Optimization of β-Lactam/β-Lactamase Inhibitor Dosing

Infections caused by extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria are associated with increased mortality and cost of care. These pathogens are particularly challenging to treat due to their resistance to many antibiotics. Although β-lactam/β-lactamase inhibitors have proven in vitro activity against ESBL-producing pathogens, their use for ESBL infections remains controversial due to reports of treatment failure and a limited understanding of the pharmacokinetic/pharmacodynamics (PK/PD) governing these combinations. As a result, carbapenems have remained the preferred agents for treating infections due to ESBL-producing organisms. However, the heavy reliance on these carbapenems may have contributed to the rapid dissemination of carbapenemases that further limit treatment options. This has heightened the need to optimize the use of available antibiotics against these clinically-challenging pathogens. Thus, the goal of this project was to improve the rational basis for the dosing and pairing of β-lactams and β-lactamase inhibitors that would extend their usefulness against resistant organisms. We used a commercially available and widely used combination (piperacillin/tazobactam) to illustrate our approach. In our third chapter, we explored the prevalence and mechanism of resistance for extended-spectrum β-lactamases produced by Klebsiella pneumoniae isolated at a local tertiary care hospital. In so doing, we were able to focus our efforts on the most clinically-relevant β-lactamases to our geographic region. Using a collection of β-lactamase-producing clinical isolates, in our fourth chapter, we demonstrated a novel approach to susceptibility profiling for β-lactam/β-lactamase inhibitor combinations that could better inform dosing. Using a theoretical concept called the instantaneous MIC (MICi), we illustrated how susceptibility may be dependent on inhibitor concentrations and differed for each clinical isolate. In chapter 4, we also illustrated that the efficacy of combinations such as piperacillin/tazobactam was dependent on the concentration-response relationship between the β-lactamase producing isolate and the inhibitor (tazobactam). We showed that the current fixed dose ratio for piperacillin/tazobactam was inadequate against our test isolates, even when they tested susceptible by current susceptibility standards. Instead, escalated exposures of tazobactam were required to optimize dosing for certain clinical isolates. Finally, in chapter 5, we showed that for isolates that failed to respond to optimal piperacillin/tazobactam dosing, pairing piperacillin to an alternative inhibitor improved efficacy. The results from our studies have contributed to a better understanding of the PK/PD governing the joint effect of β-lactam/β-lactamase inhibitor combinations like piperacillin/tazobactam. Moreover, our results also highlighted additional considerations for the optimal pairing of β-lactams and β-lactamase inhibitors. Our findings should provide an improved scheme for the design and evaluation of these combinations for clinical use.