Urinary tract infection (UTI) is one of the most common causes of serious bacterial infections in infants <90 days of age. UTI occurs in 0.1–1% of term neonates1–4 and is a cause of fever in 5–13.6% of febrile infants <8 weeks of age.5–9 One study found that 85% of serious bacterial infections in infants <90 days of age resulted from UTI.10 In children with UTI, the rate of concurrent bacteremia has been reported as 0–31%.5,11–16
Identification at presentation of infants who will subsequently be diagnosed with bacteremia may enable identification of those prone to complications.15 The purpose of this study was to identify risk factors at presentation associated with bacteremia in febrile infants aged 0–60 days.
MATERIALS AND METHODS
We conducted a retrospective cohort study in which we identified all infants aged 0–2 months admitted to the pediatric emergency room at the Hadassah-Hebrew University Medical Center during a period of 1 year (2007), with subsequent positive urine cultures. The microbiologic data of our hospital are computerized and the WHOnet search tool was used to identify patients with positive urine cultures. After identifying all patients, clinical data were extracted from their medical records.
Our institutional policy of urine culture sampling in this age group is to draw the specimen by either suprapubic aspiration (SPA) or sterile urine catheter in all infants with fever or other complaints that may be compatible with UTI—among them, unexplained prolonged/nonresolving vomiting and/or prolonged unexplained jaundice or failure to thrive. Duration of fever was determined in blocks of 8 hours, which is the standard temperature measurement interval in our hospital.
Obtaining blood cultures is a routine procedure in every infant up to 2 months of age with suspected bacterial infection. The standard volume of blood obtained for the blood cultures at this age in our hospital is 0.5–1.5 mL blood added to each aerobic and anaerobic bottle. Biochemical analyses of leukocyte esterase and nitrite in urine was performed through a rapid dipstick method. A urine microscopic examination for white blood cells (WBCs) and bacteria was performed routinely if the volume of urine was sufficient for both culture and urinalysis. All imaging was assessed by a pediatric radiologist with over 10 years’ experience. The study was approved by Hadassah-Hebrew University Medical Center’s Ethics Committee.
Infants were classified as having a UTI if they met the following criteria: clinical symptoms of infection (fever, vomiting, poor feeding, jaundice, failure to thrive or diarrhea) together with any pathogen growth from the urine sample obtained by SPA or ≥104 colony forming units (CFU)/mL with a single pathogen from urine obtained by catheterization.17
Bacteremia was defined as growth of a pathogen in the blood culture. UTI accompanied by bacteremia was defined when the same bacterium, with identical in vitro antibiotic susceptibility pattern, was cultured from both blood and urine. Abnormal body temperature was defined as hyperthermia (>38°C) or hypothermia (<36°C). Abnormal WBC count was defined as leukopenia or leukocytosis, and abnormal polymorphonuclear count was defined according to age-related norms.18 Abnormal levels of C-reactive protein (CRP) were >0.5 mg%. Cerebrospinal fluid (CSF) pleocytosis was defined as WBC in CSF above 32 cells/mm3 in infants <30 days of age and >10 cells/mm3 in infants >30 days.19,20 Increased blood creatinine was defined as creatinine level above the 50th percentile for age.21
The charts of all infants <2 months of age brought to the pediatric emergency department and diagnosed with UTI were assessed. Those with and without bacteremia were compared, according to the following variables: age, gender, ethnicity, duration of complaint before presentation in the emergency department, presence of abnormal body temperature, time to defervescence, abnormal blood WBC or polymorphonuclear count, CRP, increased blood creatinine, urine leukocyte esterase test, urine nitrites and presence of any abnormalities in abdominal ultrasound (US) or voiding cystourethrogram.
Statistical analysis was performed using the IBM SPSS statistics 19.0 software. Categorical variables were compared using the Fisher Exact test or χ2; continuous variables were compared using the Mann-Whitney U test.
We identified 82 episodes of UTI developed by 81 infants during the study period. Most episodes were in males 58 (72.8%), 35 episodes (42.7%) occurred in 34 infants of non-Jewish origin; 58/82 (70.7%) episodes were in infants aged 0–30 days and 24 (29.3%) were in those aged 31–60 days. Presenting signs and symptoms included: fever in 67/82 (81.7%) or hypothermia in 1 (1.2%), jaundice in 14 (17.0%), diarrhea in 7 (8.5%), vomiting in 6 (7.3%), dehydration in 3 (3.7%), signs of respiratory tract infection in 15 (18.3%); apathy in 23 (28.0%), cyanosis or apnea in 9 (10.9%), dyspnea in 2 (2.4%), pallor in 4 (4.9%) and cutis marmorata in 4 (4.9%). Duration of complaints before admission was 1–4 days in 79 episodes (median 1 day); in 1 infant, the sole complaint was failure to thrive and in 2, it was hyperbilirubinemia of 3 weeks duration. Lumbar puncture was performed in 67 episodes, 17 of them were in children 28–60 days of age. In 2 children, 7 and 27 days of age, the tap was bloody and cell count was impossible. CSF pleocytosis was found in 2 children (9 and 22 days of age), one of them with positive polymerase chain reaction for enterovirus and in the other no cause was identified. CSF cultures were negative in all episodes.
Urine was collected by SPA in 44 (53.7%) episodes, by newly inserted sterile catheters in 28 (34.1%); in another 10 (12.2%) episodes, the origin of urine was either SPA or catheter, but unspecified. Bacteria growing from urine cultures were: E. coli 58/82 (70.7%) of isolates, Enterococcus faecalis 11/82 (13.4%) and Klebsiella pneumoniae 7/82 (8.5%). Other isolates found in individual infants were Morganella morganii, Klebsiella oxytoca, Staphylococcus aureus, group B Streptococcus and 2 polymicrobial (E. coli + Enterobacter cloacae or E. coli + K. pneumoniae).
Blood cultures were available in 81 of the 82 episodes. In 14/81 (17.3%), E. coli was cultured from the blood. No other pathogens were isolated from blood cultures. One infant had 2 bacteremic UTI episodes.
US was recommended for all infants and performed during hospitalization or after discharge. US was available for our evaluation in 12/13 (92.3%) infants with bacteremia; in 4/12 (33.3%), it was abnormal, including bilateral ureteral dilatation, left double collecting system, hydronephrosis or pyonephritis (one each). US was available in 37/67 (55.2%) nonbacteremic infants; in 8/37 (21.6%), it was abnormal: congestion (n = 2), single kidney (n = 2) or mild dilatation, pyelonephritis, dysplastic kidney, suspected double collecting system (1 each).
Voiding cystourethrogram was available for our evaluation in 5 bacteremic infants. In one, who had 2 bacteremic episodes and bilateral dilatation in US, vesico-uretheral reflux grade 4 was found. In 18 nonbacteremic infants, 3 (17%) had vesico-uretheral reflux grade 2 (1 child with congestion on US) or grade 2–3 (2 children with normal US).
Factors Associated With UTI With Bacteremia
Blood creatinine levels on admission were significantly higher in infants with bacteremia, whereas regression of values suggests that creatinine levels in nonbacteremic infants were closely correlated with age-related norms (Fig. 1). In 3/14 bacteremic episodes versus 0/57 nonbacteremic episodes, creatinine level was above 95th percentile for age (P = 0.0064). Univariate analysis revealed non-Jewish origin, CRP and positive urine leukocyte esterase test were also significant variables (Table 1). There were no differences between bacteremic and nonbacteremic infants in reported duration of complaints before admission and degree of body temperature.
A multivariate analysis revealed that increased blood creatinine (P = 0.004) on admission and non-Jewish origin (P= 0.006) were the only significant factors associated with bacteremia. There are 58 boys in the study, 21 circumcised, 14 not circumcised and in the remaining 13 boys the status of circumcision was not reported. The rate of reported circumcision was 3/8 (37.5%) among bacteremic boys (all 3 from non-Jewish origin) and 18/27 (66.7%) among nonbacteremic boys (4 non-Jewish; P = 0.22). Even if it is assumed that all Jewish boys >8 days of age (the age of ritual circumcision) were circumcised, circumcision was not associated with bacteremic episodes 5/10 (50%) among bacteremic boys and 29/38 (76%) among nonbacteremic boys (P = 0.13).
Clinical Course and Outcome
Five infants, all nonbacteremic, were hospitalized in the intensive care unit during the course of UTI, because of apnea (n = 3), bradycardia (n = 1) or desaturation (n = 1), 2 of them had signs of respiratory infection, none required mechanical ventilation. None of the patients developed septic shock or bacterial meningitis.
Time to defervescence in 80 episodes was 8–140 hours, average 29 hours; in bacteremic children (n = 14), it was 8–140 hours, average 48 hours. In nonbacteremic children: 11/66 were afebrile, in those febrile, time to defervescence was 8–116 hours, average 24 hours (P = 0.018). Fever lasted >24 hours since initiation of treatment in 20/80 episodes (25%), in 8/14 bacteremic (57%) and 12/66 (18%) nonbacteremic episodes (P = 0.002).
Follow-up creatinine was obtained in 18 episodes, including 6 episodes in which the initial level was above the 50th percentile for age and in 3 of them with creatinine level above 95th percentile for age. All follow-up values were within normal range.
No deaths occurred during the course of UTI in our study. All children recovered without sequella. Median duration of hospitalization was 7 days (range 1–17 days.) The 14 bacteremic infants were hospitalized longer than those without bacteremia: median 10 (range 7–17) days versus 7 (range 1–14) days (P < 0.001).
To the best of our knowledge, our finding that blood creatinine levels above the 50th percentile for age are a predictive factor for bacteremia in 0- to 2-month-old infants with UTI has not been previously reported. One study reports that creatinine values did not differ in bacteremic versus nonbacteremic children with UTI aged 7 days to 9.5 years.22 The association between increased blood creatinine and bacteremia could be underreported, as many published studies include both young infants and older children.11–16,23 Creatinine levels undergo physiologic changes during the first weeks of life. Higher values are acceptable in the first days, representing maternal creatinine and gradually drop during succeeding weeks.24,25 We identified relatively increased creatinine as a factor associated with bacteremia while comparing creatinine level with the age-related norms for each week of life. As renal blood flow is only 10% of cardiac output in the first week of life, and creatinine clearance normally rises gradually thereafter,24,26 even mild blood pressure reduction accompanying bacteremia may cause additional decrease of renal blood flow and subsequent increase in creatinine, more evident in young infants than in older children. Notably, only UTI episodes caused by E. coli were associated with bacteremia in our study. There is a possibility that E. coli causing bacteremia is more harmful to renal parenchyma. The same virulence factors responsible for the higher rate of bacteremia associated with certain E. coli strains were found responsible for damage to human renal epithelial cells in cell culture.27–34 Structural abnormalities and vesico-uretheral reflux, a potential cause of increased blood creatinine, were found in the same frequency in the bacteremic and nonbacteremic episodes.
We have no explanation as to why non-Jewish origin was found to be associated with bacteremia. Delay in diagnosis could explain this difference—but duration of symptoms until emergency room presentation was similar in infants of non-Jewish and Jewish origin (P = 0.431). Based on our current results, it seems that circumcision does not have influence on the occurrence of bacteremia. Other parameters associated with bacteremia in univariate analysis in our study were CRP and positive urine leukocyte esterase test. Several studies found that younger age, ill appearance, feeding problems, high inflammation markers such as WBC, presence of bands, CRP and urine leukocyte counts >9 cells/high power field can predict bacteremia, although others have not found this association.11–16,23,35,36
The rate of bacteremia (17%) in our study was in the middle of the range reported in other studies (0–31%). The wide range in occurrence of bacteremia may be explained by the different numbers and age ranges of children included in these studies.5,7,8,11–16,19,35
Several studies have reported the benign course of UTI in infants, even when accompanied by bacteremia, although the bacteremia rate was low in these studies,4–9 making comparison between bacteremic and nonbacteremic episodes problematic.11,13,35,36 The course of illness was relatively benign in the children in our study too, except for longer time to defervescence in the bacteremic children. However, identification at admission of those infants who are bacteremic may be important according to the results of one much bigger study with high number (n = 123) of bacteremic infants aged 29–60 days which reported a significantly higher frequency of complications (defined as: death, shock, bacterial meningitis, intensive care unit or step-down intensive care unit admission or transfer, need for ventilator support, need for surgical intervention or other substantial clinical complication) in infants with bacteremic UTI compared with those with UTI without bacteremia (10/123, 8.1% vs. 41/1754, 2.3%).15 Ill appearance at presentation can help predict these adverse events, but clinical judgment depends on the personal experience of the treating physician. Increased blood creatinine level provides an additional clue, independent of personal judgment, which may help identify infants at higher risk for bacteremia and for complications. Median duration of hospitalization and parenteral therapy was 7 days in our study, being significantly longer in bacteremic infants, similar to other studies.36,37
There is a tendency to shorten significantly parenteral therapy for UTI at any age or even to provide oral therapy initially based on several studies which showed equal efficacy of oral and parenteral therapy for children with UTI, regardless of bacteremia. However, the proportion of children with bacteremia was small in these studies and the proportion of infants in the first 3 months of life was low, some of the studies excluded infants <1 month of age.13,38–40 Similar outcome was shown for children who received oral cefixime since admission when compared with parenteral cefotaxime for 3 days and later switch to oral cefixime, including negative repeated blood cultures, although only 13 children were <7 weeks old and the proportion of bacteremic children is not mentioned.13 Another study in children with median age 8 months (range 1–99 months) showed no significant differences between oral amoxicillin-clavulonate (n = 244) and parenteral ceftriaxone (n = 258) treatment for the initial 3 days, regarding to time to defervescence, white cell count, percentage with sterile urine and scarring on scintigraphy at 12 months, but they did not include children <1 month of age, and they excluded those with increased creatinine clearance. In addition, the rate of bacteremia was not mentioned.39 Another study in 365 children aged 6 months to 16 years with pyelonephritis reported the same renal scarring rate in those who received oral ceftibuten or intravenous ceftriaxone for 3 days followed by oral ceftibuten, but only 1 child had bacteremia.40 A recent Cochrane review concluded that children with acute pyelonephritis can be treated effectively with orally administered antibiotics.38 Given the current available data, however, the authors of the review were unable to perform subgroup analyses distinguishing infants, children and adolescents.
Still, an approach to suspected bacteremia in infants <3 months of age is to provide initial parenteral therapy and to observe carefully in the inpatient setting; bacteremic infants were hospitalized even in the center which routinely treat neonates with UTI with intravenous antibiotics in ambulatory setting.19 Several retrospective studies reported that bacteremic children with UTI (age range from 0 to 18 years) were provided with longer parenteral therapy when compared with nonbacteremic.36,37 Whether all febrile infants <1 month of age will be usually hospitalized and receive parenteral therapy, in centers which consider oral therapy in the older infants, identification of those at high risk for bacteremia may help to focus the parenteral treatment and inpatient observation on these specific infants; impaired renal function provides another clue to the decision.
Our study has a number of limitations. First, it is a single-center retrospective study. Second, the number of patients included was not high and not all parameters in all patients were available for analysis. In addition, no data on follow-up creatinine are available in all infants. Radionuclide scan results are likewise unavailable for determining whether those with bacteremia are at high risk for cortical renal scars. We did, however, study all infants aged 0–2 months with UTI treated in our hospital throughout an entire year and found significant results.
In conclusion, we showed that bacteremia in infants aged 0–60 days admitted with UTI is associated with blood creatinine above the 50th percentile appropriate for age, with longer time to defervescence and with longer hospitalization. Increased blood creatinine levels on admission can provide an additional clue, independent of personal judgment, to help identify infants at higher risk for bacteremia, prolonged hospitalization and potential complications. Prospective analysis of blood creatinine at admission of infants with UTI is required to confirm our data.
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