In pursuit of the triple crown: mechanism-based pharmacodynamic modelling for the optimization of three-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 fibre infection model (HFIM) coupled with mechanism-based modelling (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 three-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-hr prolonged infusion every 8 hr and RIF 600 mg every 24 hr resulted in bacterial counts below the quantitative limit within 24 hr 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. Discussion: An in vitroein 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.

Evaluation Strategies for Triple‐Drug Combinations against Carbapenemase‐Producing Klebsiella Pneumoniae in an In Vitro Hollow‐Fiber Infection Model

“…A recent HFIM study evaluated the use of a PMB single-dose ("burst") regimen of 5.53 mg/kg in combination with meropenem and rifampicin, which resulted in bacterial eradication of a KPC-2-producing strain. 40 Similar PD activity was observed against the BRKP76 isolate in our study but not against BAA2146 highlighting the need to evaluate similar dosing regimens in additional isolates. Differences in the PD outcome could be attributable to differences in the resistance mechanisms of the two isolates (i.e., KPC-2 vs. NDM-1).…”

“…PMB‐based triple‐drug combinations have previously been found to provide the flexibility needed to reduce the PMB footprint and consequently the likelihood of resistance emerging. A recent HFIM study evaluated the use of a PMB single‐dose (“burst”) regimen of 5.53 mg/kg in combination with meropenem and rifampicin, which resulted in bacterial eradication of a KPC‐2‐producing strain 40 . Similar PD activity was observed against the BRKP76 isolate in our study but not against BAA2146 highlighting the need to evaluate similar dosing regimens in additional isolates.…”

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

“…99 Therefore, MBMs have been developed that are able to describe and predict the full time-course of bacterial growth, killing, and resistance emergence in response to different antibiotic exposure profiles. [100][101][102][103][104][105] These MBMs have also quantified the impact of different renal function on bacterial killing and development of resistance for antibiotic monotherapies and combination treatments, 32,84,106,107 and have been able to predict optimized regimens. 106,108,109 In the future, these approaches are likely to enhance the ability to define optimal exposure targets and PK profile shapes.…”

“…Furthermore, traditional PK/PD targets are not well‐suited for combination therapy with two or more antibiotics 99 . Therefore, MBMs have been developed that are able to describe and predict the full time‐course of bacterial growth, killing, and resistance emergence in response to different antibiotic exposure profiles 100–105 . These MBMs have also quantified the impact of different renal function on bacterial killing and development of resistance for antibiotic monotherapies and combination treatments, 32,84,106,107 and have been able to predict optimized regimens 106,108,109 .…”

Escalating antimicrobial resistance among Enterobacteriaceae: focus on carbapenemases

“…patients with CPase-producing K. pneumoniae has been reported 194 . Combinations of 3-drugs [MERO, PMX, and rifampin (RIF)] have been evaluated in a hollow fiber infection model in the laboratory 195 . A single-dose of PMB, combined with prolonged infusion MERO 8 gm every 8 hours, and RIF 600 mg every 24 hours was associated with bacterial counts below the quantitative limit within 24 hours and remained undetectable throughout the 10-day experiment.…”