Pi Is 1875957219305261
Pi Is 1875957219305261
Pi Is 1875957219305261
ScienceDirect
Original Article
a
Nationwide Children’s Hospital, Department of Pediatrics, United States
b
Indiana University, Department of Pediatrics, Division of Nephrology, United States
Received Apr 16, 2019; received in revised form Jul 30, 2019; accepted Oct 21, 2019
Available online 5 November 2019
Key Words Background: The 2011 American Academy of Pediatrics clinical practice guideline recommends
cystitis; when to obtain renal and bladder ultrasound (RBUS) and voiding cystourethrography (VCUG)
cystourethrogram; following febrile urinary tract infection (UTI) for children age 2e24 months. However, there
ultrasound; is not consensus about when to obtain imaging in neonates. The objective of this study is to
urinalysis evaluate UTI diagnostic criteria along with RBUS and VCUG in neonates admitted to the NICU
in the first 3 months of life.
Methods: A retrospective electronic medical record review was performed of neonates
admitted to Nationwide Children’s Hospital system NICUs between January 2010 and December
2014 with UTI as a primary or secondary diagnosis. Urine culture results were evaluated versus
established UTI criteria and renal US and VCUG results were compared.
Results: Of 81 patients with a straight catheterized urine culture obtained, 28 patients met
laboratory criteria for diagnosis of UTI and all but 4 had a RBUS. Urine cultures had an equal
distribution of Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Coagulase
negative staphylococcus. RBUS showed dilation of the collecting system in 37.5% of patients
with UTI compared to 41.3% without UTI. VCUG showed vesicourteral reflux (VUR) on 41.7%
of those with UTI compared to 34.8% without UTI. For patients with UTI, the sensitivity of RBUS
for VUR on VCUG was 60% with CI [0.17, 0.93] and specificity was 43% with CI [0.12, 0.80]. In
patients without UTI, sensitivity of RBUS for VUR on VCUG was 63% with CI [0.26, 0.90] and
specificity was 71% with CI [0.42, 0.90].
Conclusions: Fewer than half of neonates that were diagnosed clinically with UTI met labora-
tory criteria for a UTI. Positive urine cultures grew a wide variety of organisms. The sensitivity
of renal ultrasound for VUR is only about 60%.
Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
* Corresponding author. 699 Riley Hospital Dr, Indianapolis, IN 46201, United States. Fax: þ1 317 278.3599.
E-mail address: [email protected] (A.L. Schwaderer).
https://doi.org/10.1016/j.pedneo.2019.10.003
1875-9572/Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
196 L. Walawender et al
2. Methods
3.2. Urine culture results
A retrospective electronic medical record review was per-
For all urine samples obtained, 20 (25%) cultures exhibited
formed of neonates admitted to Nationwide Children’s
no growth, 36 (44%) grew < 50,000 CFU/mL, 4 (5%) grew
Hospital (NCH) system NICUs between January 2010 and
50,000e100,000 CFU/mL, and 21 (26%) grew >100,000 CFU/
December 2014. Infants with an ICD9 code 599.0 (urinary
mL. Only 46 (57%) patients had urinalysis sent. Of these,
tract infection) as a primary or secondary diagnosis were
15 (33%) were leukocyte esterase positive and 4 (9%) were
included. Patients were excluded if there was no evidence
nitrite positive. Twenty-eight (35%) patients met laboratory
of a catheterized urine sample sent for culture in the first 3
criteria for diagnosis of UTI and 53 (65%) did not meet UTI
months of life or the urine sample was obtained at another
criteria (Fig. 1). There were not significant differences in
institution.
the demographics in neonates that met UTI criteria versus
All patients had been clinically diagnosed with a UTI.
those who did not (Table 1).
However, the exact reasons for this diagnosis were not al-
ways clear from chart review. Therefore, this study defined
laboratory criteria for UTI diagnosis as either: (a) a urine 3.3. Organisms
culture with 50,000 CFU/mL or (b) a urine culture with
10,000 to 49,999 CFU/mL and positive leukocyte esterase or A wide variety of organisms were identified. Gram-negative
nitrites on urinalysis. This definition was used because of organisms were most prominent, accounting for 23 (74%)
the current clinical practice guidelines and the fact that and 36 (80%) of the organisms that grew in urine cultures in
some NICUs will use a minimum of 10,000 CFU/mL on urine those that did and did not meet UTI criteria, respectively.
culture when UA findings also indicate UTI.1,2 Patients were Urine cultures from the 28 (35%) patients that met lab
then categorized as either having a UTI or not based upon criteria for UTI grew 16 organisms. Multiple organisms grew
these laboratory criteria. in 7 (25%) patients in the UTI group and 10 (19%) patients in
Neonatal UTI Diagnosis 197
Figure 1 Flow chart of UTI diagnosis. White boxes indicate no UTI present, light grey boxed indicate indeterminate UTI status,
dark grey boxes indicate that UTI criteria was met and the black box indicates excluded patients.
the non-UTI group. Enterobacter cloacae, E. coli, Klebsiella 3.4. Imaging workup and results
pneumoniae, and Coagulase negative staphylococcus each
grew in 13% of cultures. Regarding the 53 (65%) patients RBUS was obtained within 4 months of the infection in 24
that did not meet laboratory criteria for UTI, 13 organisms (86%) patients that met laboratory criteria for UTI and 45
were identified on cultures that grew at less than (85%) of those that did not. A VCUG was obtained within 6
10,000 CFU/mL and 10 different organisms were months of the infection in 12 (43%) patients that met lab-
identified on cultures that grew greater than or equal to oratory criteria for UTI and 23 (43%) of those that did not.
10,000 CFU/mL with Enterococcus faecalis being the most RBUS showed hydronephrosis or dilation of the collecting
common organism in each group. There were no significant system in 9 (37.5%) of patients with UTI compared to 18
differences in the types of organisms that grew in cultures (40.0%) without UTI. VCUG showed reflux in 5 (41.7%) of
that met UTI criteria versus those that did not (Table 2). those with UTI compared to 8 (34.8%) without UTI.
Table 1 Demographics.
Met UTI criteria n Z 28 Did not meet UTI criteria n Z 53 P value
a
Gestational age (median days 25% and 75%) 207 (183, 257) 203 (179, 244) 0.48
Mean day of life at urine culture 45 21 51 22 0.26
collection standard deviationb
M/F 17:11 (1.5:1) 34:19 (1.8:1) 0.76
a
Data non parametric, analyzed with ManneWhitney test.
b
Data parametric, analyzed with t test.
198 L. Walawender et al
Of the patients that met laboratory criteria for UTI, RBUS for VUR on VCUG was 63% with CI [0.26, 0.90] and
RBUS showed hydronephrosis or dilation of the collecting specificity was 71% with CI [0.42, 0.90].
system in nine (37.5%) patients. Seven of these patients had
VCUG obtained and three showed VUR. Five of the patients 3.5. Source data
without hydronephrosis or dilation on the RBUS had VCUG
obtained and two showed VUR. For the patients that did not Source data is presented as supplemental file S1.
meet laboratory criteria for UTI, RBUS showed hydro-
nephrosis or dilation of the collecting system in 18 (40.0%)
patients. Nine of these patients had VCUG obtained, and 4. Discussion
five showed VUR. Thirteen of the patients without hydro-
nephrosis or dilation on the RBUS had VCUG obtained and In this study we evaluate urine culture results and imaging
three showed VUR. All VUR identified was grade II or III results in a neonatal population. We identified that a wide
except for 1 patient that had grade IV. A summary of the range of organisms grow in neonatal urine cultures, that
imaging results is presented in Table 3. children who are evaluated for UTI often do not meet
For patients with UTI, the sensitivity of RBUS for VUR on published threshold of CFU/mL to be considered positive,
VCUG was 60% with CI [0.17, 0.93] and specificity was 43% and that sensitivity of renal ultrasound results to identify
with CI [0.12, 0.80]. In patients without UTI, sensitivity of VUR is only w60%.
We used a laboratory definition of UTI that included not The sensitivity of RBUS for VUR is only w60%. RBUS was
only patients with 50,000 CFU/mL or greater on urine cul- not very sensitive or specific for VUR in either group of pa-
ture but also those patients with 10,000e49,999 CFU/mL if tients. Given that the majority of the VUR identified in our
there was positive (“small”or greater) leukocyte esterase patients was low grade and similar rates of VUR were iden-
or nitrites on urinalysis. Even with this less stringent defi- tified in all groups except for patients that did not meet
nition, fewer than half of the patients clinically diagnosed laboratory criteria for UTI and had normal RBUS, it is
with UTI actually met lab criteria. There is a wide variety of reasonable to suggest that all neonates with clinically diag-
definitions currently being used to define a UTI by lab nosed UTI should have RBUS obtained. Moreover, given the
criteria in the neonatal population. In a study by Weems low sensitivity and specificity of RBUS for VUR, it is reason-
et al., UTI was defined as a positive urine culture with able to also obtain VCUG on all neonates with UTI. Effec-
colony counts ranging from 100 to >100,000 CFU/mL.2 A tively, RBUS is being utilized to grossly evaluate the structure
study by Foglia and Lorch defined a positive culture as at of the kidneys and bladder and VCUG to assess for VUR.
least 1000 CFU/mL of a single organism or at least Lastly, there was a wide variety of organisms that were
10,000 CFU/mL of 2 organisms.4 This variety of definitions identified on cultures. A retrospective chart review
in conjunction with the large percentage of patients in our completed by Clarke et al. looked at urine cultures of infants
study that did not meet lab criteria but were clinically admitted to the NICU and major organisms identified were E.
diagnosed with UTI exemplifies the need for better UTI coli, C. negative staphylococci, and Klebsiella species.12 We
criteria in this unique population. identified similar organisms with E. faecalis being the most
Only w13% of cultures grew E. coli in the neonates in frequently identified. E. coli is prevalent in older patients
this study. In contrast E. coli grows in >80% of urine cul- and accounts for 85e90% of infections.13 This was not the
tures in older children.7 Sequencing technology and most frequent organism identified in our study. It is likely
expanded culture techniques have demonstrated that the that the incompletely developed neonatal immune system
urine microbiota at baseline and during disease states is has not only increased their risk of infection but makes them
more diverse than what is identified by clinical susceptible to additional organisms compared to older chil-
cultures.8e10 Criteria for largely E. coli pediatric UTIs may dren.13 A better understanding of which organisms
not be applicable to primarily non-E. coli neonatal UTIs. commonly cause neonatal UTIs would help to further define
Also the organisms were similar between patients that met guidelines for when a neonate should be diagnosed with a
criteria for UTI and those that did not (Table 2). Thus it UTI and require renal imaging. This study has limitations as a
does not appear that organisms considered “uropatho- retrospective chart review and due to the number of pa-
genic” are highly prevalent in the results that met UTI tients that received a VCUG. Future directions consist of
criteria, nor are organisms considered “contaminants” optimizing neonatal criteria for UTI diagnosis. Additionally,
highly prevalent in results that did not meet UTI criteria. there needs to be long-term follow up of renal function and
We submit that UTI diagnostic criteria should include a infectious outcomes in neonates that had VCUG compared to
lower CFU/mL threshold and enhanced cultures may war- those that did not. Up to a quarter of cultures grew multiple
rant evaluation in the neonatal population.11 organisms. Because our cultures were obtained by cathe-
Renal ultrasound was obtained fairly consistently in terization, as long as growth of at least one organism met UTI
patients clinically determined to have UTI. Of patients criteria it was considered a UTI. Whether presence of mul-
that met laboratory criteria for UTI, 86% were evaluated tiple organisms in catheter-obtained NICU samples repre-
with a renal ultrasound, which is similar to those that did sents contaminants should be addressed in future studies
not meet lab criteria at 85%. Interestingly, the patients and NICU UTI diagnostic guidelines. We chose the 4-and 6-
that did not meet lab criteria but had renal imaging ob- month time periods to include US and VCUG respectively
tained had higher percentage of hydronephrosis or dilation because studies past this time period might be due to a new
on renal ultrasound (40.0%) compared to those that met problem. It is possible that we missed some imaging studies
lab criteria (37.5%). However, VCUG to further evaluate related to the urine culture that were performed at very late
abnormal RBUS findings was inconsistently obtained (59%), time periods.
but patients that met lab criteria for UTI were more
frequently evaluated with VCUG (78%). VUR was found
more frequently in those that did not meet lab criteria, 5. Conclusions
55% compared to 43% of those that met lab criteria, but
this difference was not statistically significant. In patients Overall our findings regarding the sensitivity of RBUS to
with a normal RBUS that also had a VCUG, VUR was found identify VUR are similar to the limited previously published
in 40% of patients that met lab criteria compared to 23% of studies of UTIs in the NICU and neonatal population.2,5 We
those that did not meet criteria. Wallace et al., note that demonstrated that a wide range of bacteria are responsible
few studies demonstrate the accuracy of detecting VUR for neonatal UTIs. The organisms that grew in cultures were
with RBUS in neonates, and those that exist suggest poor not different between the patients that met UTI criteria and
sensitivity for low grade VUR with moderate to good those that did not. This suggests that the cultures that did
sensitivity for higher grade VUR but cases can still be not meet UTI criteria may not be contaminants but lower
missed. In the study by Wallace et al., the sensitivity of levels of growth of infecting organisms. This study further
RBUS for VUR in infants younger than 2 months of age that highlights the wide variation of clinical practice when diag-
were diagnosed with UTI was evaluated and found to be nosing UTIs and obtaining renal imaging in these patients.
33% for grade IeV VUR but 86% when limited to grade Ultimately, this reinforces the need for clinical guidelines
IVV VUR.5 specific to this unique patient population to be developed
200 L. Walawender et al
because extrapolating the clinical practice guidelines for Months with a febrile urinary tract infection. AJR Am J
infants age 2e24 months would likely underdiagnose UTIs in Roentgenol 2015;205:894e8.
neonates and lead to insufficient renal imaging. 6. Lowry R. VassarStats: website for statistical computation.
Vassar College; 2004.
7. Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ,
Declaration of Competing Interest McTaggart SJ, et al. Antibiotic prophylaxis and recurrent uri-
nary tract infection in children. N Engl J Med 2009;361:
ALS has consulted for Allena Pharmaceuticals on a topic 1748e59.
unrelated to this manuscript. Otherwise, the authors have 8. Thomas-White K, Brady M, Wolfe AJ, Mueller ER. The bladder is
no conflicts of interests relevant to this article. not sterile: history and current discoveries on the urinary
microbiome. Curr Bladder Dysfunct Rep 2016;11:18e24.
9. Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S,
Acknowledgements Brincat C, et al. The clinical urine culture: enhanced tech-
niques improve detection of clinically relevant microorgan-
isms. J Clin Microbiol 2016;54:1216e22.
ALS and DSH received support from Lilly Endowment, Inc.
10. Thomas-White KJ, Kliethermes S, Rickey L, Lukacz ES,
Physician Scientist Initiative. ALS also received support Richter HE, Moalli P, et al. Evaluation of the urinary microbiota
from Nationwide Children Hospital internal funds. of women with uncomplicated stress urinary incontinence. Am
J Obstet Gynecol 2017;216:55.e1e55.e16.
References 11. Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ,
Mueller ER, et al. Urine is not sterile: use of enhanced urine
culture techniques to detect resident bacterial flora in the
1. Subcommittee on Urinary Tract Infection, Steering Committee
adult female bladder. J Clin Microbiol 2014;52:871e6.
on Quality Improvement and Management, Roberts KB. Urinary
12. Clarke D, Gowrishankar M, Etches P, Lee BE, Robinson JL.
tract infection: clinical practice guideline for the diagnosis and
Management and outcome of positive urine cultures in a
management of the initial UTI in febrile infants and children 2
neonatal intensive care unit. J Infect Public Health 2010;3:
to 24 months. Pediatrics 2011;128:595e610.
152e8.
2. Weems MF, Wei D, Ramanathan R, Barton L, Vachon L,
13. Becknell B, Schober M, Korbel L, Spencer JD. The diagnosis,
Sardesai S. Urinary tract infections in a neonatal intensive care
evaluation and treatment of acute and recurrent pediatric
unit. Am J Perinatol 2015;32:695e702.
urinary tract infections. Expert Rev Anti Infect Ther 2015;13:
3. Bauer S, Eliakim A, Pomeranz A, Regev R, Litmanovits I,
81e90.
Arnon S, et al. Urinary tract infection in very low birth weight
preterm infants. Pediatr Infect Dis J 2003;22:426e30.
4. Foglia EE, Lorch SA. Clinical predictors of urinary tract infec- Appendix A. Supplementary data
tion in the neonatal intensive care unit. J Neonatal Perinatal
Med 2012;5:327e33. Supplementary data to this article can be found online at
5. Wallace SS, Zhang W, Mahmood NF, Williams JL, Cruz AT,
https://doi.org/10.1016/j.pedneo.2019.10.003.
Macias CG, et al. Renal ultrasound for infants younger than 2