Enhancing the Time-to-Positivity Paradigm for Guidance of Antimicrobial Therapy: A Model-Based Approach

Time to positivity (TTP) is a diagnostic parameter in clinical microbiology that measures the duration required for a blood culture to indicate microbial growth. While TTP is intended to support clinical decisions, its current use is largely empirical. If used at all, TTP is always prior to therapy and informs clinicians of infection severity. Clinicians could then react by adjusting clinical management (e.g., through more frequent monitoring, transfer to intensive care unit (ICU), broader spectrum antibiotics, or highest FDA-approved doses). This practice limits both the effectiveness of TTP and its clinical adoption. To address these limitations, we introduce an enhanced TTP approach that systematically informs antimicrobial therapy design. Our method integrates (a) modified operation of standard TTP instrumentation and (b) novel mathematical modeling that uses TTP data for systematic guidance of antimicrobial therapy involving one or more antimicrobial agents. We evaluate this approach through in vitro studies using ceftazidime/avibactam against Acinetobacter baumannii and cefiderocol/avibactam against Pseudomonas aeruginosa. In both cases, therapeutic outcomes predicted by our model-based analysis of enhanced TTP data were consistent with experimental results in a hollow fiber infection model. To our knowledge, this represents the first enhancement of the TTP assay. With further development, enhanced TTP could become a powerful tool for optimizing antimicrobial therapy in clinical settings.