Sara Vo Latz 2019

Plazomicin: A New Aminoglycoside
Louis D. Saravolatz, MD, MACP, FIDSA and Gary E. Stein, PharmD
Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz640/5536695 by Eli M Oboler Library Serials user on 23 July 2019
Ascension-St John Hospital, Wayne State University School of Medicine and Central
Michigan University College of Medicine
Grosse Pointe Woods, Michigan
Michigan State University School of Medicine
East Lansing, Michigan
Corresponding Author:
Louis D Saravolatz, MD, MACP, FIDSA
19251 Mack Ave.
Grosse Pointe Woods, Michigan, 48236
Phone: 313-343-3362
Fax: 313-343-7784
E mail: louis.saravolatz@stjohn.org
Summary: Plazomicin, a novel parenteral aminoglycoside, has been developed for
multidrug-resistant Enterobacteriaceae and is approved for the treatment of complicated
urinary tract infections and pyelonephritis. Its adverse event profile is comparable to
meropenem except for an increased rise in serum creatinine.
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
ABSTRACT:
Plazomicin (ACHN-490) is a novel parenteral aminoglycoside developed to target
multidrug-resistant Enterobacteriaceae. It has recently been approved by the Food and
Drug Administration (FDA) for the management of complicated urinary tract infections
and pyelonephritis caused by susceptible organisms. When compared to meropenem,
plazomicin was not inferior. The adverse event profile for plazomicin was comparable
to meropenem except for an increased additional rise in serum creatinine in the
plazomicin arm compared to the meropenem arm. This review focuses on the mode of
action, antimicrobial activity, pharmacokinetics, clinical indications, and safety profile of
this drug. Considerations for formulary addition and its place in therapy are also
discussed.
Key words: plazomicin, aminoglycoside, CRE
2
Introduction
Plazomicin (formerly ACHN–490) is a novel aminoglycoside that has been developed to
target multidrug-resistant (MDR) Enterobacteriaceae including organisms capable of
producing aminoglycoside modifying enzymes, extended spectrum beta-lactamases,
and carbapenemases (1,2). These resistant pathogens may lead to serious bacterial
infections including but not limited to nosocomial pneumonia or bacteremia that have
become problematic throughout the world. Older aminoglycosides including amikacin,
gentamicin, and tobramycin have limited activity against bacterial strains capable of
producing aminoglycoside modifying enzymes and with the advent of carbapenem
resistant Enterobacteriaceae (CRE), clinicians have limited options against the
multidrug-resistant organisms. We will review plazomicin’ s chemistry, mode of action,
pharmacokinetics, microbiology, clinical indications, adverse events, and place in
therapy to assist the infectious disease physician.
Chemistry and Mode of Action
Plazomicin is a semi-synthetic aminoglycoside antimicrobial derived from
sisomicin, the dehydro analog of gentamicin C1a. Sisomicin, like gentamicin, is affected
by multiple aminoglycoside modifying enzymes (AMEs) which can be produced by
Gram-negative bacteria (3). The addition of a N1 2(S)-hydroxy aminobutyryl and a
hydroxethyl substituent at the 6’ position of sisomicin blocks the action of most AMEs
(4). These chemical modifications allow for increased activity of plazomicin against
isolates harboring AMEs but not against 16S ribosomal methyltransferases that result in
reduced affinity of aminoglycosides to the ribosomal target (5). Additional
3
aminoglycoside resistance mechanisms such as efflux pumps can also induce
plazomicin resistance.
The transport of aminoglycosides across cytoplasmic membranes is energy-
dependent and this rate-limiting step can be blocked by divalent cations, a reduction in
pH, and anaerobic conditions. Thus, the antimicrobial activity of these agents is reduced
in an anaerobic environment, such as an abscess, or in acidic urine. The primary
intracellular site of action of the aminoglycosides is the 30S ribosomal subunit where
they disrupt ribosomal protein synthesis. Several molecular alterations ensue that inhibit
translation and promotes bactericidal activity (6). The blocking substituents incorporated
in plazomicin result in a modest reduction in antibacterial potency compared to
sisomicin and gentamicin but restore activity in the presence of AMEs (7).
Microbiology
Plazomicin has demonstrated potent in vitro activity and has minimum inhibitory
concentration (MIC) 90s of ≤1 mg/L against the Enterobacteriaceae except for Proteus
mirabilis, and Morganella morganii (table 1) (1,2,8,9,10). The susceptibility break point
for plazomicin is ≤2 mg/L (FDA breakpoint). In addition, plazomicin is active against
many aminoglycoside non-susceptible organisms as well as aminoglycoside susceptible
isolates. Plazomicin also demonstrates equivalent activity against extended spectrum
beta-lactamase (ESBL) producing and non-ESBL producing E. coli and Klebsiella
pneumoniae with 90% of isolates being inhibited by an MIC of ≤1 mg/L. Overall,
plazomicin’ s gram-negative in vitro activity is similar to or superior to other
4
aminoglycosides against the Enterobacteriaceae except for Proteus mirabilis,
Morganella morganii, and Providencia spp (2,11). Plazomicin was not more active than
amikacin, gentamicin, and tobramycin against problematic resistant gram-negative
bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii and
demonstrated less activity against these organisms when compared to its activity
against Enterobacteriaceae. Plazomicin, like other aminoglycosides, demonstrates poor
in vitro activity against Stenotrophomonas maltophilia.
Plazomicin has been evaluated against 99 isolates of Acinetobacter spp from European
countries (10) and demonstrated an MIC 90 of >128 mg/L with a percent susceptibility
of 40.0%. This weak activity was not superior to several comparator agents including
amikacin, gentamicin, meropenem, and levofloxacin, which demonstrated susceptibility
percentages between 34 and 41%. Colistin was active against 90% of these strains of
Acinetobacter spp.
Zhang et al tested plazomicin against 110 unique CRE patient isolates including 107
Klebsiella pneumonia producing carbapenemases and found only one isolate resistant
to plazomicin (12). Only 3 (2.7%) were susceptible to meropenem and none to
imipenem. These isolates demonstrated variable susceptibility to amikacin (23.6%),
gentamicin (81.8%), kanamycin (8.2%) and tobramycin (3.6%). The MIC 90 value for
plazomicin was the lowest of all drugs tested (1.0 mg/L) and for the 96 carbapenemase
producing Klebsiella pneumoniae, MIC 90 =0.5 mg/L.
5
When plazomicin was tested against 95 polymyxin resistant Enterobacteriaceae,
including both mcr–1 positive isolates and mcr–1 negative isolates, plazomicin inhibited
89.5% of these isolates at an MIC ≤2 mg/L. When evaluating comparator antibiotics
including amikacin, gentamicin, tobramycin, doripenem, meropenem, tigecycline,
levofloxacin, aztreonam, piperacillin/tazobactam, trimethoprim/ sulfamethoxazole,
ceftriaxone, and ceftazidime, the highest percentage susceptibility among all these
agents was only 21% for amikacin (13). Although plazomicin is active against the most
common aminoglycoside resistance mechanisms, the AMEs, it is not active against the
less common 16S ribosomal RNA methyl–transferases. However, it is active against
Enterobacteriaceae that express resistance mechanisms to other antibiotic classes
including metallo-beta-lactamases (14). In addition, plazomicin inhibited 87% of
Enterobacteriaceae isolates carrying bla oxa-48–like at a MIC of 2 mg/L (10). Since tests
for determining genetic type of resistance for Enterobacteriaceae are not readily available,
clinicians should continue to rely on susceptibility testing for plazomicin.
In an evaluation of plazomicin against ESBL producing E. coli, ESBL producing K
pneumoniae, carbapenem resistant Enterobacteriaceae and colistin resistant
Enterobacteriaceae, plazomicin was more active than the other tested aminoglycosides
and comparable to meropenem/vaborbactam and avibactam/ceftazidime (table 2)
(1,11,13,15,16).
6
Plazomicin demonstrated similar activity to other aminoglycosides against Gram-
positive isolates (table 3) (1). The MIC 90s against both methicillin susceptible and
methicillin-resistant Staphylococcus aureus was 1 mg/L. Plazomicin also exhibited
potent activity against Staphylococcus epidermidis with a MIC 90= 0.5 mg/L.
Noteworthy, plazomicin is not active against streptococci with MIC 90s of 32 mg/L for
Streptococcus pneumoniae, >64 mg/L for Streptococcus agalactiae and 32 mg/L for
Streptococcus pyogenes. Plazomicin is also not active against strains of enterococci
with MIC 90s of > 64 and 16mg/L for Enterococcus faecalis and Enterococcus faecium,
respectively (17).
Plazomicin combined with other antibiotics has been evaluated in synergy studies
against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides
and beta-lactams (18). Synergy between plazomicin and piperacillin/tazobactam or
ceftazidime was observed by checkerboard studies and confirmed by time kill assays.
Antagonism was not seen. This research suggests plazomicin may have a role in
combination therapy for serious Gram-negative infections caused by multi-drug resistant
Enterobacteriaceae. Plazomicin has also been tested in combination with other
antibiotics, mainly carbapenems, against Acinetobacter baumannii (19). Synergy was
consistently seen when combining meropenem or imipenem with plazomicin.
7
Pharmacokinetics
Plazomicin, as with other aminoglycoside antimicrobials, is poorly absorbed and
must be administered parenterally. The aminoglycosides do not penetrate most cells
and have a volume of distribution (Vd) of approximately 25% of body weight, which is
similar to the volume of extracellular fluid. The mean Vd of plazomicin in healthy adults
and those with complicated urinary tract infections (cUTI) was found to be 18 and 31 L,
respectively (20). A mean maximum serum concentration (Cmax) of 51 mg/L and an area
under the concentration time curve (AUC) of 226 mg∙h/L was observed following a
single intravenous (IV) dose (15 mg/kg) of plazomicin in patients with cUTI (21). The
binding of plazomicin to plasma proteins is approximately 20%.
Plazomicin is primarily excreted by the kidneys. It is not metabolized to any
appreciable extent and does not induce or inhibit cytochrome P450 drug-metabolizing
enzymes. The mean serum elimination half-life of plazomicin is approximately 3.5h in
patients with normal renal function (22).
The renal clearance of plazomicin is similar to its total body clearance.
Approximately 90% of unchanged plazomicin is recovered in the urine within one week
following a single 15 mg/kg IV dose. It is recommended that the dose of plazomicin be
decreased in patients with moderate (creatinine clearance < 60 mL/min) renal
impairment to 10 mg/kg per day and severe (CrCl < 30 mL/min) impairment to 10 mg/kg
every 48h to minimize toxicity (23). Patients with a total body weight greater than an
ideal body weight by greater than 25% or more, clinicians should use an adjusted body
weight based on the equation: Adjusted body weight = IBW + 0.4 × [TBW – IBW] (24)
8
The inactivation of aminoglycosides by beta-lactams has been observed both in
vitro and in vivo (25,26). In a simulated Y-site administration study, no visual changes
were observed between plazomicin and any beta-lactam antibiotic evaluated (27). Of
note, daptomycin and levofloxacin did exhibit an increase in turbidity when mixed with
plazomicin.
Clinical indications
Plazomicin has received Food and Drug Administration (FDA) approval for the
treatment of adults 18 years and older with complicated urinary tract infections (cUTI)
and pyelonephritis caused by susceptible microorganisms. This approval was only for
those infections in patients who have limited or no alternative treatment options.
A phase 2, multicenter, randomized, double blind, study of the efficacy and safety of
plazomicin (10mg/kg and 15 mg/kg) compared with levofloxacin 750mg intravenously
was conducted in 145 patients for the treatment of cUTI and acute pyelonephritis (28).
A lower rate of microbiologic recurrence occurring 1 month after the last dose of study
drug was observed in the 15 mg/kg plazomicin treatment group compared to the
levofloxacin treatment group (6.5% versus 23.5%). This study supported proceeding
with the phase 3 trial using plazomicin with a dose of 15 mg/kg.
There was one multicenter, multinational, randomized, double blind phase 3 trial
designed in accordance with FDA guidelines and conducted to evaluate the efficacy and
safety of plazomicin in cUTI and pyelonephritis which is referred to as the "EPIC" study
9
(29). The study compared plazomicin (15mg/kg intravenously once daily) versus
meropenem (1 gram intravenously every 8 hours) for a minimum of 4 days followed by
an option of oral levofloxacin 500 mg daily. Therapeutic drug monitoring was not
performed. The primary objectives were to demonstrate the noninferiority of plazomicin
compared to meropenem based upon the difference in the composite of microbiological
eradication and clinical cure rates in the microbiological modified intent to treat (MITT)
populations on day 5, and at the test of cure visit between 15 and 19 days after the start
of therapy. The trials used a noninferiority margin of 15%. There were 609 patients
enrolled, 604 (99.2%) were included in the safety and MITT populations, and 388
(63.7%) were included in the microbiologic modified intention-to-treat population.
Baseline characteristics were balanced between the treatment groups. The most
common uropathogen was Escherichia coli followed by Klebsiella pneumoniae. There
were 107 patients (28.0%) that had uropathogens with an extended spectrum beta-
lactamase phenotype, 115 (30.1%) had multidrug-resistant uropathogens and 101
(26.4%) had uropathogens that were not susceptible to other aminoglycosides. On day
5, the composite cure rate for plazomicin was 168/191 (88%) versus meropenem
180/197 (91.4%) (difference, -3.4%; 95% confidence interval (CI), -10.0 to 3.1). The
test of cure, which includes a positive outcome requiring both microbiologic and clinical
cure rates for plazomicin and meropenem were 156/191 (81.7%) and 138/197 (70.1%)
respectively (difference, 11.6%; 95% CI, 2.7 to 20.3).
The plazomicin Combating Antibiotic Resistant Enterobacteriaceae trial (CARE) was a
multicenter, randomized, open label trial of patients with bloodstream infections or
10
hospital-acquired or ventilator associated bacterial pneumonia caused by suspected or
confirmed CRE (30). The CARE study was a small open label trial of only 39 patients
who were randomized and 37 had confirmed CRE (29 with bloodstream infections and 8
with hospital-acquired or ventilator associated bacterial pneumonia). The trial
compared plazomicin (15 mg/kg) versus colistin (5 mg colistin base per kilogram per
day) in combination with adjunctive meropenem or tigecycline, for 7-14 days. In this
study, drug concentration monitoring was performed for plazomicin, and dose
modifications were made to target an AUC 24 of 200-400 mg.h/L. Therapeutic drug
monitoring is available through a commercial assay from Thermo Fisher. The primary
outcome was all cause mortality at 28 days or clinically significant disease related
complications. The primary endpoint occurred in 4/17 (24%) of patients receiving
plazomicin and in 10/20 (50%) who received colistin (difference, -26%; 95% CI -55 to 6).
There was a mortality benefit in favor of plazomicin, 2/14 (14%) versus colistin 8/15
(53%). Although this small study did observe an all-cause mortality benefit favoring
plazomicin over colistin, these findings did not provide sufficient power to support formal
hypothesis testing. Thus, plazomicin did not receive approval for bacteremic infections.
The limitations of research conducted to date with plazomicin include indications
confined to the genitourinary tract as well as under representation from countries
outside of Europe, of non-white race, and severely ill patients including those with
bacteremia.
11
Adverse Events
Any adverse events reported in the EPIC trials were comparable in the plazomicin and
the meropenem arm. Events occurring in more than 1% of the patient's including
diarrhea, hypertension, headache, nausea, vomiting, and hypotension were similar in
both arms of the study. Specifically, adverse events related to cochlear and vestibular
function occurred in only one patient in each of the treatment arms. Adverse renal
events as determined by a blinded review included increase in blood creatinine level,
decrease in creatinine clearance, acute kidney injury, renal failure, renal impairment,
and chronic kidney disease, occurred in 11 (3.6%) of the plazomicin arm versus 4
(1.3%) in the meropenem arm. Increases in serum creatinine of > 0.5 mg/dl occurred in
21 (7.0%) in the plazomicin arm versus 12 (4.0 %) in the meropenem arm. The rate of
full recovery for the rise in serum creatinine, at the end of intravenous therapy, occurred
in 6 of 11 (54.5%) in the plazomicin arm versus 4 of 9 (44.4%) in the meropenem arm.
At the last follow-up visit, full recovery of renal function occurred in 9 of 11 (81.8%) in
the plazomicin arm versus 9 of 9 (100%) in the meropenem arm. This suggested that
plazomicin conferred an increased additional 2.3% serum creatinine rise over the
background rate in this patient population at any time during the study. In addition, a
small number (10/300 in the plazomicin arm versus 3/297 in the meropenem arm)
demonstrated an increase in serum creatinine levels approximately one week after
completion of therapy. The incidence of nephrotoxicity was also higher in patients with
a plazomicin plasma trough concentrations greater than or equal to 3 mcg/mL (36%,
10/28) compared to patients with plazomicin plasma trough concentrations of <3
mcg/mL (5%,11/215) (24). Noteworthy, there were no cases of Clostridoides difficile in
12
the plazomicin group and only one in the comparator group. A single death occurred in
the EPIC trial. The patient had been randomized to the plazomicin arm and died on
study day 18 from metastatic uterine cancer discovered within 48 hours following the
enrollment into the study.
Adverse events related to potential ototoxicity appeared uncommon as reports were not
based upon cochlear and vestibular assessments in the phase 3 trial. Even though
there is a known associated risk of ototoxicity with aminoglycosides, the potential for
ototoxicity related to plazomicin treatment could not be defined from the phase 3 trial.
In an earlier study, cochlear and vestibular function was evaluated at baseline and up to
6 months after treatment with plazomicin (20). The evaluation, though conducted in
healthy subjects, did not disclose any evidence of ototoxicity and further supports the
low potential of ototoxicity with plazomicin.
Neuromuscular blockade leading to respiratory depression, a risk associated with the
aminoglycoside class, was not observed in the clinical studies of plazomicin to date.
Nonetheless, caution should be used when administering plazomicin to a patient with a
neuromuscular disorder such as myasthenia gravis or those receiving neuromuscular
blocking agents such as succinylcholine, which may result in a delay in recovery of
neuromuscular function.
13
Place in Therapy
The worldwide emergence of multi drug-resistant (MDR) gram-negative bacteria
has led to a resurgence in the clinical use of aminoglycoside and polymyxin antibiotics.
Plazomicin, a next generation aminoglycoside, maintains bactericidal activity against
most aminoglycoside-resistant Enterobacteriaceae (11). Moreover, this agent is active
in vitro against many isolates also possessing extended-spectrum β-lactamase (ESBL)
and carbapenemase enzymes as mentioned earlier (31). Thus, plazomicin may fit into a
unique role in antimicrobial therapy, since there are few therapeutic options for the
treatment of these MDR pathogens.
Plazomicin also possesses some dosing advantages over other antibiotics, such
as the newer β-lactam/β-lactamase inhibitors, that have activity against MDR gram-
negative bacteria. Plazomicin can be administered over 30 minutes once daily. This
administration schedule is helpful in the treatment of hospitalized patients and
especially useful for patients receiving outpatient parenteral antimicrobial therapy (32).
The major concern with extensive therapeutic use of this new agent is the paucity
of clinical trial data outside of cUTIs (33,34). Aminoglycosides remain important
therapeutic agents for serious infections such as nosocomial pneumonia, complicated
intra-abdominal infections, and septicemia when pathogens such as carbapenem
resistant Acinetobacter baumannii and other nonfermenting negative gram-negative
bacilli such as seen in the CARE study which required combination therapy (19, 30).
This would most likely be related to the organism causing the infection as opposed to
the site of infection (35). However, good in vitro activity does not necessarily predict
clinical efficacy with this class of antimicrobials (36). For example, low alveolar lining
14
fluid concentrations as well as inactivation in acidic pH within inflamed lung tissue often
leads to a poor outcome with aminoglycoside treatment in patients with pneumonia.
Therefore, additional clinical trials with plazomicin in various infections, especially
pneumonias, are warranted before acceptance of this antibiotic for expanded use.
Another uncertainty with the use of plazomicin is aminoglycoside-associated
toxicity, especially nephrotoxicity and ototoxicity. Monitoring renal function is a priority
when utilizing plazomicin as clinical trials have shown an increased rate of
nephrotoxicity when evaluated against beta-lactams as the comparator in clinical trials.
Plazomicin dosing recommendations were developed to optimally administer this drug,
but toxicity remains a concern with this class of antibiotics (37). Thus, the monitoring of
plazomicin concentrations are required in all patients receiving extended treatment with
this agent. Trough concentrations should be maintained at less than or equal to 3 mg/L
The cost of therapy with plazomicin will also be an issue with medical care
providers. The high acquisition cost of this aminoglycoside is like other newer
antimicrobials developed for the treatment of MDR gram-negative pathogens (38,39).
This expense along with the cost of therapeutic monitoring will necessitate diligent
antimicrobial stewardship.
Finally, Achaogen has filed for bankruptcy as of April 2019, thus placing the
future of plazomicin in question. This is especially of concern as antibiotics are only
used for a few days compared to drugs for other medical conditions including diabetes
and hypertension. Big Pharma has withdrawn from antibiotic discovery because of the
lack of profitability and thus whether plazomicin will be acquired by another company
remains uncertain.
15
Summary statement:
Although there are limited clinical indications based on completed clinical trials for this
antibiotic, one could envision plazomicin being used for other infections including
bacteremia, nosocomial pneumonia and intraabdominal infections due to highly
resistant Enterobacteriaceae for which there are limited available alternatives.
Conflicts of interest: LDS served as the chair of the data safety monitoring board for the
Achaogen EPIC trial and was compensated for this activity and GES was compensated
for speakers training for Achaogen.
16
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Plazomicin: A New Aminoglycoside

Louis D. Saravolatz, MD, MACP, FIDSA and Gary E. Stein, PharmD

Michigan University College of Medicine

Grosse Pointe Woods, Michigan

Michigan State University School of Medicine

East Lansing, Michigan

Summary: Plazomicin, a novel parenteral aminoglycoside, has been developed for

multidrug-resistant Enterobacteriaceae and is approved for the treatment of complicated

meropenem except for an increased rise in serum creatinine.

Plazomicin (ACHN-490) is a novel parenteral aminoglycoside developed to target

and pyelonephritis caused by susceptible organisms. When compared to meropenem,

to meropenem except for an increased additional rise in serum creatinine in the

action, antimicrobial activity, pharmacokinetics, clinical indications, and safety profile of

Key words: plazomicin, aminoglycoside, CRE

Plazomicin (formerly ACHN–490) is a novel aminoglycoside that has been developed to

producing aminoglycoside modifying enzymes, extended spectrum beta-lactamases,

become problematic throughout the world. Older aminoglycosides including amikacin,

producing aminoglycoside modifying enzymes and with the advent of carbapenem

resistant Enterobacteriaceae (CRE), clinicians have limited options against the

multidrug-resistant organisms. We will review plazomicin’ s chemistry, mode of action,

pharmacokinetics, microbiology, clinical indications, adverse events, and place in

therapy to assist the infectious disease physician.

Chemistry and Mode of Action

Plazomicin is a semi-synthetic aminoglycoside antimicrobial derived from

by multiple aminoglycoside modifying enzymes (AMEs) which can be produced by

Gram-negative bacteria (3). The addition of a N1 2(S)-hydroxy aminobutyryl and a

reduced affinity of aminoglycosides to the ribosomal target (5). Additional

in an anaerobic environment, such as an abscess, or in acidic urine. The primary

in plazomicin result in a modest reduction in antibacterial potency compared to

for plazomicin is ≤2 mg/L (FDA breakpoint). In addition, plazomicin is active against

many aminoglycoside non-susceptible organisms as well as aminoglycoside susceptible

isolates. Plazomicin also demonstrates equivalent activity against extended spectrum

beta-lactamase (ESBL) producing and non-ESBL producing E. coli and Klebsiella

pneumoniae with 90% of isolates being inhibited by an MIC of ≤1 mg/L. Overall,

plazomicin’ s gram-negative in vitro activity is similar to or superior to other

bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii and

against Enterobacteriaceae. Plazomicin, like other aminoglycosides, demonstrates poor

in vitro activity against Stenotrophomonas maltophilia.

amikacin, gentamicin, meropenem, and levofloxacin, which demonstrated susceptibility

to plazomicin (12). Only 3 (2.7%) were susceptible to meropenem and none to

imipenem. These isolates demonstrated variable susceptibility to amikacin (23.6%),

producing Klebsiella pneumoniae, MIC 90 =0.5 mg/L.

89.5% of these isolates at an MIC ≤2 mg/L. When evaluating comparator antibiotics

including amikacin, gentamicin, tobramycin, doripenem, meropenem, tigecycline,

levofloxacin, aztreonam, piperacillin/tazobactam, trimethoprim/ sulfamethoxazole,

less common 16S ribosomal RNA methyl–transferases. However, it is active against

Enterobacteriaceae that express resistance mechanisms to other antibiotic classes

including metallo-beta-lactamases (14). In addition, plazomicin inhibited 87% of

clinicians should continue to rely on susceptibility testing for plazomicin.

In an evaluation of plazomicin against ESBL producing E. coli, ESBL producing K

pneumoniae, carbapenem resistant Enterobacteriaceae and colistin resistant

and comparable to meropenem/vaborbactam and avibactam/ceftazidime (table 2)

Streptococcus pyogenes. Plazomicin is also not active against strains of enterococci

against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides

and beta-lactams (18). Synergy between plazomicin and piperacillin/tazobactam or

combination therapy for serious Gram-negative infections caused by multi-drug resistant

Enterobacteriaceae. Plazomicin has also been tested in combination with other

antibiotics, mainly carbapenems, against Acinetobacter baumannii (19). Synergy was

consistently seen when combining meropenem or imipenem with plazomicin.

Plazomicin, as with other aminoglycoside antimicrobials, is poorly absorbed and

binding of plazomicin to plasma proteins is approximately 20%.

Plazomicin is primarily excreted by the kidneys. It is not metabolized to any

enzymes. The mean serum elimination half-life of plazomicin is approximately 3.5h in

patients with normal renal function (22).