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Concomitant Bacterial Meningitis in Infants With Urinary Tract Infection

Thomson, Joanna MD, MPH*; Cruz, Andrea T. MD, MPH; Nigrovic, Lise E. MD, MPH; Freedman, Stephen B. MDCM, MSc§; Garro, Aris C. MD, MPH; Ishimine, Paul T. MD; Kulik, Dina M. MD**; Uspal, Neil G. MD††; Grether-Jones, Kendra L. MD‡‡; Miller, Aaron S. MD, MSPH§§; Schnadower, David MD, MPH¶¶; Shah, Samir S. MD, MSCE*‖‖; Aronson, Paul L. MD; Balamuth, Fran MD, PhDfor the Pediatric Emergency Medicine Collaborative Research Committee (PEM CRC) HSV Study Group

The Pediatric Infectious Disease Journal: September 2017 - Volume 36 - Issue 9 - p 908–910
doi: 10.1097/INF.0000000000001626
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To determine age-stratified prevalence of concomitant bacterial meningitis in infants ≤60 days with a urinary tract infection, we performed a 23-center, retrospective study of 1737 infants with urinary tract infection. Concomitant bacterial meningitis was rare, but more common in infants 0–28 days of age [0.9%; 95% confidence interval (CI): 0.4%–1.9%) compared with infants 29–60 days of age (0.2%; 95% CI: 0%–0.8%).

From the *Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Sections of Pediatric Emergency Medicine and Pediatric Infectious Diseases, Baylor College of Medicine, Houston, Texas; Division of Emergency Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts; §Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Departments of Pediatrics and Emergency Medicine, Brown University and Rhode Island Hospital, Providence, Rhode Island; Division of Emergency Medicine, Rady Children’s Hospital, San Diego, California and Department of Emergency Medicine, University of California, San Diego; **Division of Pediatric Emergency Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; ††Division of Emergency Medicine, Seattle Children’s Hospital, Seattle, Washington; ‡‡Department of Emergency Medicine, University of California, Davis Medical Center, Sacramento, California; §§Division of Pediatric Infectious Diseases, Cardinal Glennon Children’s Hospital, and ¶¶Division of Emergency Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; and ‖‖Division of Infectious Disease, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio

Accepted for publication January 16, 2017.

The investigators listed in the acknowledgments section should also be designated as Collaborators in PubMed.

The network data center managed by Baylor College of Medicine was supported by the Section of Emergency Medicine, American Academy of Pediatrics (AAP) and Baylor College of Medicine.

S.B.F. is supported by the Alberta Children’s Hospital Foundation’s Professorship in Child Health and Wellness. The other authors have no conflicts of interest to disclose.

Address for correspondence: Joanna Thomson, MD, MPH, Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave MLC 9016, Cincinnati, OH 45208. E-mail: Joanna.Thomson@cchmc.org.

Evaluation for serious bacterial infection in young febrile infants typically includes cultures of urine, blood and cerebrospinal fluid (CSF).1 Urinary tract infections (UTIs) are the most common serious bacterial infection in infants 0–60 days of age, occurring in 5%–15% of young febrile infants evaluated in the emergency department (ED).2

Clinicians often grapple with the necessity of performing a lumbar puncture in infants with a UTI, weighing the potential harms of an invasive procedure against the risk of missing a case of bacterial meningitis. Prior studies have reported low rates of concomitant meningitis in infants with UTIs, but these studies have been limited by small sample sizes3 or have excluded the youngest infants.4 As approximately 6%–10% of infants with a UTI will have concomitant bacteremia4 and because meningitis is most often a result of hematogenous spread across the immature blood–brain barrier in this age group, infants with UTIs are at risk for bacterial meningitis.

To quantify the risk of bacterial meningitis in young children with UTIs, we performed a multicenter, cross-sectional study to determine the age-stratified rates of concomitant bacterial meningitis in infants ≤60 days of age.

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MATERIALS AND METHODS

Study Design

Our study was a planned secondary analysis of a 23-center, retrospective, cross-sectional study conducted by the Pediatric Emergency Medicine Clinical Research Network Herpes Simplex Virus study group. All centers obtained study approval with a waiver of informed consent from the institutional review boards at their respective institutions with permission for data sharing.

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Study Population

Infants ≤60 days of age who presented to the ED between January 1, 2005, and December 31, 2013, were included if a CSF culture was obtained within 24 hours of ED presentation. For this secondary analysis, only infants with UTIs were included. UTI was defined as the growth of a single pathogenic organism from a catheterized specimen with either ≥50,000 colony forming units/mL “or” 10,000–50,000 colony forming units/mL with an abnormal urinalysis [ie, positive leukocyte esterase and/or nitrite and/or >5 white blood cells (WBCs) per high powered field].4 Urine samples obtained by methods other than catheterization were excluded. Eligible infants were identified using electronic search strategies optimized for each study site.

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Data Collection

Depending on the available data systems, data elements were electronically or manually abstracted from medical records. Data included the following: age, gender, ED triage temperature, laboratory values (complete blood count with differential, urinalysis, CSF cell counts, CSF glucose, protein concentrations and CSF Gram stain) and bacterial culture results (blood, urine and CSF). The period of data collection varied from site to site to coincide with the introduction of each institution’s electronic medical record.

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Primary Outcome

The primary outcome was the rate of bacterial meningitis in infants with UTI. In accordance with prior studies,5 we defined concomitant bacterial meningitis as growth of the same pathogenic organism in CSF culture that was present in the patient’s urine culture.

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Study Definitions

The following bacterial organisms were classified a priori as contaminants: Abiotrophia, Actinomyces, Aerococcus, Bacillus (non-anthracis and non-cereus), Bifidobacterium, Brevibacterium, Corynebacterium, Lactobacillus, Micrococcus, Propionibacterium acnes, Rothia, coagulase-negative staphylococci, Stomatococcus, alpha streptococci, gamma streptococci and Viridans group streptococci. CSF pleocytosis was defined using age-specific CSF WBC reference values (ie, ≥19 for infants 0–28 days of age and ≥9 for infants 29–60 days of age).6

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Statistical Analysis

Continuous data are described with median values and interquartile ranges because of nonnormal distributions. Categorical data are described with frequencies and percentages. The prevalence of UTI with concomitant bacterial meningitis is presented with 95% confidence intervals (CIs) for infants 0–28 and 29–60 days of age.

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RESULTS

Of the 23,882 infants with both CSF and urine cultures identified across the 23 centers, 1737 infants had a UTI (7.3%; 95% CI: 6.9%–7.6%). The cohort was 62.7% male with a median age of 30 days (interquartile range: 18–44). The following abnormalities were present on urinalysis in infants with UTI: positive leukocyte esterase, 90.9% (1438/1582); positive nitrite, 35.9% (572/1595) and >5 WBC per high powered field, 84.3% (1128/1338).

Of the 1737 infants with a UTI, 175 had growth of a pathogenic organism on blood culture without concomitant bacterial meningitis (10.6%; 95% CI: 8.6%–11.6%). Most infants with UTI and bacteremia had growth of the same organism from blood and urine cultures (n = 170/175, 97.1%). Concomitant bacterial meningitis was present in 9 infants (0.5%; 95% CI: 0.2%–1.0%) (Table 1). All 9 infants with UTI and concomitant bacterial meningitis also had bacteremia with growth of the same pathogenic organism from urine, CSF and blood cultures. The following bacterial pathogens were isolated: Escherichia coli (n = 6), Klebsiella pneumoniae (n = 1), Staphylococcus aureus (n = 1) and Group B Streptococcus (n = 1). Concomitant bacterial meningitis was more common in infants 0–28 days of age (n = 7/803, 0.9%; 95% CI: 0.4%–1.8%) compared with infants 29–60 days of age (n = 2/934, 0.2%; 95% CI: 0%–0.7%).

TABLE 1

TABLE 1

Two additional infants with UTI had growth of discordant organisms on CSF culture. One 13-day-old infant had E. coli isolated from urine culture and S. aureus from CSF culture, and a 36-day-old infant had K. pneumoniae from urine culture and Acinetobacter lwoffii from CSF culture. Both infants had negative blood cultures as well as normal CSF WBC and protein values for age.6,7 Neither infant was treated for meningitis as CSF cultures were thought to represent contaminants.

Among the 658 infants 0–28 days of age with CSF cell counts, 158 had CSF pleocytosis (24.0%; 95% CI: 20.8%–27.5%); 6 of the 7 with concomitant bacterial meningitis had cell counts available and 4 of these 6 had CSF pleocytosis. Among the 803 infants 29–60 days with CSF cell counts, 234 had CSF pleocytosis (29.1%; 95% CI: 26.0%–32.4%); 1 of the 2 with concomitant bacterial meningitis had cell counts available and did not have CSF pleocytosis.

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DISCUSSION

In this 23-center study of 1623 infants ≤60 days with UTI, only 9 infants had concomitant bacterial meningitis. All 9 of these infants also had bacteremia. The prevalence of concomitant bacterial meningitis was higher for infants 0–28 days of age than those 29–60 days of age, suggesting that risk of concomitant meningitis for infants with UTI is greatest in the first month of life.

Our results are similar to previous studies. In a retrospective, single-center cohort that included 467 Australian infants 0–2 months of age with culture-confirmed UTI and a paired CSF sample, 2 infants had concomitant bacterial meningitis.5 Both of these cases occurred in infants <1 month of age; thus, the prevalence of concomitant meningitis for infants <1 month of age was 1.2% (95% CI: 0.15%–4.36%), and for the 1–2 months of age group, it was 0% (95% CI: 0%–1.25%). Similarly, in a multicenter study of 1895 infants 29–60 days of age with UTI, only 2 (0.1%) had concomitant bacterial meningitis.4 While the exact age of those infants was not provided, both infants in our study with concomitant bacterial meningitis in the 29–60-day age range were at the lower end of the age spectrum. Our study expands on this knowledge by providing a large sample size inclusive of the youngest infants, while yielding generalizable results from our 23-center cohort.

Our findings suggest that a selective, rather than universal, approach to lumbar puncture in infants with UTI may be appropriate, especially in well appearing infants 29–60 days of age.4,5 Although obtaining CSF for culture on all infants with UTI assures that no case of concomitant bacterial meningitis will be missed, lumbar punctures are painful for infants, distressing to families, and are associated with rare complications (eg, meningitis from introduction of infectious organism, bleeding, cerebral herniation). Furthermore, traumatic or unsuccessful lumbar punctures can lead to diagnostic confusion and potentially unnecessary or prolonged hospitalizations.8 Growth of contaminant organisms in spinal fluid and sterile CSF pleocytosis in the presence of a UTI may also lead to longer durations of parenteral antibiotic therapy and hospitalization.9,10

As all 9 cases of UTI with concomitant bacterial meningitis also had positive blood cultures, clinicians should have heightened suspicion for concomitant bacterial meningitis in infants with bacteremic UTIs. Despite the challenges of interpreting CSF obtained after the initiation of antibiotics, we believe that it is prudent to perform a lumbar puncture in infants with a UTI and concomitant bacteremia who did not have CSF obtained on initial evaluation to accurately determine treatment duration and route of antibiotic administration.

Our study has several limitations. First, we do not have data on antibiotic administration before performance of the diagnostic lumbar puncture. Although antibiotic pretreatment occurs rarely in the youngest infants, pretreatment with antibiotics may have led to our underestimating the true prevalence of meningitis. Second, we only included infants who had a CSF culture obtained in the parent study, and therefore, we may have overestimated the risk of concomitant bacterial meningitis in all infants with UTIs. Despite this limitation, our concomitant bacterial meningitis rates were low. Finally, we do not have data regarding the clinical appearance of infants. This may be particularly relevant in interpreting the rate of concomitant meningitis in infants 29–60 days of age, as some clinicians perform lumbar punctures only on ill-appearing infants in this age group. It is also possible that some infants with meningitis may have been identified on the basis of clinical features alone.

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ACKNOWLEDGMENTS

The authors thank the Pediatric Emergency Medicine Collaborative Research Committee (PEM CRC) Herpes Simplex Virus (HSV) Study Group site investigators: Pamela J. Okada, MD, Alesia H. Fleming, MD, MPH, Rakesh D. Mistry, MD, MS, Joseph L. Arms, MD, Prashant Mahajan, MD, MPH, MBA, Christopher M. Pruitt, MD, Todd W. Lyons, MD, Amy D. Thompson, MD, Sarah J. Curtis, MD, MSc, Suzanne M. Schmidt, MD, Stuart A. Bradin, DO and Jeffrey Louie, MD.

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REFERENCES

1. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med. 1993;329:1437–1441.
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3. Tebruegge M, Pantazidou A, Curtis N. Question 1. How common is co-existing meningitis in infants with urinary tract infection? Arch Dis Child. 2011;96:602–606.
4. Schnadower D, Kuppermann N, Macias CG, et al; American Academy of Pediatrics Pediatric Emergency Medicine Collaborative Research Committee. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126:1074–1083.
5. Tebruegge M, Pantazidou A, Clifford V, et al. The age-related risk of co-existing meningitis in children with urinary tract infection. PLoS One. 2011;6:e26576.
6. Kestenbaum LA, Ebberson J, Zorc JJ, et al. Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants. Pediatrics. 2010;125:257–264.
7. Shah SS, Ebberson J, Kestenbaum LA, et al. Age-specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med. 2011;6:22–27.
8. Pingree EW, Kimia AA, Nigrovic LE. The effect of traumatic lumbar puncture on hospitalization rate for febrile infants 28 to 60 days of age. Acad Emerg Med. 2015;22:240–243.
9. Schnadower D, Kuppermann N, Macias CG, et al; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Sterile cerebrospinal fluid pleocytosis in young febrile infants with urinary tract infections. Arch Pediatr Adolesc Med. 2011;165:635–641.
10. Shah SS, Zorc JJ, Levine DA, et al. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infections. J Pediatr. 2008;153:290–292.
Keywords:

urinary tract infection; meningitis

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