Antimicrobial Reports

Safety and Efficacy of Ceftazidime–Avibactam in the Treatment

of Children ≥3 Months to <18 Years With Complicated
Urinary Tract Infection: Results from a Phase 2 Randomized,
Controlled Trial
John S. Bradley, MD,* Emmanuel Roilides, MD, PhD,† Helen Broadhurst, MSc,‡ Karen Cheng, MB, ChB,§
Li-Min Huang, MD,¶ Veronica MasCasullo, MD,║ Paul Newell, MBBS,‡ Gregory G. Stone, PhD,**
Margaret Tawadrous, MD,** Dalia Wajsbrot, MSc,†† Katrina Yates, PhD,‡ and Annie Gardner, MS,‡‡

was 7–14 days. Primary objective was assessment of safety. Secondary

Background: Ceftazidime–avibactam is effective and well tolerated in
objectives included descriptive efficacy and pharmacokinetics. A blinded
adults with complicated urinary tract infection (cUTI), but has not been
Downloaded from http://journals.lww.com/pidj by BhDMf5ePHKbH4TTImqenVMLLdHdrcqOQ0DkK8LgA+M+4ksv0wAPFgMG7uMMKBKfJ03lOcJABRC4= on 12/08/2019

observer determined adverse event (AE) causality and clinical outcomes up

evaluated in children with cUTI.
Methods: This single-blind, multicenter, active-controlled, phase 2 study
(NCT02497781) randomized children ≥3 months to <18 years with cUTI
(3:1) to receive intravenous (IV) ceftazidime–avibactam or cefepime for
≥72 hours, with subsequent optional oral switch. Total treatment duration
Accepted for publication April 8, 2019.
From the *Rady Children’s Hospital/UCSD, San Diego, CA; †3rd Depart-
ment of Pediatrics, Aristotle University School of Health Sciences, Hip-
pokration Hospital, Thessaloniki, Greece; ‡AstraZeneca, Alderley Park,
Cheshire, United Kingdom; §Pfizer, Sandwich, Kent, United Kingdom;
¶National Taiwan University Hospital, Taipei, Taiwan; ║Allergan plc,
Madison, NJ; **Pfizer, Groton, CT; ††Pfizer, New York, NY; and ‡‡Pfizer,
Cambridge, MA.
This study was originally sponsored by AstraZeneca. AstraZeneca’s rights to
ceftazidime–avibactam were acquired by Pfizer in December 2016. The
study is now funded by Pfizer and Allergan.
J.S.B.’s, E.R.’s and L.-M.H.’s institutions received funds from AstraZeneca
and Pfizer to conduct and consult on this study; J.S.B., E.R. and L.-M.H.
received no funds for the creation of this manuscript. E.R. has received
research grants from Astellas, Gilead and Pfizer Inc; and is a scientific
advisor and member of speaker bureau for Astellas, Gilead, Merck and
Pfizer Inc. H.B. and P.N. are former employees of AstraZeneca and P.N.
is a current shareholder in AstraZeneca. P.N is a current employee of F2G
Ltd, Manchester, United Kingdom. K.C., M.T., D.W., G.G.S. and A.G. are
employees of Pfizer, all of whom may own stocks and options from Pfizer.
V.M.C. is an employee of Allergan. K.Y. was a contractor to AstraZeneca at
the time of study conduct.
to the late follow-up visit (20–36 days after the last dose of IV/oral therapy).
Results: In total, 95 children received ≥1 dose of IV study drug (ceftazi-
dime–avibactam, n = 67; cefepime, n = 28). The predominant baseline
Gram-negative uropathogen was Escherichia coli (92.2%). AEs occurred
in 53.7% and 53.6% patients in the ceftazidime–avibactam and cefepime
groups, respectively. Serious AEs occurred in 11.9% (ceftazidime–avi-
bactam) and 7.1% (cefepime) patients. One serious AE (ceftazidime–avi-
bactam group) was considered drug related. In the microbiologic intent-
to-treat analysis set, favorable clinical response rates >95% were observed
for both groups at end-of-IV and remained 88.9% (ceftazidime–avibactam)
and 82.6% (cefepime) at test-of-cure. Favorable per-patient microbiologic
response at test-of-cure was 79.6% (ceftazidime–avibactam) and 60.9%
(cefepime).
Conclusions: Ceftazidime–avibactam was well tolerated in children with
cUTI, with a safety profile consistent with that of adults with cUTI and
of ceftazidime alone, and appeared effective in children with cUTI due to
Gram-negative pathogens.
Key Words: ceftazidime–avibactam, cefepime, pediatric, complicated uri-
nary tract infection, phase 2
(Pediatr Infect Dis J 2019;38:920–928)

Upon request, and subject to certain criteria, conditions and exceptions see
(https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more
information), Pfizer will provide access to individual de-identified participant
data from Pfizer-sponsored global interventional clinical studies conducted
for medicines, vaccines and medical devices (1) for indications that have
been approved in the United States and/or EU or (2) in programs that have
been terminated (ie, development for all indications has been discontinued).
Pfizer will also consider requests for the protocol, data dictionary, and statisti-
cal analysis plan. Data may be requested from Pfizer trials 24 months after
study completion. The de-identified participant data will be made available to
researchers whose proposals meet the research criteria and other conditions,
and for which an exception does not apply, via a secure portal. To gain access,
data requestors must enter into a data access agreement with Pfizer.
Clinical Trial registry name and registration number: https://clinicaltrials.gov/
(identifier: NCT02497781)
Address for correspondence: John Bradley, MD, Rady Children’s Hospital,
3020 Children’s Way, MC 5041, San Diego, CA 92123. E-mail: jsbrad-
ley@ucsd.edu
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 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This
is an open-access article distributed under the terms of the Creative Com-
mons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
ISSN: 0891-3668/19/3809-0920
DOI: 10.1097/INF.0000000000002395
T
here is an increasing prevalence of multidrug-resistant (MDR)
uropathogens that are resistant to commonly prescribed anti-
biotics, such as ampicillin, cephalosporins and trimethoprim–
sulfamethoxazole.1–4 The occurrence of extended-spectrum
β-lactamase-producing Enterobacteriaceae, carbapenem-resistant
Enterobacteriaceae and MDR Pseudomonas aeruginosa are of par-
ticular concern,5 and highlight the need for novel therapeutics that
have activity against MDR Gram-negative pathogens.
Ceftazidime–avibactam combines ceftazidime (a third-
generation cephalosporin with activity against Pseudomonas spp.)
with avibactam (a non-β-lactam β-lactamase inhibitor). Avibactam
has potent activity against serine-based Ambler class A and class C
β-lactamases (both intrinsic and plasmid mediated), as well as some
class D enzymes.6 Therefore, combination with avibactam restores
the spectrum of activity of ceftazidime against many strains of pre-
viously resistant Enterobacteriaceae and Pseudomonas spp.7
Urinary tract infections (UTIs) are relatively common in
children.2 Recurrent UTIs are observed in 30%–50% of children
after initial infection, are especially common in patients with
abnormal urinary tract pathology, such as obstructive uropathy, and
can be associated with significant morbidity.8 The most common
bacterial pathogen associated with pediatric UTIs is Escherichia
coli,1 with other Gram-negative pathogens less frequently isolated

920 | www.pidj.com The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019
The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019 CAZ-AVI Pediatric cUTI Study

including Proteus spp., Klebsiella spp., Enterobacter spp., Pseu-
domonas spp. and Enterococcus spp.1,9
The safety and efficacy of ceftazidime–avibactam in adults
with complicated UTIs (cUTIs), including those caused by ceftazi-
dime–non-susceptible Gram-negative pathogens, have been dem-
onstrated in the phase 3 REPRISE and RECAPTURE studies,10,11
and a phase 1 study investigated the pharmacokinetics and safety of
ceftazidime–avibactam in 32 hospitalized children.12
This phase 2 study was conducted as part of the global
clinical development program for ceftazidime–avibactam, which
included postapproval regulatory commitments in the United States
and Europe to evaluate ceftazidime–avibactam in pediatric patients
with cUTI to support extension of the current labeled indication for
ceftazidime–avibactam in adults to pediatric patients with cUTI.13,14
The primary objective was to evaluate the safety and tolerability of
ceftazidime–avibactam versus cefepime in hospitalized children ≥3
months to <18 years with cUTI. Secondary objectives were to eval-
uate the efficacy and pharmacokinetics of ceftazidime–avibactam
in this patient population.
MATERIALS AND METHODS
Study Design and Patients
This single-blind, randomized, multicenter, active-con-
trolled, phase 2 study (NCT02497781) was conducted between
September 2015 and September 2017 at 25 study sites in 9 coun-
tries in compliance with regulatory agency guidelines for pedi-
atric clinical trials. Eligible subjects were hospitalized children
≥3 months to <18 years who were diagnosed with cUTI, includ-
ing acute pyelonephritis, that required treatment with intravenous
(IV) antibiotics. Diagnosis of acute pyelonephritis was according
to investigators’ judgment. Full inclusion and exclusion criteria,
as assessed at screening, are provided in the Text, Supplemental
Digital Content 1, http://links.lww.com/INF/D522. The study was
carried out in accordance with good clinical practice guidelines
and the Declaration of Helsinki. Written informed consent was
obtained before screening from parents/caregivers, and informed
assent from patients (if age appropriate). The final study protocol
was approved by the relevant independent ethics committees and/
or institutional review boards.
Children were randomized 3:1 to receive IV infusions of
either ceftazidime–avibactam or cefepime (see Table 1 and Fig-
ure, Supplemental Digital Content 2, http://links.lww.com/INF/
D523 for dosing information). IV treatment was administered for
≥3 days, with an optional switch to oral therapy at the investiga-
tors’ discretion on day 4, provided the patient had demonstrated
sufficient clinical response and tolerance to oral fluids and/or food
(subject to investigators’ interpretation). Planned total duration of
treatment (IV ± optional oral switch) was 7–14 days. Randomiza-
tion was stratified by age, with patients assigned to 1 of 4 age- and
weight-based dosage cohorts, with adjustment for renal function
(Table 1). Although prophylactic antibiotic use was prohibited
between the time of the first dose of study drug and the end-of-
treatment (EOT) assessment, prophylactic use was permitted after
EOT until the end of the study.
Study Assessments
Safety and tolerability data were captured from the time of
informed consent up to the late follow-up (LFU) visit (20–36 days
after the last dose of IV or oral study drug) and included adverse
events (AEs), vital signs, electrocardiogram and physical examina-
tions and laboratory evaluations. All reported AEs were coded from
the verbatim terms reported by study site personnel to the appropri-
ate MedDRA (version 20.0) preferred term. A blinded observer at
the site determined AE causality.
Efficacy assessments performed by the site-specific blinded-
observer, included clinical outcomes at the end of 72 hours of treat-
ment, end-of-IV treatment (EOIV; within 24 hours of last dose),
EOT (within 48 hours of completion of the last dose of oral therapy
for patients who switched, or within 24 hours of last infusion of
study drug for those who did not receive oral therapy) and test-of-
cure (TOC; 8–15 days after the last dose of study drug) visits (see
Table, Supplemental Digital Content 3, http://links.lww.com/INF/
D524). Children who were considered clinically cured at TOC were
reassessed at LFU for evidence of clinical relapse (20–36 days after
the last dose of study drug). Microbiologic response was assessed at
EOIV, EOT, TOC and LFU visits (see Table, Supplemental Digital
Content 4, http://links.lww.com/INF/D525). Efficacy assessments
also included the combined clinical and microbiologic responses at
EOIV and TOC visits, and the occurrence of emergent infections.
Blood samples were taken from patients treated with cef-
tazidime–avibactam on day 3 for determination of ceftazidime and
avibactam plasma concentrations. Urine samples were also taken
for culture and routine urinalysis at baseline and at EOIV, EOT,
TOC and LFU visits. The LFU visit could be carried out via tele-
phone for any patient who had not experienced clinical relapse, did
not have ongoing AEs at TOC, or did not develop AEs since TOC.
Therefore, urine culture was only carried out for those patients who
had an in-person LFU visit, with the TOC urine culture represent-
ing the final microbiologic assessment in most children. If clini-
cally indicated, blood samples were obtained for culture and routine
analysis at baseline and at any time until LFU.

TABLE 1.  Ceftazidime–Avibactam Dosage Regimens by Age, Weight, and CrCL

Cohort
[Weight Age Range CrCl (≥50 mL/min)* CrCl (≥30 to <50 mL/min)*
(kg)]

1 (≥40) ≥12 years to <18 years 2000 mg ceftazidime/500 mg avibactam for patients ≥40 kg 1000 mg ceftazidime/250 mg avibactam
1 (<40) ≥12 years to <18 years 50 mg/kg ceftazidime/12.5 mg/kg avibactam 25 mg/kg ceftazidime/6.25 mg/kg avibactam
2 (≥40) ≥6 years to <12 years 2000 mg ceftazidime/500 mg avibactam for patients ≥40 kg 1000 mg ceftazidime/250 mg avibactam
2 (<40) ≥6 years to <12 years 50 mg/kg ceftazidime/12.5 mg/kg avibactam for patients <40 kg 25 mg/kg ceftazidime/6.25 mg/kg avibactam
3 ≥2 years to <6 years 50 mg/kg ceftazidime/12.5 mg/kg avibactam 25 mg/kg ceftazidime/6.25 mg/kg avibactam
4a ≥1 years to <2 years 50 mg/kg ceftazidime/12.5 mg/kg avibactam 25 mg/kg ceftazidime/6.25 mg/kg avibactam
4b ≥6 months to <1 year 50 mg/kg ceftazidime/12.5 mg/kg avibactam 25 mg/kg ceftazidime/6.25 mg/kg avibactam
≥3 months to <6 months 40 mg/kg ceftazidime/10 mg/kg avibactam 20 mg/kg ceftazidime/5 mg/kg avibactam
Comparator: cefepime administered IV q8h per local label recommendations (dose not to exceed 2000 mg per single infusion). Both treatment groups: Optional oral switch allowed
on day 4; after minimum of 72 hours IV therapy (9 doses if administered 3 times a day, and 6 doses if administered 2 times a day), to ciprofloxacin, cefixime, amoxicillin/clavulanic
acid, or sulfamethoxazole/trimethoprim, dosed per local label recommendations.
CrCl indicates creatinine clearance; IV, intravenous.
*All ceftazidime-avibactam doses administered intravenously over 2-hour infusion q8h.

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.pidj.com | 921

Bradley et al The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019
FIGURE 1.  Patient flow and analysis sets. ITT, intent-to-treat; PK, pharmacokinetic; TOC, test-of-cure.
Characterization of β-lactam resistance mechanisms was
performed for selected isolated pathogens (see Text, Supplemental
Digital Content 5, http://links.lww.com/INF/D526).
Statistical Analyses
The study was not powered for inferential statistical com-
parisons between treatment groups; descriptive statistics were used
to summarize safety and efficacy data. Sample size calculation was
determined by likelihood of observing AEs and is described in the
Text, Supplemental Digital Content 6, http://links.lww.com/INF/D527.
Safety was assessed for the Safety Analysis Set, which comprised all
randomized patients who received ≥1 dose of IV study drug. The anal-
ysis sets used to assess the study endpoints are described in Table, Sup-
plemental Digital Content 7, http://links.lww.com/INF/D528.
RESULTS
Patients
Overall, 101 children were enrolled and 97 were randomized
(ceftazidime–avibactam, n = 68; cefepime, n = 29) (Fig. 1). The
safety analysis set comprised 95 randomized patients who received
IV study drug (ceftazidime–avibactam, n = 67; cefepime, n = 28)
(Fig. 1); cohorts 1, 2, 3 and 4 included 19 (20.0%), 22 (23.2%), 18
(18.9%) and 36 (27.4%) patients, respectively (Table 2). Overall,
88 (90.7%) patients completed IV study drug treatment, and 90
(92.8%) patients completed the study up to the TOC visit. Three
patients discontinued study treatment due to AEs (detailed below).
In addition, in the ceftazidime–avibactam group, 1 patient (cohort
4) discontinued IV study treatment due to patient/parent/legal
representative decision after 3 days, and in the cefepime group,
2 patients (both in cohort 3) discontinued study treatment due to
enrollment culture/susceptibility results after 2 and 3 days, respec-
tively, and 1 patient (cohort 1) discontinued IV treatment after 13
days. Across all cohorts, the median (range) exposure to IV-only
study drugs was 4.0 (1–11) days for ceftazidime–avibactam and
4.0 (2–11) days for cefepime. Of the randomized patients, 60/69
(90.0%) and 26/28 (93.0%) in the ceftazidime–avibactam and
922 | www.pidj.com
cefepime groups, respectively, were switched to oral therapy. The
median (range) exposure to IV ± optional oral therapy was 11.0
(1–17) days for ceftazidime–avibactam and 11.5 (2–27) days for
cefepime. Overall, ~88% of patients received 8–15 calendar days
IV ± optional oral therapy. Proportions of patients receiving IV-
only and IV ± optional oral therapy by treatment duration catego-
ries (1–3; 4–6; 7–10; 11–15 and >15 days) are shown in the Figure,
Supplemental Digital Content 8, http://links.lww.com/INF/D529.
Patient demographics and baseline characteristics for the
safety analysis set are shown in Table 2 and were generally bal-
anced across treatment groups within each cohort. A total of 79
(83.2%) patients had a diagnosis of acute pyelonephritis at screen-
ing. Among 21 (22.1%) patients with ≥1 complicating factor at
screening (Table 2), the most frequent was a functional or anatomi-
cal abnormality of the urogenital tract [n = 11 (1.6%)]. A total of 15
(15.8%) patients [ceftazidime–avibactam: 9 (13.4%); cefepime: 6
(21.4%)] had urologic abnormalities.
Baseline Uropathogens
Overall, 77 of 97 randomized patients were included in the
microbiologic intent-to-treat (micro-ITT) set (Fig. 1). Twenty of 97
randomized patients [14 (20.6% ceftazidime–avibactam); 6 (20.7%
cefepime)] did not have a study-qualifying baseline pathogen and
were therefore excluded from the micro-ITT analysis set; of the
20 patients excluded, 3 (4.4%) patients in the ceftazidime–avibac-
tam group and 1 (3.4%) patient in the cefepime group were also
excluded from the micro-ITT analysis set due to having a Gram-
positive pathogen identified at baseline (Fig. 1). Baseline Gram-
negative uropathogens were typical of those found in cUTI. In
the micro-ITT analysis set, all reported Gram-negative pathogens
were Enterobacteriaceae, with E. coli [identified in 71/77 (92.2%)
patients overall] being the most commonly reported across all
cohorts (see Table, Supplemental Digital Content 9, http://links.
lww.com/INF/D530). In total, 54 of 77 children in the micro-
ITT analysis set [37 (68.5%) ceftazidime–avibactam; 17 (73.9%
cefepime)] had blood cultures performed at baseline; no patients
had concomitant baseline Gram-negative bacteremia.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
 TABLE 2.  Patient Demographics and Baseline Characteristics (Safety Analysis Set)

Cohort/Treatment Group

1: ≥12 years to <18 years 2: ≥6 years to <12 years 3: ≥2 years to <6 years 4: ≥3 months to <2 years All cohorts

Ceftazidime– Ceftazidime– Ceftazidime– Ceftazidime– Ceftazidime–

Cefepime Cefepime Cefepime Cefepime Cefepime
Cohort avibactam avibactam avibactam avibactam avibactam
(N = 6) (N = 5) (N = 7) (N = 10) (N = 28)
Parameter (N = 13) (N = 17) (N = 11) (N = 26) (N = 67)

Mean age (range), years 15.7 (13–18) 16.3 (14–18) 8.1 (6–11) 8.3 (7–10) 3.5 (2–6) 3.5 (2–6) 1.0 (0.3–2) 1.0 (0.3–2) 6.1 (0.3–18) 6.2 (0.3–18)
Female, n (%) 12 (92.3) 6 (100) 15 (88.2) 3 (60.0) 10 (90.9) 6 (85.7) 19 (73.1) 6 (60.0) 56 (83.6) 21 (75.0)
Race, n (%)
 White 7 (53.8) 5 (83.3) 12 (70.6) 4 (80.0) 8 (72.7) 5 (71.4) 22 (84.6) 9 (90.0) 49 (73.1) 23 (82.1)
 Asian 4 (30.8) 1 (16.7) 4 (23.5) 1 (20.0) 3 (27.3) 2 (28.6) 1 (3.8) 1 (10.0) 12 (17.9) 5 (17.9)
 American Indian or Alaska Native 1 (7.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
 Other* 1 (7.7) 0 (0) 1 (5.9) 0 (0) 0 (0) 0 (0) 3 (11.5) 0 (0) 5 (7.5) 0 (0)
Mean (SD) BMI, kg/m2 21.6 (4.6) 22.5 (2.5) 17.8 (4.6) 19.1 (4.4) 16.4 (1.8) 14.6 (2.6) NA† NA† 18.6† (4.5) 18.5† (4.6)

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

Renal status, n (%), mL/min/1.73 m2
 CrCl ≥30 to <50 0 (0) 0 (0) 0 (0) 1 (20.0) 0 (0) 0 (0) 1 (3.8) 0 (0) 1 (1.5) 1 (3.6)
 CrCl ≥50 to <80 2 (15.4) 3 (50.0) 6 (35.3) 0 (0) 3 (27.3) 2 (28.6) 12 (46.2) 2 (20.0) 23 (34.3) 7 (25.0)
 CrCl ≥80 11 (84.6) 3 (50.0) 11 (64.7) 4 (80.0) 8 (72.7) 5 (71.4) 13 (50.0) 8 (80.0) 43 (64.2) 20 (71.4)
Diagnosis, n (%)
 cUTI without pyelonephritis 2 (15.4) 0 (0) 5 (29.4) 1 (20.0) 2 (18.2) 3 (42.9) 3 (11.5) 0 (0) 12 (17.9) 4 (14.3)
 Acute pyelonephritis 11 (84.6) 6 (100) 12 (70.6) 4 (80.0) 9 (81.8) 4 (57.1) 23 (88.5) 10 (100) 55 (82.1) 24 (85.7)
Complicating factors, n (%)‡
 No complicating factors 11 (84.6) 6 (100) 11 (64.7) 4 (80.0) 9 (81.8) 3 (42.9) 22 (84.6) 8 (80.0) 53 (79.1) 21 (75.0)
 At least 1 complicating factor 2 (15.4) 0 (0) 6 (35.3) 1 (20.0) 2 (18.2) 4 (57.1) 4 (15.4) 2 (20.0) 14 (20.9) 7 (25.0)
The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019

   Recurrent UTI 1 (7.7) 0 (0) 4 (23.5) 0 (0) 1 (9.1) 1 (14.3) 1 (3.8) 0 (0) 7 (10.4) 1 (3.6)
 Functional or anatomical abnormality of 1 (7.7) 0 (0) 3 (17.6) 1 (20.0) 1 (9.1) 2 (28.6) 1 (3.8) 2 (20.0) 6 (9.0) 5 (17.9)
the urogenital tract
  Vesicoureteral reflux 0 (0) 0 (0) 2 (11.8) 0 (0) 0 (0) 3 (42.9) 3 (11.5) 1 (10.0) 5 (7.5) 4 (14.3)
  Intermittent bladder catheterization 0 (0) 0 (0) 0 (0) 1 (20.0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3.6)
Urologic abnormalities, n (%) 1 (7.7) 0 (0) 3 (17.6) 0 (0) 1 (9.1) 4 (57.1) 4 (15.4) 2 (20.0) 9 (13.4) 6 (21.4)
Any prior systemic antibiotic use, n (%)§ 4 (30.8) 1 (16.7) 4 (23.5) 2 (40.0) 5 (45.5) 4 (57.1) 14 (53.8) 4 (40.0) 27 (40.3) 11 (39.3)
BMI indicates body mass index; CrCl, creatinine clearance; cUTI, complicated UTI.
*Other category for race excludes “Native Hawaiian or Pacific Islander” and “Black or African American” for which there were no patients.
†BMI is not calculated for children <24 months of age (cohort 4). Therefore, N values for the “all cohorts” data are as follows: ceftazidime-avibactam, N = 41; Cefepime, N = 18.
‡Patients may be counted in more than 1 complicating factor category for type of infection. Patients with multiple complicating factors that fall into 1 complicating factor category are counted once for that complicating factor category.
§A prior medication is defined as a medication that was taken anytime in the 2 weeks before study entry up to the date and time of randomization, regardless of whether this was stopped before the date and time of randomization.

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CAZ-AVI Pediatric cUTI Study
Bradley et al The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019
Safety
Overall, AEs, whether believed to be related to therapy or
not, occurred in 36/67 patients (53.7%) in the ceftazidime–avibac-
tam group and in 15/28 patients (53.6%) in the cefepime group
(Table 3). The most frequently reported AEs up to the LFU visit
were diarrhea and UTI (5 [7.5%] patients each) for the ceftazi-
dime–avibactam group, and diarrhea (3 [10.7%]) for the cefepime
group (Table 3). No AEs indicative of UTI were reported up to the
end of IV study therapy; however, 7 (10.4%) and 2 (7.1%) patients
in the ceftazidime–avibactam and cefepime groups, respectively,
had UTI, pyelonephritis acute or cystitis which occurred 7–41 days
after completion of IV study therapy, and which were not consid-
ered study drug related. On further assessment of these 9 patients,
5 (4 in the ceftazidime–avibactam and 1 in the cefepime group,
respectively) had functional or anatomical urinary tract abnormali-
ties, 1 had a history of recurrent pyelonephritis and 3 (2 and 1 in the
ceftazidime–avibactam and cefepime groups, respectively) had a
history of pyelonephritis. Hence, AEs of cUTIs that occurred after
completion of study therapy were considered reflective of the natu-
ral history of the underlying condition in this patient population, in
which recurrence of a de novo infection may occur due to underly-
ing risk factors (eg, abnormal genitourinary anatomy) rather than
acute treatment failure.
The majority of AEs were nonserious and considered by
the observer to be of mild intensity. Six of 67 (9.0%) patients
in the ceftazidime–avibactam arm had ≥1 AE of severe intensity.
These were 1 case each of abdominal pain, constipation, nephro-
lithiasis, nervous system disorder, tachycardia and viral infection,
and 2 cases of pyelonephritis acute. Two of 28 (7.1%) patients
in the cefepime arm had AEs of severe intensity: 1 case each
of cystitis and pyelonephritis acute. In the ceftazidime–avibac-
tam group, 7 (10.4%) patients had AEs that were considered by
blinded observer to be possibly related to the study drug: 1 patient
had moderate nausea, vomiting and dizziness; 2 had mild diar-
rhea; 1 had severe Nervous system disorder (only considered to be
temporally related); 1 had mild dermatitis diaper; 1 had mild rash
and 1 had moderate rash. In the cefepime group, 1 (3.6%) patient
had moderate diarrhea and mild intertrigo considered possibly
study drug related. There were no AEs with an outcome of death.
Overall, serious adverse events (SAEs) occurred in 8/67 (11.9%)
patients in the ceftazidime–avibactam group and 2/28 (7.1%) in
the cefepime group (Table 3). One SAE was considered possi-
bly drug related; the patient (ceftazidime–avibactam arm; cohort
1) had a severe event of nervous system disorder, occurring 2
days after the start of IV study drug infusion. This patient had
an ongoing medical history of anxiety, depression and hyperten-
sion secondary to polycystic kidney disease, and had experienced
similar symptoms before enrollment in the study. The event led to
discontinuation from the study and resolved on study day 3. All
other events considered treatment related by the blinded observer
were known adverse drug reactions for the study therapies. In
addition to the patient described above, 2 further patients in the
ceftazidime–avibactam arm had AEs leading to treatment discon-
tinuation: the first was a patient (cohort 1) who experienced mod-
erate dizziness, nausea and vomiting on day 2 that was considered
possibly study drug related; in addition to study medication, this
patient received a dose of 1 g ceftriaxone sodium (received day
−1 to day 1) for treatment of the underlying disease. The second
was a patient (cohort 2) who experienced severe asymptomatic
tachycardia of 150 bpm, 2 hours after start of IV study drug infu-
sion, which was considered unrelated by the blinded observer. No
patient in the cefepime arm had an AE that led to discontinuation
of treatment. All AEs that led to study discontinuation resolved.
924 | www.pidj.com
No new clinically significant changes in laboratory param-
eters, vital signs, electrocardiogram or physical examination data
were identified, and no patients met laboratory criteria for potential
Hy Law, which assesses hepatic function for drug toxicity.
Efficacy
The per-patient favorable clinical, microbiologic and com-
bined responses at TOC are shown in Table 4 for the micro-ITT
analysis set. At the earliest assessment (end of 72 hours), 49/54
(90.7%) patients in the ceftazidime–avibactam group and 22/23
(95.7%) in the cefepime group had a favorable clinical response
(micro-ITT analysis set). Favorable clinical response was sustained
at the TOC visit [48/54 (88.9%) overall for ceftazidime–avibactam
and 19/23 (82.6%) overall for cefepime]. At LFU, 81.5% (44/54)
patients in the ceftazidime–avibactam group and 82.6% (19/23)
patients in the cefepime group had a favorable outcome; 11.1%
(6/54) and 17.4% (4/23) patients, respectively, did not have clinical
outcome assessed at LFU because they were not assessed as clinical
cures at the TOC visit.
Favorable per-patient microbiologic response at TOC was
43/54 (79.6%) in the ceftazidime–avibactam group and 14/23
(60.9%) in the cefepime group (micro-ITT analysis set). For sub-
jects who were doing well clinically, an LFU return visit and urine
culture was optional. Therefore, favorable microbiologic response
rates were lower at LFU for both groups than at preceding visits
[ceftazidime–avibactam: 16/54 (29.6%); cefepime: 4/23 (17.4%)];
this was primarily due to a high percentage of indeterminate
responses (ie, urine not collected for culture) at LFU [ceftazidime–
avibactam: n = 32/54 (59.3%); cefepime: n = 14/23 (60.9%)]. Per-
patient favorable microbiologic response rates at TOC in the micro-
biologically evaluable (ME) analysis set were 36/41 (87.8%) in the
ceftazidime–avibactam arm and 11/16 (68.8%) in the cefepime arm
and at LFU were 10/16 (62.5%) and 4/9 (44.4%), respectively.
Two children in the ceftazidime–avibactam group (both in
cohort 2) and 1 in the cefepime group (cohort 3) had baseline E.
coli isolates that were nonsusceptible to ceftazidime [based on an
interpretive criterion of a minimum inhibitory concentration (MIC)
>4 mg/L] and to cefepime (MIC >8 mg/L). From the ceftazidime–
avibactam group, one isolate, with a ceftazidime MIC of 32 mg/L
and a cefepime MIC of >16 mg/L, was from a patient in Taiwan
and possessed CTX-M-55, while the other isolate, with a ceftazi-
dime MIC of 64 mg/L and a cefepime MIC of >16 mg/L, was from
a patient in Turkey and possessed CTX-M-15 and TEM-1. These
2 patients who received ceftazidime–avibactam were considered
clinical cures at TOC and had favorable microbiologic responses
at TOC. From the cefepime group, the isolate with MIC of cef-
tazidime 16 mg/L and of cefepime >16 mg/L was from a patient
in Taiwan and possessed CTX-M-55. This patient was a clinical
failure at TOC and had an indeterminate microbiologic response at
TOC, based on lack of urine culture. All isolates were susceptible
to ceftazidime–avibactam in vitro (MIC ≤ 8 mg/L).
Per-pathogen favorable microbiologic response rates at TOC
are shown in the Table, Supplemental Digital Content 10, http://
links.lww.com/INF/D531. Overall, 86.5% (32/37) of patients treated
with ceftazidime–avibactam in the ME analysis set with an E. coli
isolate at baseline had a favorable microbiologic response at TOC
(including patients with ceftazidime–non-susceptible pathogens).
There were 3 (7%) emergent (new) infections (all 3 were
reported as adverse events of “UTI”) at the TOC visit in the cef-
tazidime–avibactam group and none in the cefepime group in the
ME set. Of the 3 new infections, 2 patients were reported to have
both underlying urologic abnormalities and complicating factors.
For the first of these 2 patients (cohort 2), the underlying diagno-
sis was cUTI, the baseline pathogen was E. coli and the emergent
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
 TABLE 3.  Adverse Events Occurring in ≥2 Patients in Either Treatment Group and SAEs Occurring in Any Patient by System Organ Class and
Preferred Term (Safety Analysis Set)

Cohort/Treatment Group, n (%)

1: ≥12 years to <18 years 2: ≥6 years to <12 years 3: ≥2 years to <6 years 4: ≥3 months to <2 years All Cohorts

System Ceftazidime– Ceftazidime– Ceftazidime– Ceftazidime– Ceftazidime–

Cefepime Cefepime Cefepime Cefepime Cefepime
Organ Class Avibactam Avibactam Avibactam Avibactam Avibactam
(N = 6) (N = 5) (N = 7) (N = 10) (N = 28)
  Preferred Term (N = 13) (N = 17) (N = 11) (N = 26) (N = 67)

Patients with any AE 8 (61.5) 3 (50.0) 10 (58.8) 2 (40.0) 4 (36.4) 3 (42.9) 14 (53.8) 6 (60.0) 36 (53.7) 15 (53.6)
Gastrointestinal disorders 2 (15.4) 1 (16.7) 2 (11.8) 1 (20.0) 1 (9.1) 1 (14.3) 4 (15.4) 2 (20.0) 9 (13.4) 5 (17.9)
 Abdominal pain 1 (7.7) 0 (0) 1 (5.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 0 (0)
 Diarrhea 0 (0) 0 (0) 0 (0) 1 (20.0) 1 (9.1) 0 (0) 4 (15.4) 2 (20.0) 5 (7.5) 3 (10.7)
 Nausea 1 (7.7) 1 (16.7) 1 (5.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 1 (3.6)
 Vomiting 2 (15.4) 1 (16.7) 0 (0) 0 (0) 0 (0) 1 (14.3) 0 (0) 0 (0) 2 (3.0) 2 (7.1)
General disorders and admin site conditions 0 (0) 0 (0) 1 (5.9) 0 (0) 1 (9.1) 1 (14.3) 1 (3.8) 1 (10.0) 3 (4.5) 2 (7.1)
 Pyrexia 0 (0) 0 (0) 0 (0) 0 (0) 1 (9.1) 0 (0) 1 (3.8) 1 (10.0) 2 (3.0) 1 (3.6)
Infections and infestations 4 (30.8) 0 (0) 7 (41.2) 0 (0) 2 (18.2) 1 (14.3) 8 (30.8) 4 (40.0) 21 (31.3) 5 (17.9)

© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

 Gastroenteritis 0 (0) 0 (0) 1 (5.9) 0 (0) 0 (0) 0 (0) 1 (3.8) 0 (0) 2 (3.0) 0 (0)
 Nasopharyngitis 0 (0) 0 (0) 2 (11.8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 0 (0)
 Pyelonephritis acute 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (7.7) 1 (10.0) 2 (3.0) 1 (3.6)
 Rhinitis 2 (15.4) 0 (0) 1 (5.9) 0 (0) 0 (0) 0 (0) 1 (3.8) 2 (20.0) 4 (6.0) 2 (7.1)
 Upper respiratory tract infection 2 (15.4) 0 (0) 1 (5.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (4.5) 0 (0)
 Urinary tract infection 1 (7.7) 0 (0) 2 (11.8) 0 (0) 1 (9.1) 0 (0) 1 (3.8) 0 (0) 5 (7.5) 0 (0)
 Viral upper respiratory tract infection 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (7.7) 0 (0) 2 (3.0) 0 (0)
 Vulvitis 0 (0) 0 (0) 2 (11.8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 0 (0)
Respiratory, thoracic and mediastinal 0 (0) 0 (0) 0 (0) 1 (20.0) 0 (0) 0 (0) 3 (11.5) 0 (0) 3 (4.5) 1 (3.6)
disorders
 Cough 0 (0) 0 (0) 0 (0) 1 (20.0) 0 (0) 0 (0) 2 (7.7) 0 (0) 2 (3.0) 1 (3.6)
The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019

Skin and subcutaneous tissue disorders 0 (0) 0 (0) 2 (11.8) 1 (20.0) 2 (18.2) 0 (0) 3 (11.5) 3 (30.0) 7 (10.4) 4 (14.3)
 Rash 0 (0) 0 (0) 1 (5.9) 1 (20.0) 2 (18.2) 0 (0) 0 (0) 1 (10.0) 3 (4.5) 2 (7.1)
Patients with any SAE 2 (15.4) 0 (0) 1 (5.9) 0 (0) 2 (18.2) 0 (0) 3 (11.5) 2 (20.0) 8 (11.9) 2 (7.1)
 Abdominal pain 1 (7.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
 Constipation 1 (7.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
 Cystitis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (10.0) 0 (0) 1 (3.6)
 Pyelonephritis acute 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (7.7) 1 (10.0) 2 (3.0) 1 (3.6)
 Urinary tract infection 0 (0) 0 (0) 1 (5.9) 0 (0) 1 (9.1) 0 (0) 1 (3.8) 0 (0) 3 (4.5) 0 (0)
 Viral infections 0 (0) 0 (0) 0 (0) 0 (0) 1 (9.1) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
 Nervous system disorder 1 (7.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
 Nephrolithiasis 1 (7.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.5) 0 (0)
Patients with multiple AEs/SAEs are counted once for each system organ class and/or preferred term. Only AEs that started on or after the time of first infusion of IV study therapy are included.
Criteria for determination of AEs/S are provided in the Supplemental Digital Content (see Text, Supplemental Digital Content 12).
AE indicates adverse event; IV, intravenous; SAE, serious adverse event.

www.pidj.com | 925
CAZ-AVI Pediatric cUTI Study
Bradley et al The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019

infection was caused by Enterococcus faecalis. For the second

A favorable clinical outcome is defined as clinical cure. A favorable per-patient microbiologic response is defined as eradication of the pathogen(s). If a patient has more than 1 pathogen, the outcome has to be favorable for each
patient (cohort 2), the underlying diagnosis was cUTI, the baseline
(N = 23)

(40.6, 78.6)

(63.8, 93.8)

(40.6, 78.6)
Cefepime

14 (60.9)

6 (26.1)
3 (13.0)
19 (82.6)

3 (13.0)

14 (60.9)

5 (21.7)
4 (17.4)
pathogen was Enterobacter cloacae and the emergent infection was

1 (4.3)
caused by E. coli. The third new infection occurred in a patient
All cohorts

enrolled with pyelonephritis (cohort 1); the baseline pathogen was

E. coli, and the emergent infections were caused by E. faecalis and
Staphylococcus haemolyticus. No antibiotic prophylaxis before
Ceftazidime–
Avibactam
(N = 54)

emergence of the new infection(s) was reported for any of these 3

TABLE 4.  Per-Patient Favorable Clinical, Microbiologic Response and Combined Response at Test-of-Cure Visit (Micro-ITT Analysis Set)

39 (72.2)

8 (14.8)
7 (13.0)
48 (88.9)

43 (79.6)

6 (11.1)
(59.3, 82.8)

3 (5.6)
(78.5, 95.2)

3 (5.6)

5 (9.3)
(67.5, 88.7)
patients between EOT and LFU. Baseline isolates were susceptible
to both ceftazidime–avibactam and cefepime in all cases.
Clinical relapse at LFU occurred in 4/54 (7.4%) patients
in the ceftazidime–avibactam group (1 patient in cohort 2, 1 in
(N = 10)

cohort 3 and 2 in cohort 4) and no patients in the cefepime group

(22.4, 77.6)

(39.4, 90.7)

(22.4, 77.6)
Cefepime

5 (50.0)

3 (30.0)
2 (20.0)
7 (70.0)

2 (20.0)
1 (10.0)
5 (50.0)

3 (30.0)
2 (20.0)
4: ≥3 months to <2 years

(micro-ITT analysis set) (see Table, Supplemental Digital Content

11, http://links.lww.com/INF/D532). Of the 4 patients with clinical
relapse, 3 were reported to have both underlying urologic abnor-
malities and complicating factors.
Ceftazidime–
Avibactam

The microbiologic outcome of persistence at a particular

(N = 22)

17 (77.3)

3 (13.6)
21 (95.5)

17 (77.3)

3 (13.6)
2 (9.1)
(57.1, 90.8)

(80.7, 99.5)

1 (4.5)

2 (9.1)
(57.1, 90.8)

visit was carried forward to subsequent visits. In the micro-ITT

0

analysis set, 6 patients (11%) in the ceftazidime–avibactam group

and 5 (22%) in the cefepime group had persistent infections at LFU,
based on the assessment of local culture results by the investigator.
Per-Patient Response, n (%)

Unfortunately, colony counts on urine cultures were not collected in

(37.1, 97.7)
(N = 5)
Cefepime

2 (40.0)

2 (40.0)
1 (20.0)
4 (80.0)

1 (20.0)

2 (40.0)

1 (20.0)
2 (40.0)
(9.4, 79.1)

(9.4, 79.1)

the clinical trial database; therefore, ability to confirm true infection

3: ≥2 years to <6 years

versus colonization/contamination was limited. The baseline patho-

gen was E. coli in all cases, and all isolates were susceptible to study
drug. No persistent infections with increasing MIC were seen.
Ceftazidime–
Avibactam
(N = 10)

Plasma Concentrations
8 (80.0)

1 (10.0)
1 (10.0)
9 (90.0)

1 (10.0)
8 (80.0)

1 (10.0)
1 (10.0)
(49.7, 95.6)

(61.9, 98.9)

(49.7, 95.6)

Median plasma concentrations of ceftazidime and avibac-

0

tam are presented in Figure 2.

DISCUSSION
(37.1, 97.7)

(37.1, 97.7)
(N = 5)
Cefepime

(62.1, 100)
4 (80.0)

1 (20.0)

4 (80.0)

1 (20.0)
5 (100)
2: ≥6 years to <12 years

This study is the first prospective, randomized study to report

0

0
0

the safety and efficacy of ceftazidime–avibactam in hospitalized

children with cUTI (including acute pyelonephritis). Ceftazidime–
avibactam was well tolerated in children ≥3 months to <18 years.
Ceftazidime–
Avibactam

The overall safety profile was in line with the expected safety pro-
(N = 13)

10 (76.9)

2 (15.4)

11 (84.6)

2 (15.4)

12 (92.3)
1 (7.7)
(50.3, 93.0)

(59.1, 96.7)

1 (7.7)

file for ceftazidime–avibactam from adults, the established safety

(69.3, 99.2)
0

profile of ceftazidime alone and the pattern of AEs expected for

this patient population15; no new clinically relevant safety concerns
were identified for ceftazidime–avibactam in this study.
Favorable clinical response rates >90% were observed for
(N = 3)
Cefepime

(46.4, 100)

(46.4, 100)

(46.4, 100)

both treatment groups early during treatment at 72 hours (90.7%

1: ≥12 years to <18 years

3 (100)

3 (100)

3 (100)
0
0

0
0

0
0

for ceftazidime–avibactam and 95.7% for cefepime) and remained

>81% for both groups at the LFU visit. Favorable per-patient micro-
biologic response at TOC was ~80% for the ceftazidime–avibactam
group and ~61% in the cefepime group. Of note, there was a high
*A 2-sided 95% CI computed using the Jeffreys method.
Ceftazidime–
Avibactam
(N = 9)

proportion of urine samples not collected at the LFU visit; as this

4 (44.4)

3 (33.3)
2 (22.2)
7 (77.8)

1 (11.1)
1 (11.1)
6 (66.7)

2 (22.2)
1 (11.1)
(17.3, 74.6)

(45.6, 95.1)

(34.8, 89.6)

visit could be conducted by telephone for patients without clinical

pathogen for it to be counted as a favorable response.

relapse or ongoing or new AEs since TOC. While the investiga-

tors assumed that children who had no clinical symptoms should
be assigned a favorable response, the definitions for microbiologic
Unfavorable outcome

Unfavorable outcome

Unfavorable outcome

response provided at the beginning of the study meant that the urine
Favorable outcome

Favorable outcome

Favorable outcome

CI indicates confidence interval.

cultures that were collected at LFU had a greater chance of being

Indeterminate

Indeterminate

Indeterminate
Cohort

positive, in both groups. By definition, those without a culture

were considered “indeterminate” (rather than presumed eradica-
95% CI*

95% CI*

95% CI*

tion), leading to a high percentage of indeterminate microbiologic

responses recorded at the LFU visit (ie, source specimen was not
available to culture, so no “favorable” or “presumed favorable”
microbiologic response was assumed). Consequently, favorable
Combined

Microbio-

microbiologic response rates were lower at LFU for both treat-

Clinical

logic

ment groups than at the preceding visits. While this study was not
powered for inferential statistical comparisons between treatment

926 | www.pidj.com © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019 CAZ-AVI Pediatric cUTI Study
FIGURE 2.  Median plasma concentrations (log scale) of cef-
tazidime (A) and avibactam (B) on day 3 of the study (PK
analysis set). Log-scale median and CV values presented are
for the all cohort analysis set. Vertical lines represent error
bars. Blood samples (1 mL per sample for cohorts 1 and 2,
and 0.5 mL per sample for cohorts 3 and 4) were collected
from patients randomized to ceftazidime–avibactam treat-
ment on day 3 following a dose administration that was
convenient for the plasma sample collections at the follow-
ing time points: anytime within 15 min before or after stop-
ping ceftazidime–avibactam infusion, anytime between 30
and 90 min after stopping ceftazidime–avibactam infusion,
and anytime between 300 min (5 h) and 360 min (6 h) after
stopping ceftazidime–avibactam infusion. CV indicates coef-
ficient of variation; PK, pharmacokinetic.
groups, the high clinical/microbiologic response rates observed
were consistent with studies of ceftazidime–avibactam conducted
in adult patients with cUTI.10,11,16
The most common pathogen isolated was E. coli, which
is in line with expectations for patients with cUTI.1,9,17 Favora-
ble per-pathogen microbiologic response at TOC was 86.5% for
ceftazidime–avibactam-treated patients with an E. coli isolate at
baseline, including patients with ceftazidime- and cefepime-non-
susceptible pathogens (ME analysis set). These findings are also
similar to those from adult patients with cUTI.10,11 Of note, there
were no cases of Pseudomonas in the study. This suggests that the
infections were predominantly community acquired in healthy indi-
viduals, who had not received extensive antibiotic pretreatment.18
In the present study, 2 children in the ceftazidime–avibactam
group and 1 in the cefepime group had a ceftazidime- and cefepime-
non-susceptible pathogen isolated at baseline. Observations from
adult studies have previously demonstrated the ability of avibactam
to restore the activity of ceftazidime against extended-spectrum
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
β-lactamase-producing ceftazidime-non-susceptible pathogens in
a clinical setting.10,11,16 Of note, in a recent systematic review and
meta-analysis, the prevalence of extended-spectrum β-lactamase-
producing Enterobacteriaceae in 7374 pediatric patients with cUTI
was found to be 14%, with vesicoureteral reflux and history of prior
UTI identified as risk factors.19 Anatomical abnormalities repre-
sent a risk factor for recurrent or more complicated infections in
general.20 Four patients in the current study demonstrated clinical
relapse at LFU and, of these, 3 were reported to have both underly-
ing urologic abnormalities and complicating factors. Furthermore,
of the 3 patients in the ceftazidime–avibactam group with emergent
infections, 2 had both underlying urologic abnormalities and com-
plicating factors. Of note, no persistent infections with increasing
MIC were seen in this study.
AEs of UTI were reported in 5 (7.5%) children in the cef-
tazidime–avibactam arm and no patients in the cefepime arm, cys-
titis in no patients in the ceftazidime–avibactam arm and 1 (3.6%)
in the cefepime arm, and pyelonephritis acute in 2 (3.0%) in the
ceftazidime–avibactam and 1 (3.6%) in the cefepime arm. In line
with Good Clinical Practice, AEs were recorded by investigators
regardless of suspected causality; therefore, it was possible for a
child with high risk of recurrent UTI to have a subsequent episode
within the follow-up period and for this to be recorded as an AE of
UTI, cystitis or pyelonephritis acute. As AEs were captured until
end of LFU, AE/SAEs classified as UTI, cystitis or pyelonephritis
acute could reflect either relapse or a new infection with a new
pathogen. Importantly, no AE/SAEs of UTI, cystitis or pyelone-
phritis acute were considered related to the study drug.
Although this small study was not powered for inferential
statistical comparisons between treatment groups, the safety find-
ings in children with cUTI extend the previous determination of the
safety profile of ceftazidime–avibactam in adult patients.10,11,16 The
safety collection and analysis conducted in this study was appropri-
ate for a phase 2 pediatric study, and the methodology for this was
a standard approach to investigation of infections in children.21,22 It
is well recognized that most randomized controlled trials are too
small to be able to provide more than observational safety data;
to be powered for statistical analysis of safety, studies generally
require several thousand patients in each arm, and this would still
not be sufficiently large for analysis of more rare AEs.23
Population pharmacokinetic modeling for the estimation
of pharmacokinetic parameters and probability of pharmacoki-
netic/pharmacodynamic target attainment are ongoing and will be
reported separately.
In addition, alongside the current study in pediatric cUTI
patients, the recently completed prospective, randomized phase
2 study in children with cIAI will provide further insight regard-
ing the role of ceftazidime–avibactam in pediatric patients
(NCT02475733).24
In conclusion, the safety findings from this study in children
with cUTI extend the previous determination of the safety profile of
ceftazidime–avibactam in adult patients. Ceftazidime–avibactam
was well tolerated, with a safety profile consistent with ceftazi-
dime monotherapy in pediatric patients. Ceftazidime–avibactam
appeared effective in the treatment of pediatric cUTI caused by
Gram-negative pathogens, with favorable clinical and micro-
biologic response rates observed against the predominant cUTI
pathogen (E. coli), including ceftazidime-non-susceptible isolates.
Ceftazidime–avibactam may therefore offer physicians a valuable
treatment option in the initial treatment of children with cUTI
caused by susceptible pathogens in an era of increasing prevalence
of MDR Gram-negative pathogens.
www.pidj.com | 927
Bradley et al The Pediatric Infectious Disease Journal  •  Volume 38, Number 9, September 2019
ACKNOWLEDGMENTS
The authors thank the patients and families involved in this
study. The authors also thank Rodrigo Mendes, Mariana Castan-
heira, Leah N. Woosley and Timothy B. Doyle of JMI Laboratories
for sequencing of the molecular characterization data. Medical
writing support was provided by Melanie More and Mark Waterlow
of Prime, Knutsford, Cheshire, United Kingdom, funded by Pfizer.
Ultimate responsibility for opinions, conclusions and data interpre-
tation lies with the authors.
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© 2019 The Author(s). Published by Wolters Kluwer Health, Inc.