Journal of the Pediatric Infectious Diseases Society

ORIGINAL ARTICLE

Management and Outcomes in Children with Third-

Generation Cephalosporin-Resistant Urinary Tract
Infections
Marie E. Wang,1 Tara L. Greenhow,2 Vivian Lee,3 Jimmy Beck,4 Michael Bendel-Stenzel,5 Nicole Hames,6 Corrie E. McDaniel,4 Erin E. King,5
Whitney Sherry,6 Deepika Parmar,7,a Sara T. Patrizi,7,b Nivedita Srinivas,1,8 and Alan R. Schroeder,1,9
1
Division of Pediatric Hospital Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital Stanford, Stanford, California, USA, 2Division of Infectious
Diseases, Kaiser Northern California, San Francisco, California, USA, 3Division of Hospital Medicine, Children’s Hospital Los Angeles and Department of Pediatrics, University
of Southern California Keck School of Medicine, Los Angeles, California, USA, 4Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s

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Hospital, Seattle, Washington, USA, 5Division of Hospital Medicine, Children’s Minnesota, Minneapolis, Minnesota, USA, 6Division of Pediatric Hospital Medicine, Emory
University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA, 7Department of Pediatrics, Kaiser Northern California, Oakland, California, USA,
8
Division of Pediatric Infectious Diseases, Stanford University School of Medicine, Stanford, California, USA, and 9Division of Pediatric Critical Care Medicine, Stanford University
School of Medicine, Stanford, California, USA

Background. Third-generation cephalosporin-resistant urinary tract infections (UTIs) often have limited oral antibiotic op-
tions with some children receiving prolonged parenteral courses. Our objectives were to determine predictors of long parenteral
therapy and the association between parenteral therapy duration and UTI relapse in children with third-generation cephalosporin-
resistant UTIs.
Methods. We conducted a multisite retrospective cohort study of children <18 years presenting to acute care at 5 children’s
hospitals and a large managed care organization from 2012 to 2017 with a third-generation cephalosporin-resistant UTI from
Escherichia coli or Klebsiella spp. Long parenteral therapy was ≥3 days and short/no parenteral therapy was 0–2 days of concordant
parenteral antibiotics. Discordant therapy was antibiotics to which the pathogen was non-susceptible. Relapse was a UTI from the
same organism within 30 days.
Results. Of the 482 children included, 81% were female and the median age was 3.3 years (interquartile range: 0.8-8). Fifty-
four children (11.2%) received long parenteral therapy (median duration: 7 days). Predictors of long parenteral therapy included
age <2 months (adjusted odds ratio [aOR] 67.3; 95% confidence interval [CI]: 16.4-275.7), limited oral antibiotic options (aOR 5.9;
95% CI: 2.8-12.3), and genitourinary abnormalities (aOR 5.4; 95% CI: 1.8-15.9). UTI relapse occurred in 1 of the 54 (1.9%) children
treated with long parenteral therapy and in 6 of the 428 (1.5%) children treated with short/no parenteral therapy (P = .57). Of the 105
children treated exclusively with discordant antibiotics, 3 (2.9%, 95% CI: 0.6%-8.1%) experienced UTI relapse.
Conclusions. Long parenteral therapy was associated with age <2 months, limited oral antibiotic options, and genitourinary ab-
normalities. UTI relapse was rare and not associated with duration of parenteral therapy. For UTIs with limited oral options, further
research is needed on the effectiveness of continued discordant therapy.
Key words. children; treatment; urinary tract infection.

Urinary tract infections (UTIs), one of the most common
bacterial infections in children [1], have shown increasing
antimicrobial resistance over the last 2 decades [2, 3]. An esti-
mated 5% of pediatric community-acquired UTIs worldwide
Received 9 May 2020; editorial decision 28 December 2020; accepted 6 January 2021;
Published online February 17, 2021.
a
Present Affiliation: UCSF Benioff Children’s Hospital, San Francisco, CA, USA.
b
Present Affiliation: Stanford University School of Medicine and Lucile Packard Children’s
Hospital Stanford, Stanford, CA, USA.
Corresponding Author: Marie E. Wang, MD, MPH, Division of Pediatric Hospital Medicine,
Stanford University School of Medicine, 300 Pasteur Drive MC 5776, Stanford, CA, USA. E-mail:
marie.wang@stanford.edu.
Journal of the Pediatric Infectious Diseases Society   2021;10(5):650–8
© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the
Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/jpids/piab003
are caused by extended-spectrum beta-lactamase (ESBL)-
producing organisms [3]. Children hospitalized with ESBL
UTIs have significantly longer lengths of stay than children
with non-ESBL UTIs, resulting in patient/family stress, in-
creased costs, and potential for iatrogenic harm [3–5]. The
increased length of stay has been attributed to the transition
that occurs from empiric discordant therapy (in vitro non-
susceptibility of the pathogen to the antibiotic) to definitive
concordant therapy and prolonged parenteral courses due to
limited oral antibiotic options [3, 4].
The American Academy of Pediatrics (AAP) UTI guide-
lines state that most children can be treated orally but do not
offer specific recommendations for resistant organisms [6].
Given that these infections have fewer oral antibiotic options,
more data are needed regarding their optimal management.
Resistance to third-generation cephalosporins is often used as

650 • jpids 2021:10 (May) • Wang et al

a surrogate marker for ESBL UTIs due to lack of ESBL testing at
some laboratories [2].
We recently reported results from a multisite study
demonstrating that most children with third-generation
cephalosporin-resistant UTIs started empirically on discordant
antibiotics improved by the time urine cultures resulted (typi-
cally after 2-3 days) [7]. In this investigation, we describe the
definitive management and outcomes of these children with
third-generation cephalosporin-resistant UTIs after urine cul-
ture results are finalized. Our objectives were to determine pre-
dictors of long (≥3 days) concordant parenteral therapy and to
evaluate the association between duration of parenteral therapy
and UTI relapse.
METHODS
Study Location and Design
We conducted a multisite retrospective cohort study at 5
children’s hospitals and 1 large managed care organization
from January 1, 2012, to June 30, 2017. Sites were located in
California (3), Georgia (1), Minnesota (1), and Washington (1)
as detailed in Supplementary Table 1. The study was approved
by the institutional review board at each participating site.
Study Population
We included children ≤18 years old presenting to an acute
care setting (emergency department, inpatient setting, or
general pediatrics/urgent care clinic) with a third-generation
cephalosporin-resistant UTI. UTI was defined per AAP
Guidelines as having both: (1) pyuria, defined as >5 white
blood cells per high power field or any leukocyte esterase and
(2) urine culture with ≥50 000 colony-forming units per mil-
liliter of growth [6]. Third-generation cephalosporin-resistant
UTI was defined as a UTI from Enterobacterales, specifically
Escherichia coli or Klebsiella spp., non-susceptible (ie, inter-
mediate or resistant) to ceftriaxone/cefotaxime. We studied
third-generation cephalosporin-resistant isolates, similar to
other investigations [2, 8], because some institutions’ labora-
tories within our study did not specifically test for ESBL resist-
ance. Site laboratories completed urinalyses, urine dipsticks,
and urine cultures according to standard procedures, and an-
tibiotic susceptibilities were determined according to Clinical
and Laboratory Standards Institute (CLSI) guidelines [9]. Given
that practitioners are more likely to react to the laboratory des-
ignation of susceptibility rather than the minimum inhibitory
concentration (MIC) levels for ceftriaxone/cefotaxime, we did
not collect MIC data. Urine cultures were obtained via straight
catheterization or clean catch. If the collection method was
not documented, subjects without documentation of a urinary
catheter were included. Children were excluded if they had a
history of urologic surgery other than circumcision, were im-
munocompromised (received immunosuppressants in the
Management and Outcomes of Resistant UTIs • jpids 2021:10 (May) • 651
prior 6 months or had underlying malignancy or immunode-
ficiency), had a complex chronic condition (except for renal
abnormalities) [10], did not have a patient encounter docu-
mented or a urinalysis associated with the urine culture, were
transferred to/from an outside facility, had a concurrent bacte-
rial infection requiring prolonged antibiotics (eg, meningitis),
or had a UTI in the prior 30 days, to ensure that captured cases
were index cases and not relapses. Only one case per patient
was included. Patients were identified through microbiology or
medical record query and site investigators reviewed charts to
confirm eligibility and extract demographic, clinical, and lab-
oratory data. For the 5 children’s hospitals, all eligible cases
were included. For the large managed care organization, due
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to limited resources for chart review at that site, we decided a
priori to use simple random sampling to select approximately
70% of cases meeting the inclusion criteria for review to meet
the target sample size. Data were entered into a secure Research
Electronic Data Capture tool hosted at Stanford University [11].
Definitions
Definitive therapy was defined as the antibiotics received to treat
the UTI once the organism and susceptibilities were known.
This therapy was classified as concordant (isolate susceptible)
or discordant (isolate non-susceptible, ie, intermediate or re-
sistant), consistent with prior studies [12–15]. The “limited oral
antibiotic options” variable was defined as non-susceptibility to
all of the following oral antibiotics to which susceptibility was
tested: amoxicillin-clavulanate, ciprofloxacin, trimethoprim-
sulfamethoxazole, and nitrofurantoin. These antibiotics were
chosen because they are the most common oral options for third-
generation cephalosporin-resistant isolates. If all options were not
tested, the isolate was considered to have “limited oral antibiotic
options” if it was non-susceptible to all the tested options. Because
nitrofurantoin is not recommended for pyelonephritis [16], it was
only considered an oral option for patients ≥2 years without symp-
toms concerning for pyelonephritis (defined as fever, abdominal/
flank pain, poor oral intake, or nausea/vomiting). Genitourinary
abnormalities were defined as renal abnormalities or vesicoureteral
reflux. Clinical response at the time that urine culture suscepti-
bilities were available was assessed by physician chart review for
patients started on discordant therapy for whom this information
was available in follow-up documentation [7]. Clinical response
was classified as “improved” (complete or partial resolution of pre-
senting signs or symptoms) or “not improved” (persistence of pre-
senting signs or symptoms).
Outcomes
The outcome of concordant parenteral therapy duration was cat-
egorized as: (1) long parenteral therapy, defined as ≥3 days of
concordant parenteral therapy or (2) short/no parenteral therapy,
defined as 0–2 days of concordant parenteral therapy and also
included treatment with only oral antibiotics or no definitive
treatment. For example, if a patient received 2 days of ceftriaxone
while awaiting urine culture results, followed by 2 days of
meropenem, the patient would be categorized as “short/no par-
enteral therapy” because they received 2 days of concordant par-
enteral therapy. A duration of ≥3 days was chosen based on prior
literature [17] and author consensus. UTI relapse was defined as
a third-generation cephalosporin-resistant UTI with the same or-
ganism species within 30 days of the initial UTI and urine culture
[17–20] and was determined by physician chart review. Half of the
study population came from institutions that had access to records
from outside institutions. We also noted if there was a documenta-
tion of a health care visit in their electronic medical record within
6 months of the initial UTI.
Sample Size and Statistical Methods
Based on preliminary data from the central study institution, we
estimated that 50% of the patients would be treated with long
parenteral therapy, and based on prior literature, we estimated
that the UTI relapse rate would be 1.5% [19]. In order to have
80% power to detect an absolute risk difference of 5%, our target
sample size was 480. We conducted multivariable mixed-effects
logistic regression to determine predictors of long parenteral
therapy with hospital site as a random effect. Covariates were
determined a priori based on prior literature and included sex,
Figure 1. Study profile.
652 • jpids 2021:10 (May) • Wang et al
age, limited oral antibiotic options, and genitourinary abnormal-
ities. We conducted a sensitivity analysis including the variable
of clinical response, which was available for 48% of the cohort.
Coefficients were “marginalized” so that estimates represented
the average effect across hospitals [21]. We compared the propor-
tion of patients with UTI relapse using unadjusted analysis with
Fisher’s exact test due to the low number of events. Data were
analyzed using Stata version 15 (StataCorp, College Station, TX).
RESULTS
Study Population
Overall, 1259 children ≤18 years of age met inclusion criteria
(Figure 1). We excluded 777 children, most commonly due to his-
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tory of urologic surgery, complex chronic condition, or immuno-
compromised status. A total of 482 children with third-generation
cephalosporin-resistant UTIs were included. Table 1 describes
patient characteristics. The majority (80.9%) were female and the
median age was 3.3 years (interquartile range [IQR]: 0.8–8). The
median age of males (0.3 years, IQR 0.2–1.1) was lower than that
of females (4.4 years, IQR 1.6–8.3), P < .001. Most of the isolates
(453/482, 94.0%) were resistant to ceftriaxone/cefotaxime, and 29
(6.0%) had intermediate susceptibility. Antibiotic susceptibilities are
presented in Supplementary Table 2. Median total duration of anti-
biotic therapy was 10 days (IQR: 9-12).
Table 1. Demographic, Clinical, and Laboratory Characteristics of discordant parenteral therapy (mean duration: 2 days) prior to con-
Children With Third-Generation Cephalosporin-Resistant UTIs
cordant therapy. Twenty-three (43%) were only hospitalized once
n = 482 N, %a urine cultures finalized. The long parenteral therapy group had a
Sex (n, %) higher proportion who were male, <2 months of age, had genitou-
Male 92 (19.1) rinary abnormalities, and had limited oral antibiotic options com-
Female 390 (80.9)
pared with the short/no parenteral therapy group (Table 2). Most
Age (median, IQR) 3.3 (0.8-8)
children in this group were treated with a carbapenem (Table 3).
Age category (n, %)
Less than 2 mo 28 (5.8)
Short/No Parenteral Therapy
2-23 mo 158 (32.8)
2-4 y 101 (21.0)
Overall, 428 (88.8%) children received short/no parenteral
5-17 y 195 (40.5) therapy; 6 (1.4%) received 1–2 days of concordant parenteral
Genitourinary abnormalities (n, %) 25b (5.2) therapy, 407 (95.1%) were treated with only oral antibiotics, and
Prior UTI (n, %) 106 (22.0) 15 (3.5%) did not receive definitive treatment (Table 3).
Prior third-generation cephalosporin-resistant UTI (n, %) 8 (1.7)

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When urine cultures finalized, most of the children (302/428,
Setting of initial evaluation (n, %)
70.6%) received concordant antibiotics, 105 (24.5%) received
Emergency Department 268 (55.6)
General pediatrics/urgent care clinic 211 (43.8)
discordant antibiotics, and 6 (1.4%) had documentation of an
Inpatient 3 (0.6) antibiotic change with no mention of the new antibiotic name.
Ill appearance (n, %) 8 (1.7) Of those treated with discordant antibiotics, 88 were continued
Presenting symptoms on empiric discordant antibiotics (44 with clear documenta-
Abdominal and/or back pain 88 (18.3)
tion of continuation of discordant antibiotics and 44 with no
Abnormal urine odor 83 (17.2)
documentation of antibiotic change) and 17 were switched to
Dysuria 203 (42.1)
Fever 275 (57.1)
different discordant antibiotics following the return of cul-
Fussiness and/or irritability 49 (10.2) ture results. Selected comments from chart review describing
Nausea and/or vomiting 100 (20.7) reasons for continued discordant antibiotics are presented in
Poor oral intake 76 (15.8) Supplementary Table 3 and include clinical improvement, pa-
Otherc 115 (23.9)
tient/family preference, and consultant recommendations.
≥1 symptom 475 (98.5)
Sixty-nine children (16.1%) in the short/no parenteral
Urine culture collection method
Straight catheterization 171 (35.5) therapy group had limited oral antibiotic options. In this group,
Clean catch 288 (59.8) the most common definitive antibiotics were nitrofurantoin
Method not recorded 23 (4.8) (31) and cephalosporins (18); 30 of the 31 (97%) children who
Urine culture colony count (n, %) received nitrofurantoin reported symptoms concerning for py-
50 000-100 000 CFU/mL 74 (15.4)
elonephritis (eg, fever) and 12 of the 31 children (39%) were
Greater than 100 000 CFU/mL 408 (84.6)
Urine culture organism (n, %)
<2 years.
Escherichia coli 476 (98.8) Seven patients without symptoms recorded were treated
Klebsiella spp. 6 (1.2) with: long parenteral therapy (1) and short/no parenteral
Bacteremia 3d (0.6) therapy (6: concordant antibiotics [3], discordant antibiotics
Limited oral antibiotic options 100 (20.7) [1], unknown antibiotics [1], and no treatment [1]).
Abbreviations: IQR, interquartile range; UTI, urinary tract infection, CFU/mL, colony-forming units per milliliter.
a
Percentages may not add up to 100 due to rounding.
b
11/25 patients with genitourinary abnormalities had vesicoureteral reflux (6 had grade 1–3, 2 had grade 4–5,
and 3 did not have grade documented); 21/25 had renal abnormalities (eg, duplicated or dilated collecting Predictors of Long Parenteral Therapy
system, hydronephrosis, renal cysts, and pelviectasis).
In multivariable regression, predictors of long parenteral
c
The most common symptoms in the “Other” category included other genitourinary symptoms (eg, frequency/
urgency), constitutional symptoms, and GI symptoms not included in the above categories. A total of 466/482 therapy included: age <2 months (adjusted odds ratio [aOR]
(96.7%) patients had at least 1 symptom from the above categories without including the “Other” category.
d
Two patients had bacteremia with the same third-generation cephalosporin-resistant organism from their 67.3; 95% confidence interval [CI]: 16.4-275.7 compared
urine culture. One patient had 2 E. coli organisms in urine culture, 1 ceftriaxone-resistant strain, and 1 with age 5-17 years), limited oral antibiotic options (aOR 5.9;
ceftriaxone-susceptible strain and also had bacteremia with the ceftriaxone-susceptible strain.
95% CI: 2.8-12.3), and genitourinary abnormalities (aOR 5.4;
95% CI: 1.8-15.9) (Table 2). Male sex was borderline signif-
Definitive Treatment icant (aOR 2.1; 95% CI: 1.0-4.7). In a sensitivity analysis in-
Long Parenteral Therapy cluding clinical response information for 230 patients started
Fifty-four children (11.2%) received long parenteral therapy with on discordant therapy, the association between lack of im-
a median duration of 7 days (IQR: 7-10, range 3-21); 43 of the 54 provement in clinical response and long parenteral therapy
(80%) children received parenteral therapy exclusively. Thirty-one was not significant (aOR 1.7, 95% CI: 0.5-5.2; Supplementary
(57%) were hospitalized at presentation, 27 of whom received Table 4).

Management and Outcomes of Resistant UTIs • jpids 2021:10 (May) • 653

Table 2. Predictors of Long Parenteral Therapy in Children With Third-Generation Cephalosporin-Resistant UTIs

Short/no Parenteral Therapy (n = 428) Long Parenteral Therapy (n = 54)

n, (%) n, (%) Unadjusted Odds Ratios (95% CI) Adjusted Odds Ratiosa (95% CI)
Sex
Male 63 (14.7) 29 (53.7) 6.7 (3.7-12.2) 2.1 (1.0-4.7)
Female 365 (85.3) 25 (46.3) Ref. Ref.
Age category
<2 mo 7 (1.6) 21 (38.9) 114.0 (33.2-391.2) 67.3 (16.4-275.7)
2–23 mo 136 (31.8) 22 (40.7) 6.1 (2.3-16.6) 2.6 (0.9-7.5)
2–4 y 95 (22.2) 6 (11.1) 2.4 (0.7-8.1) 2.0 (0.6-6.6)
5–17 y 190 (44.4) 5 (9.3) Ref. Ref.
Limited oral antibiotic options
Yes 69 (16.1) 31 (57.4) 4.3 (2.4-7.7) 5.9 (2.8-12.3)
No 359 (83.9) 23 (42.6) Ref. Ref.
Genitourinary abnormalities

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Yes 16 (3.7) 9 (16.7) 5.2 (2.2-12.3) 5.4 (1.8-15.9)
No 412 (96.3) 45 (83.3) Ref. Ref.

Abbreviation: CI, confidence interval.

a
Our single mixed-effects model included these 4 factors as fixed effects and hospital site as a random effect to adjust for clustering. Estimated coefficients from the mixed-effects models were marginalized to reflect the average
effect across hospitals. Intra-class correlation coefficient was 17% (95% CI 4%-49%), P = .002.

UTI Relapse
UTI relapse occurred in 7 of the 482 children (1.5%, 95% CI:
0.6%-3.0%). In the long parenteral therapy group, UTI relapse
occurred in 1 of the 54 (1.9%, 95% CI: 0.1%-9.9%) children com-
pared with 6 of the 428 (1.4%, 95% CI: 0.5%-3.0%) children in the
short/no parenteral therapy group, for an absolute risk difference
of −0.4% (95% CI: −4.2% to 3.3%; Table 4).
Within the short/no parenteral therapy group, UTI relapse oc-
curred in 3 of the 302 children (1.0%, 95% CI: 0.2%-2.9%) treated
with concordant therapy and 3 of the 105 children (2.9%, 95% CI:
0.6%–8.1%) treated with discordant therapy. The absolute risk dif-
ference between the discordant and concordant therapy groups
was 1.8% (95% CI: −1.5% to 5.1%). Subgroup analyses by suscep-
tibility to ceftriaxone are presented in Supplementary Table 5.

Table 3. Definitive Antibiotic Treatment, by Age Group, in Children With Third-Generation Cephalosporin-Resistant UTIs

All Children (n = 482) N, %a Less Than 2 months (n = 28) N, % 2-23 Months (n = 158) N, % 2-4 Years (n = 101) N, % 5-17 Years (n = 195) N, %
Long parenteral therapy (n, %) 54 (11.2)a 21 (75.0) 22 (13.9) 6 (5.9) 5 (2.6)
Beta-lactam/beta-lactamase inhibitorb 7 (1.5) 5 (17.9) 1 (0.6) 0 (0) 1 (0.5)
Carbapenemc 39 (8.1) 10 (35.7) 19 (12.0) 6 (5.9) 4 (2.1)
Cephalosporind 4 (0.8) 2 (7.1) 2 (1.3) 0 (0) 0 (0)
Gentamicine 4 (0.8) 4 (14.3) 0 (0) 0 (0) 0 (0)
Short/no parenteral therapy (n, %) 428 (88.8) 7 (25.0) 136 (86.1) 95 (94.1) 190 (97.4)
Amoxicillin-clavulanate 60 (12.4) 5 (17.9) 28 (17.7) 12 (11.9) 15 (7.7)
Cephalosporinf 85 (17.6) 0 (0) 30 (19.0) 21 (20.8) 34 (17.4)
Ciprofloxacin 30 (6.2) 0 (0) 7 (4.4) 4 (4.0) 19 (9.7)
Nitrofurantoin 89 (18.5) 2 (7.1) 20 (12.7) 23 (22.8) 44 (22.6)
Trimethoprim-sulfamethoxazole 136 (28.2) 0 (0) 40 (25.3) 30 (29.7) 66 (33.8)
Otherg 7 (1.5) 0 (0) 2 (1.3) 2 (2.0) 3 (1.5)
Unknownh 6 (1.2) 0 (0) 3 (1.9) 0 (0) 3 (1.5)
Nonei 15 (3.1) 0 (0) 6 (3.8) 3 (3.0) 6 (3.1)

Percentages may not add up to 100 due to rounding.

a
11 patients were transitioned to definitive oral therapy. Age/therapy breakdown was: age <2 months (3 children: amoxicillin-clavulanate [1] and trimethoprim-sulfamethoxazole [2]), age 2-23 months (4 children: amoxicillin-
clavulanate [2] and trimethoprim-sulfamethoxazole [2]), age 2-4 years (3 children: amoxicillin-clavulanate [2] and trimethoprim-sulfamethoxazole [1]), and age 5-17 years (1 child: trimethoprim-sulfamethoxazole).
b
Beta-lactam/beta-lactamase inhibitors included ampicillin-sulbactam (1) and piperacillin-tazobactam (6).
c
Carbapenems included ertapenem (8) and meropenem (31).
d
Parenteral cephalosporins included cefepime (2), cefoxitin (1), and ceftazidime (1).
e
One patient was treated concurrently with cefotaxime.
f
Oral cephalosporins included cephalexin (64), cefprozil (3), cefdinir (14), and cefixime (4). One patient in this group grew 2 strains of E. coli in the urine, 1 ceftriaxone-resistant strain, and 1 ceftriaxone-susceptible strain. The
patient received 3 days of ceftriaxone followed by cefixime due to bacteremia from a ceftriaxone-susceptible strain.
g
Other included: amoxicillin (2), minocycline (2), doxycycline (1), cefdinir and amoxicillin-clavulanate concurrently (1), and 1 patient who was treated with 3 days of nitrofurantoin followed by 2 days of ertapenem after which anti-
biotics were stopped.
h
These 6 patients had documentation of switching antibiotics after culture results returned with no mention of antibiotic name.
i
Five patients were started on empiric antibiotics (4 on discordant antibiotics) during the initial evaluation, which were stopped when the culture results returned since they had improved and the urine cultures were considered
either contaminant or asymptomatic bacteriuria. The remaining 10 patients were not started on antibiotics.

654 • jpids 2021:10 (May) • Wang et al

Table 4. UTI Relapse in Children With Third-Generation Cephalosporin-Resistant UTIs
(a). Percentage With UTI Relapse
# UTI Relapses/Total
All patients 7/482
Long parenteral therapy 1/54
Short/no parenteral therapy 6/428
(b) UTI Relapse Case Details
Case Age/Sex
1 2 mo M
2 1yF
3 4yF
4 5yF
5 5yF
6 8yF
7 16 y F
The first line was made bold since it represented the numbers for the entire study population.
Abbreviations: CI, confidence interval. UTI, urinary tract infection; VUR, vesicoureteral reflux.
About three-quarters of patients (357/482, 74%) were seen
at institutions with access to records from outside institutions
or had documentation of a healthcare visit in their EMR within
6 months of the initial UTI.
Peripherally Inserted Central Catheter Complications
Two of the 16 patients (13% or 4% of the entire long paren-
teral therapy group) who underwent peripherally inserted
central catheter (PICC) placement experienced PICC com-
plications. One had a PICC line thrombosis and received 4
weeks of anticoagulation. One had a PICC line breakage and
replacement.
DISCUSSION
In this multisite retrospective cohort study of 482 children with
third-generation cephalosporin-resistant UTIs, long parenteral
therapy was more common in children <2 months old, those
with genitourinary abnormalities, and those whose culture sus-
ceptibilities conferred limited oral antibiotic options. Among
children ≥2 months old, only 8% received long parenteral
therapy. UTI relapse was rare and not associated with parenteral
therapy duration. These findings suggest that when oral anti-
biotic options are available, third-generation cephalosporin-
resistant UTIs can be treated effectively with oral therapy and
should be considered first-line definitive treatment unless
children cannot tolerate oral medications. Unexpectedly, a
substantial proportion (>20%) of our study cohort was treated
definitively with discordant antibiotics, and few patients ex-
perienced UTI relapse. Therefore, this study also provides in-
formation on current practice patterns, especially when there
are limited oral antibiotic options, and provides groundwork
for future studies investigating the outcomes of patients treated
with discordant therapy.
% With UTI Relapse (95% CI) P-value Risk Difference, % (95% CI)
1.5 (0.6-3.0)
1.9 (0.1-9.9) .57 −0.4 (−4.2 to 3.3)
1.5 (0.5-3.0)
Definitive Therapy Genitourinary Abnormalities
Meropenem Grade 1 hydronephrosis and grade 1-III VUR
Cephalexin None
Cephalexin None
Cefdinir None
Nitrofurantoin None
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Trimethoprim-sulfamethoxazole None
Nitrofurantoin None
Most of the studies on pediatric third-generation
cephalosporin-resistant UTIs describe hospitalized children
with ESBL UTIs and have documented favorable outcomes on
non-carbapenem parenteral therapy [22–24]. However, few
have reported outcomes for those treated with oral therapy.
Our study used a multisite cohort with tertiary and community
sites and found that 422 of the 482 (87.6%) patients received
only oral therapy. This is a higher percentage than reported by 2
US-based studies, which demonstrated that 62% of 76 children
with ESBL infections (85% from urine) from a single center and
57% of 210 children with ESBL infections (89% from urine)
from 4 children’s hospitals were treated as outpatients [25, 26].
This difference is likely explained by cohort selection, since our
study only included UTIs and excluded children with complex
chronic conditions. We also found that UTI relapse occurred in
only 1.5% of children and the risk of UTI relapse did not differ
by parenteral therapy duration. These results suggest that the
AAP UTI guidelines recommending oral antibiotics can also be
applied to third-generation cephalosporin-resistant UTIs.
We found that age <2 months was the most significant
factor associated with long parenteral therapy. This is similar
to previous studies of pediatric UTI management showing that
parenteral courses ≥4 days were more common in younger in-
fants, though the percentage of infants <2 months old receiving
≥4 days of parenteral therapy has decreased from 50% in 2005
to 19% in 2015 [17, 19]. The higher percentage (75%) of infants
<2 months receiving long parenteral therapy in our study may
be explained by limited oral antibiotic options, concerns about
side effects of certain oral antibiotics (eg, sulfonamides and
quinolones), and the overall vulnerability of young infants [27].
The association of limited oral antibiotic options with long par-
enteral therapy is consistent with prior studies demonstrating
longer lengths of stay for children with ESBL UTIs when com-
pared with children with non-ESBL UTIs [3–5].
Management and Outcomes of Resistant UTIs • jpids 2021:10 (May) • 655
 Management of third-generation cephalosporin-resistant
UTIs can be challenging when there are limited oral options.
Providers should weigh potential harms of prolonged paren-
teral therapy and hospitalization against the risk of UTI relapse.
Unfortunately, many of these potential harms and risks have not
been well characterized in the literature, making it challenging
for providers to engage in adequate shared decision-making
with patients and families. In our study, nearly 30% of patients
treated with long parenteral therapy had a PICC placed and
13% experienced complications, which is within the 8%–30%
complication rate from larger studies [28–31].
There were a few unexpected findings in our study that
may be considered when treating a resistant UTI with lim-
ited oral antibiotic options. First, 69 of the 100 children
whose isolates conferred limited oral antibiotic options
were nonetheless treated with either discordant antibiotics
or nitrofurantoin, which is recommended only in cystitis
[16] and not in children ≤24 months, but given to some pa-
tients with symptoms concerning for pyelonephritis and/
or ≤24 months of age. In these cases, providers may have
felt that the specific presentation was not consistent with
pyelonephritis or may have felt that the potential harms
associated with prolonged parenteral therapy outweighed
those of treating with an agent that was discordant or not
recommended. Second, regardless of the availability of oral
antibiotic options, 105 of the 482 (21.8%) children were
treated definitively with discordant antibiotics with a low
UTI relapse rate. It is possible that if a patient’s symptoms
improved while on discordant therapy, providers may have
continued that treatment instead of changing antibiotics (if
a concordant oral option was available) or recommending
hospitalization and prolonged parenteral therapy (if there
were limited oral options). Comments from chart review
showed that parental preference and specialist recom-
mendations may have also influenced this decision. Several
studies of children with ESBL UTIs have demonstrated in-
itial clinical and microbiologic improvement while on dis-
cordant therapy [22, 23, 32–34], and we previously reported
that the majority of patients in this study started on dis-
cordant antibiotics had improved by the time urine cultures
finalized [7]. One possible explanation for this favorable re-
sponse is that in vitro susceptibility may not always reflect
in vivo response, since some antibiotics may achieve high
urinary concentrations [35]. Further studies are needed to
evaluate the effectiveness of continued discordant therapy
in children with resistant UTIs who are improving and have
limited oral antibiotic treatment options.
This study has several strengths. To our knowledge, this is the
first multisite US-based study with data from tertiary children’s
hospitals and community settings to examine the outcomes of
children with third-generation cephalosporin-resistant UTIs.
656 • jpids 2021:10 (May) • Wang et al
Eligibility was confirmed through chart review and we applied
the AAP UTI definition to decrease the risk of misclassification.
There are also several limitations. First, our regression model
may not have included all relevant characteristics that influenced
the decision regarding the route of therapy. Clinical response in-
formation was only available for about half of the cohort; however,
the results were similar in a sensitivity analysis that included this
information. Second, cases of UTI relapse and changes to therapy
may have been missed if a patient re-presented to a different insti-
tution whose medical records were not accessible. However, inves-
tigators either had access to outside records or there was evidence
of follow-up in the same institution for 74% of patients. This sug-
gests that the assessment of this outcome may be more reliable
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than studies using administrative databases with follow-up data
available only from the initial institution [17, 19]. Of the patients
classified as receiving definitive discordant therapy, about 60%
had clear documentation of an antibiotic switch or continuation
of discordant therapy. Third, the study may not be adequately
powered to detect small differences in the percentage of patients
with UTI relapse. Our target sample size was based on an esti-
mate that 50% would receive long parenteral therapy when only
11% of our sample did. However, the upper 95% CI of the risk dif-
ference between the long and short/no parenteral therapy groups
was only 3.3%, meaning that even in a “worst-case scenario,” the
number-needed-to-treat (approximately 30) with long parenteral
antibiotics to prevent one relapse would be fairly high, especially
when juxtaposing this number with the number-needed-to-harm
(approximately 8) for complications from a PICC line. We were
also not able to account for the severity of disease or response to
therapy in assessing risk for relapse and were not able to conduct
an adjusted analysis due to the rarity of the outcome. Nevertheless,
we believe that the rarity of the outcome regardless of parenteral
therapy duration is in and of itself one of the main takeaways of
the study. Fourth, although we incorporated pyuria into our def-
inition of UTI, some patients may have had asymptomatic bac-
teriuria. However, only a small number of patients did not have
symptoms documented and most of them were treated, sug-
gesting clinical suspicion for UTI. It is possible that symptoms
were present but not recorded or abstracted from the chart. Fifth,
since this was a retrospective study, we were unable to determine if
documented relapses were caused by a genetically identical strain
as the index infection. Finally, the results cannot be generalized to
patients not included in the study population, most notably those
with urologic surgery, immunocompromised status, and complex
chronic conditions.
CONCLUSIONS
In a large US-based cohort of children with third-generation
cephalosporin-resistant UTIs, we found that long parenteral
therapy was more likely in infants <2 months of age, those with
genitourinary abnormalities and limited oral antibiotic op-
tors consider relevant to the content of the manuscript have been disclosed.
tions, and uncommon in children ≥2 months old. UTI relapse
was rare and not associated with parenteral therapy duration.
References
These results suggest that third-generation cephalosporin-
resistant UTIs can be treated effectively with oral antibiotics
when oral options are available. Furthermore, UTI relapse
was also uncommon among children treated definitively with
discordant antibiotics. When there are limited oral antibiotic
options for third-generation cephalosporin-resistant UTIs,
providers should weigh the potential harms of hospitalization
and prolonged parenteral therapy against the risk of treatment
failure when recommending a definitive course of therapy.
While treating definitively with discordant therapy may be
an option, further investigations evaluating this approach are
needed.
Supplementary Data
Supplementary materials are available at Journal of the Pediatric Infectious
Diseases Society online (http://jpids.oxfordjournals.org).
Notes
In Memoriam. The authors wish to dedicate this paper to the memory
of Dr Michael Bendel-Stenzel, a coauthor who died tragically in an au-
tomobile accident on September 25, 2020. He was 55 years old. Michael
was remarkable and yet unassuming in many ways. He was a graduate of
Gustavus Adolphus College, studying athletic training and music, followed
by medical school at the University of Minnesota where he was inducted
into the prestigious Alpha Omega Alpha honor society. He completed
residency and fellowship at the University of Minnesota, specializing in
Pediatric Nephrology. He joined Children’s Minnesota in 2008 as one of the
first pediatric hospitalists and has since shared his love of bow ties, extensive
knowledge, and kindness with all those around him. He served as the Lead
for Clinical Outcomes and has completed numerous quality improvement
projects locally and nationally with the American Academy of Pediatrics.
He was inordinately generous with his time, often helping anyone around
him with tasks large and small. Michael’s greatest passions were his love for
his family, devotion to patients, music, Cheerios, golf, and travel. He and his
wife Ellen were devoted philanthropists supporting many local charitable
and arts institutions. He has made innumerable contributions to the health
of children through his research, knowledge-sharing, and joyful care of hos-
pitalized children. He will be missed dearly, but his tremendous legacy and
impact will endure.
Acknowledgments. The authors would like to thank Gomathi Krishnan,
PhD, for her valuable assistance with data extraction.
Authors’ Contributions. M. E. W. designed the study, collected local
data, performed the data analyses, interpreted the data, drafted the ini-
tial manuscript, and reviewed and revised the manuscript critically for
important intellectual content. T. L. G., V. L., J. B., M. B.-S., N. H., C. E.
M., E. E. K., W. S., D. P., and S. T. P. collected local data, interpreted the
data, and reviewed and revised the manuscript critically for important
intellectual content. N. S. contributed to the design of the study, collected
local data, interpreted the data, and reviewed and revised the manuscript
critically for important intellectual content. A. R. S. designed the study,
collected local data, interpreted the data, and reviewed and revised the
manuscript critically for important intellectual content. All authors ap-
proved the final manuscript as submitted and agree to be accountable for
all aspects of the work.
Financial support. No external funding for this manuscript.
Potential conflicts of interest. The authors have no conflicts of interest
relevant to this article to disclose. The author has submitted the ICMJE
Management and Outcomes of Resistant UTIs • jpids 2021:10 (May) • 657
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