This PACULit episode reviews a pharmacokinetic modeling and simulation study evaluating a cystatin C–guided dosing nomogram for cefepime in critically ill adults. By integrating cystatin C–based estimates with creatinine, the dosing strategy (eGFRcr-cys) aims to improve attainment of the pharmacodynamic target—free cefepime above the MIC for 100% of the dosing interval (fT>MIC)—over a 24-hour period compared with standard creatinine-based dosing. The study reports predicted 76% attainment at 24 hours versus 38% with actual dosing, a higher median predicted free AUC0-24, and a reduction in extreme AUC values from 20% to 7%, suggesting enhanced efficacy with potentially fewer toxic exposures. While Safety outcomes were not prospectively measured, the findings highlight reduced exposure variability and potential neurotoxicity risk mitigation. Limitations include reliance on predictions rather than clinical outcomes and lack of prospective validation. The episode discusses the rationale for cystatin C in critical illness, implications for dosing in patients with fluctuating renal function (including those on CRRT), practical considerations around assay availability and cost, and directions for future trials to confirm clinical benefits and feasibility of cystatin C–guided cefepime dosing.