Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.
KEYWORDS: aminoglycosides, plazomicin, susceptibility
ABSTRACT
Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.
TEXT
Plazomicin is a semisynthetic aminoglycoside derived from sisomicin that contains structural modifications enabling it to retain activity in the presence of the vast majority of aminoglycoside-modifying enzymes (AMEs) (1, 2). AMEs are the most common mechanisms of resistance to aminoglycoside agents in Gram-positive and Gram-negative bacteria and confer resistance to different aminoglycoside molecules, including clinically used agents such as gentamicin, tobramycin, and, less frequently, amikacin (3).
Plazomicin was recently approved for clinical use by the FDA for treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae, all of which are susceptible to this agent. The in vitro activity of plazomicin was evaluated against isolates collected in 2014 to 2015 from hospitals located in the United States and Europe (4, 5). These studies demonstrated that plazomicin is active against Enterobacterales, including isolates carrying prevalent AME genes (6), carbapenem-resistant isolates, Staphylococcus species isolates regardless of methicillin resistance pattern, and selected Pseudomonas aeruginosa isolates (4, 5). Additionally, this new aminoglycoside was very active against Enterobacterales from Canada (7) and Brazil (8); carbapenem-resistant Enterobacteriaceae (CRE) isolates from the United Kingdom, United States (9), and Spain (10); multidrug-resistant (MDR) isolates from Greece; and a large collection of polymyxin-resistant Enterobacterales isolates (11).
In this study, we report the activity of plazomicin against all 8,783 Enterobacterales isolates collected in 32 U.S. hospitals during 2016 (n = 4,231) and 2017 (n = 4,552) as a part of the SENTRY Antimicrobial Surveillance Program. Furthermore, we analyzed the susceptibility rates of plazomicin, amikacin, gentamicin, and tobramycin by applying current breakpoints published by different organizations, including breakpoints generated with the same scientific rigor that was employed by regulatory agencies to evaluate the plazomicin MIC breakpoints.
Isolates tested were consecutively collected from bloodstream infections (n = 2,473), urinary tract infections (n = 2,550), pneumonias in hospitalized patients (n = 1,751), skin and skin structure infections (n = 1,207), and intra-abdominal infections (n = 802) according to common protocols. Only 1 isolate per patient episode was included. Species identification was confirmed, when necessary, by matrix-assisted laser desorption ionization–time of flight mass spectrometry using the Bruker Daltonics MALDI Biotyper (Billerica, MA), following manufacturer instructions.
Antimicrobial susceptibility testing was performed by the reference broth microdilution method as described by CLSI (12). Quality control was performed according to CLSI guidelines, and MIC results were within acceptable ranges as published in CLSI documents (12, 13).
Plazomicin was active against 97.0% of the 8,783 Enterobacterales isolates (MIC50/90, 0.5/1 mg/liter) at the FDA-approved susceptibility breakpoint of ≤2 mg/liter (14) (Table 1). The activity of plazomicin was similar among E. coli, K. pneumoniae, E. cloacae, Citrobacter spp., and Serratia marcescens isolates; this new agent inhibited >99% of these isolates at the FDA susceptibility breakpoint (14) (Table 1).
TABLE 1.
Activity of plazomicin against 8,783 Enterobacterales from the United States, 2016–2017
| Organism | Isolates (n [cumulative %]) inhibited at MIC (mg/liter) of: |
MIC (mg/liter) |
Susceptible (FDA breakpointsa) (%) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | 128 | >128 | MIC50 | MIC90 | ||
| Enterobacteriaceae (n = 8,783) | 3,206 (67.2) | 2,029 (90.3) | 584 (97.0) | 227 (99.6) | 26 (99.9) | 3 (99.9) | 1 (99.9) | 1 (99.9) | 0 (99.9) | 6 (100.0) | 0.5 | 1 | 97.0 |
| CRE (n = 98) | 14 (76.5) | 16 (92.9) | 3 (95.9) | 2 (98.0) | 1 (99.0) | 0 (99.0) | 0 (99.0) | 0 (99.0) | 1 (100.0) | 0.25 | 1 | 95.9 | |
| Escherichia coli (n = 4,053) | 2,172 (58.0) | 1,491 (94.8) | 198 (99.7) | 12 (100.0) | 0.5 | 1 | 99.7 | ||||||
| Klebsiella pneumoniae (n = 1,771) | 192 (98.5) | 17 (99.4) | 2 (99.5) | 1 (99.6) | 0 (99.6) | 1 (99.7) | 0 (99.7) | 0 (99.7) | 0 (99.7) | 6 (100.0) | 0.25 | 0.5 | 99.5 |
| Klebsiella oxytoca (n = 361) | 172 (92.0) | 25 (98.9) | 3 (99.7) | 1 (100.0) | 0.5 | 0.5 | 99.7 | ||||||
| Klebsiella aerogenes (n = 270) | 104 (95.6) | 12 (100.0) | 0.25 | 0.5 | 100.0 | ||||||||
| Enterobacter cloacae species complex (n = 762) | 204 (95.9) | 24 (99.1) | 4 (99.6) | 2 (99.9) | 0 (99.9) | 1 (100.0) | 0.25 | 0.5 | 99.6 | ||||
| Serratia marcescens (n = 521) | 215 (44.1) | 271 (96.2) | 18 (99.6) | 1 (99.8) | 1 (100.0) | 1 | 1 | 99.6 | |||||
| Citrobacter freundii species complex (n = 159) | 85 (88.7) | 16 (98.7) | 1 (99.4) | 1 (100.0) | 0.5 | 1 | 99.4 | ||||||
| Citrobacter koseri (n = 85) | 27 (94.1) | 4 (98.8) | 1 (100.0) | 0.25 | 0.5 | 100.0 | |||||||
| Morganella morganii (n = 128) | 11 (8.6) | 53 (50.0) | 43 (83.6) | 18 (97.7) | 3 (100.0) | 1 | 4 | 83.6 | |||||
| Providencia spp. (n = 57) | 8 (14.0) | 15 (40.4) | 21 (77.2) | 5 (86.0) | 6 (96.5) | 0 (96.5) | 1 (98.2) | 1 (100.0) | 2 | 8 | 77.2 | ||
| Proteus mirabilis (n = 587) | 13 (2.7) | 85 (17.2) | 286 (65.9) | 184 (97.3) | 15 (99.8) | 1 (100.0) | 2 | 4 | 65.9 | ||||
| Proteus vulgaris group (n = 29) | 3 (10.3) | 16 (65.5) | 7 (89.7) | 2 (96.6) | 1 (100.0) | 1 | 4 | 89.7 | |||||
FDA breakpoints were accessed from reference 14.
Among 264 isolates nonsusceptible to plazomicin, 227 exhibited MIC values of 4 mg/liter and were categorized as intermediate. Among the plazomicin intermediate isolates, 184 were P. mirabilis (MIC50/90, 2/4 mg/liter) and another 25 isolates belonged to other Proteus (MIC50/90, 1/4 mg/liter), Providencia (MIC50/90, 2/8 mg/liter), or Morganella (MIC50/90, 1/4 mg/liter) species (Table 1). Proteus, Providencia, and Morganella species exhibited slightly higher MIC50 and MIC90 values than the overall Enterobacterales collection. Among the remaining isolates with intermediate plazomicin MIC values were 12 E. coli, 2 E. cloacae, and 1 each of C. freundii, K. oxytoca, K. pneumoniae, and S. marcescens.
Among 37 isolates resistant to plazomicin (MIC, ≥8 mg/liter), there were 28 isolates of the species displaying elevated modal plazomicin MICs (i.e., Proteus, Providencia, and Morganella) in addition to 7 K. pneumoniae, 1 E. cloacae, and 1 S. marcescens isolates. Six K. pneumoniae isolates had plazomicin MIC values of ≥64 mg/liter; were resistant to amikacin, gentamicin, and tobramycin; and carried 16S rRNA methyltransferases armA (3 isolates), rmtF1 (2 isolates), or rmtF2 (1 isolate) as determined by whole-genome sequencing analysis. The remaining 1 K. pneumoniae, 1 E. cloacae, and 1 S. marcescens isolates had plazomicin MIC values of 8 or 16 mg/liter, did not carry 16S rRNA methyltransferases, and were resistant to amikacin (MIC, 32 mg/liter) and gentamicin (MIC, ≥16 mg/liter), with 1 isolate having a low tobramycin MIC (≤0.5 mg/liter). Interestingly, 6 of the 9 plazomicin-resistant isolates were detected in hospitals within the Mid-Atlantic Census Division, and none carried metallo-β-lactamases that have been associated with the presence of 16S rRNA methyltransferases.
This Enterobacterales collection included 98 CRE isolates that exhibited imipenem (P. mirabilis and indole-positive Proteeae were not included due to their intrinsically elevated MIC values) and/or meropenem MIC values of ≥4 mg/liter. Plazomicin was active against 95.8% of these isolates, whereas amikacin, gentamicin, and tobramycin inhibited only 78.6%, 45.9%, and 22.4% of the isolates, respectively, applying CLSI breakpoint criteria (13), which have been adopted by the FDA (14) (Table 2). These values are lower when using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (15): 67.3%, 39.8%, and 20.4% for amikacin, gentamicin, and tobramycin, respectively (Table 2).
TABLE 2.
Susceptibility rates for aminoglycosides against Enterobacterales isolates from U.S. hospitals applying different breakpoint criteria
| Antimicrobial agent by organism groupa | Breakpoint setting organization |
||||
|---|---|---|---|---|---|
| CLSIb | EUCASTc | USCAST (pneumonia)d | USCASTd | FDAe | |
| Susceptibility breakpoints (mg/liter) | |||||
| Plazomicin | NAf | NA | NA | ≤4 | ≤2 |
| Amikacin | ≤16 | ≤8 | NA | ≤4 | ≤16 |
| Gentamicin | ≤4 | ≤2 | ≤1 | ≤2 | ≤4 |
| Tobramycin | ≤4 | ≤2 | ≤1 | ≤2 | ≤4 |
| Percentage susceptible | |||||
| All Enterobacterales (n = 8,783) | |||||
| Plazomicin | NA | NA | NA | 99.6 | 97.0 |
| Amikacin | 99.4 | 98.5 | NA | 94.2 | 99.4 |
| Gentamicin | 90.1 | 89.5 | 86.8 | 89.5 | 90.1 |
| Tobramycin | 89.9 | 87 | 81 | 87.0 | 89.9 |
| CRE (n = 98) | |||||
| Plazomicin | NA | NA | NA | 98.0 | 95.9 |
| Amikacin | 78.6 | 67.3 | NA | 49.0 | 78.6 |
| Gentamicin | 45.9 | 39.8 | 32.7 | 39.8 | 45.9 |
| Tobramycin | 22.4 | 20.4 | 15.3 | 20.4 | 22.4 |
| MDR (n = 881) | |||||
| Plazomicin | NA | NA | NA | 97.3 | 89.8 |
| Amikacin | 94.3 | 87.3 | NA | 69.4 | 94.3 |
| Gentamicin | 43.9 | 41.4 | 38.3 | 41.4 | 43.9 |
| Tobramycin | 32.1 | 25.5 | 21.0 | 25.5 | 32.1 |
| XDR (n = 102) | |||||
| Plazomicin | NA | NA | NA | 92.2 | 89.2 |
| Amikacin | 72.5 | 61.8 | NA | 43.1 | 72.5 |
| Gentamicin | 30.4 | 23.5 | 16.7 | 23.5 | 30.4 |
| Tobramycin | 7.8 | 1.0 | 0.0 | 1.0 | 7.8 |
| PDR (n = 3) | |||||
| Plazomicin | NA | NA | NA | 100.0 | 100.0 |
| Amikacin | 100.0 | 100.0 | NA | 66.7 | 100.0 |
| Gentamicin | 33.3 | 0.0 | 0.0 | 0.0 | 33.3 |
| Tobramycin | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Nonsusceptible to 2 aminoglycosides (n = 680) | |||||
| Plazomicin | NA | NA | NA | 98.7 | 96.8 |
| Amikacin | 95.6 | 91.0 | NA | 73.2 | 95.6 |
| Gentamicin | 4.4 | 4.1 | 2.2 | 4.1 | 4.4 |
| Tobramycin | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Nonsusceptible to 3 aminoglycosides (n = 23) | |||||
| Plazomicin | NA | NA | NA | 60.9 | 52.2 |
| Amikacin | 0.0 | 0.0 | NA | 0.0 | 0.0 |
| Gentamicin | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Tobramycin | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
Enterobacterales isolates were classified as MDR and extensively drug resistant (XDR) when nonsusceptible to at least one agent in ≥3 antimicrobial classes or at least one agent in all but ≤2 antimicrobial classes, respectively (16). The following antimicrobial class representatives and CLSI interpretive criteria were used: ceftriaxone, ≥2 mg/liter; meropenem, ≥2 mg/liter; piperacillin-tazobactam, ≥32/4 mg/liter; levofloxacin, ≥4 mg/liter; gentamicin, ≥8 mg/liter; tigecycline, ≥4 mg/liter; and colistin, ≥4 mg/liter (16, 17). PDR isolates were resistant to all antimicrobial classes tested (17).
Plazomicin was active against 89.8% and 89.2% of the MDR (n = 881) and XDR (n = 102) isolates included in this study, respectively. When applying the CLSI breakpoints, 94.3%, 43.9%, and 32.1% of the MDR isolates were susceptible to amikacin, gentamicin, and tobramycin, respectively; and 72.5%, 30.4%, and 7.8% of the XDR isolates were susceptible to these agents, respectively (Table 2).
A recent document published by the U.S. Committee on Antimicrobial Susceptibility Testing (USCAST) describes the rationale for lowering the breakpoints of older aminoglycosides based on modern pharmacokinetic/pharmacodynamic (PK/PD) parameters that were not available when these compounds first were approved and introduced to the market (18). Applying the published USCAST breakpoints, the susceptibility rates of amikacin and gentamicin against CRE isolates reduced further to 49.0% and 39.8%, respectively (19). Lower susceptibility rates were also observed against MDR (69.4% and 41.4% for amikacin and gentamicin, respectively) and XDR (43.1% and 23.5%, for amikacin and gentamicin, respectively) isolates applying the USCAST breakpoints instead of CLSI interpretative criteria (13). These susceptibility rates were even lower for gentamicin when using the USCAST pneumonia breakpoint (≤1 mg/liter for susceptible) (Table 2).
Last, we analyzed isolates that were nonsusceptible to any 2 of the older aminoglycoside agents (amikacin, gentamicin, and tobramycin) or all 3 when applying the CLSI breakpoints. Isolates nonsusceptible to at least 2 older aminoglycoside agents were mostly susceptible to plazomicin when applying the FDA and USCAST breakpoints (96.8% and 98.7%, respectively). Amikacin inhibited 95.6% of the isolates nonsusceptible to 2 aminoglycosides with the current CLSI/FDA breakpoints, and 91.0% of these were susceptible to amikacin when using EUCAST interpretative criteria; however, when using USCAST breakpoints, only 73.2% of the isolates were susceptible to amikacin. Virtually all of these isolates were resistant to gentamicin, and all were resistant to tobramycin. Plazomicin displayed 52.2% (FDA) to 60.9% (USCAST) activity against isolates nonsusceptible to all 3 aminoglycosides (Table 2).
Plazomicin exhibited activity against Enterobacterales isolates from U.S. hospitals collected in 2016 and 2017. Additionally, these data demonstrate that plazomicin is more active than older aminoglycosides against difficult-to-treat isolates, such as CRE and XDR, for which therapeutic options are limited. More important, when analyzing CRE, MDR, and XDR isolates using breakpoints determined by state-of-the-art PK/PD parameters, the difference in susceptibility rates is greater, making plazomicin a more attractive alternative for the treatment of serious infections caused by MDR, XDR, and CRE isolates than older aminoglycosides.
Resistance to plazomicin is caused mainly by the activity of 16S rRNA ribosomal methyltransferases that protect the ribosome and prevent the binding of virtually all aminoglycoside molecules, causing high resistance levels. As demonstrated in this study and prior investigations, the occurrence of 16S rRNA ribosomal methyltransferases is rare in the United States (4); in this 2-year surveillance of >8,000 isolates, only 6 (0.07%) of these enzymes were observed. Additionally, AAC(2′)-Ia and APH(2″)-IVa have been shown to use plazomicin as a substrate, but these enzymes are uncommon and limited to Providencia stuartii and Enterococcus spp. isolates (1).
This study and others demonstrate that plazomicin exhibits in vitro activity against Enterobacterales isolates that do not carry 16S rRNA ribosomal methyltransferases that are uncommon in U.S. hospitals (20). This agent has significantly greater activity than gentamicin and tobramycin against CRE, MDR, and XDR isolates, which have limited effective therapeutic options. Furthermore, when applying interpretative criteria established with similar PK/PD parameters to those used to determine plazomicin breakpoints, the activities of amikacin, gentamicin, and tobramycin were found to be much lower against CRE, MDR, and XDR isolates.
ACKNOWLEDGMENTS
We thank all SENTRY Antimicrobial Surveillance Program Participants for their invaluable contributions.
This study was performed by JMI Laboratories. No other funding was received for manuscript preparation or data analysis. The SENTRY Antimicrobial Surveillance Program was supported by Achaogen from 2014 to 2018.
JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc.; Albany College of Pharmacy and Health Sciences; Allecra Therapeutics; Allergan; AmpliPhi Biosciences Corp.; Amplyx; Antabio; American Proficiency Institute; Arietis Corp.; Arixa Pharmaceuticals, Inc.; Astellas Pharma Inc.; Athelas; Basilea Pharmaceutica Ltd.; Bayer AG; Becton, Dickinson and Company; bioMérieux SA; Boston Pharmaceuticals; Bugworks Research Inc.; CEM-102 Pharmaceuticals; Cepheid; Cidara Therapeutics, Inc.; CorMedix Inc.; DePuy Synthes; Destiny Pharma; Discuva Ltd.; Dr. Falk Pharma GmbH; Emery Pharma; Entasis Therapeutics; Eurofarma Laboratorios SA; U.S. Food and Drug Administration; Fox Chase Chemical Diversity Center, Inc.; Gateway Pharmaceutical LLC; GenePOC Inc.; Geom Therapeutics, Inc.; GlaxoSmithKline plc; Harvard University; Helperby; HiMedia Laboratories; F. Hoffmann-La Roche Ltd.; ICON plc; Idorsia Pharmaceuticals Ltd.; Iterum Therapeutics plc; Laboratory Specialists, Inc.; Melinta Therapeutics, Inc.; Merck & Co., Inc.; Microchem Laboratory;, Micromyx; MicuRx Pharmaceuticals, Inc.; Mutabilis Co.; Nabriva Therapeutics plc; NAEJA-RGM; Novartis AG; Oxoid Ltd.; Paratek Pharmaceuticals, Inc.; Pfizer, Inc.; Polyphor Ltd.; Pharmaceutical Product Development, LLC; Prokaryotics Inc.; Qpex Biopharma, Inc.; Ra Pharmaceuticals, Inc.; Roivant Sciences, Ltd.; Safeguard Biosystems; Scynexis, Inc.; SeLux Diagnostics, Inc.; Shionogi and Co., Ltd.; SinSa Labs; Spero Therapeutics; Summit Pharmaceuticals International Corp.; Synlogic; T2 Biosystems, Inc.; Taisho Pharmaceutical Co., Ltd.; TenNor Therapeutics Ltd.; Tetraphase Pharmaceuticals; The Medicines Company; Theravance Biopharma; University of Colorado; University of Southern California-San Diego; University of North Texas Health Science Center; VenatoRx Pharmaceuticals, Inc.; Vyome Therapeutics Inc.; Wockhardt; Yukon Pharmaceuticals, Inc.; Zai Lab; Zavante Therapeutics, Inc. We have no speakers’ bureaus or stock options to declare.
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