Tailoring meropenem treatment for critically ill patients with hospital-acquired or ventilator associated pneumonia: a personalized PK/PD approach

Critically ill patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) pose a formidable challenge in clinical management due to the profound alterations in their pharmacokinetics (PK). Meropenem is a treatment option for HAP/VAP and its efficacy target is its concentration (Css) to minimum inhibitory concentration (MIC) ratio (Css/MIC) of 4-8. This thesis aims to investigate strategies for optimizing meropenem PK and PD in critically ill patients with HAP/VAP. To enhance meropenem PK optimization in critically ill patients, I evaluated the performance of various methods for estimating renal function, which is crucial for dosing adjustments. These methods included the measurement of creatinine clearance (mCLCR) and its estimation using empiric equations. For PD optimization of meropenem in patients with HAP/VAP, I developed a PK/PD model to quantify the relationships between meropenem concentrations and changes in C-reactive protein (C-RP), an inflammation biomarker. Then, I simulated C-RP fate for different Css/MIC scenarios. In the first project, results showed that dose adjustments of meropenem should be based on mCLCR. The use of equations for GFR estimation may result in significant under- or overestimation of meropenem dosages. In the second project, I successfully built a PK/PD model. Simulations demonstrated that higher Css/MIC ratios were associated with greater and faster reductions in C-RP from baseline. This research endeavors to personalize the treatment of critically ill patients with HAP/VAP treated with meropenem. It is essential to optimize both PK and PD aspects of therapy. The measurement of creatinine clearance (mCLCR) is essential, and empirical estimation formulas should not be relied upon. Regarding the PD, C-RP serves as a biomarker reflecting meropenem’s efficacy and can be used in clinical practice to assess whether the PK/PD efficacy target has been achieved.