Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Epidemiology and Surveillance

In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes

Mariana Castanheira, Andrew P. Davis, Rodrigo E. Mendes, Alisa W. Serio, Kevin M. Krause, Robert K. Flamm
Mariana Castanheira
aJMI Laboratories, North Liberty, Iowa, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew P. Davis
aJMI Laboratories, North Liberty, Iowa, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rodrigo E. Mendes
aJMI Laboratories, North Liberty, Iowa, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alisa W. Serio
bAchaogen, South San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin M. Krause
bAchaogen, South San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert K. Flamm
aJMI Laboratories, North Liberty, Iowa, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/AAC.00313-18
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Plazomicin and comparator agents were tested by using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 U.S. hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC50/MIC90, 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, by applying CLSI breakpoints. The activities of plazomicin were similar among Enterobacteriaceae species, with MIC50 values ranging from 0.25 to 1 μg/ml, with the exception of Proteus mirabilis and indole-positive Proteeae that displayed MIC50 values of 2 μg/ml. For 97 carbapenem-resistant Enterobacteriaceae (CRE), which included 87 isolates carrying blaKPC, plazomicin inhibited all but 1 isolate at ≤2 μg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5 and 95.5% of the gentamicin-resistant isolates, 96.9 and 96.5% of the tobramycin-resistant isolates, and 64.3 and 90.0% of the amikacin-resistant isolates according to CLSI and EUCAST breakpoints, respectively. The activities of plazomicin against Pseudomonas aeruginosa (MIC50/MIC90, 4/16 μg/ml) and Acinetobacter species (MIC50/MIC90, 2/16 μg/ml) isolates were similar. Plazomicin was active against coagulase-negative staphylococci (MIC50/MIC90, 0.12/0.5 μg/ml) and Staphylococcus aureus (MIC50/MIC90, 0.5/0.5 μg/ml) but had limited activity against Enterococcus spp. (MIC50/MIC90, 16/64 μg/ml) and Streptococcus pneumoniae (MIC50/MIC90, 32/64 μg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying blaKPC from U.S. hospitals, supports the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

INTRODUCTION

The worldwide emergence of multidrug-resistant (MDR) organisms, including carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii, highlights the need for new therapeutic options to treat infections (1). In the early 2000s, the Infectious Diseases Society of America recognized the urgent need for surveillance initiatives and new therapeutic options for the group of organisms known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species), which includes Gram-negative organisms as well as troublesome Gram-positive species (2).

New therapeutic options for Gram-positive and -negative organisms were recently approved for clinical therapy in the United States and Europe (3); however, developing new agents with broad-spectrum activity is important given the significance of adequate empirical treatment for successful patient outcomes (4, 5).

Aminoglycosides are broad-spectrum agents that have been used for several decades to treat serious infections caused by nonfastidious Gram-negative bacteria, staphylococci, enterococci, and viridans group streptococci. Aminoglycosides are also used in combination with other agents displaying synergistic activity with this class, such as β-lactams, fluoroquinolones, polymyxins, and vancomycin (3). The most common mechanisms of resistance to aminoglycosides are aminoglycoside-modifying enzymes (AMEs) that are broadly disseminated among Gram-negative and Gram-positive species and carried by mobile genetic structures that also often harbor β-lactamases and other resistance genes (6, 7).

Plazomicin is a semisynthetic aminoglycoside derived from sisomicin and contains structural modifications that make this molecule stable in the presence of most AMEs (8, 9). Plazomicin has in vitro activity against nonfastidious Gram-negative pathogens and Staphylococcus spp., including methicillin-resistant S. aureus isolates (10, 11).

In this study, we evaluated the activities of plazomicin and comparator antimicrobial agents tested against 4,825 clinical isolates collected in U.S. hospitals during 2014 and 2015. Enterobacteriaceae isolates displaying elevated carbapenem MIC values were evaluated for carbapenemase genes, and a separate analysis focused on the activities of plazomicin and comparators against these subsets.

RESULTS

Activities of plazomicin and comparator agents.Plazomicin (MIC50 and MIC90, 0.5 and 2 μg/ml, respectively) inhibited 99.2% of 4,362 Enterobacteriaceae isolates tested at ≤4 μg/ml (Table 1). For common Enterobacteriaceae species, plazomicin inhibited 99.9% of the 1,506 K. pneumoniae isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml, respectively), 99.9% of the 1,346 Escherichia coli isolates (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively), and 99.4% of the 359 Klebsiella oxytoca isolates (MIC50 and MIC90, 0.5 and 0.5 μg/ml, respectively) at ≤4 μg/ml (Table 1).

View this table:
  • View inline
  • View popup
TABLE 1

Antimicrobial activity of plazomicin tested against 4,825 clinical isolates collected in 70 U.S. hospitals during 2014 to 2015

Plazomicin inhibited all 104 Enterobacter cloacae species complex isolates (here E. cloacae) (MIC50 and MIC90, 0.5 and 0.5 μg/ml, respectively) at ≤2 μg/ml and all 120 Enterobacter aerogenes (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively), 159 Citrobacter freundii species complex (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively), 145 Citrobacter koseri (MIC50 and MIC90, 0.25 and 0.5 μg/ml, respectively), and 107 Serratia marcescens (MIC50 and MIC90, 1 and 2 μg/ml, respectively) isolates at ≤4 μg/ml (Table 1).

Overall, plazomicin inhibited 90.7%, 91.1%, 98.4%, and 99.1% of the Morganella morganii, Providencia species, Proteus mirabilis, and Proteus vulgaris group isolates at ≤4 μg/ml, respectively (Table 1). Plazomicin MIC50 values for Morganella morganii, Proteus mirabilis, and Proteus vulgaris (2, 2, and 2 μg/ml, respectively) were identical to the MIC50 values displayed by amikacin (2, 2, and 2 μg/ml, respectively), while gentamicin (0.5, 1, and 0.5 μg/ml, respectively) and tobramycin (0.5, 0.5, and 0.5 μg/ml, respectively) (data not shown) had 2- to 4-fold-lower MIC50 values. Plazomicin displayed MIC50 values (range, 0.25 to 1 μg/ml) lower than those observed for amikacin (2 to 1 μg/ml) for all remaining Enterobacteriaceae species and were similar to those observed for gentamicin (0.5 μg/ml for all species) and tobramycin (range, 0.25 to 2 μg/ml). The MIC50 values of all 4 aminoglycosides were very similar (range, 1 to 2 μg/ml) for Providencia species isolates (data not shown).

Amikacin (MIC50 and MIC90, 1 and 4 μg/ml, respectively), gentamicin (MIC50 and MIC90, 0.5 and 4 μg/ml, respectively), and tobramycin (MIC50 and MIC90, 0.5 and 4 μg/ml, respectively) inhibited 98.9%, 90.3%, and 90.3%, respectively, of the 4,362 Enterobacteriaceae isolates tested by using the CLSI breakpoints (Table 2). Among other comparator agents, meropenem (MIC50 and MIC90, 0.03 and 0.06 μg/ml, respectively; 97.9% susceptible) and tigecycline (MIC50 and MIC90, 0.25 and 1 μg/ml, respectively; 99.0% susceptible according to U.S. Food and Drug Administration [FDA] breakpoints) were most active against the Enterobacteriaceae isolates tested (Table 2).

View this table:
  • View inline
  • View popup
TABLE 2

Activities of plazomicin and comparator agents tested against Enterobacteriaceae isolates

Plazomicin had activity against the majority of Enterobacteriaceae isolates resistant to gentamicin and tobramycin (Table 3), inhibiting 96.5% and 95.5% of the gentamicin-resistant isolates according to CLSI and EUCAST breakpoint criteria, respectively, and 96.9% and 96.5% of the tobramycin-resistant isolates according to the same criteria. Only 14 isolates were resistant to amikacin when applying the CLSI criteria, and plazomicin inhibited 9 (64.3%) of these isolates at ≤4 μg/ml. Plazomicin inhibited 90.0% of the 50 amikacin-resistant isolates identified by using the EUCAST breakpoints at ≤4 μg/ml. Five amikacin-resistant isolates had plazomicin MIC values of ≥128 μg/ml and were resistant to gentamicin and tobramycin.

View this table:
  • View inline
  • View popup
TABLE 3

Activities of plazomicin and comparator aminoglycosides against phenotypes and genotypes of Enterobacteriaceae isolates and other Gram-negative species

For 103 P. aeruginosa isolates, the plazomicin MIC50 and MIC90 values were 4 and 16 μg/ml, respectively. These values were 2-fold higher than those for amikacin and gentamicin (MIC50 and MIC90, 2 and 8 μg/ml, respectively, for both) and 8- to 16-fold higher than those for tobramycin (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively) (Tables 1 and 3). Amikacin (97.1% susceptible according to CLSI breakpoints), tobramycin (94.2% susceptible according to CLSI breakpoints), and colistin (98.1% susceptible according to EUCAST breakpoints) (data not shown) were the most active comparators against P. aeruginosa isolates.

For 95 Acinetobacter species isolates, plazomicin MIC50 and MIC90 values were 4 and 16 μg/ml, respectively (Table 1). Amikacin (MIC50 and MIC90, 4 and >32 μg/ml, respectively), gentamicin (MIC50 and MIC90, 1 and >8 μg/ml, respectively), and tobramycin (MIC50 and MIC90, 1 and >8 μg/ml, respectively) (Table 3) inhibited 83.0%, 69.5%, and 77.9% of the isolates, respectively, according to CLSI breakpoint criteria. Among other comparators, only colistin (94.7% susceptible using CLSI or EUCAST criteria), ampicillin-sulbactam (72.3% using CLSI criteria), and imipenem (70.5% using both criteria) inhibited >70.0% of the isolates (data not shown).

All 72 coagulase-negative staphylococci (plazomicin MIC50 and MIC90, 0.12 and 0.5 μg/ml, respectively) were inhibited by plazomicin at ≤0.5 μg/ml, and 69 S. aureus (plazomicin MIC50 and MIC90, 0.5 and 0.5 μg/ml, respectively) (Table 1) isolates tested were inhibited by plazomicin at ≤2 μg/ml, including methicillin-resistant isolates (30 isolates tested) (Table 1). Gentamicin inhibited 72.2% and 97.1% of the respective coagulase-negative staphylococcus and S. aureus isolates tested at the CLSI breakpoints (data no shown).

Plazomicin had limited antimicrobial activity against Streptococcus pneumoniae (n = 66; MIC50 and MIC90, 32 and 64 μg/ml, respectively) and Enterococcus spp. (n = 58; MIC50 and MIC90, 16 and 64 μg/ml, respectively) (Table 1). As expected, other aminoglycosides also had activities similar to those of plazomicin against these organisms (data not shown).

Activity of plazomicin against carbapenem-resistant and carbapenemase-producing Enterobacteriaceae.A total of 97 (2.2% of Enterobacteriaceae) CRE isolates were identified in this study. Plazomicin (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively) inhibited 99.0% of these isolates at an MIC of ≤2 or ≤4 μg/ml (Table 2). CRE isolates were highly resistant to comparator agents, but nearly all of them were susceptible to tigecycline (100.0% susceptible according to U.S. FDA breakpoints) (Table 2). Amikacin (MIC50 and MIC90, 16 and 32 μg/ml, respectively), gentamicin (MIC50 and MIC90, 2 and >8 μg/ml, respectively), and tobramycin (MIC50 and MIC90, >8 and >8 μg/ml, respectively) inhibited only 64.9%, 56.7%, and 13.4% of the isolates, respectively, at current CLSI breakpoints (Table 2).

Among 113 isolates displaying imipenem and/or meropenem MIC values of ≥2 μg/ml, carbapenemases were detected in 87 isolates, including 79 K. pneumoniae, 4 K. oxytoca, 2 C. freundii, 1 E. cloacae, and 1 S. marcescens isolates. All isolates carried a blaKPC variant: 56 carried blaKPC-3, 29 carried blaKPC-2, 1 carried blaKPC-4, and 1 carried blaKPC-17. These isolates were detected in all U.S. census divisions but were observed mainly in the Middle Atlantic division (52 isolates; 59.8% of the carbapenemase-producing Enterobacteriaceae [CPE]).

Plazomicin (MIC50 and MIC90, 0.25 and 1 μg/ml, respectively) inhibited 86 of the 87 (98.9%) isolates carrying blaKPC at ≤2 or ≤4 μg/ml (Tables 2 and 3). One isolate exhibited a plazomicin MIC at >128 μg/ml, was resistant to all aminoglycosides, and carried the 16S rRNA methyltransferase gene rmtF1. Amikacin (MIC50 and MIC90, 16 and 32 μg/ml, respectively), gentamicin (MIC50 and MIC90, 4 and >8 μg/ml, respectively), and tobramycin (MIC50 and MIC90, >8 and >8 μg/ml, respectively) inhibited 63.2 and 42.5%, 55.2 and 48.3%, and 11.5 and 9.2% of the respective CPE isolates according to current CLSI/EUCAST breakpoint criteria.

Carbapenemase-negative isolates included 16 K. pneumoniae isolates, 4 S. marcescens isolates, and 3 isolates of other species. Plazomicin demonstrated comparable activities against the carbapenemase-negative (MIC50 and MIC90, 0.5 and 1 μg/ml, respectively) and CPE (MIC50 and MIC90, 0.25 and 1 μg/ml, respectively) isolates, and the highest plazomicin MIC value observed was at 2 μg/ml. In contrast, the aminoglycoside comparators were more potent against the 26 carbapenemase-negative isolates than against the CPE isolates. Amikacin (MIC50 and MIC90, 4 and 16 μg/ml, respectively), gentamicin (MIC50 and MIC90, 1 and >8 μg/ml, respectively), and tobramycin (MIC50 and MIC90, 2 and >8 μg/ml, respectively) inhibited 92.3%, 69.2%, and 57.7% of the carbapenemase-negative isolates, respectively, when applying the CLSI breakpoints (Table 2).

DISCUSSION

Patients with prolonged hospitalization, including those in intensive care or long-term-care facilities, immunocompromised patients, and others with malignant conditions, often develop infections, and many of the infections are caused by MDR organisms (1). These organisms include members of the Enterobacteriaceae family, including CRE, and pandrug- and extensively drug-resistant P. aeruginosa, A. baumannii, and Gram-positive species, including E. faecium and S. aureus. The urgent need for monitoring initiatives and new potential therapeutic options for these organisms has been recognized by the medical and scientific communities, and although various new antimicrobial agents for Gram-positive infections have been approved, the number of non-β-lactam candidates for treating Gram-negative infections in late-stage development is still limited (2–5).

In this study, plazomicin displayed activity against CRE and CPE isolates detected in U.S. hospitals. The majority of the CRE isolates (and all CPE isolates) carried blaKPC, and only 1 of these isolates had a plazomicin MIC value of >4 μg/ml. CRE isolates displayed elevated rates of resistance to all β-lactams and comparator agents, including gentamicin and amikacin, which inhibited 63.2% or fewer of the blaKPC-carrying isolates at current CLSI or EUCAST breakpoints. Furthermore, plazomicin displayed activity against most isolates resistant to gentamicin and tobramycin according to CLSI or EUCAST breakpoints and inhibited >63% of the amikacin-resistant isolates.

Combination therapy is often used to treat infections caused by CRE, and this might include an aminoglycoside. The in vitro results presented here suggest that there is a potential role for this new agent in the antimicrobial armamentarium against difficult-to-treat MDR organisms. These data are supported by the results of 2 recent phase 3 clinical trials that evaluated plazomicin in complicated urinary tract infections and in serious infections due to CRE (i.e., bloodstream infections, hospital-acquired and ventilator-associated bacterial pneumonia, and complicated urinary tract infections) (ClinicalTrials.gov registration numbers NCT02486627 [https://clinicaltrials.gov/ct2/show/NCT02486627] and NCT01970371 [https://clinicaltrials.gov/ct2/show/NCT01970371]).

Plazomicin demonstrated activity against Enterobacteriaceae, Staphylococcus spp. regardless of methicillin resistance, and some P. aeruginosa and Acinetobacter species isolates. A tentative breakpoint of 4 μg/ml was applied during the plazomicin development program and thus was also applied here for the analysis of the Enterobacteriaceae population, based on pharmacokinetic/pharmacodynamic (PK/PD) data, which was supported by animal efficacy data (12). By applying this tentative breakpoint, the in vitro activity of plazomicin was similar to or greater than those of other aminoglycosides against important organism groups, which include multidrug-resistant isolates, that can pose a challenge for current antimicrobial chemotherapy options.

MATERIALS AND METHODS

Bacterial isolates.A total of 4,825 clinical isolates, including 4,362 Enterobacteriaceae, 265 Gram-positive cocci, 103 P. aeruginosa isolates, and 95 Acinetobacter spp., collected during 2014 and 2015 in 70 hospitals located in 61 U.S. cities were evaluated as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. This surveillance program collects key pathogens in targeted numbers (1 per patient episode) deemed to cause urinary tract infections (1,414 isolates), bloodstream infections (1,178), pneumonia in hospitalized patients (1,125), skin and skin structure infections (566), and intra-abdominal infections (441). Other infection sources (101 isolates) were also accepted for uncommon species. Species identification was confirmed, when necessary, by matrix-assisted laser desorption ionization–time of flight mass spectrometry using the Bruker Daltonics MALDI Biotyper (Bruker Daltonics, Billerica, MA, USA), according to the manufacturer's instructions.

Antimicrobial susceptibility testing.All isolates were tested for susceptibility to plazomicin and comparator agents using the reference broth microdilution method described by the CLSI (13). Categorical interpretations for all comparator agents were found in CLSI criteria in document M100 (14), EUCAST breakpoint tables (15), and/or the FDA website (16). Quality control was performed by using E. coli ATCC 25922, S. aureus ATCC 29213, P. aeruginosa ATCC 27853, Enterococcus faecalis ATCC 29212, and S. pneumoniae ATCC 49619. All quality control MIC results were within acceptable ranges as reported in CLSI documents.

Definitions.CRE was defined as any isolate exhibiting an imipenem, meropenem, or doripenem MIC value of >2 μg/ml. Proteus mirabilis and indole-positive Proteeae were selected by using meropenem and doripenem only due to the intrinsically elevated imipenem MIC values.

Characterization of carbapenemases.Isolates nonsusceptible to imipenem or meropenem were screened by PCR followed by DNA sequencing of blaKPC, blaIMP, blaVIM, blaNDM, blaOXA-48, blaGES (blaGES-2, blaGES-4, blaGES-5, blaGES-6, and blaGES-8), blaNMC-A, blaSME, and blaIMI (17). Isolates yielding negative results for these genes were tested for less common carbapenemases, including genes encoding FRI-1, BKC-1, GIM-1/-2, SIM-1, SPM-1, KHM-1, AIM-1, BIC-1, and DIM-1 (18).

Amplicons generated were sequenced on both strands, and the nucleotide sequences obtained were analyzed by using the Lasergene software package (DNAStar, Madison, WI, USA) and compared to available sequences via an NCBI BLAST search (http://www.ncbi.nlm.nih.gov/blast/).

ACKNOWLEDGMENTS

We thank the JMI staff for their technical expertise in all stages of this study and manuscript preparation.

This study was performed by JMI Laboratories and supported by Achaogen, which included funding for services related to preparing the manuscript.

JMI Laboratories was contracted to perform services in 2017 for Achaogen; Allecra Therapeutics; Allergan; Amplyx Pharmaceuticals; Antabio; API; Astellas Pharma; AstraZeneca; Athelas; Basilea Pharmaceutica; Bayer AG; BD; Becton, Dickinson and Co.; Boston Pharmaceuticals; CEM-102 Pharma; Cempra; Cidara Therapeutics, Inc.; CorMedix; CSA Biotech; Cutanea Life Sciences, Inc.; Entasis Therapeutics, Inc.; Geom Therapeutics, Inc.; GSK; Iterum Pharma; Medpace; Melinta Therapeutics, Inc.; Merck & Co., Inc.; MicuRx Pharmaceuticals, Inc.; N8 Medical, Inc.; Nabriva Therapeutics, Inc.; NAEJA-RGM; Novartis; Paratek Pharmaceuticals, Inc.; Pfizer; Polyphor; Ra Pharma; Rempex; Riptide Bioscience, Inc.; Roche; Scynexis; Shionogi; Sinsa Labs, Inc.; Skyline Antiinfectives; Sonoran Biosciences; Spero Therapeutics; Symbiotica; Synlogic; Synthes Biomaterials; TenNor Therapeutics; Tetraphase; The Medicines Company; Theravance Biopharma; VenatoRx Pharmaceuticals, Inc.; Wockhardt; Yukon Pharma; Zai Laboratory; and Zavante Therapeutics, Inc. There are no speakers' bureaus or stock options to declare. A.W.S. and K.M.K. are employees of Achaogen and contributed with the design of the study and review of the manuscript but not with analyzing or interpreting the results.

FOOTNOTES

    • Received 14 February 2018.
    • Returned for modification 2 March 2018.
    • Accepted 12 May 2018.
    • Accepted manuscript posted online 4 June 2018.
  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

REFERENCES

  1. 1.↵
    1. Pogue JM,
    2. Kaye KS,
    3. Cohen DA,
    4. Marchaim D
    . 2015. Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Clin Microbiol Infect 21:302–312. doi:10.1016/j.cmi.2014.12.025.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Boucher HW,
    2. Talbot GH,
    3. Bradley JS,
    4. Edwards JE,
    5. Gilbert D,
    6. Rice LB,
    7. Scheld M,
    8. Spellberg B,
    9. Bartlett J
    . 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12. doi:10.1086/595011.
    OpenUrlCrossRefPubMedWeb of Science
  3. 3.↵
    1. Bassetti M,
    2. Merelli M,
    3. Temperoni C,
    4. Astilean A
    . 2013. New antibiotics for bad bugs: where are we? Ann Clin Microbiol Antimicrob 12:22. doi:10.1186/1476-0711-12-22.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Savage RD,
    2. Fowler RA,
    3. Rishu AH,
    4. Bagshaw SM,
    5. Cook D,
    6. Dodek P,
    7. Hall R,
    8. Kumar A,
    9. Lamontagne F,
    10. Lauzier F,
    11. Marshall J,
    12. Martin CM,
    13. McIntyre L,
    14. Muscedere J,
    15. Reynolds S,
    16. Stelfox HT,
    17. Daneman N
    . 2016. The effect of inadequate initial empiric antimicrobial treatment on mortality in critically ill patients with bloodstream infections: a multi-centre retrospective cohort study. PLoS One 11:e0154944. doi:10.1371/journal.pone.0154944.
    OpenUrlCrossRef
  5. 5.↵
    1. Zaragoza R,
    2. Artero A,
    3. Camarena JJ,
    4. Sancho S,
    5. Gonzalez R,
    6. Nogueira JM
    . 2003. The influence of inadequate empirical antimicrobial treatment on patients with bloodstream infections in an intensive care unit. Clin Microbiol Infect 9:412–418. doi:10.1046/j.1469-0691.2003.00656.x.
    OpenUrlCrossRefPubMedWeb of Science
  6. 6.↵
    1. Ramirez MS,
    2. Tolmasky ME
    . 2010. Aminoglycoside modifying enzymes. Drug Resist Updat 13:151–171. doi:10.1016/j.drup.2010.08.003.
    OpenUrlCrossRefPubMedWeb of Science
  7. 7.↵
    1. Mingeot-Leclercq MP,
    2. Glupczynski Y,
    3. Tulkens PM
    . 1999. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother 43:727–737.
    OpenUrlFREE Full Text
  8. 8.↵
    1. Aggen JB,
    2. Armstrong ES,
    3. Goldblum AA,
    4. Dozzo P,
    5. Linsell MS,
    6. Gliedt MJ,
    7. Hildebrandt DJ,
    8. Feeney LA,
    9. Kubo A,
    10. Matias RD,
    11. Lopez S,
    12. Gomez M,
    13. Wlasichuk KB,
    14. Diokno R,
    15. Miller GH,
    16. Moser HE
    . 2010. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 54:4636–4642. doi:10.1128/AAC.00572-10.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Cox G,
    2. Ejim L,
    3. Stogios PJ,
    4. Koteva K,
    5. Borderleau E,
    6. Evdokimova E,
    7. Sieron AO,
    8. Serio AW,
    9. Krause KM,
    10. Wright GD
    . 2018. Plazomicin retains antibiotic activity against most aminoglycoside modifying enzymes. ACS Infect Dis 4:980–987. doi:10.1021/acsinfecdis.8b00001.
    OpenUrlCrossRef
  10. 10.↵
    1. Karaiskos I,
    2. Souli M,
    3. Giamarellou H
    . 2015. Plazomicin: an investigational therapy for the treatment of urinary tract infections. Expert Opin Invest Drugs 24:1501–1511. doi:10.1517/13543784.2015.1095180.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Zhanel GG,
    2. Lawson CD,
    3. Zelenitsky S,
    4. Findlay B,
    5. Schweizer F,
    6. Adam H,
    7. Walkty A,
    8. Rubinstein E,
    9. Gin AS,
    10. Hoban DJ,
    11. Lynch JP,
    12. Karlowsky JA
    . 2012. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther 10:459–473. doi:10.1586/eri.12.25.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Abdelraouf K,
    2. Kim A,
    3. Krause KM,
    4. Nicolau DP
    . 2017. Assessment of the in vivo of plazomicin alone or in combination with meropenem or tigecycline against Enterobacteriaceae isolates exhibiting various resistance mechanisms in an immunocompetent murine septicemia model, poster 1506. Abstr IDWeek 2017, 4 to 8 October 2017, San Diego, CA.
  13. 13.↵
    CLSI. 2012. M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 9th ed. CLSI, Wayne, PA.
  14. 14.↵
    CLSI. 2017. M100-S27. Performance standards for antimicrobial susceptibility testing: 27th informational supplement. CLSI, Wayne, PA.
  15. 15.↵
    EUCAST. 2017. Breakpoint tables for interpretation of MICs and zone diameters. Version 7.0, January 2017. http://www.eucast.org/clinical_breakpoints/. Accessed January 2017.
  16. 16.↵
    U.S. Food and Drug Administration. 2017. Tigecycline–injection products. FDA-identified interpretive criteria. U.S. Food and Drug Administration, Silver Spring, MD. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm587585.htm. Accessed June 2018.
  17. 17.↵
    1. Castanheira M,
    2. Mendes RE,
    3. Woosley LN,
    4. Jones RN
    . 2011. Trends in carbapenemase-producing Escherichia coli and Klebsiella spp. from Europe and the Americas: report from the SENTRY antimicrobial surveillance programme (2007-09). J Antimicrob Chemother 66:1409–1411. doi:10.1093/jac/dkr081.
    OpenUrlCrossRefPubMedWeb of Science
  18. 18.↵
    1. Poirel L,
    2. Walsh TR,
    3. Cuvillier V,
    4. Nordmann P
    . 2011. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis 70:119–123. doi:10.1016/j.diagmicrobio.2010.12.002.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Download PDF
Citation Tools
In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes
Mariana Castanheira, Andrew P. Davis, Rodrigo E. Mendes, Alisa W. Serio, Kevin M. Krause, Robert K. Flamm
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00313-18; DOI: 10.1128/AAC.00313-18

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes
Mariana Castanheira, Andrew P. Davis, Rodrigo E. Mendes, Alisa W. Serio, Kevin M. Krause, Robert K. Flamm
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00313-18; DOI: 10.1128/AAC.00313-18
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • INTRODUCTION
    • RESULTS
    • DISCUSSION
    • MATERIALS AND METHODS
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

aminoglycosides
plazomicin
carbapenem-resistant Enterobacteriaceae

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596