Late-onset sepsis due to urinary tract infection in very preterm neonates is not uncommon

Children admitted to the neonatal intensive care unit (NICU) are at increased risk of infections. Infection is an important determinant of length of stay, morbidity, and mortality. The risk of urinary tract infection (UTI) is reported 13.6–16.4% in term infants who present with fever or other signs of infection [1‐3]. The overall occurrence of UTI is reported higher in preterm infants as compared to term infants [4]. In both groups, the incidence of UTI increases with postnatal age, varying from 1 to 2% in the first 72 h after birth up to 25% later on [4, 5]. Therefore, routine early-onset sepsis (EOS) work-up in infants does not include urine cultures [5]. UTI in preterm infants may be secondary to bacteremia, but it may also start as primary infection in the urinary tract leading to bacteremia [6]. In both scenarios, diagnosing the UTI is of importance since infection may cause kidney damage or may be secondary to a congenital abnormality of the kidney and the urinary tract (CAKUT).

In preterm infants admitted at the NICU, data regarding urine cultures in the evaluation of late-onset sepsis (LOS) are limited [7]. Nevertheless, since the overall risk of UTI rises with decreasing gestational age, low birth weight, and postnatal age above 72 h after birth, urine should be analyzed when LOS is suspected [4, 5, 7, 8]. However, the presence of other risk factors for infection might make clinicians reluctant to obtain urine cultures during the primary sepsis evaluation [9]. The use of central arterial or venous lines in these infants, providing a direct source of bacteremia, is such a risk factor and often the cause of blood stream infections [10]. This might suggest that a central line infection has a higher probability than a primary UTI to cause sepsis in these infants. Furthermore, presumed complications of sterile catheterization or suprapubic aspiration hamper urine collection and alternative collection methods such as bag collection have high rates of contamination [11]. An internal survey demonstrated that half of the NICUs in The Netherlands consistently include urine analysis as part of LOS work-up while the remaining centers only collect urine when additional UTI related symptoms are present. Therefore, rationale and recommendations are needed to either underline or discourage routine urine culturing when premature infants with central lines are evaluated for LOS.

The aim of this study was to evaluate the risk of UTI among premature infants with central lines who were evaluated for LOS. In addition, concordant blood cultures and ultrasonography images were analyzed to investigate the consequences of not (timely) diagnosing the UTI. Recorded data included side effects of sampling urine such as registered pain or complications, the treatment, and the presence of urinary tract malformations.

This study was designed to investigate the risk of UTI in NICU-admitted premature infants (gestational age < 32 weeks) with central lines who were suspected of LOS. We found a high risk (11.3%) of UTI in this specific population. Our data show that UTI is not uncommon and that the source of infection in 1 out of 10 episodes is the urinary tract. Interestingly, in these neonates, only in 40% urine was cultured. Prior to this study, we hypothesized that this was related to the assumption of clinicians that UTI is rare in this population because the presence of central lines is a more likely sepsis risk factor. Moreover, lack of a rigid and evidence-based protocol for this group of infants, such as available protocols for term neonates [14], might explain the motivation of the clinician not to prioritize urine analysis.

In addition, urine collection in premature infants by catheterization or suprapubic aspiration might be challenging. To overcome this, often, bag collection was used to screen the urine within the first sepsis evaluation and often repeated by an alternative method for a clean catch to culture when the screening indicated possible infection or contamination. However, repeating the collection results in a delay during which the patient most often has received antibiotics, which might cause false negative urine cultures. Alternative methods such as bladder stimulation and paravertebral lumbar massage techniques are reported with high rates of contamination [11, 15]. In this cohort, UTI was found in three infants by using the method of bag collection showing mono-cultural growth without any sings of contamination. Although the possibility of contamination is not excluded, only three out of 56 BC urine cultures (5%) were considered positive. Moreover, based on these positive cultures, infants were treated with systemic therapy, and following urine cultures after treatment were sterile.

UTI was found in 24 infants, more than half (54%, n = 13) caused by Candida albicans who received systemic treatment. Candidiasis is known as a frequent cause of infection in NICU-admitted patients [16‐19] and is related with a high mortality. From the 13 infants suffering from Candida albicans infection, most also had positive Candida growth from other cultures such as blood and skin. However, in six episodes, Candida was not detected in blood cultures, and concordant growth in skin and/or saliva cultures was only detected in three episodes, indicating that the Candida infection might have been missed, and the treatment might have been delayed if the urine cultures were not performed. So, in these patients, urine analysis was of crucial importance for their treatment and prognosis.

During the study period, fluconazole prophylaxis to reduce the risk of Candida infection was not routinely used at our NICU. Since the introduction of routine fluconazole prophylaxis in 2013, in premature infants with a gestational age < 27 weeks and/or birth weight < 750 g, only one case of Candida UTI was detected (positive urine cultures obtained by SUC). This might indicate that strict fluconazole prophylaxis might result in less UTI due to candida infections. However, urine analysis as part of LOS evaluation remains of crucial importance (in this case blood and surface cultures showed no pathogenic growth). Prospective studies in cohorts with fluconazole prophylaxis are needed to investigate the frequency of UTI in this population.

By conducting this cohort study, we conclude the following: