The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome

Objectives: Beta-lactam antibiotics are often subject to therapeutic drug monitoring, but breakpoints of target attainment are mostly based on expert opinions. Studies that show a correlation between target attainment and infection resolution are missing. This analysis investigated whether there is a difference in infection resolution based on two breakpoints of target attainment.

Methods: An outcome group out of 1392 critically ill patients treated with meropenem or piperacillin-tazobactam was formed due to different selection criteria. Afterwards, three groups were created: group 1=free drug concentration (f) was < 100% of the time (T) above the minimal inhibitory concentration (MIC) (< 100% fT > _MIC), group 2=100% fT > _MIC < _4xMIC, and group 3=100% fT > _4xMIC. Parameters for infection control, renal and liver function, and estimated and observed in-hospital mortality were compared between those groups. Statistical analysis was performed with one-way analysis of variance, Tukey post hoc test, U test, and bivariate logistic regression.

Results: The outcome group consisted of 55 patients (groups 1-3, 17, 24, and 14 patients, respectively). Patients allocated to group 2 or 3 had a significantly faster reduction of the C-reactive protein in contrast to patients allocated to group 1 (p = 0.033 and p = 0.026). Patients allocated to group 3 had a worse renal function, a higher Acute Physiology and Chronic Health Evaluation (APACHE II) score, were older, and had a significantly higher in-hospital mortality compared to group 1 (p = 0.017) and group 2 (p = 0.001). The higher mortality was significantly influenced by worse liver function, higher APACHE II, and higher Sequential Organ Failure Assessment (SOFA) score and norepinephrine therapy.

Conclusion: Achieving the target 100% fT > _MIC leads to faster infection resolution in the critically ill. However, there was no benefit for patients who reached the highest target of 100% fT > _4xMIC, although the mortality rate was higher possibly due to confounding effects. In conclusion, we recommend the target 100% fT > _MIC < _4xMIC for critically ill patients.

Trial registration: NCT03985605.