An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam

Plain Language Summary Carbapenem-resistant gram-negative pathogens, specifically, Enterobacteriaceae, remain an urgent public health threat, and safe, effective treatment options are limited. The antibiotic agents meropenem and vaborbactam were selected to be combined to leverage their individual properties for efficacy against carbapenem-resistant gram-negative pathogens, the most prevalent being Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are associated with high morbidity and mortality and excess healthcare costs and have traditionally required treatment with low-efficacy, high-toxicity antimicrobials such as the polymyxins. The authors present a review of the pre-clinical, clinical, pharmacokinetic (PK), and pharmacodynamic (PD) data on meropenem-vaborbactam, and data on difficult to treat organisms, and on special patient populations obtained post-marketing. Pre-clinical in vitro and in vivo PK/PD data support this optimized combination of these agents with meropenem-vaborbactam demonstrating low MIC50/MIC90 values against KPC-producing Enterobacteriaceae. Phase 1 PK trials confirmed the PK parameters, including in subjects with renal impairment and in target extravascular body sites such as the pulmonary epithelial lining fluid. In vitro, the combination of meropenem-vaborbactam has shown potent activity against resistant gram-negative pathogens; importantly, this includes KPC-producing Klebsiella pneumoniae. The approved optimized dosing regimen [4 g every 8 h (Q8h) as a 3-h infusion] achieves the PK/PD targets to achieve both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. Phase 3 trials showed the clinical success of meropenem-vaborbactam in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections.