Background: A novel fixed combination of aztreonam (ATM) and avibactam (AVI) offers promising potential to treat infections with carbapenem-resistant Enterobacterales (CRE) producing metallo-β-lactamases (MBL). This study aimed to assess the accuracy of population pharmacokinetic (PK) models for ATM-AVI in predicting in vivo concentrations in a critically ill patient with CRE infection during its first clinical use. Methods: A 70-year-old male with septic shock due to hospital-acquired pneumonia (HAP) caused by MBL-producing Klebsiella pneumoniae was treated with ATM-AVI. Trough and peak serum concentrations (32 samples over 7 days) were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Population PK models were used to simulate complete concentration–time profiles. Bland–Altman analysis assessed model performance by comparing predicted and measured concentrations. Results: Median ATM trough concentrations (18.4 mg/L) remained above the minimum inhibitory concentration (MIC) of 1 mg/L for the pathogen. The Bland–Altman analysis demonstrated reasonable agreement between predicted and observed concentrations, with a relative bias (rBias) of −50.5% for ATM and −14.4% for AVI. ATM-AVI ratios remained stable. Clinical improvement and sterile blood cultures within 12 days led to intensive care unit (ICU) discharge. Conclusions: Population PK models for ATM-AVI accurately predicted in vivo concentrations in a severely ill patient with HAP. Therapeutic drug monitoring (TDM) with PK modeling ensured optimal antimicrobial exposure and contributed to clinical recovery.
