The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Once-Daily Plazomicin for Complicated

Urinary Tract Infections
Florian M.E. Wagenlehner, M.D., Daniel J. Cloutier, Pharm.D.,
Allison S. Komirenko, Pharm.D., Deborah S. Cebrik, M.S., M.P.H.,
Kevin M. Krause, M.B.A., Tiffany R. Keepers, Ph.D., Lynn E. Connolly, M.D., Ph.D.,
Loren G. Miller, M.D., M.P.H., Ian Friedland, M.D., and Jamie P. Dwyer, M.D.,
for the EPIC Study Group*​​

A BS T R AC T

BACKGROUND
The increasing multidrug resistance among gram-negative uropathogens necessitates From the Justus Liebig University, Gies-
new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal sen, Germany (F.M.E.W.); Achaogen, South
San Francisco (D.J.C., A.S.K., D.S.C.,
activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae. K.M.K., T.R.K., L.E.C., I.F.), the David
METHODS ­Geffen School of Medicine, University of
California Los Angeles (UCLA), Los An-
We randomly assigned 609 patients with complicated urinary tract infections (UTIs), geles (L.G.M.), and Los Angeles Biomed-
including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg ical Research Institute at Harbor–UCLA
per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with op- Medical Center, Torrance (L.G.M.) — all
in California; and Vanderbilt University
tional oral step-down therapy after at least 4 days of intravenous therapy, for a total of Medical Center, Nashville (J.P.D.). Address
7 to 10 days of therapy. The primary objective was to show the noninferiority of plazo- reprint requests to Dr. Wagenlehner at the
micin to meropenem in the treatment of complicated UTIs, including acute pyelone- Clinic for Urology, Pediatric Urology and
Andrology, Justus Liebig University Giessen,
phritis, with a noninferiority margin of 15 percentage points. The primary end points Rudolf-Buchheim Str. 7, 35392 Giessen,
were composite cure (clinical cure and microbiologic eradication) at day 5 and at the Germany, or at ­f lorian​.­wagenlehner@​
test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified ­chiru​.­med​.­uni-giessen​.­de.

intention-to-treat population. * A complete list of the principal investi-

gators in the EPIC Study is provided in
RESULTS the Supplementary Appendix, available
Plazomicin was noninferior to meropenem with respect to the primary efficacy end at NEJM.org.
points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 N Engl J Med 2019;380:729-40.
patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem DOI: 10.1056/NEJMoa1801467
Copyright © 2019 Massachusetts Medical Society.
group (difference, –3.4 percentage points; 95% confidence interval [CI], –10.0 to 3.1).
At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and
70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7
to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group
than in the meropenem group were found to have microbiologic eradication, including
eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8%
vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum β-lactamases
(82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer
patients in the plazomicin group than in the meropenem group had microbiologic re-
currence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creati-
nine levels of 0.5 mg or more per deciliter (≥40 μmol per liter) above baseline occurred
in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group.
CONCLUSIONS
Once-daily plazomicin was noninferior to meropenem for the treatment of complicated
UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resis-
tant strains. (Funded by Achaogen and the Biomedical Advanced Research and Develop-
ment Authority; EPIC ClinicalTrials.gov number, NCT02486627.)

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 The n e w e ng l a n d j o u r na l
U
rinary tract infections (UTIs) are
common bacterial infections that are as-
sociated with substantial morbidity, mor-
tality, and economic burden.1 Complicated UTIs
are UTIs in patients who have underlying condi-
tions, such as anatomical abnormalities, or risk
factors, such as indwelling urinary catheters.
Acute pyelonephritis is an infection of the renal
pelvis and kidney.2-4 In the period from 2006
through 2009, a total of 10.8 million patients
presented to U.S. emergency departments with a
primary diagnosis of UTI. Of these, 17% were
admitted for further disease management, and
14% had pyelonephritis.5
Enterobacteriaceae are the most common
causes of complicated UTIs, and multidrug re-
sistance within this family is a global concern.6
Patients with multidrug-resistant UTIs are three
times as likely to receive inappropriate empirical
antibiotic therapy as patients who do not have
multidrug-resistant infections. They also have
longer hospital stays, incur higher hospital
costs, and have a higher risk of septic shock and
death.7,8
The previous mainstays of empirical therapy
for complicated UTIs, such as fluoroquinolones
and cephalosporins, are not widely recommended
because of concerns about resistance.3 Carbapen-
ems, which have been traditionally reserved for
the treatment of multidrug-resistant infections,
are increasingly being used to treat complicated
UTIs.9 The incidence of multidrug resistance has
continued to increase — and now includes car-
bapenem resistance; therefore, alternative treat-
ment options are needed.10,11
Aminoglycosides are an alternative treatment
for complicated UTIs that are caused by multidrug-
resistant organisms, such as extended-spectrum
β-lactamase–producing Enterobacteriaceae or car­
bapenem-resistant Enterobacteriaceae.6 However,
bacterial strains that are resistant to cephalospo-
rins and carbapenems commonly produce amino-
glycoside-modifying enzymes, which result in
resistance to many aminoglycosides.12,13 U.S. sur-
veillance data from 2014–2015 show that ap-
proximately 80% of the carbapenem-resistant
Enterobacteriaceae isolates tested positive for one
or more aminoglycoside-modifying enzyme genes.
Amikacin, gentamicin, and tobramycin had re-
duced activity against these isolates, with only
59.7% of these isolates susceptible to amikacin,
49.4% to gentamicin, and 0% to tobramycin.13
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of m e dic i n e
Plazomicin is an aminoglycoside that is engi-
neered to evade modification by aminoglycoside-
modifying enzymes, and it maintains activity in
the presence of most mechanisms that lead to
resistance in Enterobacteriaceae, including mu-
tations in sites targeted by fluoroquinolones and
the production of aminoglycoside-modifying en-
zymes, extended-spectrum β-lactamases, and car­
bapenemases.12-17 A phase 3 trial has assessed
the efficacy and safety of plazomicin in patients
with serious infections due to carbapenem-resis-
tant Enterobacteriaceae.18 The current trial as-
sessed the efficacy and safety of plazomicin as
compared with meropenem in patients with com-
plicated UTIs, including acute pyelonephritis.
Me thods
Trial Design and Oversight
The Evaluating Plazomicin in cUTI (EPIC) trial
was a multicenter, multinational, randomized,
double-blind, phase 3 trial that was designed in
accordance with FDA guidelines4,19 and was con-
ducted from January through September 2016.
The primary objective of the trial was to show
the noninferiority of plazomicin to meropenem
in the treatment of complicated urinary tract
infections, including acute pyelonephritis. Patients
were enrolled at 68 sites in North America and
Europe. The institutional review board or ethics
committee at each site approved the final proto-
col, and all patients or their representatives
provided written informed consent. An indepen-
dent data and safety monitoring committee re-
viewed interim trial data. Full details of the trial
design are provided in the protocol and statisti-
cal analysis plan, available with the full text of
this article at NEJM.org.
The trial was designed by Achaogen and the
first author. Data were collected by Achaogen
and analyzed in collaboration with three of the
academic authors. A data confidentiality agree-
ment was in place between Achaogen and the
investigators. All the authors vouch for the ac-
curacy and completeness of the data and for the
fidelity of the trial to the protocol. The first
draft of the manuscript was written by a medical
writer from a contract research organization
who was paid by Achaogen, and all the authors
contributed to subsequent drafts, provided final
approval of the manuscript, and made the deci-
sion to submit the manuscript for publication.
 Plazomicin for Complicated Urinary Tr act Infections
Eligibility Criteria
Eligible patients were 18 years of age or older
and had a creatinine clearance of more than 30 ml
per minute, pyuria, and clinical symptoms of a
complicated UTI or acute pyelonephritis that
would require at least 4 days of intravenous
therapy with an antibiotic agent. Complicated
UTIs were indicated by at least two signs or
symptoms (chills, rigors, or fever [temperature
>38°C]; dysuria or urinary frequency or urgency;
lower abdominal or pelvic pain; or nausea or
vomiting) and at least one complicating factor
(a history of urinary retention [in male patients],
current indwelling urinary catheter, obstructive
uropathy, or any functional or anatomical abnor-
mality). Acute pyelonephritis was indicated by at
least two of the following symptoms: chills,
rigors, or fever; flank pain; tenderness in the
costovertebral angle; and nausea or vomiting.
Details of eligibility criteria are provided in Ta-
ble S1 in the Supplementary Appendix, available
at NEJM.org.
Randomization and Treatment
Patients were randomly assigned in a 1:1 ratio to
receive plazomicin or meropenem. Randomiza-
tion was performed by the site pharmacist or
designated staff member according to a prespeci-
fied randomization schedule. Block randomiza-
tion was automated through an interactive Web-
based or voice-response system and was stratified
according to region and baseline diagnosis
(complicated UTI or acute pyelonephritis). The
sponsor, investigators, trial staff participating in
patient care or clinical evaluations, and patients
were unaware of the group assignments. Desig-
nated staff members who prepared the trial
drugs had knowledge of the group assignments.
Patients were assigned to receive plazomicin
(15 mg per kilogram of body weight once daily)
or meropenem (1 g every 8 hours), administered
intravenously, with the option for oral step-down
therapy after a minimum of 4 days of intrave-
nous therapy, for a total of 7 to 10 days of
therapy. Levofloxacin (500 mg once daily) was
the preferred oral agent, but other agents were
permitted if levofloxacin was contraindicated.
Therapeutic drug monitoring was not imple-
mented. Doses of all trial drugs were adjusted
on the basis of creatinine clearance, which was
estimated with the use of the Cockcroft–Gault
formula.20 Details on the criteria for oral step-
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down therapy are provided in the Supplementary
Appendix.
Analysis Populations, End Points,
and Assessments
The intention-to-treat population included all
randomly assigned patients. The safety popula-
tion and the modified intention-to-treat popula-
tion included all patients in the intention-to-treat
population who received any amount of a trial
drug. The microbiologic modified intention-to-
treat population included patients in the modi-
fied intention-to-treat population who had at
least one qualifying baseline pathogen (≥105
colony-forming units [CFU] per milliliter) that
was susceptible to both meropenem (minimum
inhibitory concentration [MIC] of ≤1 μg per mil-
liliter21) and plazomicin (MIC of ≤4 μg per milli-
liter). We also evaluated a population that in-
cluded all protocol-adherent patients in the
microbiologic modified intention-to-treat popu-
lation who had an available urine culture at day
5, at the test-of-cure visit, or both (microbiologic
per-protocol population). Isolate and susceptibil-
ity testing were conducted at a central laboratory
(JMI Laboratories).
The primary efficacy end points were com-
posite cure (clinical cure and microbiologic eradi-
cation) at day 5 and at the test-of-cure visit (15
to 19 days after initiation of intravenous therapy
with the assigned trial drug) in the microbiologic
modified intention-to-treat population. Clinical
cure was defined as a reduction in severity (at
day 5 and at the end of intravenous therapy) or
complete resolution (at the test-of-cure visit) of all
core symptoms with no new symptoms or as a
return to the patient’s status before development
of the UTI, with no use of nontrial antibiotics
for the current complicated UTI. Microbiologic
eradication was defined as a reduction in the
baseline uropathogen from 105 CFU or more per
milliliter to less than 104 CFU per milliliter.
Additional end points assessed in the micro-
biologic modified intention-to-treat population
were clinical cure and microbiologic eradication
at day 5, at the end of intravenous therapy
(within 24 hours after the last dose of intrave-
nous trial drug and before oral therapy), at the
test-of-cure visit, and during late follow-up (days
24 to 32); and microbiologic response at the test-
of-cure visit according to baseline pathogen. To
evaluate consistency with the results in the over-
731
 The n e w e ng l a n d j o u r na l
all population, composite cure at the test-of-cure
visit was assessed in prespecified subgroups de-
fined according to geographic region (region 1 or
2), baseline diagnosis (complicated UTI or acute
pyelonephritis), presence of bacteremia, treatment
received (intravenous only or intravenous plus
oral), presence of indwelling catheter (yes or no),
and previous antibiotic use (yes or no) and in
post hoc subgroups defined according to age
(<65 or ≥65 years), renal function (creatinine
clearance ≤60 ml per minute or >60 ml per min-
ute), and sex. Definitions of efficacy end points
are provided in Table S2 in the Supplementary
Appendix.
Safety analyses included assessments of ad-
verse events and laboratory values. Serum creati-
nine levels were assessed at baseline, daily during
intravenous treatment, at the end of intravenous
treatment, at the test-of-cure visit, and at late
follow-up. Decreased renal function was pre-
specified as an increase in the serum creatinine
level of 0.5 mg or more per deciliter (≥40 μmol
per liter) above baseline at any time during the
trial.22,23
Statistical Analysis
We calculated that 394 patients would need to be
enrolled for the trial to have at least 85% power
to show the noninferiority of plazomicin to
meropenem in the treatment of complicated UTIs
and acute pyelonephritis, with a noninferiority
margin of 15 percentage points, at a one-sided
significance level of 0.025 for each primary end
point, assuming that composite cure would oc-
cur in 64.0% of patients at day 5 and in 73.2%
at the test-of-cure visit in both treatment groups.
Patients whose assessments did not result in
definitive findings were considered to have had
treatment failure with respect to all efficacy end
points assessed in the microbiologic modified
intention-to-treat population. Two-sided 95%
confidence intervals for the observed differ-
ences in composite cure rates (plazomicin mi-
nus meropenem) at day 5 and at the test-of-cure
visit were calculated with the use of the New-
combe method with continuity correction. A
determination of noninferiority required that
the lower limits of the 95% confidence inter-
vals at day 5 and at the test-of-cure visit be
greater than −15 percentage points (details are
provided in the Supplementary Appendix).19 No
corrections for multiple comparisons were per-
formed. The confidence intervals for the other
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of m e dic i n e
assessments are provided for descriptive pur-
poses and have also not been corrected for mul-
tiple comparisons.
R e sult s
Patients
Of the 609 patients enrolled, 604 (99.2%) were
included in the safety and modified intention-to-
treat populations and 388 (63.7%) were included
in the microbiologic modified intention-to-treat
population. The most common reason for exclu-
sion from the microbiologic modified intention-
to-treat population was the absence of a qualify-
ing baseline uropathogen. Details regarding
patient disposition are provided in Figure S1 in
the Supplementary Appendix.
Baseline characteristics were balanced be-
tween the treatment groups (Table 1, and Table
S3 in the Supplementary Appendix). The mean
age was 59.4 years, and 72.2% of patients had
impaired renal function. There were more pa-
tients with complicated UTIs than with acute
pyelonephritis (58.2% vs. 41.8%), and 13.1% of
patients had an indwelling urinary catheter. The
mean duration of intravenous therapy was 5.5
days in each group; the mean duration of intrave-
nous plus oral therapy was 9.2 days in the plazo-
micin group and 8.9 days in the meropenem
group. Most patients (80.6% in the plazomicin
group and 76.6% in the meropenem group) re-
ceived oral step-down therapy, which was primar-
ily levofloxacin. Of the 154 patients with a uro-
pathogen at baseline that was not susceptible to
levofloxacin, 59 received oral levofloxacin (27
patients in the plazomicin group and 32 in the
meropenem group). A total of 60% of the patients
who had a uropathogen that was not susceptible
to levofloxacin received the maximum 7 days of
intravenous therapy. Common alternative oral
antibiotics were trimethoprim–sulfamethoxazole,
amoxicillin–clavulanate, and cefixime.
The most common uropathogen was Escherichia
coli, followed by Klebsiella pneumoniae. Of the 382
patients with Enterobacteriaceae in the micro-
biologic modified intention-to-treat population,
107 patients (28.0%) had uropathogens with an
extended-spectrum β-lactamase phenotype, 115
(30.1%) had multidrug-resistant uropathogens,
and 101 (26.4%) had uropathogens that were not
susceptible to other aminoglycosides (amikacin,
gentamicin, or tobramycin). MICs for plazomi-
cin and meropenem among baseline uropatho-
 Plazomicin for Complicated Urinary Tr act Infections

Table 1. Characteristics of the Patients at Baseline (Microbiologic Modified Intention-to-Treat Population).*

Characteristic Plazomicin (N = 191) Meropenem (N = 197)

Age — yr 58.8±18.0 60.0±17.9
Male sex — no. (%) 84 (44.0) 99 (50.3)
Race — no. (%)†
White 189 (99.0) 197 (100.0)
Black 1 (0.5) 0
Other 1 (0.5) 0
Geographic region — no. (%)‡
Region 1 4 (2.1) 2 (1.0)
Region 2 187 (97.9) 195 (99.0)
Body-mass index§ 26.7±5.1 27.1±5.1
Infection type — no. (%)
Complicated urinary tract infection 107 (56.0) 119 (60.4)
Acute pyelonephritis 84 (44.0) 78 (39.6)
Calculated creatinine clearance — no./total no. (%)¶
>90 ml/min 57/188 (30.3) 45/194 (23.2)
>60–90 ml/min 70/188 (37.2) 75/194 (38.7)
>30–60 ml/min 61/188 (32.4) 71/194 (36.6)
≤30 ml/min 0/188 3/194 (1.5)
Missing data 3/191 (1.6) 3/197 (1.5)
Urosepsis — no. (%)‖ 39 (20.4) 34 (17.3)
Bacteremia — no. (%)** 25 (13.1) 23 (11.7)
Enterobacteriaceae uropathogens — no./total no. (%)†† 189/191 (99.0) 193/197 (98.0)
Not susceptible to levofloxacin 71/189 (37.6) 83/193 (43.0)
Not susceptible to at least one aminoglycoside 51/189 (27.0) 50/193 (25.9)
Not susceptible to amikacin 1/189 (0.5) 1/193 (0.5)
Not susceptible to gentamicin 37/189 (19.6) 41/193 (21.2)
Not susceptible to tobramycin 43/189 (22.8) 44/193 (22.8)
Not susceptible to any two aminoglycosides 29/189 (15.3) 35/193 (18.1)
Not susceptible to all three aminoglycosides 1/189 (0.5) 1/193 (0.5)
ESBL phenotype‡‡ 50/189 (26.5) 57/193 (29.5)
Not susceptible to carbapenem§§ 9/189 (4.8) 6/193 (3.1)
Multidrug resistant¶¶ 55/189 (29.1) 60/193 (31.1)

* Plus–minus values are means ±SD. The microbiologic modified intention-to-treat population included all patients
who underwent randomization, received at least one dose of the assigned trial drug, and had at least one qualifying
baseline pathogen that was susceptible to meropenem and that had a minimum inhibitory concentration (MIC) for
plazomicin of 4 μg per milliliter or less. Percentages may not total 100 because of rounding.
† Race was reported by the participants.
‡ Region 1 included the United States, Mexico, and Spain. Region 2 included Bulgaria, the Czech Republic, Estonia,
Georgia, Hungary, Latvia, Poland, Romania, Russia, Serbia, and Ukraine.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Creatinine clearance was calculated with the use of the ideal body weight if the total body weight exceeded the ideal
body weight by 25% or more.24 Patients were eligible for inclusion in the trial if they had a serum creatinine level of
more than 30 ml per minute as calculated at the local laboratory (Table S1 in the Supplementary Appendix). However,
three patients in the meropenem group were subsequently confirmed to have a creatinine clearance at screening of
30 ml or less per minute as calculated at a central laboratory.
‖ Urosepsis was determined on the basis of criteria for systemic inflammatory response syndrome.25
** Baseline blood cultures were required in patients who had acute pyelonephritis or urosepsis or whose baseline urine
culture was obtained through a preexisting indwelling catheter.
†† Patients with more than one uropathogen in the same category were counted only once in that category.
Susceptibility was determined on the basis of breakpoints established by the Clinical and Laboratory Standards
Institute (see the Supplementary Appendix).21
‡‡ Extended-spectrum β-lactamase (ESBL) phenotype was defined as pathogens that had an MIC for ceftazidime, aztre-
onam, or ceftriaxone of at least 2 μg per milliliter, as determined at a central laboratory.
§§ The pathogens were not susceptible to imipenem or doripenem but were susceptible to meropenem.
¶¶ Multidrug resistance was defined as resistance to at least one antibiotic from at least three different classes.26

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Primary and Additional Efficacy End Points (Microbiologic Modified Intention-to-Treat Population).*

Plazomicin Meropenem Difference

Time of Assessment and End Point (N = 191) (N = 197) (95% CI)†
number (percent) percentage points
Day 5
Primary end point: composite cure at day 5 168 (88.0) 180 (91.4) −3.4 (−10.0 to 3.1)
Clinical cure 171 (89.5) 182 (92.4) −2.9 (−9.1 to 3.3)
Microbiologic eradication 188 (98.4) 193 (98.0) 0.5 (−3.1 to 4.1)
End of intravenous therapy
Composite cure 179 (93.7) 187 (94.9) −1.2 (−6.5 to 4.0)
Clinical cure 184 (96.3) 190 (96.4) −0.1 (−4.6 to 4.3)
Microbiologic eradication 186 (97.4) 192 (97.5) −0.1 (−4.1 to 3.9)
Test-of-cure visit
Primary end point: composite cure at 156 (81.7) 138 (70.1) 11.6 (2.7 to 20.3)
15 to 19 days after start of therapy
Clinical cure 170 (89.0) 178 (90.4) −1.4 (−7.9 to 5.2)
Microbiologic eradication 171 (89.5) 147 (74.6) 14.9 (7.0 to 22.7)
Late follow-up‡
Composite cure 147 (77.0) 119 (60.4) 16.6 (7.0 to 25.7)
Sustained clinical cure§ 169 (88.5) 168 (85.3) 3.2 (−4.0 to 10.3)
Sustained eradication¶ 161 (84.3) 128 (65.0) 19.3 (10.4 to 27.9)
Clinical relapse 3 (1.6) 14 (7.1) Not calculated
Microbiologic recurrence‖ 7 (3.7) 16 (8.1) Not calculated

* Composite cure was defined as clinical cure and microbiologic eradication. Clinical cure was defined as a reduction in
severity (at day 5 and at the end of intravenous therapy) or complete resolution (at the test-of-cure visit) of all core
symptoms with no new symptoms or as a return to the patient’s status before development of the urinary tract infec-
tion (UTI). Microbiologic eradication was defined as a reduction in the baseline uropathogen from 105 colony-forming
units (CFU) or more per milliliter to less than 104 CFU per milliliter.
† Confidence intervals were calculated with the use of the Newcombe method with continuity correction and were not
corrected for multiple comparisons.
‡ Late follow-up was conducted 24 to 32 days after initiation of intravenous therapy.
§ Patients were considered to have sustained clinical cure if they had not had clinical failure at the test-of-cure visit and if
they had complete resolution or a return to their status before development of the complicated UTI, with no new symp-
toms at the last follow-up visit.
¶ Patients were considered to have sustained eradication if a urine culture obtained at the last follow-up visit showed that
the baseline uropathogen or uropathogens had been reduced to less than 104 CFU per milliliter after showing eradica-
tion at the test-of-cure visit (or if no urine culture was obtained at the last follow-up visit and the patients met criteria
for sustained clinical cure).
‖ Patients were considered to have microbiologic recurrence if they had a urine culture obtained at any time after docu-
mented eradication at the test-of-cure visit, up to and including the last follow-up visit, that showed an increase in the
baseline pathogen or pathogens to 104 CFU or more per milliliter.

gens are provided in Table S4 in the Supplemen- –10.0 to 3.1). At the test-of-cure visit, composite
tary Appendix. cure was observed in 81.7% (156 of 191 patients)
and 70.1% (138 of 197 patients), respectively
End Points (difference, 11.6 percentage points; 95% CI, 2.7
Plazomicin was noninferior to meropenem with to 20.3). The lower limit of the 95% confidence
respect to the primary efficacy end points (Ta- interval for the between-group difference in the
ble 2). At day 5, composite cure was observed in rate of composite cure at the test-of-cure visit
88.0% of the patients (168 of 191 patients) in the exceeded zero. The directionality of the between-
plazomicin group and in 91.4% (180 of 197 pa- group difference in the rate of composite cure at
tients) in the meropenem group (difference, –3.4 the test-of-cure visits in subgroups was consis-
percentage points; 95% confidence interval [CI], tent with that in the overall population (Fig. 1).

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 Plazomicin for Complicated Urinary Tr act Infections

Subgroup Meropenem Plazomicin Percentage-Point Difference (95% CI)

no. of patients with composite cure/no. of patients (%)
Overall 138/197 (70.1) 156/191 (81.7) 11.6 (2.7 to 20.3)
Diagnosis at baseline
Complicated UTI 82/119 (68.9) 84/107 (78.5) 9.6 (–2.6 to 21.3)
Acute pyelonephritis 56/78 (71.8) 72/84 (85.7) 13.9 (0.4 to 27.1)
Presence of bacteremia 13/23 (56.5) 18/25 (72.0) 15.5 (–13.7 to 41.9)
Treatment received
Intravenous only 28/46 (60.9) 29/37 (78.4) 17.5 (–4.3 to 36.6)
Intravenous plus oral 110/151 (72.8) 127/154 (82.5) 9.6 (–0.2 to 19.3)
Catheter
Present 15/29 (51.7) 18/29 (62.1) 10.3 (–16.6 to 35.5)
Absent 123/168 (73.2) 138/162 (85.2) 12.0 (2.8 to 20.9)
Age
<65 yr 68/95 (71.6) 90/101 (89.1) 17.5 (5.7 to 29.0)
≥65 yr 70/102 (68.6) 66/90 (73.3) 4.7 (–8.9 to 17.9)
Sex
Male 68/99 (68.7) 65/84 (77.4) 8.7 (–5.1 to 21.7)
Female 70/98 (71.4) 91/107 (85.0) 13.6 (1.6 to 25.4)
Creatinine clearance
≤60 ml/min 49/74 (66.2) 43/61 (70.5) 4.3 (–12.5 to 20.3)
>60 ml/min 87/120 (72.5) 112/127 (88.2) 15.7 (5.2 to 25.9)
−20 −15 −10 −5 0 5 10 15 20 25 30 35 40 45

Meropenem Better Plazomicin Better

Figure 1. Composite Cure at the Test-of-Cure Visit, According to Patient Subgroups in the Microbiologic Modified Intention-to-Treat Population.
The percentage-point difference is for plazomicin minus meropenem; some values may differ from the expected value because of
rounding. All subgroups were prespecified except for age, creatinine clearance, and sex. The 95% confidence intervals have not been
corrected for multiple comparisons. Post hoc analyses used the Gail–Simon test for qualitative interaction in all subgroups (qualitative
interaction, 0.0; P = 0.5). The vertical red line indicates the noninferiority margin of 15 percentage points. Results for patients according
to geographic region are not reported, since 6 of 388 (1.5%) patients were enrolled in region 1 (United States, Mexico, and Spain) and
382 of 388 (98.5%) patients were enrolled in region 2 (Bulgaria, the Czech Republic, Estonia, Georgia, Hungary, Latvia, Poland, Romania,
Russia, Serbia, and Ukraine). Results for patients according to previous antibiotic use (yes or no) are not reported because of the small
number of patients who received previous antibiotic therapy (2 patients in the plazomicin group and no patients in the meropenem
group). UTI denotes urinary tract infection.

The between-group difference favoring plazomi-
cin that was observed in the subgroup that re-
ceived only intravenous treatment was greater
than that observed in the subgroup that received
intravenous plus oral treatment (percentage-point
difference, 17.5 vs. 9.6), which suggests that oral
therapy did not account for the between-group
difference observed at the test-of-cure visit.
Rates of microbiologic eradication were simi-
lar in the two treatment groups at day 5 and at
the end of intravenous therapy and were higher
in the plazomicin group than in the meropenem
group at the test-of-cure visit and at late follow-
up (Table 2). Among patients with infections
caused by extended-spectrum β-lactamase–pro-
ducing Enterobacteriaceae, microbiologic eradi-
cation at the test-of-cure visit was observed in
82.4% of the patients in the plazomicin group
and in 75.0% in the meropenem group. In addi-
tion, a higher percentage of patients in the plazo-
micin group than in the meropenem group were
found to have microbiologic eradication of En-
terobacteriaceae that were not susceptible to other
aminoglycosides (78.8% vs. 68.6%) (Table 3).
At late follow-up, the rate of composite cure
remained higher in the plazomicin group than
in the meropenem group (Table 2). Clinical re-
lapse at late follow-up occurred in 1.6% of the
patients in the plazomicin group and in 7.1% in
the meropenem group, and microbiologic recur-
rence occurred in 3.7% and 8.1%, respectively.
Most clinical relapses in the meropenem group
occurred in patients who had asymptomatic bac-
teriuria (microbiologic persistence and clinical
cure) at the test-of-cure visit. Tables S5 and S6 in
the Supplementary Appendix show the outcomes
for the modified intention-to-treat population
and the microbiologic per-protocol population.

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 The n e w e ng l a n d j o u r na l
Safety
The most frequent adverse events in the plazo-
micin group were diarrhea, hypertension, head-
ache, nausea, vomiting, and hypotension (Ta-
ble 4). Adverse events associated with a decline
in renal function occurred in 11 of 303 patients
(3.6%) in the plazomicin group and in 4 of 301
patients (1.3%) in the meropenem group. Poten-
tially ototoxic events were identified in 2 pa-
tients (1 in each group). Serious adverse events
were reported in 1.7% of patients in each treat-
ment group (Table S8 in the Supplementary Ap-
pendix).
During the trial, 21 of 300 patients (7.0%) in
the plazomicin group and 12 of 297 patients
(4.0%) in the meropenem group had an increase
in serum creatinine level of 0.5 mg or more per
deciliter above the baseline level (Table 4, and
Table S9 in the Supplementary Appendix). Of
these, the increase occurred after completion of
intravenous therapy in 10 of 300 patients (3.3%)
in the plazomicin group and in 3 of 297 patients
(1.0%) in the meropenem group; of the 10 pa-
tients in the plazomicin group who had serum
creatinine increases after completion of intrave-
nous therapy, 9 had had moderate renal impair-
ment at baseline. In general, increases were less
than 1.0 mg per deciliter (<80 μmol per liter)
from baseline and returned to less than 0.5 mg
per deciliter from the baseline value by the last
follow-up. Among patients in the plazomicin
group, risk factors for an increase in serum cre-
atinine level of 0.5 mg or more per deciliter were
moderate renal impairment (14 of 21 patients)
and receipt of plazomicin therapy for more than
5 days (12 of 21 patients); 8 of 21 patients had
both risk factors.
A total of 12 patients discontinued treatment
because of adverse events (6 patients [2%] in
each group) (Table S10 in the Supplementary Ap-
pendix). In both groups, these adverse events
were most commonly associated with renal
function; in accordance with the protocol, pa-
tients with creatinine clearance of 30 ml or less
per minute were to discontinue the trial drug.
No deaths related to a trial drug were ob-
served. One patient who received a single dose of
plazomicin died on day 18 from metastatic uter-
ine cancer that had been diagnosed 48 hours
after the patient underwent randomization. No
deaths occurred in the meropenem group.
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of m e dic i n e
Discussion
In the EPIC trial, plazomicin was noninferior to
meropenem in the treatment of patients with
complicated UTIs, including acute pyelonephri-
tis, with higher rates of microbiologic eradica-
tion and composite cure observed at the test-of-
cure visit in the plazomicin group than in the
meropenem group. The lower incidence of mi-
crobiologic recurrence and clinical relapse in
the plazomicin group than in the meropenem
group at late follow-up suggests that the great-
er microbiologic eradication with plazomicin
has additional clinical benefit for patients with
complicated UTIs, including acute pyelone­
phritis.
Although the propensity for complicated UTIs
to recur — necessitating frequent retreatment
with antibiotics and increasing the potential for
the development of resistance — is well known,3
comprehensive evaluations of the risk of recur-
rence of complicated UTIs and relapse are lack-
ing. This trial assessed the sustained effects of
antibacterial therapy in patients with complicated
UTIs and showed that asymptomatic bacteriuria
was more common after treatment with merope-
nem than after treatment with plazomicin and
was associated with subsequent clinical relapse.
Asymptomatic bacteriuria is common among
patients with complicated UTIs after completion
of therapy,27 and treatment is generally not rec-
ommended for most patients because of the
perceived low risk of clinical consequences.3,28,29
However, findings from this trial suggest that
additional data should be generated to guide ap-
proaches for managing asymptomatic bacteriuria
in patients at risk for recurrent complicated UTIs.
Unlike recent phase 3 trials involving patients
with complicated UTIs,30-32 the EPIC trial excluded
patients from the microbiologic modified inten-
tion-to-treat population who had pathogens that
were resistant to the comparator; thus, the results
were not biased toward plazomicin. Meropenem
was a reliably active comparator to evaluate the
efficacy of plazomicin for multidrug-resistant
pathogens. The higher observed rate of composite
cure at the test-of-cure visit in the plazomicin
group, including in patients with important re-
sistant pathogens, such as extended-spectrum
β-lactamase–producing Enterobacteriaceae and
Enterobacteriaceae that are not susceptible to
 Plazomicin for Complicated Urinary Tr act Infections

Table 3. Microbiologic Eradication at the Test-of-Cure Visit According to Pathogen (Microbiologic Modified Intention-to-Treat Population).*

Baseline Uropathogen Plazomicin (N = 191) Meropenem (N = 197) Difference (95% CI)†

no. of uropathogens eradicated/

total no. of uropathogens percentage points
Enterobacteriaceae 177/198 (89.4) 157/208 (75.5) 13.9 (6.2 to 21.5)
Not susceptible to at least one aminoglycoside 41/52 (78.8) 35/51 (68.6) 10.2 (−8.1 to 27.8)
Not susceptible to amikacin 1/1 (100.0) 0/1
Not susceptible to gentamicin 27/37 (73.0) 31/42 (73.8) −0.8 (−21.8 to 19.7)
Not susceptible to tobramycin 36/44 (81.8) 32/45 (71.1) 10.7 (−8.6 to 29.0)
Not susceptible to any two aminoglycosides 22/29 (75.9) 28/36 (77.8) −1.9 (−24.8 to 19.8)
Not susceptible to all three aminoglycosides 1/1 (100.0) 0/1
Not susceptible to carbapenem‡ 7/9 (77.8) 5/6 (83.3) −5.6 (−46.3 to 44.7)
ESBL phenotype§ 42/51 (82.4) 45/60 (75.0) 7.4 (−9.6 to 23.1)
Multidrug resistant¶ 44/57 (77.2) 45/64 (70.3) 6.9 (−10.1 to 23.0)
Escherichia coli 120/128 (93.8) 106/142 (74.6) 19.1 (10.0 to 27.9)
Not susceptible to at least one aminoglycoside 20/23 (87.0) 16/26 (61.5) 25.4 (−2.4 to 48.3)
Not susceptible to amikacin 0/0 0/0
Not susceptible to gentamicin 10/12 (83.3) 14/19 (73.7) 9.6 (–26.6 to 38.3)
Not susceptible to tobramycin 16/18 (88.9) 15/24 (62.5) 26.4 (–4.4 to 50.0)
Not susceptible to any two aminoglycosides 6/7 (85.7) 13/17 (76.5) 9.2 (–37.2 to 39.2)
Not susceptible to all three aminoglycosides 0/0 0/0
Not susceptible to carbapenem‡ 0/0 0/0
ESBL phenotype§ 18/20 (90.0) 19/28 (67.9) 22.1 (−5.7 to 44.0)
Multidrug resistant¶ 19/23 (82.6) 21/33 (63.6) 19.0 (−8.0 to 40.8)
Klebsiella pneumoniae 27/33 (81.8) 32/43 (74.4) 7.4 (−13.9 to 26.5)
Not susceptible to at least one aminoglycoside 14/18 (77.8) 15/20 (75.0) 2.8 (−27.3 to 31.4)
Not susceptible to amikacin 1/1 (100.0) 0/1
Not susceptible to gentamicin 12/16 (75.0) 13/18 (72.2) 2.8 (−29.7 to 33.5)
Not susceptible to tobramycin 14/18 (77.8) 14/18 (77.8) 0.0 (−29.8 to 29.8)
Not susceptible to any two aminoglycosides 12/16 (75.0) 12/16 (75.0) 0.0 (−32.2 to 32.2)
Not susceptible to all three aminoglycosides 1/1 (100.0) 0/1
Not susceptible to carbapenem‡ 0/0 1/1 (100.0)
ESBL phenotype§ 15/20 (75.0) 20/26 (76.9) −1.9 (−29.7 to 24.1)
Multidrug resistant¶ 15/20 (75.0) 18/24 (75.0) 0 (−28.3 to 26.9)
Proteus mirabilis 9/11 (81.8) 4/7 (57.1) 24.7 (−21.4 to 64.5)
Enterobacter cloacae 13/16 (81.3) 3/3 (100.0) −18.8 (−46.3 to 51.6)

* Patients may have had more than one uropathogen at baseline.

† Confidence intervals have not been corrected for multiple comparisons. Confidence intervals were calculated with the use of the Newcombe
method with continuity correction and were calculated only if the total number of uropathogens across both treatment groups was 10 or
more. Susceptibility was determined on the basis of breakpoints established by the Clinical and Laboratory Standards Institute (see the
Supplementary Appendix).21
‡ The pathogens were not susceptible to imipenem or doripenem but were susceptible to meropenem.
§ ESBL phenotype was defined as pathogens that had an MIC for ceftazidime, aztreonam, or ceftriaxone of at least 2 μg per milliliter, as deter-
mined by a central laboratory.
¶ Multidrug resistance was defined as a resistance to at least one antibiotic from at least three different classes.26

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 4. Safety Analysis (Safety Population).*

Variable Plazomicin (N = 303) Meropenem (N = 301)

Patients with any adverse event — no. (%) 59 (19.5) 65 (21.6)
Adverse events reported in ≥1% of patients in the plazomicin group
— no. (%)
Diarrhea 7 (2.3) 5 (1.7)
Hypertension 7 (2.3) 7 (2.3)
Headache 4 (1.3) 9 (3.0)
Nausea 4 (1.3) 4 (1.3)
Vomiting 4 (1.3) 3 (1.0)
Hypotension 3 (1.0) 2 (0.7)
Adverse events related to renal function — no. (%)† 11 (3.6) 4 (1.3)
Adverse events related to cochlear or vestibular function — no. (%)‡ 1 (0.3) 1 (0.3)
Patients with any serious adverse event — no. (%)§ 5 (1.7) 5 (1.7)
Increase of ≥0.5 mg/dl in serum creatinine level — no./total no. (%)
Any time during the trial¶ 21/300 (7.0) 12/297 (4.0)
Onset during intravenous therapy‖ 11/300 (3.7) 9/297 (3.0)
Full recovery at end of intravenous therapy** 6/11 (54.5) 4/9 (44.4)
Full recovery at last follow-up visit** 9/11 (81.8) 9/9 (100.0)
Onset after end of intravenous therapy 10/300 (3.3) 3/297 (1.0)

* The safety population included all randomly assigned patients who received any amount of a trial drug. A summary
of patients who had uropathogens that developed resistance to the trial drug is provided in Table S7 in the Supple­
mentary Appendix. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
† This category includes an increase in blood creatinine level, a decrease in creatinine clearance, acute kidney injury,
­renal failure, renal impairment, and chronic kidney disease; the events were identified in a blinded review and were
classified according to the preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0.
‡ This category includes hypoacusis and tinnitus; the events were identified in a blinded review and were classified ac-
cording to the preferred terms in MedDRA.
§ Serious adverse events in the plazomicin group were acute kidney injury, metastatic neoplasm, pneumonia, urinary cal-
culus, and urosepsis; serious adverse events in the meropenem group were acute pyelonephritis, Clostridium difficile coli-
tis, orchitis, pancreatitis, pyrexia, septic shock, and urinary tract infection (see Table S8 in the Supplementary Appendix).
¶ Any time during the trial includes the period during intravenous therapy, after the end of intravenous therapy, or both.
‖ Onset during intravenous therapy was defined as on or after the start of the first dose of intravenous trial drug through
the scheduled visit at the end of intravenous therapy.
** Full recovery was defined as a serum creatinine level less than 0.5 mg per deciliter above the baseline value.

aminoglycosides, was therefore unrelated to me- is known to be associated with aminoglycoside

ropenem resistance.
This trial assessed possible nephrotoxicity
through analyses of adverse events and changes
in serum creatinine level as markers of de-
creased renal function. Because published re-
ports of clinical trials of other aminoglycosides
do not systematically include analyses of serum
creatinine levels after completion of treatment,
an important finding in this trial was that a
small number of patients in the plazomicin
group had increases in serum creatinine levels
approximately 1 week after completion of ther-
apy. Risk factors for decreased renal function
were consistent with drug accumulation, which
toxicity,33 and with the general observation that
chronic renal dysfunction is a predictor of acute
renal dysfunction.34 Conversely, among patients
with normal renal function (creatinine clearance
>90 ml per minute), the incidence of nephrotox-
icity was lower in the plazomicin group than in
the meropenem group. Renal function was de-
termined on the basis of ideal body weight, and
plazomicin doses on the basis of adjusted body
weight, which may have prevented obese pa-
tients from receiving a dose that was too high
and may have helped to minimize the risk of
new-onset renal dysfunction.
The proportion of patients who received oral

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 Plazomicin for Complicated Urinary Tr act Infections

step-down therapy with levofloxacin despite
having a baseline pathogen that was not suscep-
tible to levofloxacin was similar in the two treat-
ment groups, which therefore minimized the
possible effect on the test-of-cure results. The
majority of these patients received the intrave-
nous trial drug for the prespecified maximum
duration. Subgroup analyses showed that com-
posite cure rates were higher among patients
who received meropenem plus oral step-down
therapy than among patients who received me-
ropenem alone. The rates of composite cure
were more consistent in the subgroups of pa-
tients who received plazomicin, which suggests
that the higher rate of composite cure with
plazomicin than with meropenem observed at
the test-of-cure visit was not confounded by a
switch to oral therapy.
A limitation of the trial is that patients from
countries outside Europe and patients of non-
white race were underrepresented, a limitation
that is similar to that in previous studies of
complicated UTIs.31,32,35 However, this factor most
likely did not affect the results, because the
pharmacokinetics of plazomicin and meropenem
are not expected to be affected by ethnic group.
In addition, the analysis in the microbiologic
modified intention-to-treat population excluded
patients with pathogens resistant to the trial
drugs, so geographic differences in resistance
rates also would not have affected the results.
In conclusion, the EPIC trial met the primary
objective of showing the noninferiority of plazo-
micin to meropenem in composite cure at day 5
and at the test-of-cure visit. These findings sup-
port the use of once-daily plazomicin in adult
patients with complicated UTIs or acute pyelone-
phritis, including infections caused by extended-
spectrum β-lactamase–producing Enterobac­
teriaceae and Enterobacteriaceae that are not
susceptible to other aminoglycosides.
Supported by Achaogen and by federal funds from the Bio-
medical Advanced Research and Development Authority, U.S.
Department of Health and Human Services Office of the Assistant
Secretary for Preparedness and Response, under contract no.
HHSO100201000046C. Editorial support was funded by Achaogen.
Dr. Wagenlehner reports receiving advisory board fees and
participating in a study for Achaogen, Bionorica, OM Pharma/
Vifor Pharma, and Shionogi, receiving advisory board fees from
AstraZeneca, Janssen, Leo Pharma, MerLion, MSD, Pfizer, Rosen-
Pharma, VenatoRx, and GlaxoSmithKline, and participating in
a study for Enteris BioPharma, Helperby Therapeutics, and
Deutsches Zentrum für Infektionsforschung (Giessen-Marburg-
Langen); Dr. Cloutier and Mr. Krause, being employed by and
holding stock in Achaogen; Dr. Komirenko, Dr. Keepers, Ms.
Cebrik, and Dr. Connolly, being formerly employed by and hold-
ing stock in Achaogen; Dr. Miller, receiving grant support and
advisory board fees from Achaogen, advisory board fees from
Tetraphase, and grant support from Cepheid, Merck, Abbott,
Gilead Sciences, Genentech, AtoxBio, and Paratek; Dr. Fried-
land, being formerly employed by, holding stock in, and receiv-
ing consulting fees from Achaogen; and Dr. Dwyer, receiving
consulting fees from Achaogen, ContraFect, Theravance, and
Spero Therapeutics. No other potential conflict of interest rele-
vant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank Kate Bradford for editorial support with an earlier
version of the manuscript.

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