Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 2014 May;58(5):2554–2563. doi: 10.1128/AAC.02744-13

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

A Walkty a,b,c,, H Adam b,c, M Baxter c, A Denisuik c, P Lagacé-Wiens b,c, J A Karlowsky b,c, D J Hoban b,c, G G Zhanel a,c
PMCID: PMC3993217  PMID: 24550325

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 MIC90 of ≤1 μg/ml. Plazomicin was active against aminoglycoside-nonsusceptible Escherichia coli, with MIC50 and MIC90 values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum β-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of the isolates inhibited by an MIC of ≤1 μg/ml. The MIC50 and MIC90 values for plazomicin against Pseudomonas aeruginosa were 4 μg/ml and 16 μg/ml, respectively, compared with 4 μg/ml and 8 μg/ml, respectively, for amikacin. Plazomicin had an MIC50 of 8 μg/ml and an MIC90 of 32 μg/ml versus 64 multidrug-resistant P. aeruginosa isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having MIC50 and MIC90 values of 0.5 μg/ml and 1 μg/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.

INTRODUCTION

Multidrug-resistant (MDR) Gram-negative bacilli are being encountered in the clinical setting with increased frequency (14). Common examples include extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, carbapenemase-producing Enterobacteriaceae, and MDR Pseudomonas aeruginosa. These organisms are capable of causing serious infections, including bacteremia, pneumonia, and urinary tract infections (14). Furthermore, some publications have demonstrated an association between infection with MDR Gram-negative bacilli and adverse clinical outcomes, including increased mortality (59). The treatment of infections caused by these pathogens is challenging for clinicians, as often there are few viable therapeutic options. The Infectious Diseases Society of America (IDSA) recognizes the need for new antimicrobial agents with activity against Gram-negative bacilli (10). Their “10 × '20 Initiative” calls for the development and regulatory approval of 10 novel, efficacious, and safe antimicrobial agents by the year 2020 (10).

The aminoglycosides are among the oldest classes of antibiotics. They were originally introduced for therapeutic use in 1944 (11). Aminoglycosides demonstrate a broad spectrum of activity against bacteria, including members of the family Enterobacteriaceae, P. aeruginosa, and Staphylococcus spp. (11). However, the therapeutic use of aminoglycosides in recent years has been limited by concerns of toxicity (nephrotoxicity and ototoxicity) and increasing antimicrobial resistance (11). Resistance to aminoglycosides may be mediated by the production of aminoglycoside-modifying enzymes (AMEs), efflux, reduced permeability into the bacterial cell, and target site alteration by ribosomal methylases (1113). Of these mechanisms, aminoglycoside-modifying enzymes provide the greatest contribution to resistance in clinical isolates (11, 14). The 3 major groups of AMEs are acetyltransferases, nucleotidyltransferases, and phosphotransferases (11). MDR Gram-negative bacilli are often resistant to aminoglycosides due to the effects of these enzymes (1, 15).

Plazomicin (formerly ACHN-490) is a next-generation aminoglycoside that was synthetically derived from sisomicin (13, 16). Unlike other aminoglycosides in clinical use, the in vitro activity of plazomicin does not appear to be compromised by most clinically relevant AMEs (13, 16, 17). This suggests that plazomicin may be of use in the treatment of infections caused by MDR Gram-negative bacilli. The purpose of this study was to evaluate the in vitro activity of plazomicin against a large collection of Gram-negative and Gram-positive clinical isolates obtained as a part of the Canadian Ward Surveillance study (CANWARD). CANWARD is an ongoing national surveillance study designed to assess the prevalence of antimicrobial resistance among bacterial isolates recovered from patients admitted to or evaluated at Canadian hospitals.

(This paper was presented in part at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], San Francisco, CA, 9 to 12 September 2012.)

MATERIALS AND METHODS

Bacterial isolates.

Twelve (2011) to 15 (2012) tertiary care medical centers representing 8 of the 10 Canadian provinces submitted pathogens from patients attending hospital clinics, emergency rooms, medical and surgical wards, and intensive care units (CANWARD). The sites were geographically distributed in a population-based fashion. From January 2011 through October 2012, inclusive, each study site was asked to submit clinical isolates (consecutive, one per patient per infection site) from inpatients and outpatients with bloodstream (n = 100), respiratory (n = 100), urine (n = 25), and wound/intravenous (i.v.) (n = 25) infections. The medical centers submitted clinically significant isolates, as defined by their local site criteria. Isolate identification was performed by the submitting site and confirmed at the reference site as required (i.e., when morphological characteristics and antimicrobial susceptibility patterns did not fit the reported identification). The isolates were shipped on Amies semisolid transport medium to the coordinating laboratory (Health Sciences Centre, Winnipeg, Manitoba, Canada), subcultured onto the appropriate medium, and stocked in skim milk at −80°C until MIC testing was carried out.

In total, 6,593 isolates were collected over the 2 years of the study. The demographic distribution of these isolates, by specimen source, was 43.5% from blood, 36.8% from respiratory, 10.2% from urine, 9.5% from wound, and by patient location was 28.8% from a medical ward, 23.9% from an emergency room, 22.7% from an intensive care unit, 17.1% from a hospital clinic, and 7.5% from a surgical ward. Only species for which ≥30 isolates were tested against plazomicin were included in the analysis (with the exception of ESBL-producing Klebsiella pneumoniae).

Antimicrobial susceptibility testing.

Following two subcultures from frozen stock, the in vitro activities of plazomicin and clinically relevant comparator antimicrobials were determined by broth microdilution in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines (18, 19). The antimicrobial agents used in this study were obtained as laboratory-grade powders from their respective manufacturers. Plazomicin was obtained from Achaogen (San Francisco, CA). Antimicrobial MIC interpretive standards were defined according to CLSI breakpoints (18). Tigecycline MICs were interpreted using Food and Drug Administration (FDA)-defined breakpoints. At present, no breakpoints have been set for plazomicin.

ESBL-producing E. coli and K. pneumoniae.

Screening for ESBL production among Escherichia coli and K. pneumoniae clinical isolates was performed as described by CLSI (18). Phenotypic confirmatory testing was done by the disk diffusion method according to CLSI guidelines, using disks containing ceftazidime (30 μg), ceftazidime-clavulanate (30 μg and 10 μg), cefotaxime (30 μg), and cefotaxime-clavulanate (30 μg and 10 μg) (18).

Methicillin-resistant S. aureus confirmation.

All methicillin-resistant Staphylococcus aureus (MRSA) isolates were phenotypically confirmed using the cefoxitin disk test, as described by CLSI in the document M100-S23 (18). PCR amplification of the mecA gene was also performed.

MDR P. aeruginosa.

MDR P. aeruginosa isolates were defined as isolates demonstrating nonsusceptibility to at least one antimicrobial from three or more different classes. For the purpose of this report, the five antimicrobial classes considered were aminoglycosides (amikacin, gentamicin, and tobramycin), fluoroquinolones (ciprofloxacin), antipseudomonal cephalosporins (ceftazidime), antipseudomonal penicillins (piperacillin-tazobactam), and antipseudomonal carbapenems (meropenem).

RESULTS

Plazomicin was evaluated against 5,015 clinical isolates, including 2,773 Gram-negative bacilli and 2,242 Gram-positive cocci. The in vitro activities of plazomicin and comparator antimicrobials against commonly encountered Gram-negative bacilli are presented in Table 1. The MIC90 of plazomicin versus E. coli was 4 times lower than that of tobramycin and amikacin and 16 times lower than that of gentamicin. The in vitro activity of plazomicin versus E. coli did not differ for aminoglycoside-susceptible and aminoglycoside-nonsusceptible isolates. The plazomicin MIC50 and MIC90 values were 0.5 μg/ml and 1 μg/ml, respectively, for gentamicin-susceptible and gentamicin-nonsusceptible E. coli (Table 2). Identical MIC50 and MIC90 values were also obtained for plazomicin versus E. coli isolates that were susceptible and nonsusceptible to tobramycin (Table 2). Plazomicin was equally active against ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae isolates (Table 3). More than 90% of the E. coli and K. pneumoniae isolates were inhibited in vitro by ≤1 μg/ml of plazomicin, irrespective of whether they produced an ESBL enzyme. Plazomicin demonstrated potent in vitro activity versus other members of the family Enterobacteriaceae (Table 1), with all species except Proteus mirabilis having an MIC90 value of ≤1 μg/ml. In general, the in vitro activity of plazomicin was comparable to that of conventional aminoglycosides versus Enterobacteriaceae other than E. coli. However, it should be noted that for most species evaluated here, relatively few isolates demonstrating resistance to conventional aminoglycosides were included.

TABLE 1.

In vitro activities of plazomicin and comparators against Gram-negative organisms

Organism (n) and antibiotic MIC (μg/ml)
% of isolates that are:
50% 90% Range Susceptible Intermediate Resistant
Escherichia coli (1,146)
    Plazomicin 0.5 1 ≤0.12–4 NDa ND ND
    Amikacin 2 4 ≤1–32 99.7 0.3 0.0
    Gentamicin ≤0.5 16 ≤0.5 to >32 89.0 0.5 10.5
    Tobramycin ≤0.5 4 ≤0.5 to >64 90.4 4.8 4.8
    Cefazolin 2 64 ≤0.5 to >128 71.6 9.9 18.5
    Ceftazidime ≤0.25 2 ≤0.25 to >32 92.9 0.8 6.3
    Ceftriaxone ≤0.25 0.5 ≤0.25 to >64 90.7 0.3 9.0
    Ciprofloxacin ≤0.06 >16 ≤0.06 to >16 73.5 0.2 26.4
    Ertapenem ≤0.03 0.06 ≤0.03–8 99.8 0.0 0.2
    Meropenem ≤0.03 ≤0.03 ≤0.03–1 100.0 0.0 0.0
    Piperacillin-tazobactam ≤1 4 ≤1 to >512 97.7 0.6 1.7
    Tigecycline 0.25 0.5 0.12–2 100.0 0.0 0.0
    Trimethoprim-sulfamethoxazole ≤0.12 >8 ≤0.12 to >8 71.1 ND 28.3
Klebsiella pneumoniae (395)
    Plazomicin 0.25 0.5 ≤0.12 to >64 ND ND ND
    Amikacin ≤1 ≤1 ≤1 to >64 99.7 0.0 0.3
    Gentamicin ≤0.5 ≤0.5 ≤0.5 to >32 98.2 0.0 1.8
    Tobramycin ≤0.5 ≤0.5 ≤0.5 to >64 98.2 0.8 1.0
    Cefazolin 1 4 ≤0.5 to >128 88.6 3.8 7.6
    Ceftazidime ≤0.25 0.5 ≤0.25 to >32 96.5 0.0 3.5
    Ceftriaxone ≤0.25 ≤0.25 ≤0.25 to >64 95.2 1.0 3.8
    Ciprofloxacin ≤0.06 0.25 ≤0.06 to >16 94.7 0.8 4.6
    Ertapenem ≤0.03 0.06 ≤0.03–16 99.0 0.8 0.3
    Meropenem ≤0.03 0.06 ≤0.03–8 99.7 0.0 0.3
    Piperacillin-tazobactam 2 4 ≤1 to >512 97.7 0.8 1.5
    Tigecycline 0.5 1 0.06–8 96.4 3.0 0.5
    Trimethoprim-sulfamethoxazole ≤0.12 2 ≤0.12 to >8 91.6 ND 8.4
Enterobacter cloacae (173)
    Plazomicin 0.25 0.5 ≤0.12–2 ND ND ND
    Amikacin ≤1 2 ≤1–16 100.0 0.0 0.0
    Gentamicin ≤0.5 ≤0.5 ≤0.5 to >32 95.4 0.0 4.6
    Tobramycin ≤0.5 1 ≤0.5–64 95.4 2.9 1.7
    Cefazolin >128 >128 2 to >128 1.7 1.7 96.5
    Ceftazidime 0.5 >32 ≤0.25 to >32 72.3 0.6 27.2
    Ceftriaxone ≤0.25 >64 ≤0.25 to >64 69.4 1.7 28.9
    Ciprofloxacin ≤0.06 0.25 ≤0.06 to >16 93.1 1.7 5.2
    Ertapenem 0.06 1 ≤0.03–32 86.1 6.9 6.9
    Meropenem ≤0.03 0.12 ≤0.03–2 98.8 1.2 0.0
    Piperacillin-tazobactam 2 128 ≤1–256 82.1 6.9 11.0
    Tigecycline 0.5 1 0.25–8 96.5 1.7 1.7
    Trimethoprim-sulfamethoxazole ≤0.12 4 ≤0.12 to >8 89.0 ND 11.0
Klebsiella oxytoca (113)
    Plazomicin 0.25 0.5 ≤0.12–1 ND ND ND
    Amikacin ≤1 2 ≤1–4 100.0 0.0 0.0
    Gentamicin ≤0.5 ≤0.5 ≤0.5–1 100.0 0.0 0.0
    Tobramycin ≤0.5 ≤0.5 ≤0.5–2 100.0 0.0 0.0
    Cefazolin 4 >128 1 to >128 29.2 28.3 42.5
    Ceftazidime ≤0.25 0.5 ≤0.25 to >32 99.1 0.0 0.9
    Ceftriaxone ≤0.25 0.5 ≤0.25–32 93.8 0.9 5.3
    Ciprofloxacin ≤0.06 ≤0.06 ≤0.06 to >16 99.1 0.0 0.9
    Ertapenem ≤0.03 ≤0.03 ≤0.03–0.12 100.0 0.0 0.0
    Meropenem ≤0.03 ≤0.03 ≤0.03–0.06 100.0 0.0 0.0
    Piperacillin-tazobactam ≤1 128 ≤1 to >512 87.6 0.9 11.5
    Tigecycline 0.5 1 0.12–1 100.0 0.0 0.0
    Trimethoprim-sulfamethoxazole ≤0.12 ≤0.12 ≤0.12 to >8 98.2 ND 1.8
Serratia marcescens (109)
    Plazomicin 0.5 1 ≤0.12–4 ND ND ND
    Amikacin 2 2 ≤1–16 100.0 0.0 0.0
    Gentamicin ≤0.5 1 ≤0.5 to >32 99.1 0.0 0.9
    Tobramycin 1 2 ≤0.5–32 96.3 1.8 1.8
    Cefazolin >128 >128 2 to >128 0.9 0.0 99.1
    Ceftazidime ≤0.25 1 ≤0.25–2 100.0 0.0 0.0
    Ceftriaxone ≤0.25 1 ≤0.25–8 91.7 2.8 5.5
    Ciprofloxacin ≤0.06 2 ≤0.06 to >16 86.2 6.4 7.3
    Ertapenem ≤0.03 0.12 ≤0.03–1 99.1 0.9 0.0
    Meropenem 0.06 0.06 ≤0.03–0.12 100.0 0.0 0.0
    Piperacillin-tazobactam ≤1 4 ≤1–256 94.5 4.6 0.9
    Tigecycline 1 2 1–8 95.4 3.7 0.9
    Trimethoprim-sulfamethoxazole 0.5 1 ≤0.12 to >8 95.4 ND 4.6
Proteus mirabilis (85)
    Plazomicin 2 4 0.25–8 ND ND ND
    Amikacin 2 4 ≤1–8 100.0 0.0 0.0
    Gentamicin ≤0.5 1 ≤0.5 to >32 91.8 1.2 7.1
    Tobramycin ≤0.5 2 ≤0.5–16 96.5 1.2 2.4
    Cefazolin 4 8 2 to >128 1.2 72.9 25.9
    Ceftazidime ≤0.25 ≤0.25 ≤0.25–4 100.0 0.0 0.0
    Ceftriaxone ≤0.25 ≤0.25 ≤0.25–2 96.5 3.5 0.0
    Ciprofloxacin ≤0.06 4 ≤0.06 to >16 87.1 2.4 10.6
    Ertapenem ≤0.03 ≤0.03 ≤0.03–0.06 100.0 0.0 0.0
    Meropenem 0.06 0.12 ≤0.03–0.25 100.0 0.0 0.0
    Piperacillin-tazobactam ≤1 ≤1 ≤1 to ≤1 100.0 0.0 0.0
    Tigecycline 4 8 1–8 21.2 55.3 23.5
    Trimethoprim-sulfamethoxazole ≤0.12 >8 ≤0.12 to >8 80.0 ND 20.0
Enterobacter aerogenes (55)
    Plazomicin 0.25 0.5 ≤0.12–2 ND ND ND
    Amikacin ≤1 2 ≤1–4 100.0 0.0 0.0
    Gentamicin ≤0.5 ≤0.5 ≤0.5–1 100.0 0.0 0.0
    Tobramycin ≤0.5 1 ≤0.5–8 96.4 3.6 0.0
    Cefazolin 32 >128 1 to >128 14.5 5.5 80.0
    Ceftazidime ≤0.25 32 ≤0.25 to >32 78.2 5.5 16.4
    Ceftriaxone ≤0.25 16 ≤0.25 to >64 69.1 3.6 27.3
    Ciprofloxacin ≤0.06 0.5 ≤0.06–8 96.4 0.0 3.6
    Ertapenem 0.12 0.5 ≤0.03–8 90.9 5.5 3.6
    Meropenem 0.06 0.12 ≤0.03–0.5 100.0 0.0 0.0
    Piperacillin-tazobactam 2 16 ≤1–128 92.7 5.5 1.8
    Tigecycline 1 1 0.25–4 96.3 3.7 0.0
    Trimethoprim-sulfamethoxazole ≤0.12 0.5 ≤0.12–8 98.1 ND 1.9
Pseudomonas aeruginosa (593)
    Plazomicin 4 16 ≤0.12 to >64 ND ND ND
    Amikacin 4 8 ≤1 to >64 94.6 2.9 2.5
    Gentamicin 1 8 ≤0.5 to >32 89.2 4.4 6.4
    Tobramycin ≤0.5 2 ≤0.5 to >64 94.4 1.0 4.6
    Ceftazidime 2 16 ≤0.25 to >32 85.7 4.6 9.8
    Ciprofloxacin 0.25 4 ≤0.06 to >16 80.4 7.6 12.0
    Meropenem 0.5 4 ≤0.03 to >32 83.0 7.6 9.4
    Piperacillin-tazobactam 4 32 ≤1 to >512 85.8 8.3 5.9
MDRb Pseudomonas aeruginosa (64)
    Plazomicin 8 32 0.25 to >64 ND ND ND
    Amikacin 4 32 ≤1 to >64 76.6 14.1 9.4
    Gentamicin 4 >32 ≤0.5 to >32 53.1 9.4 37.5
    Tobramycin 1 64 ≤0.5 to >64 68.8 1.6 29.7
    Ceftazidime 32 >32 2 to >32 17.2 20.3 62.5
    Ciprofloxacin 4 >16 0.25 to >16 20.3 28.1 51.6
    Meropenem 4 32 0.12 to >32 28.1 23.4 48.4
    Piperacillin-tazobactam 64 256 4 to >512 20.3 15.6 64.1
Stenotrophomonas maltophilia (104)
    Plazomicin 64 >64 2 to >64 ND ND ND
    Amikacin 64 >64 4 to >64 ND ND ND
    Gentamicin 16 >32 1 to >32 ND ND ND
    Tobramycin 16 >64 1 to >64 ND ND ND
    Ceftazidime >32 >32 1 to >32 23.1 7.7 69.2
    Ciprofloxacin 2 8 0.5 to >16 ND ND ND
    Tigecycline 1 4 0.25–8 ND ND ND
    Trimethoprim-sulfamethoxazole 0.5 >8 ≤0.12 to >8 78.8 ND 21.2
a

ND, breakpoints not defined.

b

MDR is defined as isolates demonstrating nonsusceptibility to at least one antimicrobial from three of the following five antimicrobial classes: aminoglycosides (amikacin, gentamicin, and tobramycin), fluoroquinolones (ciprofloxacin), antipseudomonal cephalosporins (ceftazidime), antipseudomonal penicillins (piperacillin-tazobactam), and antipseudomonal carbapenems (meropenem).

TABLE 2.

In vitro activity of plazomicin against aminoglycoside-susceptible and nonsusceptible E. coli and P. aeruginosa

Organism and antibiotic (no. of isolates)a No. (cumulative %) of isolates with an MIC of:
≤0.25 0.5 1 2 4 8 16 32 64 >64
Escherichia coli
    Gentamicin S (1,020) 198 (19.4) 578 (76.1) 218 (97.4) 21 (99.5) 5 (100.0)
    Gentamicin NS (126) 18 (14.3) 69 (69.0) 36 (97.6) 3 (100.0)
    Tobramycin S (1,036) 203 (19.6) 590 (76.5) 216 (97.4) 22 (99.5) 5 (100.0)
    Tobramycin NS (110) 13 (11.8) 57 (63.6) 38 (98.2) 2 (100.0)
Pseudomonas aeruginosa
    Amikacin S (561) 15 (2.7) 8 (4.1) 37 (10.7) 155 (38.3) 184 (71.1) 109 (90.6) 46 (98.8) 7 (100.0)
    Amikacin NS (32) 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.3) 0 (6.3) 2 (12.5) 1 (15.6) 10 (46.9) 9 (75.0) 8 (100.0)
    Gentamicin S (529) 14 (2.6) 8 (4.2) 37 (11.2) 156 (40.6) 179 (74.5) 101 (93.6) 32 (99.6) 2 (100.0)
    Gentamicin NS (64) 1 (1.6) 0 (1.6) 0 (1.6) 1 (3.1) 5 (10.9) 10 (26.6) 15 (50.0) 15 (73.4) 9 (87.5) 8 (100.0)
    Tobramycin S (560) 14 (2.5) 8 (3.9) 37 (10.5) 154 (38.0) 179 (70.0) 102 (88.2) 42 (95.7) 16 (98.6) 8 (100.0)
    Tobramycin NS (33) 1 (3.0) 0 (3.0) 0 (3.0) 3 (12.1) 5 (27.3) 9 (54.5) 5 (69.7) 1 (72.7) 1 (75.8) 8 (100.0)
a

S, susceptible; NS, nonsusceptible.

TABLE 3.

In vitro activities of plazomicin and comparators against ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae isolates

Organism (n) and antibiotic MIC (μg/ml)
% of isolates that are:
50% 90% Range Susceptible Intermediate Resistant
ESBL-producing E. coli (84)
    Plazomicin 0.5 1 ≤0.12–2 NDa ND ND
    Amikacin 2 8 ≤1–32 96.4 3.6 0.0
    Gentamicin 1 >32 ≤0.5 to >32 58.3 0.0 41.7
    Tobramycin 8 32 ≤0.5 to >64 46.4 10.7 42.9
    Cefazolin >128 >128 32 to >128 0.0 0.0 100.0
    Ceftazidime 16 >32 1 to >32 29.8 6.0 64.3
    Ceftriaxone 64 >64 4 to >64 0.0 0.0 100.0
    Ciprofloxacin >16 >16 ≤0.06 to >16 7.1 1.2 91.7
    Ertapenem 0.06 0.25 ≤0.03–2 98.8 0.0 1.2
    Meropenem ≤0.03 ≤0.03 ≤0.03–0.06 100.0 0.0 0.0
    Piperacillin-tazobactam 4 16 ≤1–256 94.0 3.6 2.4
    Tigecycline 0.5 0.5 0.12–1 100.0 0.0 0.0
    Trimethoprim-sulfamethoxazole >8 >8 ≤0.12 to >8 40.5 ND 59.5
Non-ESBL-producing E. coli (1,062)
    Plazomicin 0.5 1 ≤0.12–4 ND ND ND
    Amikacin 2 4 ≤1–32 99.9 0.1 0.0
    Gentamicin ≤0.5 2 ≤0.5 to >32 91.4 0.6 8.0
    Tobramycin ≤0.5 2 ≤0.5 to >64 93.9 4.3 1.8
    Cefazolin 2 8 ≤0.5 to >128 77.3 10.7 12.0
    Ceftazidime ≤0.25 0.5 ≤0.25 to >32 98.0 0.4 1.6
    Ceftriaxone ≤0.25 ≤0.25 ≤0.25–64 97.9 0.4 1.7
    Ciprofloxacin ≤0.06 >16 ≤0.06 to >16 78.7 0.1 21.2
    Ertapenem ≤0.03 ≤0.03 ≤0.03–8 99.9 0.0 0.1
    Meropenem ≤0.03 ≤0.03 ≤0.03–1 100.0 0.0 0.0
    Piperacillin-tazobactam ≤1 4 ≤1 to >512 98.0 0.4 1.6
    Tigecycline 0.25 0.5 0.12–2 100.0 0.0 0.0
    Trimethoprim-sulfamethoxazole ≤0.12 >8 ≤0.12 to >8 74.1 ND 25.9
ESBL-producing K. pneumoniae (15)
    Plazomicin 0.25 1 ≤0.12 to >64 ND ND ND
    Amikacin ≤1 16 ≤1 to >64 93.3 0.0 6.7
    Gentamicin ≤0.5 >32 ≤0.5 to >32 66.7 0.0 33.3
    Tobramycin ≤0.5 16 ≤0.5 to >64 60.0 20.0 20.0
    Cefazolin >128 >128 8 to >128 0.0 0.0 100.0
    Ceftazidime 32 >32 0.25 to >32 33.3 0.0 66.7
    Ceftriaxone 32 >64 ≤0.25 to >64 6.7 13.3 80.0
    Ciprofloxacin 0.5 >16 ≤0.06 to >16 53.3 6.7 40.0
    Ertapenem 0.06 0.5 ≤0.03–0.5 100.0 0.0 0.0
    Meropenem ≤0.03 0.06 ≤0.03–0.12 100.0 0.0 0.0
    Piperacillin-tazobactam 8 128 2–512 80.0 6.7 13.3
    Tigecycline 1 2 0.5–2 100.0 0.0 0.0
    Trimethoprim-sulfamethoxazole >8 >8 0.25 to >8 13.3 ND 86.7
Non-ESBL-producing K. pneumoniae (380)
    Plazomicin 0.25 0.5 ≤0.12–1 ND ND ND
    Amikacin ≤1 ≤1 ≤1–4 100.0 0.0 0.0
    Gentamicin ≤0.5 ≤0.5 ≤0.5–16 99.5 0.0 0.5
    Tobramycin ≤0.5 ≤0.5 ≤0.5–16 99.7 0.0 0.3
    Cefazolin 1 2 ≤0.5 to >128 92.1 3.9 3.9
    Ceftazidime ≤0.25 0.5 ≤0.25 to >32 98.9 0.0 1.1
    Ceftriaxone ≤0.25 ≤0.25 ≤0.25 to >64 98.7 0.5 0.8
    Ciprofloxacin ≤0.06 0.25 ≤0.06 to >16 96.3 0.5 3.2
    Ertapenem ≤0.03 ≤0.03 ≤0.03–16 98.9 0.8 0.3
    Meropenem ≤0.03 ≤0.03 ≤0.03–8 99.7 0.0 0.3
    Piperacillin-tazobactam 2 4 ≤1 to >512 98.4 0.5 1.1
    Tigecycline 0.5 1 0.06–8 96.3 3.2 0.5
    Trimethoprim-sulfamethoxazole ≤0.12 1 ≤0.12 to >8 94.7 ND 5.3
a

ND, breakpoints not defined.

The MIC90 value of plazomicin for P. aeruginosa was 2 times higher than that for amikacin and gentamicin and 8 times higher than that for tobramycin (Table 1). P. aeruginosa isolates that were nonsusceptible to amikacin, gentamicin, and tobramycin had plazomicin MIC50 values that were 2 times (for tobramycin) to 16 times (for amikacin) higher than for isolates susceptible to these antimicrobials (Table 2). Plazomicin had an MIC90 of 32 μg/ml versus MDR P. aeruginosa, which was identical to that for amikacin. Similar to other aminoglycosides, plazomicin demonstrated poor in vitro activity against Stenotrophomonas maltophilia isolates, with an MIC50 of 64 μg/ml.

The in vitro activities of plazomicin versus common Gram-positive cocci are presented in Table 4. Plazomicin demonstrated potent activity against both methicillin-susceptible S. aureus (MSSA) and MRSA, with >90% of isolates being inhibited by an MIC of ≤1 μg/ml. Plazomicin was also active versus Staphylococcus epidermidis, with an MIC90 of 0.5 μg/ml. The in vitro activity of plazomicin versus Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae was generally poor, with MIC50 values ranging from 16 to 64 μg/ml and MIC90 values ranging from 32 to >64 μg/ml. Plazomicin demonstrated some in vitro activity versus Enterococcus faecium, with MIC50 and MIC90 values of 8 μg/ml and 16 μg/ml, respectively.

TABLE 4.

In vitro activities of plazomicin and comparators against Gram-positive organisms

Organism (n) and antibiotic MIC (μg/ml)
% of isolates that are:
50% 90% Range Susceptible Intermediate Resistant
Methicillin-susceptible Staphylococcus aureus (1,221)
    Plazomicin 1 1 ≤0.12–4 NDa ND ND
    Amikacin 4 4 ≤1 to >64 99.5 0.3 0.2
    Gentamicin ≤0.5 ≤0.5 ≤0.5 to >32 98.2 0.2 1.6
    Tobramycin ≤0.5 ≤0.5 ≤0.5 to >64 97.4 0.3 2.3
    Clindamycin ≤0.12 ≤0.12 ≤0.12 to >8 95.2 0.2 4.7
    Doxycycline ≤0.12 0.25 ≤0.12–16 98.9 0.7 0.4
    Linezolid 2 4 ≤0.12–4 100.0 ND 0.0
    Tigecycline 0.12 0.25 0.06–0.5 100.0 ND 0.0
    Trimethoprim-sulfamethoxazole ≤0.12 ≤0.12 ≤0.12 to >8 99.5 ND 0.5
    Vancomycin 1 1 ≤0.12–2 100.0 0.0 0.0
Methicillin-resistant S. aureus (266)
    Plazomicin 1 1 0.25–64 ND ND ND
    Amikacin 8 32 ≤1 to >64 80.1 16.9 3.0
    Gentamicin ≤0.5 ≤0.5 ≤0.5 to >32 98.1 0.4 1.5
    Tobramycin 1 >64 ≤0.5 to >64 56.0 0.4 43.6
    Clindamycin ≤0.12 >8 ≤0.12 to >8 64.4 0.0 35.6
    Doxycycline ≤0.12 0.25 ≤0.12–16 98.9 0.8 0.4
    Linezolid 2 4 0.5–4 100.0 ND 0.0
    Tigecycline 0.12 0.25 0.06–2 98.5 ND 1.5
    Trimethoprim-sulfamethoxazole ≤0.12 ≤0.12 ≤0.12 to >8 97.0 ND 3.0
    Vancomycin 1 1 0.5–2 100.0 0.0 0.0
Staphylococcus epidermidis (143)
    Plazomicin ≤0.12 0.5 ≤0.12–4 ND ND ND
    Amikacin ≤1 16 ≤1 to >64 97.2 0.7 2.1
    Gentamicin 1 >32 ≤0.5 to >32 53.9 7.7 38.5
    Tobramycin 2 64 ≤0.5 to >64 55.9 11.9 32.2
    Cefazolin 1 64 ≤0.5 to >128 ND ND ND
    Clindamycin ≤0.12 >8 ≤0.12 to >8 55.9 1.4 42.7
    Doxycycline 0.25 1 ≤0.12–32 96.5 2.8 0.7
    Linezolid 0.5 1 ≤0.12–4 100.0 ND 0.0
    Tigecycline 0.12 0.25 ≤0.03–1 ND ND ND
    Trimethoprim-sulfamethoxazole 1 8 ≤0.12 to >8 54.6 ND 45.5
    Vancomycin 1 2 0.5–2 100.0 0.0 0.0
Streptococcus pneumoniae (323)
    Plazomicin 32 32 ≤0.12–64 ND ND ND
    Ceftriaxoneb ≤0.12 ≤0.12 ≤0.12–4 99.1 0.6 0.3
    Clindamycin ≤0.12 16 ≤0.12 to >64 89.2 0.3 10.5
    Doxycycline ≤0.25 2 ≤0.25–16 84.8 0.9 14.2
    Meropenem ≤0.06 0.12 ≤0.06–1 92.6 4.3 3.1
    Penicillinb,c ≤0.03 0.25 ≤0.03–8 84.6 11.2 4.2
    Tigecycline ≤0.015 0.03 ≤0.015–0.06 100.0 ND ND
    Trimethoprim-sulfamethoxazole 0.25 1 ≤0.12 to >8 86.7 5.3 8.0
    Vancomycin 0.25 0.25 ≤0.12–1 100.0 ND ND
Streptococcus agalactiae (93)
    Plazomicin 64 >64 16 to >64 ND ND ND
    Ceftriaxone ≤0.12 ≤0.12 ≤0.12 to ≤0.12 100.0 ND ND
    Clindamycin ≤0.12 >64 ≤0.12 to >64 80.6 0.0 19.4
    Linezolid 1 2 0.25–2 100.0 0.0 0.0
    Meropenem ≤0.06 ≤0.06 ≤0.06 to ≤0.06 100.0 ND ND
    Penicillin 0.06 0.06 ≤0.03–0.12 100.0 ND ND
    Tigecycline 0.06 0.06 ≤0.015–0.12 100.0 ND ND
    Vancomycin 0.5 0.5 0.25–0.5 100.0 ND ND
Streptococcus pyogenes (81)
    Plazomicin 16 32 4–64 ND ND ND
    Ceftriaxone ≤0.12 ≤0.12 ≤0.12 to ≤0.12 100.0 ND ND
    Clindamycin ≤0.12 ≤0.12 ≤0.12 to >64 98.8 0.0 1.2
    Linezolid 1 2 0.25–2 100.0 ND ND
    Meropenem ≤0.06 ≤0.06 ≤0.06–0.12 100.0 ND ND
    Penicillinc ≤0.03 ≤0.03 ≤0.03–0.06 100.0 ND ND
    Tigecycline 0.03 0.06 ≤0.015–0.25 100.0 ND ND
    Vancomycin 0.5 0.5 0.25–1 100.0 ND ND
Enterococcus faecalis (45)
    Plazomicin 64 >64 2 to >64 ND ND ND
    Amikacin >64 >64 8 to >64 ND ND ND
    Gentamicin 16 >32 1 to >32 ND ND ND
    Tobramycin 16 >64 4 to >64 ND ND ND
    Amoxicillin-clavulanate 0.5 1 0.12–1 ND ND ND
    Ciprofloxacin 1 >16 0.25 to >16 71.1 6.7 22.2
    Doxycycline 8 16 ≤0.12–32 35.6 46.7 17.8
    Linezolid 2 2 1–2 100.0 0.0 0.0
    Piperacillin-tazobactam 4 4 ≤1–8 ND ND ND
    Tigecycline 0.12 0.12 ≤0.03–0.25 100.0 ND ND
    Vancomycin 1 2 1–2 100.0 0.0 0.0
Enterococcus faecium (70)
    Plazomicin 8 16 2 to >64 ND ND ND
    Amikacin 32 >64 8 to >64 ND ND ND
    Gentamicin 8 >32 1 to >32 ND ND ND
    Tobramycin >64 >64 16 to >64 ND ND ND
    Amoxicillin-clavulanate >32 >32 0.12 to >32 ND ND ND
    Ciprofloxacin >16 >16 0.25 to >16 7.1 0.0 92.9
    Doxycycline 1 8 ≤0.12–16 88.6 2.9 8.6
    Linezolid 2 4 0.5–4 75.4 24.6 0.0
    Piperacillin-tazobactam >512 >512 4 to >512 ND ND ND
    Tigecycline 0.12 0.12 ≤0.03–0.25 ND ND ND
    Vancomycin 1 >32 0.5 to >32 72.5 0.0 27.5
a

ND, breakpoints not defined.

b

CLSI nonmeningitis breakpoints were used for ceftriaxone, and oral penicillin breakpoints were used for penicillin.

c

Only 286 S. pneumoniae isolates and 74 S. pyogenes isolates were tested versus penicillin.

DISCUSSION

In this study, the in vitro activity of plazomicin was evaluated against a collection of clinically significant Gram-negative bacilli and Gram-positive cocci obtained from patients assessed at hospitals in Canada. Plazomicin demonstrated potent in vitro activity versus members of the family Enterobacteriaceae, including aminoglycoside-nonsusceptible E. coli and ESBL-producing E. coli and K. pneumoniae. Similar results have been reported by other investigators (13, 16, 17, 2024). Furthermore, many of these studies also specifically evaluated the activity of plazomicin against collections of antimicrobial-resistant isolates (2022). Galani et al. (20) assessed the in vitro activity of plazomicin against 300 MDR Enterobacteriaceae from Athens, Greece. The isolates tested in this study included ESBL producers and carbapenemase (K. pneumoniae carbapenemase [KPC] and VIM) producers. For these isolates, plazomicin had an MIC50 of 1 μg/ml and an MIC90 of 2 μg/ml (20). Similarly, Endimiani et al. (21) evaluated the in vitro activity of plazomicin against 25 KPC-producing K. pneumoniae isolates. In this publication, plazomicin demonstrated an MIC50 of 0.5 μg/ml and an MIC90 of 1 μg/ml (21). The current study adds to the literature, as it describes the in vitro activity of plazomicin against a large collection of randomly selected clinical isolates obtained across a broad geographic area (the country of Canada).

Aminoglycoside resistance among Enterobacteriaceae is most commonly mediated by AMEs (11, 14). Aggen et al. (16) previously demonstrated that almost all common AMEs, with the exception of AAC(2′)-I, have no effect on the activity of plazomicin. Data published by Landman et al. (17) support this finding. Of concern, however, the in vitro activity of plazomicin does appear to be compromised by the presence of ribosomal methylases, including the ArmA methylase and RmtC methylase (16, 22). These enzymes have been described in MDR Gram-negative bacilli (22). Among 17 NDM carbapenemase-producing Enterobacteriaceae isolates evaluated by Livermore et al. (22), 16 had a plazomicin MIC of ≥64 μg/ml. Fifteen of these isolates were found to have genes encoding 16S rRNA methylases (22). Fortunately, this resistance mechanism appears to be relatively uncommon at present. In the current study, the retained in vitro activity of plazomicin against aminoglycoside-nonsusceptible E. coli indicates that aminoglycoside resistance among these isolates was most likely mediated by AMEs. Additionally, the lack of high plazomicin MICs versus E. coli and other Enterobacteriaceae supports the current rarity of 16S rRNA methylases as a cause of aminoglycoside resistance among Enterobacteriaceae in Canada.

In this study, plazomicin demonstrated potent in vitro activity versus P. aeruginosa. While gentamicin and tobramycin had MIC90 values that were 2 times and 8 times lower than that of plazomicin, respectively, the significance of this observation needs to be interpreted with caution. The anticipated dosing, maximum serum concentration achieved, and area under the concentration time curve (AUC) are much higher for plazomicin than for gentamicin and tobramycin, so directly comparing the MICs for these antimicrobials in terms of clinical relevance is difficult (13, 25). The in vitro activity of plazomicin versus P. aeruginosa was similar to that for amikacin, an aminoglycoside for which the AUC appears to be more comparable (13). The data presented here are in agreement with results published by Landman et al. (26). These investigators evaluated plazomicin in comparison with amikacin versus 679 P. aeruginosa isolates. The MIC50 and MIC90 values of plazomicin were 8 μg/ml and 32 μg/ml, respectively, and for amikacin, 8 μg/ml and 16 μg/ml, respectively (26). In the present study, the activity of plazomicin versus MDR P. aeruginosa was similar to that of amikacin. It is interesting to note that P. aeruginosa isolates that were nonsusceptible to comparator aminoglycosides demonstrated relatively elevated MICs to plazomicin. The mechanisms resulting in elevated MICs of plazomicin versus P. aeruginosa remain poorly defined at this time, but it is likely that reduced permeability and/or efflux are contributing factors.

The excellent in vitro activity of plazomicin versus Gram-negative bacilli, including P. aeruginosa and aminoglycoside-nonsusceptible Enterobacteriaceae, suggests that there may be a role for this antimicrobial in the treatment of infections caused by these pathogens. Results from a phase 2 clinical trial of plazomicin for the treatment of complicated urinary tract infections and pyelonephritis compared to levofloxacin treatment have been reported in abstract form (27). Microbiological eradication in the modified intent-to-treat population was 58.7% (37/63 [95% confidence interval {CI}, 45.6% to 71.0%]) for plazomicin, compared with 58.6% (17/29 [95% CI, 38.9% to 76.5%]) for levofloxacin (27). Further studies are required to better define the clinical utility and adverse effect profile of this novel antimicrobial.

The data presented here also demonstrate potent in vitro activity of plazomicin versus both MSSA and MRSA. These data are in agreement with in vitro testing by Tenover et al. (28), who documented a plazomicin MIC50 of 1 μg/ml and an MIC90 of 2 μg/ml versus a collection of 493 MRSA isolates. In general, plazomicin had high MICs for other Gram-positive cocci, although modest activity was observed versus E. faecium. The clinical significance of this finding is uncertain, as conventional aminoglycosides are only used to treat enterococci in combination with a cell wall active agent versus isolates that do not demonstrate high-level aminoglycoside resistance. An MIC cutoff for high-level plazomicin resistance among enterococci has not yet been defined.

There are several important limitations to this study. The number of aminoglycoside-nonsusceptible isolates for many species was small, precluding a subset analysis versus plazomicin. The molecular mechanisms conferring aminoglycoside resistance among Gram-negative isolates were not investigated, which was related to limited resources. This is of particular relevance for P. aeruginosa, for which further work is required to better define the mechanisms leading to elevated plazomicin MICs. Finally, limited space on the antimicrobial susceptibility panels precluded testing of additional relevant comparators.

In summary, plazomicin demonstrated potent in vitro activity against Gram-negative bacilli and Gram-positive cocci when evaluated against a large collection of bacterial isolates obtained from patients seen at hospitals across Canada. Plazomicin was active against aminoglycoside-nonsusceptible E. coli, with MIC values comparable to those for susceptible isolates. Furthermore, plazomicin demonstrated equivalent activity against ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae. Plazomicin had similar activity to amikacin versus MDR P. aeruginosa. Plazomicin was also active against both MRSA and MSSA. The in vitro activity of plazomicin supports further evaluation of this antimicrobial in the clinical setting. If effective and well tolerated in clinical trials, plazomicin has the potential to help reach the “10 × '20” goal set by IDSA.

ACKNOWLEDGMENTS

We thank Barbara Weshnoweski, Ravinder Vashisht, and Nancy Laing for their technical assistance.

The CANWARD data are also displayed at www.can-r.ca, the official website of the Canadian Antimicrobial Resistance Alliance (CARA).

Footnotes

Published ahead of print 18 February 2014

REFERENCES

  • 1.Denisuik AJ, Lagacé-Wiens PR, Pitout JD, Mulvey MR, Simner PJ, Tailor F, Karlowsky JA, Hoban DJ, Adam HJ, Zhanel GG, Canadian Antimicrobial Resistance Alliance 2013. Molecular epidemiology of extended-spectrum β-lactamase-, AmpC β-lactamase- and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae isolated from Canadian hospitals over a 5 year period: CANWARD 2007–11. J. Antimicrob. Chemother. 68(Suppl 1):i57–i65. 10.1093/jac/dkt027 [DOI] [PubMed] [Google Scholar]
  • 2.Zilberberg MD, Shorr AF. 2013. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J. Hosp. Med. 8:559–563. 10.1002/jhm.2080 [DOI] [PubMed] [Google Scholar]
  • 3.Zilberberg MD, Shorr AF. 2013. Secular trends in Gram-negative resistance among urinary tract infection hospitalizations in the United States, 2000–2009. Infect. Control Hosp. Epidemiol. 34:940–946. 10.1086/671740 [DOI] [PubMed] [Google Scholar]
  • 4.Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, Cornaglia G, Garau J, Gniadkowski M, Hayden MK, Kumarasamy K, Livermore DM, Maya JL, Nordmann P, Patel JB, Paterson DL, Pitout J, Villegas MV, Wang H, Woodford N, Quinn JP. 2013. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect. Dis. 13:785–796. 10.1016/S1473-3099(13)70190-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Vardakas KZ, Rafailidis PI, Konstantelias AA, Falagas ME. 2013. Predictors of mortality in patients with infections due to multi-drug resistant gram negative bacteria: the study, the patient, the bug or the drug? J. Infect. 66:401–414. 10.1016/j.jinf.2012.10.028 [DOI] [PubMed] [Google Scholar]
  • 6.Schwaber MJ, Carmeli Y. 2007. Mortality and delay in effective therapy associated with extended-spectrum β-lactamase production in Enterobacteriaceae bacteremia: a systematic review and meta-analysis. J. Antimicrob. Chemother. 60:913–920. 10.1093/jac/dkm318 [DOI] [PubMed] [Google Scholar]
  • 7.Gasink LB, Edelstein PH, Lautenbach E, Synnestvedt M, Fishman NO. 2009. Risk factors and clinical impact of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Infect. Control Hosp. Epidemiol. 30:1180–1185. 10.1086/648451 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mouloudi E, Protonotariou E, Zagorianou A, Iosifidis E, Karapanagiotou A, Giasnetsova T, Tsioka A, Roilides E, Sofianou D, Gritsi-Gerogianni N. 2010. Bloodstream infections caused by metallo-β-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcome. Infect. Control Hosp. Epidemiol. 31:1250–1256. 10.1086/657135 [DOI] [PubMed] [Google Scholar]
  • 9.Tam VH, Rogers CA, Chang KT, Weston JS, Caeiro JP, Garey KW. 2010. Impact of multidrug-resistant Pseudomonas aeruginosa bacteremia on patient outcomes. Antimicrob. Agents Chemother. 54:3717–3722. 10.1128/AAC.00207-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Boucher HW, Talbot GH, Benjamin DK, Jr, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D, Infectious Diseases Society of America 2013. 10 × '20 progress–development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin. Infect. Dis. 56:1685–1694. 10.1093/cid/cit152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Poulikakos P, Falagas ME. 2013. Aminoglycoside therapy in infectious diseases. Expert Opin. Pharmacother. 14:1585–1597. 10.1517/14656566.2013.806486 [DOI] [PubMed] [Google Scholar]
  • 12.Doi Y, Yoshichika A. 2007. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin. Infect. Dis. 45:88-94. 10.1086/518605 [DOI] [PubMed] [Google Scholar]
  • 13.Zhanel GG, Lawson CD, Zelenitsky S, Findlay B, Schweizer F, Adam H, Walkty A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP, Karlowsky JA. 2012. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti Infect. Ther. 10:459–473. 10.1586/eri.12.25 [DOI] [PubMed] [Google Scholar]
  • 14.Miller GH, Sabatelli FJ, Hare RS, Glupczynski Y, Mackey P, Shlaes D, Shimizu K, Shaw KJ. 1997. The most frequent aminoglycoside resistance mechanisms–changes with time and geographic area: a reflection of aminoglycoside usage patterns? Clin. Infect. Dis. 24(Suppl 1):S46–S62. 10.1093/clinids/24.Supplement_1.S46 [DOI] [PubMed] [Google Scholar]
  • 15.Hirsch EB, Tam VH. 2010. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant infection. J. Antimicrob. Chemother. 65:1119–1125. 10.1093/jac/dkq108 [DOI] [PubMed] [Google Scholar]
  • 16.Aggen JB, Armstrong ES, Goldblum AA, Dozzo P, Linsell MS, Gliedt MJ, Hildebrandt DJ, Feeney LA, Kubo A, Matias RD, Lopez S, Gomez M, Wlasichuk KB, Diokno R, Miller GH, Moser HE. 2010. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob. Agents Chemother. 54:4636–4642. 10.1128/AAC.00572-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Landman D, Babu E, Shah N, Kelly P, Bäcker M, Bratu S, Quale J. 2010. Activity of a novel aminoglycoside, ACHN-490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City. J. Antimicrob. Chemother. 65:2123–2127. 10.1093/jac/dkq278 [DOI] [PubMed] [Google Scholar]
  • 18.Clinical and Laboratory Standards Institute. 2013. Performance standards for antimicrobial susceptibility testing; 23rd informational supplement. CLSI M100-S23. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
  • 19.Clinical and Laboratory Standards Institute. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically—7th ed. Approved standard M7-A7 Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
  • 20.Galani I, Souli M, Daikos GL, Chrysouli Z, Poulakou G, Psichogiou M, Panagea T, Argyropoulou A, Stefanou I, Plakias G, Giamarellou H, Petrikkos G. 2012. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J. Chemother. 24:191–194. 10.1179/1973947812Y.0000000015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Endimiani A, Hujer KM, Hujer AM, Armstrong ES, Choudhary Y, Aggen JB, Bonomo RA. 2009. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob. Agents Chemother. 53:4504–4507. 10.1128/AAC.00556-09 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N. 2011. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J. Antimicrob. Chemother. 66:48–53. 10.1093/jac/dkq408 [DOI] [PubMed] [Google Scholar]
  • 23.Georgescu C, Martin DA, Bratu S, Quale J, Landman D. 2009. Activity of ACHN-490, a novel neoglycoside antibiotic, against contemporary Gram-negative clinical isolates from Brooklyn, NY hospitals, abstr F1-842 Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA [Google Scholar]
  • 24.Biedenbach DJ, Jones RN, Armstrong ES, Aggen JB, Miller GH. 2009. Activity of ACHN-490 against complicated urinary tract infection (cUTI) pathogens from the United States and Europe, abstr F1-843 Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA [Google Scholar]
  • 25.Cass RT, Brooks CD, Havrilla NA, Tack KJ, Borin MT, Young D, Bruss JB. 2011. Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob. Agents Chemother. 55:5874–5880. 10.1128/AAC.00624-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Landman D, Kelly P, Bäcker M, Babu E, Shah N, Bratu S, Quale J. 2011. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J. Antimicrob. Chemother. 66:332–334. 10.1093/jac/dkq459 [DOI] [PubMed] [Google Scholar]
  • 27.Riddle V, Cebrik D, Armstrong E, Cass R, Clobes T, Hillan K. 2012. Plazomicin safety and efficacy in patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP), abstr L2-2118a Abstr. 52nd Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA [Google Scholar]
  • 28.Tenover FC, Tickler I, Armstrong ES, Kubo A, Lopez S, Persing DH, Miller GH. 2011. Activity of ACHN-490 against methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients in US hospitals. Int. J. Antimicrob. Agents. 38:352–354. 10.1016/j.ijantimicag.2011.05.016 [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES