The authors report on a case of a 59-year-old man hospitalized in the intensive care unit (ICU) because of severe SARS-COV-2 infection (COVID-19). Background: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 h. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of > 60 mg/L. Methods: Analysis of pharmacokinetic (PK) data and model-based dose adjustment was performed using BestDose software. Results: The patient had unexpected PK parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration (MIC) was also considered in the dosing decisions. After dose reduction to 0.5 g/8 h, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. Conclusion: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in ICU patients.