Background and Objective <p>This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose amikacin.</p> Methods <p>Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM^® 7.5.1. The probability of target attainment and the cumulative fraction of response for the local <i>Klebsiella pneumoniae</i> population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target<i>.</i> Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L.</p> Results <p>A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment &gt; 90% for minimum inhibitory concentrations &lt; 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for <i>K. pneumoniae</i>, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance &lt; 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively.</p> Conclusions <p>Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible <i>K. pneumoniae</i>.</p>