Background

The ACUTE project proposes to develop time-to positivity (Tpos) - a commonly reported index from continuously monitored bloodculture systems used in clinical microbiology laboratories- as a surrogate pharmacodynamic marker for monitoring antibiotic therapy of multidrug resistant (MDR) gram-negative bacteria.

The project will generate fundamental knowledge of how Tpos correlates with established pharmacodynamic indices for antibiotics (e.g., AUC/MIC, %T_>MIC). Proof of principle experiments will be conducted with ceftazidime-avibactam monotherapy, and combination antibiotic regimens, that are tested both in vitro, and then in sera from patients undergoing treatment for KPC-carbapenemase producing Klebsiella pneumoniae (KPC-Kp).

The objectives of this project will be accomplished through two specific aims.

• The first specific aim will establish the quantitative relationship between Tpos and representative KPC-Kp strains in the absence and presence of clinically-relevant antibiotic exposures.
• The second specific aim will measure Tpos using sera from 20 critically-ill patients receiving ceftazidime-avibactam treatment for KPC-KP bloodstream infections using “indicator” strains or the patient’s own isolate. Tpos results will be correlated with blood concentration-time courses of ceftazidime and avibactam and PK/PD target attainment (free drug T>MIC ) simulated for each patient using Bayesian estimates of individual PK parameters from population pharmacokinetic models and LC/MS/MS analysis of ceftazidime-avibactam drug concentrations in serum.

This study will form the basis for the broader development and validation of Tpos as a surrogate pharmacodynamic (PD) biomarker for monitoring antimicrobial activity of antibiotic monotherapy and combination therapy for Gram-negative infections.