Activity of plazomicin in combination with other antibiotics against multidrug-resistant Enterobacteriaceae

Abstract

Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Plazomicin is active against multi-drug resistant (MDR) Enterobacteriaceae, where combination therapy is often used to treat infections caused by these pathogens. To determine synergy with other antibiotics, plazomicin was combined with antibiotics in checkerboard assays against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides and β-lactams; 10 Escherichia coli isolates, 8 Klebsiella spp. isolates, 10 Enterobacter spp. isolates, and 2 Citrobacter freundii isolates were evaluated. Plazomicin had potent activity against MDR Enterobacteriaceae, including aminoglycoside-resistant strains, with MIC ranges of 0.5 – 2 μg/mL against E. coli isolates, 0.12 – 8 μg/mL against Klebsiella spp. isolates, 0.25 – 2 μg/mL against Enterobacter spp. isolates, and 0.06 – 0.25 μg/mL against C. freundii isolates. Synergy between plazomicin and piperacillin/tazobactam or ceftazidime was observed by checkerboard studies and confirmed by time-kill assays. No combination showed antagonism. These studies indicate that plazomicin has potential as a monotherapy and as combination therapy for treating serious Gram-negative infections caused by MDR Enterobacteriaceae.