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Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT(>MIC)) and the time free concentration remained above four multiples of the MIC (fT(>4×MIC)) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients’ demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT(>MIC) was 100% (27%–100%) and fT(>4×MIC) was 64% (0%–100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.