In Vitro Activity of Plazomicin against 5,015 Gram-Negative and Gram-Positive Clinical Isolates Obtained from Patients in Canadian Hospitals as Part of the CANWARD Study, 2011-2012

Abstract

Plazomicin is a next-generation aminoglycoside that is not affected by most clinically relevant aminoglycoside-modifying enzymes. The in vitro activities of plazomicin and comparator antimicrobials were evaluated against a collection of 5,015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with MICs interpreted according to CLSI breakpoints, when available. Plazomicin demonstrated potent in vitro activity against members of the family Enterobacteriaceae, with all species except Proteus mirabilis having an MIC 90 of <1 g/ml. Plazomicin was active against aminoglycoside-nonsusceptible Escherichia coli, with MIC 50 and MIC 90 values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum ␤-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of the isolates inhibited by an MIC of <1 g/ml. The MIC 50 and MIC 90 values for plazomicin against Pseudomonas aeruginosa were 4 g/ml and 16 g/ml, respectively, compared with 4 g/ml and 8 g/ml, respectively, for amikacin. Plazomicin had an MIC 50 of 8 g/ml and an MIC 90 of 32 g/ml versus 64 multidrug-resistant P. aeruginosa isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having MIC 50 and MIC 90 values of 0.5 g/ml and 1 g/ml, respectively. In summary, plazomicin demonstrated potent in vitro activity against a diverse collection of Gram-negative bacilli and Gram-positive cocci obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.

Plazomicin Activity against 346 Extended-Spectrum-β-Lactamase/AmpC-Producing Escherichia coli Urinary Isolates in Relation to Aminoglycoside-Modifying Enzymes

“…No significant differences were found between agar dilution MICs and microdilution MICs (MIC 50 , 0.5 mg/liter; MIC 90 , 1 mg/liter; MIC range, 0.125 to 4 mg/liter). Our findings are consistent with previous studies that showed plazomicin to be highly active against MDR clinical isolates of Enterobacteriaceae, including ESBL-producing E. coli isolates (15,16).…”

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…Similarly, the broad-spectrum agent eravacycline (a new fluorocycline) also lacks activity against A. baumannii, B. cenocepacia, and P. aeruginosa (949,952). Plazomicin is a new aminoglycoside derivative of sisomicin with significant activity against a range of Gram-positive and Gram-negative bacteria (including multidrug-resistant isolates) (953,954). However, its activity is adversely affected by increased efflux in A. baumannii and P. aeruginosa (955).…”

Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens

“…Natural product β-lactams, macrolides, tetracyclines, aminoglycosides, and glycopeptides have all been the subject of derivatization leading to newer generations of antibiotics. Steady progress in the clinical development of the aminoglycoside plazomicin, 6 the tetracycline eravacycline, 7 and the cephalosporin ceftolozane 8 for the treatment of Gram-negative infections is a recent reminder that chemical modification of established classes of natural products is still a viable route for drug discovery.…”