Antimicrobial Reports
Safety and Efficacy of Ceftolozane/Tazobactam Versus
Meropenem in Neonates and Children With Complicated
Urinary Tract Infection, Including Pyelonephritis: A Phase 2,
Randomized Clinical Trial
Emmanuel Roilides, PhD, MD,* Negar Ashouri, MD,† John S. Bradley, MD,‡ Matthew G. Johnson, MD,§
Julia Lonchar, MSc,§ Feng-Hsiu Su, MPH, MBA,§ Jennifer A. Huntington, PharmD,§
Myra W. Popejoy, PharmD,§ Mekki Bensaci, PhD,§ Carisa De Anda, PharmD,§
Elizabeth G. Rhee, MD,§ and Christopher J. Bruno, MD§
Background: Ceftolozane/tazobactam, a cephalosporin-β-lactamase
inhibitor combination, active against multidrug-resistant Gram-negative
pathogens, is approved for treatment of adults with complicated urinary
tract infections (cUTI). Safety and efficacy of ceftolozane/tazobactam in
pediatric participants with cUTI, including pyelonephritis, were assessed.
Methods: This phase 2 study (NCT03230838) compared ceftolozane/
tazobactam with meropenem for treatment of cUTI in participants from
birth to <18 years of age. The primary objective was safety and tolerabil-
ity. Key secondary end points included clinical cure and per-participant
microbiologic response rates at end of treatment (EOT) and test of cure
(TOC) visits.
Results: The microbiologic modified intent-to-treat (mMITT) population
included 95 participants (ceftolozane/tazobactam, n = 71; meropenem,
n = 24). The most common diagnosis and pathogen were pyelonephritis
(ceftolozane/tazobactam, 84.5%; meropenem, 79.2%) and Escherichia coli
(ceftolozane/tazobactam, 74.6%; meropenem, 87.5%); 5.7% (ceftolozane/
Accepted for publication November 29, 2022
From the *Third Department of Pediatrics, Infectious Diseases Unit, School of
Medicine, Aristotle University and Hippokration General Hospital, Thessa-
loniki, Greece; †Division of Infectious Diseases, CHOC Children’s Hospital,
Orange, California; ‡Department of Pediatrics, University of California San
Diego School of Medicine and Rady Children’s Hospital of San Diego, San
Diego, California; and §Merck & Co., Inc., Rahway, New Jersey.
Funding for this research was provided by Merck Sharp & Dohme LLC, a sub-
sidiary of Merck & Co., Inc., Rahway, NJ.
M.G.J., J.L., F.-H.S., J.A.H., M.B., C.D.A., E.G.R. and C.J.B. are employees of
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway,
NJ (MSD), who may own stock and/or hold stock options in the Merck &
Co., Inc., Rahway, NJ. M.W.P. was an employee of MSD at the time of study
conduct. E.R. reports grant funding and consulting fees from MSD to his
institution. E.R., N.A., and J.S.B. report funding to conduct the study from
MSD to their institutions.
All authors are responsible for the work described in this paper and meet ICMJE
authorship criteria. All authors were involved in at least one of the following:
conception, design of work or acquisition, analysis, interpretation of data,
drafting the manuscript and/or revising/reviewing the manuscript for impor-
tant intellectual content. All authors provided final approval of the version to
be published. All authors agree to be accountable for all aspects of the work
in ensuring that questions related to the accuracy or integrity of any part of
the work are appropriately investigated and resolved.
Address for correspondence: Matthew G. Johnson, MD, Merck & Co., Inc., 126
E. Lincoln Ave, Rahway, NJ 07065. E-mail: matthew.johnson1@merck.com.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.pidj.com).
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided
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mercially without permission from the journal.
ISSN: 0891-3668/23/4204-0292
DOI: 10.1097/INF.0000000000003832
292 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023
tazobactam) and 4.8% (meropenem) of E. coli isolates were extended-
spectrum β-lactamase-producers. Rates of adverse events were similar
between treatment groups (any: ceftolozane/tazobactam, 59.0% vs. mero-
penem, 60.6%; drug-related: ceftolozane/tazobactam, 14.0% vs. mero-
penem, 15.2%; serious: ceftolozane/tazobactam, 3.0% vs. meropenem,
6.1%). Rates of clinical cure for ceftolozane/tazobactam and meropenem
at EOT were 94.4% and 100% and at TOC were 88.7% and 95.8%, respec-
tively. Rates of microbiologic eradication for ceftolozane/tazobactam and
meropenem at EOT were 93.0% and 95.8%, and at TOC were 84.5% and
87.5%, respectively.
Conclusions: Ceftolozane/tazobactam had a favorable safety profile in
pediatric participants with cUTI; rates of clinical cure and microbiologic
eradication were high and similar to meropenem. Ceftolozane/tazobactam
is a safe and effective new treatment option for children with cUTI, espe-
cially due to antibacterial-resistant Gram-negative pathogens.
Key Words: cUTI, antibacterial, pyelonephritis, Escherichia coli
(Pediatr Infect Dis J 2023;42:292–298)
M
ultidrug-resistant (MDR) Gram-negative bacteria, includ-
ing Enterobacterales and Pseudomonas aeruginosa, are well
recognized as a global public health issue.1,2 Complicated urinary
tract infections (cUTI), including pyelonephritis, are character-
ized by pyuria, presence of microbial pathogen(s) on culture of
urine or blood, local and systemic signs and symptoms of infec-
tion [fever (>38°C), chills, malaise, flank pain, back pain, and/or
costo-vertebral angle pain/tenderness], and occur in the presence
of a functional or anatomical abnormality of the urinary tract or
in the presence of catheterization.3 The most common causative
pathogens for pediatric urinary tract infections are Escherichia
coli (>80%), followed by Klebsiella pneumoniae, P. aeruginosa,
Enterococcus spp.‚ and Proteus spp., with each isolated in approxi-
mately 4% of cases or less.4,5 Increasingly, neonatal and pediatric
UTI are caused by antibacterial-resistant Gram-negative pathogens,
with an estimated global pooled prevalence of extended-spectrum
β-lactamase (ESBL)–producing Enterobacterales of 14% among
pediatric UTI cases; rates are higher in patients with recurrent UTIs
caused by uropathies such as vesicoureteral reflux in some parts of
the world.6,7 Antibacterial resistance may be even more prevalent
among P. aeruginosa isolates from patients with nosocomial UTI,
with a global rate of nonsusceptibility to ceftazidime in adults and
children between 20.3% and 50%.8
UTI are common in the pediatric population, with preva-
lence rates of 7.0% among febrile infants ≤24 months of age, and
7.8% among children <19 years of age with urinary symptoms and/
or fever.9 Compared with children without uropathies, those with
The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023
vesicoureteral reflux have higher 2-year rates of recurrent UTI
(25.4% vs. 17.3%).10 Children with cUTI are at risk for complica-
tions including bacteremia, renal scarring‚ and chronic abdominal
pain.11–13 There is significant unmet medical need for new antibac-
terial agents that are approved for use in adults to be available for
the neonatal and pediatric populations to provide more options
for cUTI treatment should local resistance rates indicate the need
for alternative therapy.
Ceftolozane/tazobactam is a cephalosporin-β-lactamase
inhibitor combination14 approved to treat cUTI, including
pyelonephritis, complicated intra-abdominal infection (cIAI)‚
and nosocomial pneumonia in adults.15 In a large phase 3 study
in adults (ASPECT-cUTI), ceftolozane/tazobactam had a favora-
ble safety profile and was effective for the treatment of cUTI.16
Ceftolozane/tazobactam was recently approved for the treatment
of cUTI in pediatric patients in the United States (birth to <18
years of age).15
There are limited data related to the use of ceftolozane/
tazobactam in children and adolescents, although a pharmacoki-
netic study indicated that exposures in pediatric participants are
comparable with those observed in adults.17 This study assessed
the safety and efficacy of ceftolozane/tazobactam compared with
meropenem for the treatment of cUTI, including pyelonephritis, in
neonatal and pediatric participants.
MATERIALS AND METHODS
Study Design
This was a phase 2, randomized, double-blind study
(NCT03230838; EudraCT 2016-004153-32; protocol MK-
7625A-034) in pediatric participants with cUTI, including
pyelonephritis, conducted at 28 study sites in 8 countries across West-
ern Europe, Eastern Europe‚ and North America between April
2018 and December 2020. The study was conducted in accord-
ance with the principles of Good Clinical Practice and the protocol was
approved by the appropriate institutional review boards and regulatory
agencies. All participants had a legally acceptable representative,
and documented informed consent/assent was provided for the study.
Blinding, randomization, and masking procedures are included in Meth-
ods, Supplemental Digital Content 1, http://links.lww.com/INF/E917.
Participants
Male and female participants from birth (defined as >32
weeks gestational age and ≥7 days postnatal) to <18 years of age
were eligible. Eligible participants required intravenous (IV) anti-
bacterial therapy for the treatment of cUTI, had a pretreatment
baseline urine culture specimen obtained within 48 hours before
the administration of the first dose of study treatment, and had pyu-
ria. Participants were also required to have had clinical signs and/
or symptoms of cUTI (pyelonephritis or cUTI with a urological
abnormality); the clinical diagnosis was at the discretion of the
investigator. Participants were excluded if they had a history of
cUTI within the previous year caused by a pathogen known to be
resistant to either IV study treatment, a concomitant infection that
required nonstudy systemic antibacterial therapy (antibacterials
with only Gram-positive activity were permitted), receipt of poten-
tially therapeutic antibacterial therapy for >24 hours during the 48
hours preceding the first dose of study treatment (except in cases
of participants receiving ≥48 hours of prior antibacterial therapy
who were deemed to have failed treatment)‚ or had moderate or
severe impairment of renal function (defined as an estimated creati-
nine clearance <50 mL/min/1.73 m2). Full inclusion and exclusion
criteria are provided in Methods, Supplemental Digital Content 1,
http://links.lww.com/INF/E917.
© 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
Ceftolozane/Tazobactam for Pediatric cUTI
The microbiologic modified intent-to-treat (mMITT)
population included all randomized participants who received any
amount of study treatment and had ≥1 causative uropathogen from
a study-qualifying baseline urine culture. The safety population
consisted of all randomized participants who received any amount
of study treatment.
Treatment
Randomized participants were stratified and dosed by
age group. The selected doses were based on population phar-
macokinetic modeling and simulations.18 For participants in
the ceftolozane/tazobactam group, those 12 to <18 years of
age were given 1.0 g ceftolozane and 0.5 g tazobactam (the
dose indicated for adult patients with cUTI),15 and those from
birth to <12 years of age were given 20 mg/kg ceftolozane
and 10 mg/kg tazobactam (maximum of 1.0 g ceftolozane and
0.5 g tazobactam per dose). All participants in the merope-
nem group received 20 mg/kg (maximum of 1.0 g per dose),
with higher dosing up to 30 mg/kg for participants who were
14 days to <3 months of age permitted at the investigator’s
discretion. Each dose of ceftolozane/tazobactam or meropenem
was administered as a 60-minute (±10 minutes) infusion and
dosed every 8 hours (±1 hour) after the previous infusion.
Treatment duration was 7-14 days. After 3 days (9 doses) of
IV therapy, optional open-label, standard-of-care, oral step-down
therapy was permitted at the investigator’s discretion, with choice of
therapy guided by culture and antibacterial susceptibility results, as
well as local standard of care for treatment of cUTI. Recommended
options for oral step-down therapy were β-lactam/β-lactamase
inhibitor combinations, cephalosporins, fluoroquinolones, nitro-
furantoin, trimethoprim‚ or trimethoprim/sulfamethoxazole.
Specimen Collection
A baseline urine sample for culture was obtained ≤48 hours
before the start of administration of the first dose of study treat-
ment. Urine specimens were obtained by suprapubic aspiration,
clean urethral catheterization, indwelling urethral catheter‚ or mid-
stream clean catch. Additional details of specimen collection and
culture of urine specimens are included in Methods, Supplemental
Digital Content 1, http://links.lww.com/INF/E917.
Assessments and End Points
Clinical and microbiologic assessments were performed at
the end of treatment (EOT) visit, scheduled <24 hours after the
last IV dose of therapy or <48 hours after the last dose of oral step-
down therapy (if applicable), the test of cure (TOC) visit, occur-
ring 5–9 days after the last dose of study treatment (IV or oral) and
the end of IV therapy (EOIV) visit (<24 hours after the last of IV
therapy).
The primary end points were rates of adverse events (AEs)
and changes in laboratory values and vital signs through the last
follow-up visit, which occurred 28-35 days after the last dose of
study treatment (IV or oral). In all treated participants, AEs were
evaluated from the first dose of study treatment to the last study
evaluation. Key secondary end points included rates of clinical
success and per-participant microbiologic eradication, defined as
the proportion of participants who had a clinical response of cure
and proportion of participants who had microbiologic eradication
or presumed eradication at the EOT and TOC visits, respectively.
Additional exploratory end points included per-pathogen microbio-
logic eradication, which was determined for each uropathogen iso-
lated from the baseline study-qualifying culture, clinical response
at the EOIV visit‚ and composite success, defined as a clinical
response of success and per-participant microbiologic response of
www.pidj.com | 293
Roilides et al The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023

eradication. See additional details about end points in Methods,
Supplemental Digital Content 1, http://links.lww.com/INF/E917.
Statistical Analysis
No formal hypothesis testing was performed. For the
primary safety analysis, 95% CIs were derived for the between-
treatment differences in the percentage of participants with events,
and these analyses were performed using the unstratified Miettinen
& Nurminen method.19 Changes in laboratory and vital sign val-
ues from baseline were summarized using descriptive statistics.
For the secondary efficacy analyses, 2-sided 95% CIs based on the
Miettinen & Nurminen method19 and stratified by age group were
used to evaluate the treatment differences for clinical success and
per-participant microbiologic eradication at the EOT and TOC vis-
its. The sample size calculation is described in Methods, Supple-
mental Digital Content 1, http://links.lww.com/INF/E917.
RESULTS
Study Participants
A total of 143 participants were screened and 134 were rand-
omized. One randomized participant in the ceftolozane/tazobactam
group was not treated because of a temperature excursion of the
study treatment. The remaining 133 participants were randomized
in a 3:1 ratio and treated with ceftolozane/tazobactam (n = 100) or
meropenem (n = 33; Fig. 1). The mMITT population included 95
participants in the ceftolozane/tazobactam (n = 71) and merope-
nem (n = 24) groups. The most common reason for mMITT exclu-
sion was lack of a qualifying baseline uropathogen (ceftolozane/
tazobactam, 28.7%; meropenem, 27.3%). One participant in
the ceftolozane/tazobactam group had an AE of exacerbation of
chronic kidney disease leading to discontinuation of study treat-
ment. This AE met the protocol-defined discontinuation criterion
excluding participants with creatinine clearance <50 mL/min and
was not considered to be drug-related.
The baseline characteristics of participants in each treatment
group were comparable (Table 1). Pyelonephritis was the most com-
mon baseline diagnosis, occurring in 83.2% of participants overall.
Among those participants with cUTI, the most common underlying
problems were recurrent UTI (33.7%), congenital abnormalities
of the urogenital tract (28.4%)‚ and anatomic abnormalities of the
urogenital tract (27.4%). Other underlying problems were func-
tional abnormalities of the urogenital tract (21.1%), obstructive
uropathies (7.4%), recent bladder instrumentation (3.2%)‚ and tem-
porary indwelling catheter (2.1%). More than one underlying prob-
lem per participant may have been present. Bacteremia was present
in 3 participants in each treatment group (ceftolozane/tazobac-
tam, 4.2%; meropenem, 12.5%). Urine samples were collected by
catheter in 29 (40.8%) participants in the ceftolozane/tazobactam
group and in 9 (37.5%) participants in the meropenem group, by
midstream clean catch in 37 (52.1%) participants in the ceftolo-
zane/tazobactam group and in 13 (54.2%) participants in the mero-
penem group and by suprapubic aspiration in 5 (7.0%) participants
in the ceftolozane/tazobactam group and in 2 (8.3%) participants in
the meropenem group.
Pathogens at Baseline
Nearly all infections were monomicrobial (ceftolozane/
tazobactam, 98.6%; meropenem, 95.8%). E. coli was the most com-
mon qualifying baseline uropathogen in the mMITT population
[ceftolozane/tazobactam, 53 (74.6%); meropenem, 21 (87.5%)],
followed by K. pneumoniae [ceftolozane/tazobactam, 6 (8.5%);
meropenem, 1 (4.2%)], and P. aeruginosa [ceftolozane/tazobac-
tam, 5 (7.0%); meropenem, 2 (8.3%)]. Susceptibility rates among
aerobic Gram-negative pathogens to both drugs were high [cef-
tolozane/tazobactam, 91/92 (98.9%); meropenem, 91/94 (96.8%)].
Among the E. coli isolates (n = 74), 5.4% were ESBL producers
(ceftolozane/tazobactam, 5.7%; meropenem, 4.8%); all were suscep-
tible to ceftolozane/tazobactam. A single carbapenemase-producing
pathogen was isolated, a blaOXA-48-carrying K. pneumoniae isolate.
No K. pneumoniae isolates were ESBL producers; 100% (7/7) were
susceptible to ceftolozane/tazobactam. None of the 7 P. aeruginosa
isolates overexpressed AmpC at baseline, and all were susceptible to
ceftolozane/tazobactam. Antimicrobial activity of ceftolozane/tazo-
bactam and meropenem against key pathogens is shown in the Table,
Supplemental Digital Content 2, http://links.lww.com/INF/E918.
Safety
The mean (SD) duration of IV treatment was 6.1 (2.7) days
and 5.7 (2.2) days in the ceftolozane/tazobactam and meropenem

FIGURE 1. Study disposition of all randomized participants. aRandomized participants who received any amount of study
drug and have at least 1 acceptable causative uropathogen identified from a study-qualifying baseline urine culture. bAll
randomized participants who received any amount of study treatment. C/T indicates ceftolozane/tazobactam; mMITT,
microbiologic modified intent-to-treat.
294 | www.pidj.com © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023 Ceftolozane/Tazobactam for Pediatric cUTI

TABLE 1. Participant Demographics and Baseline Characteristics (mMITT Population)

Characteristic C/T (N = 71) MEM (N = 24)

Female, n (%) 40 (56.3) 15 (62.5)

Age, n (%)
Birth to <3 mo* 14 (19.7) 6 (25.0)
3 mo to <2 yr 20 (28.2) 6 (25.0)
2 to <6 yr 14 (19.7) 6 (25.0)
6 to <12 yr 13 (18.3) 4 (16.7)
12 to <18 yr 10 (14.1) 2 (8.3)
White race, n (%)† 70 (98.6) 24 (100.0)
Median (range) weight, kg 13.0 (2.6–75.3) 10.4 (3.8–54.0)
Baseline diagnosis, n (%)
Pyelonephritis 60 (84.5) 19 (79.2)
cUTI with a urological abnormality 11 (15.5) 5 (20.8)
Bacteremia at baseline, n (%) 3 (4.2) 3 (12.5)
Urine sample collected via urinary catheter, n (%) 29 (40.8) 9 (37.5)
Baseline CrCl (mL/min/1.73 m2),‡ n (%)
CrCl ≥80 48 (67.6) 16 (66.7)
CrCl ≥50 to <80 23 (32.4) 7 (29.2)
CrCl ≥30 to <50 0 1 (4.2)§
Failure of prior antibacterial therapy, n (%) 3 (4.2) 0
*All enrolled participants in this age group were full-term neonates.
†Race was determined by the investigator during the screening visit.
‡CrCl rates were calculated by the revised Schwartz equation at baseline.
§One participant was enrolled with a baseline CrCl of 36.6 mL/min/1.73 m2; however, a follow-up CrCl measurement was >50 mL/min/1.73 m2, and the participant remained in
the study.
C/T indicates ceftolozane/tazobactam; CrCl, creatinine clearance; MEM, meropenem, mMITT, microbiologic modified intent-to-treat.

groups, respectively. Overall mean (SD) treatment duration (both
IV and oral step-down) in the mMITT population was comparable
in both treatment groups [ceftolozane/tazobactam, 10.2 (2.7) days;
meropenem, 10.7 (2.1) days]. A total of 50 (70.4%) and 20 (83.3%)
participants transitioned to optional oral step-down therapy in the
ceftolozane/tazobactam and meropenem groups, for a mean (SD)
duration of 5.8 (1.72) days and 6.0 (1.5) days, respectively. The
most common oral step-down treatments (>10% in either treatment
group) were cefixime, amoxicillin/clavulanate potassium‚ and
cefuroxime; choice of oral step-down therapy was determined at
the investigator’s discretion.
The overall incidences of AEs (all and drug-related), seri-
ous AEs (SAEs) and AEs leading to discontinuation were com-
parable between the ceftolozane/tazobactam and meropenem
groups (Table 2). There were no AEs leading to death, drug-related
SAEs‚ or discontinuations due to drug-related AEs or SAEs. Three
participants (3.0%) in the ceftolozane/tazobactam group and 2
participants (6.1%) in the meropenem arm experienced SAEs,

TABLE 2. Adverse Events (All Treated Participants Population)

Participants With, n (%) C/T (N = 100) MEM (N = 33) Difference*† (95% CI)

≥1 AE 59 (59.0) 20 (60.6) −1.6 (−19.7 to 17.9)

Drug-related‡ AEs 14 (14.0) 5 (15.2) −1.2 (−18.0 to 10.9)
Serious AEs§ 3 (3.0) 2 (6.1) −3.1 (−16.9 to 3.9)
Serious drug-related‡ AEs 0 0 –
Death 0 0 –
Discontinuation due to AE 1 (1.0) 0 1.0 (−9.5 to 5.5)
Discontinuation due to drug-related‡ AE 0 0 –
Discontinuation due to serious AE 0 0 –
Most commonly reported AEs¶
Thrombocytosis 7 (7.0) 3 (9.1) –
Diarrhea 7 (7.0) 3 (9.1) –
Urinary tract infection 1 (1.0) 3 (9.1) –
Most commonly reported drug-related AEs║
Diarrhea 3 (3.0) 3 (9.1) –
Eosinophilia 0 1 (3.0) –
Frequent bowel movements 0 1 (3.0) –
Increased appetite 3 (3.0) 0 –
Increased aspartate aminotransferase 2 (2.0) 1 (3.0) –
Neutropenia 3 (3.0) 0 –
Phlebitis 0 1 (3.0) –
*Difference in C/T minus MEM.
†Based on Miettinen & Nurminen method.
‡Determined by the investigator to be related to the study drug.
§Serious AEs in the C/T group were pyelonephritis (2 participants) and upper respiratory tract infection (1 participant); in the MEM group, the serious AEs were hypertension
and pyrexia (1 participant each).
¶Incidence ≥7% in ≥1 treatment arm.
║Incidence ≥3% in ≥1 treatment arm.
AE indicates adverse event; CI, confidence interval; C/T, ceftolozane/tazobactam; MEM, meropenem.

© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. www.pidj.com | 295
Roilides et al The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023

all of which were unrelated to study drug. The most commonly
reported AEs and most commonly reported drug-related AEs
are listed in Table 2. Overall, 5 participants in the ceftolozane/
tazobactam group had an AE of neutropenia (which was considered
drug-related in 3 participants), and 2 additional participants in the
ceftolozane/tazobactam group had an AE of decreased neutrophil
count, 1 of which was considered drug-related. Of the 5 neutro-
penia cases, there was 1 mild and 2 each of moderate and severe,
with durations ranging from 2.1 weeks to 1.5 months (1 participant
was lost to follow-up after day 3 following withdrawal of parental
consent). Both cases of decreased neutrophil count were classified
as moderate, with one case having a duration of 1.1 months and the
other lost to follow-up due to issues with IV access. Classification
of these events was based on the investigator’s clinical judgement.
Neutropenia or decreased neutrophil counts were not seen in the
meropenem group. No clinically meaningful differences in mean
change from baseline in neutrophil-related laboratory parameters
were observed between the treatment groups. Five of the 7 par-
ticipants were reported to have recovered. The 2 remaining partici-
pants were lost to follow-up; 1 participant withdrew on day 3 of the
study because of loss of parental consent due to concern over pain
associated with pharmacokinetic sampling, and 1 participant with-
drew because of loss of parental consent due to IV access issues.
There was no follow-up on either of these participants.
Efficacy
Clinical cure rates in the mMITT population were
94.4% and 100% for the ceftolozane/tazobactam and merope-
nem treatment groups, respectively, at the EOT visit, and 88.7%
(ceftolozane/tazobactam) and 95.8% (meropenem) at the TOC visit
(Fig. 2). Likewise, microbiologic eradication rates were 93.0%
(ceftolozane/tazobactam) and 95.8% (meropenem) at the EOT visit
and 84.5% (ceftolozane/tazobactam) and 87.5% (meropenem) at
the TOC visit. (Fig. 2). Of the clinical failures at the EOT visit in
the ceftolozane/tazobactam group, 2 (2.8%) were observed failures
and 2 (2.8%) were classified as failures owing to having missing
clinical response data (indeterminate response, thus imputed as a
failure). Of the clinical failures at TOC, 1 (4.2%) in the meropenem
group was an observed failure; within the ceftolozane/tazobactam
group, 4 (5.6%) were observed failures, 1 (1.4%) was observed
indeterminate and 3 (4.2%) were classified as clinical cure, partial
improvement‚ or indeterminate at the previous visit but had miss-
ing clinical response data at the TOC visit.
These results were generally consistent for the per-pathogen
microbiologic response (Table 3), composite response (see Table,
Supplemental Digital Content 3, http://links.lww.com/INF/E919),
and all end points at the EOIV visit (see Table, Supplemental Digi-
tal Content 4, http://links.lww.com/INF/E920). Clinical cure rates
were 100% in both treatment groups for the 4 total participants with
ESBL-producing E. coli at baseline (ceftolozane/tazobactam, n = 3;
meropenem, n = 1).
DISCUSSION
This study and the companion pediatric study of cIAI20
(NCT03217136) are the first randomized, active-controlled clinical
studies to evaluate the safety and efficacy of ceftolozane/tazobactam
treatment in the pediatric population. In this phase 2 study, cef-
tolozane/tazobactam had a favorable safety profile in children
from birth (full-term neonates) to <18 years of age, comparable
to that of meropenem for the treatment of cUTI. Furthermore, the
safety profile of ceftolozane/tazobactam was consistent with that
observed in the cUTI study in adults.16 Seven participants in the
ceftolozane/tazobactam group had neutrophil-related AEs, but
none of the events were considered serious and none led to discon-
tinuation of study drug. Both participants with neutrophil-related
AEs who discontinued from the study did so for reasons unrelated
to the AE. There were no neutrophil-related AEs in the compan-
ion pediatric study mentioned above.20 Overall, no new safety con-
cerns were identified for ceftolozane/tazobactam in this study or
in the companion pediatric study of cIAI infection, and the results
align with previously reported results about the safety of ceftolo-
zane/tazobactam in adults.16 Based on these studies, ceftolozane/
tazobactam was recently approved in the United States for the treat-
ment of both cUTI and cIAI in pediatric patients (birth to less than
18 years of age).15

FIGURE 2. Clinical and microbiologic response at EOT and TOC (mMITT population). aDifference in C/T minus MEM.
b
The percent difference was based on the Miettinen & Nurminen method stratified by age group with Cochran-Mantel-
Haenszel weights. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with
the near age group stratum in the model. CI indicates confidence interval; C/T‚ ceftolozane/tazobactam; MEM, meropenem;
mMITT, microbiologic modified intent-to-treat population; TOC, test of cure.

296 | www.pidj.com © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
The Pediatric Infectious Disease Journal • Volume 42, Number 4, April 2023
TABLE 3. Per-pathogen Microbiologic Response at EOT and TOC (mMITT Population)
EOT
Eradication by Pathogen, n/N1 (%) C/T (N = 71)
All Enterobacterales 62/66 (93.9)
Escherichia coli 50/53 (94.3)
Klebsiella pneumoniae 5/6 (83.3)
Pseudomonas aeruginosa 4/5 (80.0)
C/T indicates ceftolozane/tazobactam; EOT, end of treatment; MEM, meropenem; N1, number of participants in mMITT population for each specific pathogen; TOC, test of cure.
Rates of clinical cure and microbiologic eradication were
high at EOT and TOC for both treatment groups, and the results
for exploratory efficacy endpoints were also comparable between
treatment groups. While this study was not powered for comparison
of between-group efficacy outcomes, the high clinical and micro-
biologic response rates observed were consistent with studies of
ceftolozane/tazobactam in adults with cUTI.16,21,22
In the current study, E. coli was the most common pathogen
identified in the mMITT population, followed by K. pneumoniae
and P. aeruginosa. This is consistent with other studies in children
with cUTI,23–25 suggesting that this participant population and the
causative pathogens were representative of a typical pediatric popu-
lation with cUTI. MDR pathogens were not common in this global
study; 5.7% (ceftolozane/tazobactam) and 4.8% (meropenem) of E.
coli isolates were ESBL producers. These isolates were from par-
ticipants in Hungary and Turkey. Clinical cure occurred in all cases
in both treatment groups for participants with ESBL-producing
E. coli. This is similar to clinical response rates observed in the
phase 3 clinical study of ceftolozane/tazobactam in adults with
cUTI, in which clinical success was seen in 90.2% of participants
with ESBL-producing Enterobacterales, including E. coli and
K. pneumoniae.26 Surveillance study data also demonstrate that
ceftolozane/tazobactam activity remains high against Gram-neg-
ative bacteria, including ESBL-producing strains,27–29 but MDR
P. aeruginosa is becoming more common, where resistance to
ceftazidime/avibactam has been reported to range from 2.9%30 to
18.0%,31 underscoring the need to have additional antibacterial
options available to treat serious pediatric infections.
A limitation of this study is its small sample size, which is
typical for pediatric studies. Its strength, however, is that it includes
not only adolescents and children, but also 31 participants between
3 months and 2 years of age, and 22 participants from birth to 3
months of age, making the results generalizable to a broad range
of pediatric age groups, including neonates. In addition, integrating
the safety data from this study with the phase 2 study in pediatric
participants with cIAI20 allowed for a more thorough assessment of
the safety of ceftolozane/tazobactam in the pediatric population. A
subanalysis of safety and efficacy in neonates and young infants <3
months of age will be published separately.
In this study, ceftolozane/tazobactam had a favorable safety
profile that was comparable to meropenem and to the previously
reported safety profile for ceftolozane/tazobactam in adults with
cUTI. Furthermore, ceftolozane/tazobactam achieved high clinical
cure and microbiologic eradication rates. Thus, ceftolozane/tazo-
bactam is a safe and effective new treatment option active against
antimicrobial-resistant Gram-negative bacteria for children, includ-
ing neonates and young infants with cUTI.
ACKNOWLEDGMENTS
We thank the study participants and the investigators who
made this study possible, particularly, as they dealt with the chal-
lenges imparted by the COVID-19 pandemic. Investigators included
© 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
Ceftolozane/Tazobactam for Pediatric cUTI
TOC
MEM (N = 24) C/T (N = 71) MEM (N = 24)
21/22 (95.5) 58/66 (87.9) 19/22 (86.4)
20/21 (95.2) 45/53 (84.9) 18/21 (85.7)
1/1 (100) 6/6 (100) 1/1 (100)
2/2 (100) 3/5 (60) 2/2 (100)
Emmanuel Roilides (Thessaloniki, Greece), Athanasios Michos (Ath-
ens, Greece), George A. Syrogiannopoulos (Larissa, Greece), Maria
Tsolia (Athens, Greece), Vassiliki Papaevangelou (Athens, Greece),
Laszlo Szabo (Budapest, Hungary), Tamas Szabo (Debrecen, Hun-
gary), Csaba Bereczki (Szeged, Hungary), Ferenc Dicso (Bereg, Hun-
gary), Tamas Decsi (Pecs, Hungary), Attila Szabo (Budapest, Hungary),
Mercedes Macias Parra (Mexico City, Mexico), Martin Guerrero
Becerra (Guadalajara, Mexico), Sarbelio Moreno Espinosa (Mexico
City, Mexico), Cesar Adrian Martinez Longoria (Monterrey, Mexico),
Irena Daniluk-Matras (Bydgoszcz, Poland), Marcin Tkaczyk (Lodz,
Poland), Malgorzata Pawlowska (Bydgoszcz, Poland), Przemyslaw
Janik (Torun, Poland), Beata Jurkiewicz (Lomianki, Poland), Dorota
Drozdz (Krakow, Poland), Oana Falup-Pecurariu (Brasov, Romania),
Ruxandra Beatris Neagu-Draghicenoiu (Bucuresti, Romania), Mihaela
Balgradean (Bucharest, Romania), Dan Ioan Delean (Cluj-Napoca,
Romania), Antonina Petrovna Zouzova (Smolensk, Russia), Sergey
Viktorovich Minaev (Stavropol, Russia), Maria N. Kostyleva (Moscow,
Russia), Anna Nikolaevna Galustyan (Saint Petersburg, Russia), Peter
Nourse (Cape Town, South Africa), Rajendra Bhimma (Durban, South
Africa), Jan Hendrik Reynor Becker (Pretoria, South Africa), Derya
Alabaz (Adana, Turkey), Ates Kara (Ankara, Turkey), Ener Cagri Din-
leyici (Eskisehir, Turkey), Nazan Dalgic (Istanbul, Turkey), Nataliia
Dementieva (Dnipro, Ukraine), Ihor Ksonz (Poltava, Ukraine), Tetyana
V. Lytvynova, (Kryvyy Rig, Ukraine), Natalia Karpenko (Kyiv, Ukraine),
Igor Antonyan (Kharkiv, Ukraine), Oleksandr Fofanov (Ivano-
Frankivsk, Ukraine), Nataliia Makieieva (Kharkiv, Ukraine), Negar
Ashouri, (Orange, CA, USA), John S. Bradley (San Diego, CA, USA),
Jason G. Newland (St. Louis, MO, USA), Michael N. Neely (Los Ange-
les, CA, USA), Leonard B. Weiner (Syracuse, NY, USA), Michael Bolton
(Baton Rouge, LA, USA), Sowdhamini Wallace (Houston, TX, USA),
William J. Muller (Chicago, IL, USA), and Jen-Jar Lin (Winston-Salem,
NC, USA). Medical writing and/or editorial assistance was provided by
Emily Burke, PhD, of The Lockwood Group, Stamford, CT, USA. This
assistance was funded by Merck Sharp & Dohme LLC, a subsidiary
of Merck & Co., Inc., Rahway, NJ, USA. A portion of this study was
conducted during the COVID-19 pandemic, and all standard operat-
ing procedures for study conduct, monitoring, and oversight during the
pandemic were maintained, and a risk-based approach to assess and
mitigate its impact on study conduct was employed.
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