The Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate the in vitro activities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from 2013 to 2017 from patients in Canadian hospitals as part of the CANWARD Surveillance Study. Plazomicin demonstrated potent in vitro activity against Enterobacteriaceae (MIC90 ≤ 1 µg/ml for all species tested except Proteus mirabilis and Morganella morganii), including aminoglycoside-nonsusceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates.
KEYWORDS: aminoglycosides, Gram-negative bacteria, Gram-positive bacteria, multidrug resistance, plazomicin
ABSTRACT
The Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate the in vitro activities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from 2013 to 2017 from patients in Canadian hospitals as part of the CANWARD Surveillance Study. Plazomicin demonstrated potent in vitro activity against Enterobacteriaceae (MIC90 ≤ 1 µg/ml for all species tested except Proteus mirabilis and Morganella morganii), including aminoglycoside-nonsusceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates. Plazomicin was equally active against methicillin-susceptible and methicillin-resistant isolates of Staphylococcus aureus.
INTRODUCTION
Plazomicin is a semisynthetic aminoglycoside derived from sisomicin (1). Structural modifications protect plazomicin from inactivation by aminoglycoside-modifying enzymes, with the exception of the AAC(2′)-I enzyme, the gene for which is found on the chromosome of Providencia stuartii (1–4). Plazomicin consistently retains in vitro activity against Gram-negative bacilli resistant to other antimicrobial classes, including isolates harboring extended-spectrum β-lactamase (ESBL) enzymes, carbapenemase enzymes, and acquired colistin resistance genes (e.g., mcr-1) (5–9). Similar to other aminoglycosides, plazomicin is not active against Gram-negative bacilli that possess acquired 16S rRNA methyltransferase genes, but at present these remain uncommon in many parts of the world (3, 4, 8, 10–14). Data from recent clinical trials support a role for plazomicin in the treatment of complicated urinary tract infections, and the United States Food and Drug Administration (FDA) has recently approved the use of plazomicin for this indication (15–17). Clinical trial data also suggest a possible role for plazomicin in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae (CRE) (18). The purpose of this study was to better characterize the in vitro activity of plazomicin versus a large collection of Gram-negative and Gram-positive bacteria obtained from patients across Canada as part of the ongoing Canadian ward Surveillance Study (CANWARD).
From January 2013 through October 2017, sentinel hospitals across Canada were requested on an annual basis to submit quotas of clinically significant isolates (consecutive isolates, one per patient per infection site) from inpatients and outpatients with bloodstream (n = 100), respiratory (n = 100), urine (n = 25), and wound/intravenous (n = 25) infections (CANWARD). 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). Isolates were shipped on Amies semisolid transport medium to the coordinating laboratory (Health Sciences Centre, Winnipeg, Manitoba, Canada), subcultured onto appropriate media, and stocked in skim milk at −80°C until MIC testing was carried out.
Following two subcultures from the frozen stock, the in vitro activities of plazomicin and clinically relevant comparator antimicrobials were determined by Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution testing using in-house-prepared 96-well broth microdilution panels (19). Antimicrobial MIC interpretive standards were defined according to CLSI breakpoints (20). Tigecycline MICs for Enterobacteriaceae were interpreted using FDA-defined breakpoints (susceptible, ≤2 µg/ml; intermediate, 4 µg/ml; resistant, ≥8 µg/ml), as CLSI MIC breakpoints are not currently published for this agent. FDA MIC interpretive breakpoints were used for plazomicin tested against Enterobacteriaceae (susceptible, ≤2 µg/ml; intermediate, 4 µg/ml; resistant, ≥8 µg/ml).
Phenotypic screening and confirmation of ESBL-producing Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis were performed as described by CLSI (20). Multidrug-resistant (MDR) Enterobacteriaceae and Pseudomonas aeruginosa were defined as isolates nonsusceptible to ≥1 agent in ≥3 relevant antimicrobial categories (21). All methicillin-resistant Staphylococcus aureus (MRSA) isolates were phenotypically confirmed using the cefoxitin disk test (20).
The in vitro activities of plazomicin and comparator antimicrobials against 7,712 clinical isolates of Gram-negative bacteria are summarized in Table 1. Over 99% of E. coli, K. pneumoniae, K. oxytoca, Enterobacter cloacae, and Klebsiella aerogenes isolates were susceptible to plazomicin, with the MIC90 for these species ranging from 0.5 to 1 µg/ml. Relative to other Enterobacteriaceae, the plazomicin MIC90 values for clinical isolates of P. mirabilis and Morganella morganii were higher (4 µg/ml for both of these species). The MIC90 of plazomicin versus P. aeruginosa isolates was 16 µg/ml, comparable to the MIC90 of amikacin. Gentamicin and tobramycin were both more active than plazomicin in vitro against P. aeruginosa isolates. Plazomicin was less active than amikacin, gentamicin, and tobramycin versus Acinetobacter baumannii. Plazomicin demonstrated poor in vitro activity versus Stenotrophomonas maltophilia, which is considered intrinsically resistant to all aminoglycosides.
TABLE 1.
In vitro activities of plazomicin and comparator agents against clinical isolates of Gram-negative bacteria
| Organism (no. of isolates) and agent | MIC (µg/ml) |
% of isolates |
||||
|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | |
| Escherichia coli (3,094) | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to >64 | 99.5 | 0.4 | 0.1 |
| Amikacin | 2 | 4 | ≤1 to >64 | 99.8 | 0.1 | 0.1 |
| Gentamicin | ≤0.5 | 2 | ≤0.5 to >32 | 90.9 | 0.3 | 8.8 |
| Tobramycin | ≤0.5 | 4 | ≤0.5 to >64 | 91.8 | 2.7 | 5.5 |
| Cefazolin | 2 | >128 | ≤0.5 to >128 | 70.9 | 8.8 | 20.3 |
| Ceftazidime | ≤0.25 | 4 | ≤0.25 to >32 | 90.8 | 1.5 | 7.7 |
| Ceftriaxone | ≤0.25 | 32 | ≤0.25 to >64 | 87.4 | 0.4 | 12.2 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 75.3 | 0.1 | 24.6 |
| Ertapenem | ≤0.03 | ≤0.03 | ≤0.03 to >32 | 99.7 | 0.1 | 0.2 |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 32 | 99.9 | 0 | 0.1 |
| Piperacillin-tazobactam | 2 | 4 | ≤1 to >512 | 97.1 | 1.5 | 1.4 |
| Tigecycline | 0.25 | 0.5 | ≤0.03 to 4 | 99.9 | 0.1 | 0 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12 to >8 | 73.0 | NAa | 27.0 |
| Klebsiella pneumoniae (1,039) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to >64 | 99.8 | 0.1 | 0.1 |
| Amikacin | ≤1 | 2 | ≤1 to >64 | 99.9 | 0 | 0.1 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 95.8 | 0 | 4.2 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to >64 | 94.5 | 2.6 | 2.9 |
| Cefazolin | 1 | 16 | ≤0.5 to >128 | 82.3 | 5.3 | 12.4 |
| Ceftazidime | ≤0.25 | 1 | ≤0.25 to >32 | 93.1 | 0.6 | 6.3 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 91.9 | 0.1 | 8.0 |
| Ciprofloxacin | ≤0.06 | 1 | ≤0.06 to >16 | 91.6 | 1.8 | 6.6 |
| Ertapenem | ≤0.03 | 0.06 | ≤0.03 to >32 | 98.6 | 0.3 | 1.1 |
| Meropenem | ≤0.03 | 0.06 | ≤0.03 to 16 | 99.4 | 0.2 | 0.4 |
| Piperacillin-tazobactam | 2 | 8 | ≤1 to >512 | 95.6 | 1.6 | 2.8 |
| Tigecycline | 0.5 | 1 | 0.12 to >16 | 96.2 | 3.2 | 0.6 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12 to >8 | 87.9 | NA | 12.1 |
| Enterobacter cloacae (470) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to 2 | 100 | 0 | 0 |
| Amikacin | ≤1 | 2 | ≤1 to 16 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 97.9 | 0 | 2.1 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to >64 | 96.6 | 1.1 | 2.3 |
| Cefazolin | >128 | >128 | 1 to >128 | 1.9 | 1.7 | 96.4 |
| Ceftazidime | 0.5 | >32 | ≤0.25 to >32 | 76.0 | 0.8 | 23.2 |
| Ceftriaxone | ≤0.25 | >64 | ≤0.25 to >64 | 72.8 | 2.1 | 25.1 |
| Ciprofloxacin | ≤0.06 | 0.12 | ≤0.06 to >16 | 94.3 | 1.7 | 4.0 |
| Ertapenem | 0.06 | 0.5 | ≤0.03 to >32 | 91.3 | 5.1 | 3.6 |
| Meropenem | ≤0.03 | 0.12 | ≤0.03 to >32 | 99.4 | 0.2 | 0.4 |
| Piperacillin-tazobactam | 2 | 64 | ≤1 to >512 | 85.5 | 8.3 | 6.2 |
| Tigecycline | 0.5 | 1 | 0.12 to 8 | 95.5 | 2.4 | 2.1 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 1 | ≤0.12 to >8 | 91.5 | NA | 8.5 |
| Klebsiella oxytoca (279) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to 2 | 100 | 0 | 0 |
| Amikacin | ≤1 | 2 | ≤1 to 8 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 98.6 | 0.3 | 1.1 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to 32 | 99.3 | 0.3 | 0.4 |
| Cefazolin | 8 | >128 | ≤0.5 to >128 | 27.6 | 22.2 | 50.2 |
| Ceftazidime | ≤0.25 | 0.5 | ≤0.25 to >32 | 98.6 | 0.3 | 1.1 |
| Ceftriaxone | ≤0.25 | 1 | ≤0.25 to >64 | 90.0 | 2.1 | 7.9 |
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06 to >16 | 98.9 | 0.4 | 0.7 |
| Ertapenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.12 | 100 | 0 | 0 |
| Meropenem | ≤0.03 | 0.06 | ≤0.03 to 0.5 | 100 | 0 | 0 |
| Piperacillin-tazobactam | 2 | 32 | ≤1 to >512 | 89.6 | 1.4 | 9.0 |
| Tigecycline | 0.5 | 0.5 | 0.12 to 4 | 99.3 | 0.7 | 0 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12 to >8 | 97.1 | NA | 2.9 |
| Serratia marcescens (255) | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to 8 | 97.6 | 2.0 | 0.4 |
| Amikacin | 2 | 4 | ≤1 to 16 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to 8 | 99.6 | 0.4 | 0 |
| Tobramycin | 1 | 4 | ≤0.5 to 64 | 95.7 | 2.3 | 2.0 |
| Cefazolin | >128 | >128 | 128 to >128 | 0 | 0 | 100 |
| Ceftazidime | 0.5 | 1 | ≤0.25 to >32 | 99.2 | 0.4 | 0.4 |
| Ceftriaxone | ≤0.25 | 1 | ≤0.25 to >64 | 93.7 | 2.0 | 4.3 |
| Ciprofloxacin | ≤0.06 | 1 | ≤0.06 to 16 | 94.1 | 1.6 | 4.3 |
| Ertapenem | ≤0.03 | 0.12 | ≤0.03 to 16 | 98.0 | 1.2 | 0.8 |
| Meropenem | 0.06 | 0.06 | ≤0.03 to 8 | 99.2 | 0.4 | 0.4 |
| Piperacillin-tazobactam | 2 | 4 | ≤1 to 256 | 97.6 | 1.6 | 0.8 |
| Tigecycline | 2 | 4 | 0.5 to 16 | 88.2 | 10.2 | 1.6 |
| Trimethoprim-sulfamethoxazole | 0.5 | 1 | ≤0.12 to >8 | 96.9 | NA | 3.1 |
| Proteus mirabilis (235) | ||||||
| Plazomicin | 4 | 4 | 0.5 to 32 | 44.3 | 46.3 | 9.4 |
| Amikacin | 4 | 8 | ≤1 to 32 | 98.7 | 1.3 | 0 |
| Gentamicin | ≤0.5 | 2 | ≤0.5 to >32 | 94.5 | 0.8 | 4.7 |
| Tobramycin | ≤0.5 | 1 | ≤0.5 to >64 | 95.3 | 1.3 | 3.4 |
| Cefazolin | 4 | 8 | 2 to >128 | 5.1 | 71.9 | 23.0 |
| Ceftazidime | ≤0.25 | ≤0.25 | ≤0.25 to 16 | 98.3 | 1.3 | 0.4 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 97.9 | 0.8 | 1.3 |
| Ciprofloxacin | ≤0.06 | 2 | ≤0.06 to >16 | 88.1 | 3.0 | 8.9 |
| Ertapenem | ≤0.03 | ≤0.03 | ≤0.03 to 1 | 99.6 | 0.4 | 0 |
| Meropenem | 0.06 | 0.12 | ≤0.03 to 1 | 100 | 0 | 0 |
| Piperacillin-tazobactam | ≤1 | ≤1 | ≤1 to 64 | 99.1 | 0.9 | 0 |
| Tigecycline | 4 | 8 | 0.5 to 16 | 13.6 | 55.3 | 31.1 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12 to >8 | 80.9 | NA | 19.1 |
| Klebsiella aerogenes (97) | ||||||
| Plazomicin | 0.5 | 0.5 | ≤0.12 to 2 | 100 | 0 | 0 |
| Amikacin | ≤1 | 2 | ≤1 to 8 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to 2 | 100 | 0 | 0 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to 16 | 99.0 | 0 | 1.0 |
| Cefazolin | 128 | >128 | 1 to >128 | 3.1 | 3.1 | 93.8 |
| Ceftazidime | 0.5 | >32 | ≤0.25 to >32 | 73.2 | 3.1 | 23.7 |
| Ceftriaxone | ≤0.25 | 32 | ≤0.25 to >64 | 72.2 | 0 | 27.8 |
| Ciprofloxacin | ≤0.06 | 0.12 | ≤0.06 to 8 | 96.9 | 1.0 | 2.1 |
| Ertapenem | 0.12 | 0.5 | ≤0.03 to >32 | 93.8 | 3.1 | 3.1 |
| Meropenem | 0.06 | 0.06 | ≤0.03 to 32 | 99.0 | 0 | 1.0 |
| Piperacillin-tazobactam | 4 | 32 | ≤1 to 256 | 83.5 | 14.4 | 2.1 |
| Tigecycline | 0.5 | 1 | 0.06 to 4 | 99.0 | 1.0 | 0 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 0.5 | ≤0.12 to >8 | 95.9 | NA | 4.1 |
| Morganella morganii (54) | ||||||
| Plazomicin | 2 | 4 | 0.25 to 8 | 66.7 | 27.7 | 5.6 |
| Amikacin | 2 | 4 | ≤1 to 8 | 100 | 0 | 0 |
| Gentamicin | ≤0.5 | 32 | ≤0.5 to >32 | 88.9 | 0 | 11.1 |
| Tobramycin | ≤0.5 | 4 | ≤0.5 to 64 | 96.3 | 1.8 | 1.9 |
| Cefazolin | >128 | >128 | 8 to >128 | 0 | 0 | 100 |
| Ceftazidime | ≤0.25 | 16 | ≤0.25 to >32 | 83.3 | 5.6 | 11.1 |
| Ceftriaxone | ≤0.25 | 2 | ≤0.25 to >64 | 87.0 | 7.4 | 5.6 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 83.3 | 0 | 16.7 |
| Ertapenem | ≤0.03 | 0.06 | ≤0.03 to 0.5 | 100 | 0 | 0 |
| Meropenem | 0.06 | 0.12 | ≤0.03 to 0.5 | 100 | 0 | 0 |
| Piperacillin-tazobactam | ≤1 | 2 | ≤1 to 256 | 98.1 | 0 | 1.9 |
| Tigecycline | 2 | 4 | 0.12 to 16 | 81.5 | 14.8 | 3.7 |
| Trimethoprim-sulfamethoxazole | 0.25 | >8 | ≤0.12 to >8 | 83.3 | NA | 16.7 |
| Pseudomonas aeruginosa (1,789) | ||||||
| Plazomicin | 4 | 16 | ≤0.12 to >64 | NA | NA | NA |
| Amikacin | 4 | 16 | ≤1 to >64 | 94.4 | 2.2 | 3.4 |
| Gentamicin | 1 | 8 | ≤0.5 to >32 | 89.5 | 4.4 | 6.1 |
| Tobramycin | ≤0.5 | 2 | ≤0.5 to >64 | 94.2 | 1.3 | 4.5 |
| Ceftazidime | 4 | 32 | ≤0.25 to >32 | 80.2 | 7.6 | 12.2 |
| Ciprofloxacin | 0.25 | 4 | ≤0.06 to >16 | 80.3 | 7.1 | 12.6 |
| Meropenem | 0.5 | 8 | ≤0.03 to >32 | 79.7 | 6.7 | 13.6 |
| Piperacillin-tazobactam | 4 | 64 | ≤1 to >512 | 83.0 | 8.7 | 8.3 |
| Acinetobacter baumannii (68) | ||||||
| Plazomicin | 1 | 8 | 0.25 to >64 | NA | NA | NA |
| Amikacin | ≤1 | 4 | ≤1 to >64 | 98.5 | 0 | 1.5 |
| Gentamicin | ≤0.5 | 2 | ≤0.5 to >32 | 92.6 | 1.5 | 5.9 |
| Tobramycin | ≤0.5 | 1 | ≤0.5 to >64 | 97.1 | 1.4 | 1.5 |
| Ceftazidime | 8 | 16 | 1 to >32 | 77.9 | 17.7 | 4.4 |
| Ceftriaxone | 16 | 32 | 1 to >64 | 44.1 | 33.8 | 22.1 |
| Ciprofloxacin | 0.25 | 0.5 | ≤0.06 to >16 | 97.1 | 0 | 2.9 |
| Meropenem | 0.5 | 2 | 0.06 to >32 | 98.5 | 0 | 1.5 |
| Piperacillin-tazobactam | 4 | 32 | ≤1 to >512 | 83.8 | 13.3 | 2.9 |
| Tigecycline | 0.25 | 2 | 0.12 to 16 | NA | NA | NA |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 0.5 | ≤0.12 to >8 | 94.1 | NA | 5.9 |
| Stenotrophomonas maltophilia (332) | ||||||
| Plazomicin | >64 | >64 | ≤0.12 to >64 | NA | NA | NA |
| Amikacin | >64 | >64 | ≤1 to >64 | NA | NA | NA |
| Gentamicin | 32 | >32 | ≤0.5 to >32 | NA | NA | NA |
| Tobramycin | 32 | >64 | ≤0.5 to >64 | NA | NA | NA |
| Ceftazidime | >32 | >32 | 0.5 to >32 | 22.3 | 6.9 | 70.8 |
| Ciprofloxacin | 4 | 16 | 0.12 to >16 | NA | NA | NA |
| Tigecycline | 1 | 4 | 0.12 to 16 | NA | NA | NA |
| Trimethoprim-sulfamethoxazole | 0.25 | 1 | ≤0.12 to >8 | 97.3 | NA | 2.7 |
NA, MIC breakpoint not applicable.
The in vitro activity of plazomicin versus comparator aminoglycoside-nonsusceptible E. coli, K. pneumoniae, and P. aeruginosa isolates is presented in Table 2. Plazomicin demonstrated excellent activity versus gentamicin- and tobramycin-nonsusceptible Enterobacteriaceae isolates. However, MIC values for plazomicin versus aminoglycoside-nonsusceptible P. aeruginosa isolates were higher than those versus the aminoglycoside-susceptible subset. Plazomicin retained in vitro activity versus ESBL-producing E. coli and K. pneumoniae isolates (Table 3), with MIC90 values being identical to those for non-ESBL producers. Table 4 depicts the in vitro activity of plazomicin versus MDR isolates. Overall, 99.4% of MDR E. coli isolates and 97.3% of MDR K. pneumoniae isolates remained susceptible to plazomicin. The MIC90 value for plazomicin versus MDR P. aeruginosa isolates was 64 µg/ml.
TABLE 2.
MIC distributions for plazomicin against aminoglycoside-susceptible and aminoglycoside-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa
| Organism (no. of isolates) and agenta |
No. of isolates (cumulative percentage of isolates) with the following plazomicin MIC (µg/ml): |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | >64 | |
| Escherichia coli | |||||||||||
| Amikacin S (3,087) | 21 (0.7) | 642 (21.5) | 1,731 (77.6) | 599 (97.0) | 78 (99.5) | 16 (100) | |||||
| Amikacin NS (7) | 1 (14.3) | 2 (42.9) | 3 (85.7) | 1 (100) | |||||||
| Gentamicin S (2,811) | 21 (0.7) | 596 (21.9) | 1,565 (77.6) | 540 (96.8) | 75 (99.5) | 14 (100) | |||||
| Gentamicin NS (283) | 46 (16.3) | 167 (75.3) | 61 (96.8) | 6 (98.9) | 2 (99.6) | 1 (100) | |||||
| Tobramycin S (2,839) | 21 (0.7) | 621 (22.6) | 1,579 (78.2) | 529 (96.9) | 75 (99.5) | 14 (100) | |||||
| Tobramycin NS (255) | 21 (8.2) | 153 (68.2) | 72 (96.5) | 6 (98.8) | 2 (99.6) | 1 (100) | |||||
| Klebsiella pneumoniae | |||||||||||
| Amikacin S (1,038) | 59 (5.7) | 807 (83.4) | 156 (98.5) | 13 (99.7) | 2 (99.9) | 1 (100) | |||||
| Amikacin NS (1) | 1 (100) | ||||||||||
| Gentamicin S (995) | 58 (5.8) | 777 (83.9) | 147 (98.7) | 11 (99.8) | 1 (99.9) | 1 (100) | |||||
| Gentamicin NS (44) | 1 (2.3) | 30 (70.5) | 9 (90.9) | 2 (95.5) | 1 (97.7) | 1 (100) | |||||
| Tobramycin S (982) | 56 (5.7) | 766 (83.7) | 146 (98.6) | 11 (99.7) | 2 (99.9) | 1 (100) | |||||
| Tobramycin NS (57) | 3 (5.3) | 41 (77.2) | 10 (94.7) | 2 (98.2) | 1 (100) | ||||||
| Pseudomonas aeruginosa | |||||||||||
| Amikacin S (1,688) | 7 (0.4) | 27 (2.0) | 42 (4.5) | 83 (9.4) | 481 (37.9) | 556 (70.9) | 299 (88.6) | 157 (97.9) | 34 (99.9) | 2 (100) | |
| Amikacin NS (101) | 1 (1.0) | 2 (3.0) | 13 (15.8) | 25 (40.6) | 18 (58.4) | 42 (100) | |||||
| Gentamicin S (1,602) | 7 (0.4) | 24 (1.9) | 40 (4.4) | 83 (9.6) | 476 (39.3) | 544 (73.3) | 280 (90.8) | 138 (99.4) | 10 (100) | ||
| Gentamicin NS (187) | 3 (1.6) | 2 (2.7) | 5 (5.3) | 13 (12.3) | 21 (23.5) | 32 (40.6) | 49 (66.8) | 18 (76.5) | 44 (100) | ||
| Tobramycin S (1,686) | 7 (0.4) | 25 (1.9) | 41 (4.3) | 82 (9.2) | 476 (37.4) | 543 (69.6) | 280 (86.2) | 160 (95.7) | 55 (99.0) | 12 (99.7) | 5 (100) |
| Tobramycin NS (103) | 2 (1.9) | 1 (2.9) | 1 (3.9) | 5 (8.7) | 14 (22.3) | 21 (42.7) | 10 (52.4) | 4 (56.3) | 6 (62.1) | 39 (100) | |
S, aminoglycoside susceptible; NS, aminoglycoside nonsusceptible.
TABLE 3.
In vitro activities of plazomicin and comparators against ESBL-producing and non-ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates
| Organism (no. of isolates) and agent | MIC (µg/ml) |
% of isolates |
||||
|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | |
| ESBL-producing Escherichia coli (343) | ||||||
| Plazomicin | 0.5 | 1 | 0.25 to 2 | 100 | 0 | 0 |
| Amikacin | 2 | 8 | ≤1 to 64 | 98.8 | 0.9 | 0.3 |
| Gentamicin | ≤0.5 | >32 | ≤0.5 to >32 | 67.1 | 1.7 | 31.2 |
| Tobramycin | 4 | 32 | ≤0.5 to >64 | 55.7 | 7.0 | 37.3 |
| Cefazolin | >128 | >128 | 4 to >128 | 0 | 0.3 | 99.7 |
| Ceftazidime | 16 | >32 | 0.5 to >32 | 31.8 | 11.6 | 56.6 |
| Ceftriaxone | >64 | >64 | ≤0.25 to >64 | 2.6 | 1.5 | 95.9 |
| Ciprofloxacin | >16 | >16 | ≤0.06 to >16 | 12.5 | 0 | 87.5 |
| Ertapenem | ≤0.03 | 0.12 | ≤0.03 to >32 | 98.0 | 0.8 | 1.2 |
| Meropenem | ≤0.03 | 0.06 | ≤0.03 to 32 | 99.7 | 0 | 0.3 |
| Piperacillin-tazobactam | 4 | 16 | ≤1 to >512 | 92.7 | 3.8 | 3.5 |
| Tigecycline | 0.25 | 1 | 0.12 to 2 | 100 | 0 | 0 |
| Trimethoprim-sulfamethoxazole | >8 | >8 | ≤0.12 to >8 | 32.4 | NAa | 67.6 |
| Non-ESBL-producing Escherichia coli (2,751) | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to >64 | 99.4 | 0.5 | 0.1 |
| Amikacin | 2 | 4 | ≤1 to >64 | 99.8 | 0.1 | 0.1 |
| Gentamicin | ≤0.5 | 1 | ≤0.5 to >32 | 93.8 | 0.2 | 6.0 |
| Tobramycin | ≤0.5 | 1 | ≤0.5 to >64 | 96.3 | 2.1 | 1.6 |
| Cefazolin | 2 | 8 | ≤0.5 to >128 | 79.7 | 9.9 | 10.4 |
| Ceftazidime | ≤0.25 | 0.5 | ≤0.25 to >32 | 98.1 | 0.3 | 1.6 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 98.0 | 0.2 | 1.8 |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06 to >16 | 83.1 | 0.1 | 16.8 |
| Ertapenem | ≤0.03 | ≤0.03 | ≤0.03 to 2 | 99.8 | 0.1 | 0.1 |
| Meropenem | ≤0.03 | ≤0.03 | ≤0.03 to 0.25 | 100 | 0 | 0 |
| Piperacillin-tazobactam | 2 | 4 | ≤1 to >512 | 97.6 | 1.3 | 1.1 |
| Tigecycline | 0.25 | 0.5 | ≤0.03 to 4 | 99.9 | 0.1 | 0 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12 to >8 | 78.1 | NA | 21.9 |
| ESBL-producing Klebsiella pneumoniae (73) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to 4 | 98.6 | 1.4 | 0 |
| Amikacin | 2 | 8 | ≤1 to 16 | 100 | 0 | 0 |
| Gentamicin | 16 | >32 | ≤0.5 to >32 | 49.3 | 0 | 50.7 |
| Tobramycin | 8 | 32 | ≤0.5 to >64 | 37.0 | 24.6 | 38.4 |
| Cefazolin | >128 | >128 | 8 to >128 | 0 | 0 | 100 |
| Ceftazidime | >32 | >32 | 0.5 to >32 | 17.8 | 5.5 | 76.7 |
| Ceftriaxone | >64 | >64 | ≤0.25 to >64 | 4.1 | 0 | 95.9 |
| Ciprofloxacin | 8 | >16 | ≤0.06 to >16 | 23.3 | 10.9 | 65.8 |
| Ertapenem | 0.12 | 8 | ≤0.03 to >32 | 82.2 | 5.5 | 12.3 |
| Meropenem | ≤0.03 | 0.5 | ≤0.03 to 16 | 93.2 | 2.7 | 4.1 |
| Piperacillin-tazobactam | 16 | >512 | 2 to >512 | 61.6 | 15.1 | 23.3 |
| Tigecycline | 1 | 2 | 0.5 to 4 | 91.8 | 8.2 | 0 |
| Trimethoprim-sulfamethoxazole | >8 | >8 | ≤0.12 to >8 | 6.8 | NA | 93.2 |
| Non-ESBL-producing Klebsiella pneumoniae (966) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to >64 | 99.9 | 0 | 0.1 |
| Amikacin | ≤1 | 2 | ≤1 to >64 | 99.9 | 0 | 0.1 |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 99.3 | 0 | 0.7 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to >64 | 98.9 | 0.9 | 0.2 |
| Cefazolin | 1 | 4 | ≤0.5 to >128 | 88.5 | 5.7 | 5.8 |
| Ceftazidime | ≤0.25 | 0.5 | ≤0.25 to >32 | 98.8 | 0.3 | 0.9 |
| Ceftriaxone | ≤0.25 | ≤0.25 | ≤0.25 to >64 | 98.6 | 0.1 | 1.3 |
| Ciprofloxacin | ≤0.06 | 0.25 | ≤0.06 to >16 | 96.8 | 1.0 | 2.2 |
| Ertapenem | ≤0.03 | ≤0.03 | ≤0.03 to 32 | 99.8 | 0 | 0.2 |
| Meropenem | ≤0.03 | 0.06 | ≤0.03 to 8 | 99.9 | 0 | 0.1 |
| Piperacillin-tazobactam | 2 | 8 | ≤1 to >512 | 98.1 | 0.7 | 1.2 |
| Tigecycline | 0.5 | 1 | 0.12 to >16 | 96.5 | 2.9 | 0.6 |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 0.5 | ≤0.12 to >8 | 94.0 | NA | 6.0 |
NA, MIC breakpoint not applicable.
TABLE 4.
In vitro activities of plazomicin and comparators against MDR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa
| Organism (no. of isolates) and agent | MIC (µg/ml) |
% of isolates |
||||
|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | |
| MDR Escherichia coli (358)a | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to >64 | 99.4 | 0.3 | 0.3 |
| Amikacin | 4 | 8 | ≤1 to >64 | 98.0 | 1.2 | 0.8 |
| Gentamicin | 1 | >32 | ≤0.5 to >32 | 52.8 | 2.2 | 45.0 |
| Tobramycin | 8 | 32 | ≤0.5 to >64 | 42.5 | 14.2 | 43.3 |
| Cefazolin | >128 | >128 | ≤0.5 to >128 | 6.4 | 7.0 | 86.6 |
| Ceftazidime | 8 | >32 | ≤0.25 to >32 | 46.1 | 8.4 | 45.5 |
| Ceftriaxone | 64 | >64 | ≤0.25 to >64 | 22.1 | 1.1 | 76.8 |
| Ciprofloxacin | >16 | >16 | ≤0.06 to >16 | 4.2 | 0 | 95.8 |
| Ertapenem | ≤0.03 | 0.12 | ≤0.03 to >32 | 97.2 | 1.4 | 1.4 |
| Meropenem | ≤0.03 | 0.06 | ≤0.03 to 32 | 99.7 | 0 | 0.3 |
| Piperacillin-tazobactam | 4 | 64 | ≤1 to >512 | 86.3 | 5.9 | 7.8 |
| Tigecycline | 0.25 | 1 | 0.12 to 4 | 99.7 | 0.3 | 0 |
| Trimethoprim-sulfamethoxazole | >8 | >8 | ≤0.12 to >8 | 14.2 | NAc | 85.8 |
| MDR Klebsiella pneumoniae (74)a | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to >64 | 97.3 | 1.3 | 1.4 |
| Amikacin | 2 | 8 | ≤1 to >64 | 98.6 | 0 | 1.4 |
| Gentamicin | 32 | >32 | ≤0.5 to >32 | 45.9 | 0 | 54.1 |
| Tobramycin | 8 | 32 | ≤0.5 to >64 | 31.1 | 28.4 | 40.5 |
| Cefazolin | >128 | >128 | 2 to >128 | 2.7 | 2.7 | 94.6 |
| Ceftazidime | 32 | >32 | ≤0.25 to >32 | 24.3 | 6.8 | 68.9 |
| Ceftriaxone | >64 | >64 | ≤0.25 to >64 | 6.8 | 0 | 93.2 |
| Ciprofloxacin | 16 | >16 | ≤0.06 to >16 | 14.9 | 9.4 | 75.7 |
| Ertapenem | 0.12 | 8 | ≤0.03 to >32 | 81.1 | 5.4 | 13.5 |
| Meropenem | ≤0.03 | 1 | ≤0.03 to 16 | 91.9 | 2.7 | 5.4 |
| Piperacillin-tazobactam | 16 | >512 | 2 to >512 | 63.5 | 13.5 | 23.0 |
| Tigecycline | 1 | 4 | 0.5 to 4 | 87.8 | 12.2 | 0 |
| Trimethoprim-sulfamethoxazole | >8 | >8 | 0.25 to >8 | 2.7 | NA | 97.3 |
| MDR Pseudomonas aeruginosa (256)b | ||||||
| Plazomicin | 8 | 64 | ≤0.12 to >64 | NA | NA | NA |
| Amikacin | 8 | 64 | ≤1 to >64 | 80.5 | 6.2 | 13.3 |
| Gentamicin | 4 | >32 | ≤0.5 to >32 | 61.7 | 9.4 | 28.9 |
| Tobramycin | 1 | 64 | ≤0.5 to >64 | 72.3 | 4.7 | 23.0 |
| Ceftazidime | 32 | >32 | 2 to >32 | 16.8 | 24.2 | 59.0 |
| Ciprofloxacin | 2 | >16 | ≤0.06 to >16 | 30.9 | 21.4 | 47.7 |
| Meropenem | 8 | 32 | 0.25 to >32 | 15.2 | 21.5 | 63.3 |
| Piperacillin-tazobactam | 64 | 512 | ≤1 to >512 | 20.7 | 36.3 | 43.0 |
MDR Enterobacteriaceae were defined as isolates nonsusceptible to ≥1 antimicrobial agent in ≥3 of the following antimicrobial agent categories: aminoglycosides (amikacin, gentamicin, tobramycin), antipseudomonal penicillins and β-lactamase inhibitors (piperacillin-tazobactam), carbapenems (ertapenem, meropenem), extended-spectrum cephalosporins (ceftazidime, ceftriaxone), fluoroquinolones (ciprofloxacin), folate pathway inhibitors (trimethoprim-sulfamethoxazole), and glycylcyclines (tigecycline).
MDR Pseudomonas aeruginosa isolates were defined as isolates nonsusceptible to ≥1 antimicrobial agent in ≥3 of the following antimicrobial agent categories: aminoglycosides (amikacin, gentamicin, tobramycin), antipseudomonal penicillins and β-lactamase inhibitors (piperacillin-tazobactam), antipseudomonal carbapenems (meropenem), antipseudomonal cephalosporins (ceftazidime), and fluoroquinolones (ciprofloxacin).
NA, MIC breakpoint not applicable.
The in vitro activity of plazomicin versus 4,481 Gram-positive bacterial isolates is presented in Table 5. Plazomicin had an MIC90 of 1 µg/ml for both methicillin-susceptible S. aureus (MSSA) and MRSA isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus epidermidis isolates, with MIC90 values of 0.25 µg/ml and 0.5 µg/ml, respectively. Plazomicin retained in vitro activity versus gentamicin-nonsusceptible S. aureus and S. epidermidis isolates (Table 6). Similar to the other aminoglycosides, plazomicin demonstrated poor in vitro activity versus Enterococcus faecalis, with an MIC90 of >64 µg/ml (Table 5). Plazomicin was the most active aminoglycoside evaluated versus Enterococcus faecium isolates, but it still had a relatively high MIC90 of 16 µg/ml.
TABLE 5.
In vitro activities of plazomicin and comparator agents against clinical isolates of Gram-positive bacteria
| Organism (no. of isolates) and agent | MIC (µg/ml) |
% of isolates |
||||
|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | |
| Methicillin-susceptible Staphylococcus aureus (3,009) | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to 16 | NAa | NA | NA |
| Amikacin | 2 | 4 | ≤1 to >64 | NA | NA | NA |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 98.6 | 0.1 | 1.3 |
| Tobramycin | ≤0.5 | ≤0.5 | ≤0.5 to >64 | NA | NA | NA |
| Clindamycin | ≤0.12 | ≤0.12 | ≤0.12 to >8 | 94.8 | 0.4 | 4.8 |
| Doxycycline | ≤0.12 | 0.25 | ≤0.12 to 32 | 98.8 | 0.9 | 0.3 |
| Linezolid | 2 | 4 | ≤0.12 to 4 | 100 | NA | 0 |
| Tigecycline | 0.12 | 0.25 | ≤0.03 to 2 | 99.7 | NA | NA |
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12 to >8 | 99.7 | NA | 0.3 |
| Vancomycin | 0.5 | 1 | ≤0.12 to 2 | 100 | 0 | 0 |
| Methicillin-resistant Staphylococcus aureus (687) | ||||||
| Plazomicin | 0.5 | 1 | ≤0.12 to 4 | NA | NA | NA |
| Amikacin | 8 | 32 | ≤1 to >64 | NA | NA | NA |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 to >32 | 96.2 | 0.6 | 3.2 |
| Tobramycin | ≤0.5 | >64 | ≤0.5 to >64 | NA | NA | NA |
| Clindamycin | ≤0.12 | >8 | ≤0.12 to >8 | 65.2 | 0 | 34.8 |
| Doxycycline | ≤0.12 | 1 | ≤0.12 to 16 | 97.2 | 1.2 | 1.6 |
| Linezolid | 2 | 4 | 0.5 to 4 | 100 | NA | 0 |
| Tigecycline | 0.25 | 0.25 | ≤0.03 to 1 | 98.3 | NA | NA |
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12 to >8 | 98.0 | NA | 2.0 |
| Vancomycin | 0.5 | 1 | ≤0.12 to 4 | 99.7 | 0.3 | 0 |
| Methicillin-susceptible Staphylococcus epidermidis (339) | ||||||
| Plazomicin | ≤0.12 | 0.25 | ≤0.12 to 2 | NA | NA | NA |
| Amikacin | ≤1 | 4 | ≤1 to 64 | NA | NA | NA |
| Gentamicin | ≤0.5 | 32 | ≤0.5 to >32 | 69.3 | 7.4 | 23.3 |
| Tobramycin | ≤0.5 | 16 | ≤0.5 to >64 | NA | NA | NA |
| Clindamycin | ≤0.12 | >8 | ≤0.12 to >8 | 68.4 | 2.4 | 29.2 |
| Doxycycline | 0.25 | 1 | ≤0.12 to 32 | 96.2 | 1.2 | 2.6 |
| Linezolid | 1 | 2 | ≤0.12 to 2 | 100 | NA | 0 |
| Tigecycline | 0.12 | 0.25 | ≤0.03 to 1 | NA | NA | NA |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 8 | ≤0.12 to >8 | 69.3 | NA | 30.7 |
| Vancomycin | 1 | 2 | ≤0.12 to 2 | 100 | 0 | 0 |
| Methicillin-resistant Staphylococcus epidermidis (25) | ||||||
| Plazomicin | 0.25 | 0.5 | ≤0.12 to 0.5 | NA | NA | NA |
| Amikacin | 8 | 16 | ≤1 to 32 | NA | NA | NA |
| Gentamicin | >32 | >32 | ≤0.5 to >32 | 20.0 | 0 | 80.0 |
| Tobramycin | 32 | >64 | ≤0.5 to >64 | NA | NA | NA |
| Clindamycin | >8 | >8 | ≤0.12 to >8 | 20.0 | 4.0 | 76.0 |
| Doxycycline | 0.5 | 1 | ≤0.12 to 2 | 100 | 0 | 0 |
| Linezolid | 1 | 1 | 0.5 to 2 | 100 | NA | 0 |
| Tigecycline | 0.25 | 0.25 | 0.06 to 0.5 | NA | NA | NA |
| Trimethoprim-sulfamethoxazole | 4 | 8 | ≤0.12 to 8 | 12.0 | NA | 88.0 |
| Vancomycin | 1 | 2 | 1 to 2 | 100 | 0 | 0 |
| Enterococcus faecalis (301) | ||||||
| Plazomicin | 64 | >64 | 1 to >64 | NA | NA | NA |
| Amikacin | >64 | >64 | 4 to >64 | NA | NA | NA |
| Gentamicin | 8 | >32 | ≤0.5 to >32 | NA | NA | NA |
| Tobramycin | 16 | >64 | ≤0.5 to >64 | NA | NA | NA |
| Ciprofloxacin | 1 | >16 | ≤0.06 to >16 | 75.0 | 7.9 | 17.1 |
| Doxycycline | 8 | 16 | ≤0.12 to 32 | 37.1 | 44.8 | 18.1 |
| Linezolid | 2 | 4 | 0.5 to 4 | 3.3 | 16.7 | 0 |
| Tigecycline | 0.12 | 0.25 | ≤0.03 to 1 | 99.8 | NA | NA |
| Vancomycin | 1 | 2 | 0.5 to 4 | 100 | 0 | 0 |
| Enterococcus faecium (120) | ||||||
| Plazomicin | 4 | 16 | 1 to 16 | NA | NA | NA |
| Amikacin | 32 | >64 | 8 to >64 | NA | NA | NA |
| Gentamicin | 4 | >32 | ≤0.5 to >32 | NA | NA | NA |
| Tobramycin | 64 | >64 | 4 to >64 | NA | NA | NA |
| Ciprofloxacin | >16 | >16 | 0.25 to >16 | 5.6 | 0.9 | 93.5 |
| Doxycycline | 1 | 16 | ≤0.12 to 32 | 66.7 | 9.2 | 24.1 |
| Linezolid | 2 | 4 | 0.25 to 16 | 87.5 | 11.6 | 0.9 |
| Tigecycline | 0.12 | 0.12 | ≤0.03 to 0.5 | NA | NA | NA |
| Vancomycin | 0.5 | >32 | ≤0.12 to >32 | 80.1 | 0.5 | 19.4 |
NA, MIC breakpoint not applicable.
TABLE 6.
MIC distributions for plazomicin against gentamicin-susceptible and gentamicin-nonsusceptible Staphylococcus aureus and Staphylococcus epidermidis
| Organism (no. of isolates) and agenta |
No. of isolates (cumulative percentage of isolates) with the following plazomicin MIC (µg/ml): |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | |
| Staphylococcus aureus | |||||||||
| Gentamicin S (3,626) | 28 (0.8) | 262 (8.0) | 2,063 (64.9) | 1,157 (96.8) | 106 (99.7) | 10 (100) | |||
| Gentamicin NS (69) | 5 (7.2) | 29 (49.3) | 31 (94.2) | 3 (98.6) | 1 (100) | ||||
| Staphylococcus epidermidis | |||||||||
| Gentamicin S (240) | 204 (85.0) | 33 (98.8) | 3 (100) | ||||||
| Gentamicin NS (124) | 51 (41.1) | 64 (92.7) | 8 (99.2) | 1 (100) | |||||
S, gentamicin susceptible; NS gentamicin nonsusceptible.
In this study, plazomicin demonstrated excellent in vitro activity versus members of the family Enterobacteriaceae, including ESBL-producing, aminoglycoside-nonsusceptible, and MDR subsets. Similar data have been previously reported (5, 6, 22). In a recent publication, Castanheira et al. evaluated the in vitro activity of plazomicin and comparators versus 4,362 Enterobacteriaceae clinical isolates collected in the United States between 2014 and 2015 (22). The MIC90 values of plazomicin versus E. coli and K. pneumoniae were 1 µg/ml and 0.5 µg/ml, respectively, in line with what has been reported here (22). The MIC90 for plazomicin was 2 µg/ml versus gentamicin-resistant and tobramycin-resistant members of the family Enterobacteriaceae (22). The retained in vitro activity of plazomicin versus aminoglycoside-nonsusceptible Enterobacteriaceae presumably reflects the stability of this antimicrobial to common aminoglycoside-modifying enzymes (22). Lopez-Diaz et al. recently assessed the in vitro activity of plazomicin versus 346 ESBL/AmpC-producing E. coli urinary isolates (6). Plazomicin had an MIC90 of 1 µg/ml, again, similar to the data that we have presented (6). The MIC values of plazomicin versus P. aeruginosa tend to be higher than those versus Enterobacteriaceae. In our study, the MIC50 and MIC90 values for P. aeruginosa were 4 µg/ml and 16 µg/ml, respectively. These data are consistent with what has been described elsewhere in the literature (22, 23).
In the present study, plazomicin demonstrated excellent in vitro activity versus S. aureus (both MRSA and MSSA) and coagulase-negative staphylococci. Similar in vitro activity versus MRSA has been described by Tenover et al. (24). These investigators assessed the in vitro activity of plazomicin versus 493 MRSA isolates from the United States. The MIC50 and MIC90 values for plazomicin were 1 µg/ml and 2 µg/ml, respectively (24). It should be noted that aminoglycosides are not typically used as monotherapy for the treatment of infections caused by S. aureus, and the exact role of plazomicin for the treatment of S. aureus infections remains unclear.
This study has several important limitations that deserve attention. Very few CRE isolates were included, preventing an analysis of plazomicin activity versus this subset. At present, CRE remain uncommon in Canada. Molecular mechanisms of aminoglycoside resistance were also not evaluated. Finally, the plazomicin susceptibility data presented here are likely not applicable to countries where isolates harboring 16S rRNA methyltransferases are more prevalent.
In summary, plazomicin demonstrated potent in vitro activity against Enterobacteriaceae, including aminoglycoside-nonsusceptible, ESBL-positive, and MDR isolates, tested from a recent 5-year (2013 to 2017) collection of clinical isolates obtained from patients seeking care at Canadian hospitals. These data, in addition to data from recent clinical trials, support a possible role for plazomicin in the treatment of infections due to Enterobacteriaceae, including those caused by MDR isolates.
ACKNOWLEDGMENTS
The CANWARD Surveillance Study was supported in part by the Health Sciences Centre (Winnipeg, Manitoba, Canada), the University of Manitoba (Winnipeg, Manitoba, Canada), the Public Health Agency of Canada-National Microbiology Laboratory (Winnipeg, Manitoba, Canada), and Achaogen (San Francisco, CA, USA).
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