot ≤120 ml/min, 0.5 q8h or1.0 g q12h; 120 ≤ CLtot ≤160 ml/min, 0.5 g q6h or1.0 g q8h (Hayakawa et al, 2006) Biapenan --Ultrafiltration rate: 1,000 ml/h Dialysate rate: 500 ml/h 300 mg q6h (Akashita et al, 2015) (Continued) (Eyler et al, 2014) Combined flow rate: 36-51 ml/h/kg 500 mg q24h, 750 mg q24h, 500 mg q12h, or 1,000 mg q24h (Eyler et al, 2014)…”

“…CRRT including CVVH (Isla et al, 2008;Bilgrami et al, 2010;Seyler et al, 2011;Beumier et al, 2014;Sime et al, 2018a;Onichimowski et al, 2020b), CVVHDF (Isla et al, 2008;Seyler et al, 2011;Beumier et al, 2014;Varghese et al, 2015), and CVVHD (Afshartous et al, 2014;Kawano et al, 2015;Shaw and Mueller, 2017;Nowak-Kozka et al, 2020;Onichimowski et al, 2020b) could eliminate meropenem. A wide range of meropenem dose regimens from 0.25g q24h to 2 g q8h have been shown to be effective and were recommended for CRRT with diverse effluent flow rates (Kawano et al, 2015;Grensemann et al, 2020). The variable dose regimens are closely related to the MICs of pathogens in order to achieve the different PK/PD goals (e.g., 40% T > MIC, 100% T > MIC).…”

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

“…Therefore, hepatic dysfunction may affect not only the metabolism of drugs but also their PB and V d , modifying antibiotic concentrations in the site of infection. These pharmacokinetic changes have been found in critically ill patients receiving meropenem, which required dosing modifications to reach target attainment [147].…”

Voriconazole Pharmacokinetics Are Not Altered in Critically Ill Patients with Acute-on-Chronic Liver Failure and Continuous Renal Replacement Therapy: An Observational Study

“…Voriconazole is extensively metabolized by cytochrome enzymes with 2% renal excretion of the unmetabolized drug [12]. Its volume of distribution (V) has been estimated at approximately 200 L [13,14], but V may increase as a result of capillary leak syndrome and ascites [15], necessitating higher doses. Contrarily, elimination may be decreased due to liver failure, thus requiring lower doses.…”