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Background: Optimizing antibiotic dosages in critically ill patients is challenging. There are several equations to estimate the estimating renal clearance. The combined creatinine and cystatin C equation revealed significant discordance in dosing when compared with creatinine-based equations. Currently, there are no published studies on the impact of discordant antibiotic dosing rates on clinical outcomes in critically ill patients. Objective: This study evaluated the treatment and safety outcomes between groups with discordance and concordance regarding overall antibiotic dosing adjustments based on the Cockcroft-Gault (CG) and the CKD-EPI eGFRcr-cys 2021 in critically ill patients. We also compared adverse drug events (ADEs) between the discordance and concordance groups for each antibiotic agent. Methods: A retrospective observational study was conducted on adult patients in medical intensive care units who were administered antibiotics as part of the antimicrobial stewardship program. Cystatin C and creatinine levels were measured on the same day. Differences in treatment outcomes and ADEs between the concordance and discordance groups were assessed using Pearson’s chi-squared and Mann–Whitney U tests. Results: A total of 171 patients with serum cystatin C were included. The mean ± standard deviation (SD) age and BMI were 67.23 ± 17.45 years and 22.71 ± 4.58 kg/m2. Meropenem was the most frequent antibiotic agent use (75.44%). Thirty-five patients (20.47%) were categorized into the concordance group, while one hundred and thirty-six patients (79.53%) were placed in the discordance group. There were no statistically significant differences between the concordance group and discordance group for treatment outcomes. In the discordance group, there was a significantly higher incidence of acute kidney injury (AKI) compared to the concordance group, with rates of 56.76% versus 22.22% (p = 0.009). Additionally, the discordance group also experienced a significantly higher rate of AKI with colistin, at 77.78% compared to 41.67% in the concordance group (p = 0.012). The highest discordance drug was piperacillin/tazobactam (55.26%), followed by aminoglycosides (50.00%) and vancomycin (49.02%). Conclusions: Our study showed that using a cystatin C-based equation may help prevent AKI without negatively impacting clinical outcomes. Future clinical research is required with large populations.