| Summary: | 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 <i>Enterobacteriaceae</i> and <i>Pseudomonas aeruginosa</i>. For ceftazidime/avibactam, 2000 mg/500 mg/8 h by 4 h infusion achieved >90% CFR for <i>Escherichia coli</i>; even for 4000 mg/1000 mg/6 h by continuous infusion, CFR for <i>Klebsiella pneumoniae</i> 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 <i>Pseudomonas aeruginosa</i>. For ceftolozane/tazobactam, the CFR of standard regimen was >90% for <i>Escherichia coli</i>, however, 2000 mg/1000 mg/6 h by continuous infusion achieved <90% CFRs for <i>Klebsiella pneumoniae</i> and <i>Pseudomonas aeruginosa</i>. For meropenem/vaborbactam, standard regimen achieved optimal attainments for <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i>; 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 <i>Pseudomonas aeruginosa</i>. The CFRs of three BLBLIs were similar for <i>Escherichia coli</i>, but meropenem/vaborbactam were superior for <i>Klebsiella pneumoniae</i> and <i>Pseudomonas aeruginosa</i>.
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