Pharmacokinetic/Pharmacodynamic Adequacy of Novel β-Lactam/β-Lactamase Inhibitors against Gram-Negative Bacterial in Critically Ill Patients

Abstract

The optimal regimens of novel β-lactam/β-lactamase inhibitors (BLBLIs), ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/vaborbactam, are not well defined in critically ill patients. This study was conducted to identify optimal regimens of BLBLIs in these patients. A Monte Carlo simulation was performed using the published data to calculate the joint probability of target attainment (PTA) and the cumulative fraction of response (CFR). For the target of β-lactam of 100% time with free drug concentration remains above minimal inhibitory concentrations, the PTAs of BLBLIs standard regimens were <90% at a clinical breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa. For ceftazidime/avibactam, 2000 mg/500 mg/8 h by 4 h infusion achieved >90% CFR for Escherichia coli; even for 4000 mg/1000 mg/6 h by continuous infusion, CFR for Klebsiella pneumoniae was <90%; the CFRs of 3500 mg/875 mg/6 h by 4 h infusion and 4000 mg/1000 mg/8 h by continuous infusion were appropriate for Pseudomonas aeruginosa. For ceftolozane/tazobactam, the CFR of standard regimen was >90% for Escherichia coli, however, 2000 mg/1000 mg/6 h by continuous infusion achieved <90% CFRs for Klebsiella pneumoniae and Pseudomonas aeruginosa. For meropenem/vaborbactam, standard regimen achieved optimal attainments for Escherichia coli and Klebsiella pneumoniae; 2000 mg/2000 mg/6 h by 5 h infusion, 2500 mg /2500 mg/6 h by 4 h infusion, 3000 mg/3000 mg/6 h by 3 h infusion and 4000 mg/4000 mg/8 h by 5 h infusion achieved >90% CFRs for Pseudomonas aeruginosa. The CFRs of three BLBLIs were similar for Escherichia coli, but meropenem/vaborbactam were superior for Klebsiella pneumoniae and Pseudomonas aeruginosa.

Pharmacokinetics, Pharmacodynamics, and Dosing Considerations of Novel β-Lactams and β-Lactam/β-Lactamase Inhibitors in Critically Ill Adult Patients: Focus on Obesity, Augmented Renal Clearance, Renal Replacement Therapies, and Extracorporeal Membrane Oxygenation

“…Despite growing use in critically ill patients, limited evidence exists describing such variabilities for NBLA. Recently, the adequacy of the current monograph-recommended dosing of three different NBLA in ICU patients was investigated using Monte Carlo simulation [ 13 ]. While standard dosing resulted in adequate attainment of a PD index of 40–60% of free drug concentration above MIC (%ƒT > MIC) for CAZ/AVI, C/T, and MEV, such dosing did not attain more aggressive targets (i.e., 100%ƒT > 1–4 × MIC).…”

Rationale and evidence for the use of new beta-lactam/beta-lactamase inhibitor combinations and cefiderocol in critically ill patients

“…Higher-dose regimen appear also needed in this situation (Fig. 1 ) [ 149 , 151 , 157 ]. Of note, cefiderocol is the only new β-lactam for which high-dose schemes were used in patients with ARC in pivotal randomized studies—further data are needed for new BL/BLI combinations in this population.…”

Satisfactory In Vitro Activity of Ceftolozane–Tazobactam against Carbapenem-Resistant Pseudomonas aeruginosa But Not against Klebsiella pneumoniae Isolates

“…The increasing emergence of multi-drug-resistant P. aeruginosa and K. pneumoniae strains limits the treatment options, which increases the morbidity and mortality of patients [ 7 ]. This situation enforces the search and more frequent application of new drugs such as ceftolozane–tazobactam, new drug combinations, or new applications of commonly known antimicrobials [ 3 , 7 , 8 , 9 , 10 , 11 , 12 ].…”