In Pursuit of the triple Crown: mechanism-based pharmacodynamic modeling for the optimization of 3-drug combinations against KPC-Producing Klebsiella pneumoniae.

Abstract Objectives Optimal combination therapy for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) is unknown. The present study sought to characterize the pharmacodynamics (PD) of polymyxin B (PMB), meropenem (MEM), and rifampin (RIF) alone and in combination using a hollow fiber infection model (HFIM) coupled with mechanism-based modeling (MBM). Methods A 10-day HFIM was utilized to simulate human pharmacokinetics (PK) of various PMB, MEM, and RIF dosing regimens against a clinical KPC-Kp isolate, with total and resistant subpopulations quantified to capture PD response. A MBM was developed to characterize bacterial subpopulations and synergy between agents. Simulations using the MBM and published population PK models were employed to forecast the bacterial time-course and the extent of its variability in infected patients for 3-drug regimens. Results In the HFIM, a PMB single-dose (‘burst’) regimen of 5.53 mg/kg combined with MEM 8 g using a 3-hour prolonged infusion every 8 h and RIF 600 mg every 24 h resulted in bacterial counts below the quantitative limit within 24 h and remained undetectable throughout the 10-day experiment. The final MBM consisted of two bacterial subpopulations of differing PMB and MEM joint susceptibility and the ability to form a non-replicating, tolerant subpopulation. Synergistic interactions between PMB, MEM, and RIF were well-quantified, with the MBM providing adequate capture of the observed data. Conclusions An in vitro-in silico approach answers questions related to PD optimization as well as overall feasibility of combination therapy against KPC-Kp, offering crucial insights in the absence of clinical trials.