Activity of a novel aminoglycoside, ACHN-490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City

110

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.

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

See 1 more Smart Citation

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

Walkty

Adam

Baxter

et al. 2014

110

“…On day 5, a full PK time course was obtained which included the following time points: predose and 10, 15, 20, 30, 45, and 60 min and 1.5, 2, 2.5, 3,4,6,8,12,16, and 24 h after the start of the IV infusion.…”

Section: Ethicsmentioning

confidence: 99%

Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects

Cass¹,

Brooks²,

Havrilla³

et al. 2011

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects

“…Plazomicin, a derivative of sisomicin, is a next-generation aminoglycoside that is in clinical development for the treatment of serious infections due to carbapenem-resistant Enterobacteriaceae. It has broad-spectrum in vitro activity against Klebsiella pneumoniae and other Gram-negative bacteria, including carbapenem-resistant strains (8)(9)(10)(11)(12). The agent has side-chain substituents that shield it from the action of most AMEs.…”

mentioning

confidence: 99%

Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

Almaghrabi

Clancy

Doi

et al. 2014

104

eWe measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5 ompK36 genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6=)-Ib (98%), APH(3=)-Ia (56%), AAC(3)-IV (38%), and ANT(2؆)-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 g/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r ‫؍‬ 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1؋ MIC) and 94% (4؋ MIC) of strains. All strains with AAC(6=)-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6=)-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6=)-Ib alone (P ‫؍‬ 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P ‫؍‬ 0.0006, P < 0.0001, and P ‫؍‬ 0.01, respectively). The combination of AAC(6=)-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3=)-Ia were each associated with gentamicin resistance (P ‫؍‬ 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistant K. pneumoniae strains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistant K. pneumoniae strains should be a research priority.