Ceftriaxone dosing based on the predicted probability of augmented renal clearance in critically ill patients with pneumonia

Abstract

Objectives PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (PARC,d+1; www.arcpredictor.com). Patients and methods Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (±7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n = 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and PARC,d+1 determined on the previous day. A high PARC,d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal PARC,d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% PARC,d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions Critically ill patients with CAP with a high PARC,d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

“…There are some directions for future research on dose optimisation of beta-lactam antibiotics in the critically ill. Dreesen and colleagues recently described a simulation that target attainment could be improved by doubling daily doses of ceftriaxone for patients with a prior increased risk of augmented renal clearance [32]. They showed that a machine learning approach could aid in dose optimisation.…”

Dosing Regimen for Cefotaxime Should Be Adapted to the Stage of Renal Dysfunction in Critically Ill Adult Patients—A Retrospective Study

“…Drug excretion is increased in these patients, especially for hydrophilic antibiotics that are mainly excreted via the kidneys, such as beta-lactams. ARC has already been described as a risk factor of beta-lactam underdosing [14]. Without an initial dose adjustment to renal function, appropriate antibiotic therapy is delayed.…”

Covariates in population pharmacokinetic studies of critically ill adults receiving β-lactam antimicrobials: a systematic review and narrative synthesis

“…Interestingly, presumed or established ARC, defined as either estimated CL CR (using the Cockcroft–Gault formula) > 130 mL/min or glomerular filtration rate (estimated using the CKD-EPI equation) > 96.5 mL/min/1.73 m 2 , 54 although associated with suboptimal drug exposure, was reported in only five studies, 32 , 55–58 and investigated as a covariate in two. 57 , 59 One of these studies, looking at critically ill patients with pneumonia and preserved renal function, found the inclusion of ARC to improve model fit. This remains an under-investigated covariate.…”