Given our a priori target of 90% positivity within 24 h of culture attainment for all pathogenic bacteria, our data do not support discontinuing empiric antibiotics for neonatal sepsis at 24 h, as only 84% of blood cultures were positive for “significant pathogens” at that time. While we note that more blood cultures are generally drawn soon after birth during the EOS time period, the burden of positive NICU blood cultures is much higher in infants over two weeks of age during the LOS time period. More work is needed to develop further strategies to reduce LOS in the NICU.
In the EOS time period, 90% of GN bacteria grew positive by 24 h. Thus, GN coverage could be eliminated at 24 h in EOS. This was suggested by Durrani and colleagues, who recommended changing antibiotic coverage to target only GP organisms after 24 h in LOS [22]. This could eliminate a single dose of gentamicin for EOS if every 24 h dosing is being utilized (the second dose at 24 h of culture growth would be eliminated). However, the Rainbow Babies and Children’s NICU only administers gentamicin every 24 h for infants older than 44 weeks PMA. This could be beneficial in this limited scenario, which would have affected 13% of our LOS-positive cultures.
For LOS, Mukhopadhyay et al. found that empiric antibiotics not targeting CoNS could be safely discontinued at 36 h [16]. In terms of reducing GN coverage, they found that only 76% of GN bacteria were detected by 24 h, and were only able to reduce their GN to 36 h [16]. In our cohort, only 85% of GN bacteria were positive by 24 h in LOS, making a 24 h cut-off unattractive.
Our data showed that positive blood cultures from infants with lower GA at birth had longer TTP, although PMA and TTP were not significantly associated. We do not have information on the volume of blood obtained for each blood culture. Infants with lower GA may have smaller volumes of blood sent for EOS culture due to their smaller weight, which could account for a lower TTP. However, there was no difference in TTP by PMA. While all blood cultures obtained at the Rainbow Babies and Children’s NICU are ideally at least 1 milliliter, we did not collect data on culture volume. We acknowledge that this is a limitation of our study. To further study differences in blood culture volumes, the blood culture vials would need to be weighed individually before analysis. In Rued et al., the authors found that the volume of blood obtained did not vary among patients with culture-negative sepsis, bacteremia, or sepsis rule-out, nor did it vary by sex, chronological age, weight at the time of culture collection, or the source of the sample [23]. In their study, blood cultures obtained during the night shift were associated with smaller volumes [23]. This suggests that there may be other reasons for the effect of GA on TTP rather than the amount of blood culture volume. However, one multicenter study found no difference in TTP based on GA [20]. This study additionally found no difference in TTP between the most common organism in preterm infants, E. coli, and the most common organism in term infants, GBS [20]. Enhancements to our electronic medical record now include a field in the blood culture collection order to record the volume of blood obtained at the time the culture is drawn. Thus, in the future, we could evaluate whether the blood volume of the culture affects TTP in our center. At this time, we do not have a good explanation for why infants with lower GA (even when the culture is done long after birth) have a longer TTP.
Overall, our results emphasize the importance of looking at an individual NICU’s data before implementing a practice change. In some circumstances, shortening empiric antibiotic courses while awaiting blood culture results could reduce antibiotic exposure in the NICU. However, reducing the duration from 36 h to 24 h still prevents exposure to only a couple of doses of antibiotics. Conversely, treatment for “culture-negative sepsis” leads to many more neonates being exposed to many more doses of antibiotics, causing greater harm for an unclear diagnosis. Stocker states, “Fear of missing evolving neonatal sepsis is the key driver for antibiotic overtreatment early in life.” [24]. One study by Giannoni et al. found disproportionate antibiotic exposure in the first week of life compared to the number of EOS cases. For each case of EOS, 58 neonates were started on antibiotics, and 273 antibiotic days were administered [25]. A greater impact in decreasing antibiotic exposure in the NICU would be achieved if extended antibiotic exposure to treat “culture-negative sepsis” could be avoided. This may be a more worthy target for clinicians to decrease possibly unnecessary antibiotic exposure.
Our study’s limitations include the absence of blood volume data, the inclusion of serial cultures, and potential delays in the start of incubation. We did not examine how many of the mothers who received antenatal antibiotics had infants with EOS, nor how that may have affected their TTP. We acknowledge that this is a limitation of our study. In addition, this is a single-center study.
In summary, we found that gram-negative coverage could be safely discontinued at 24 h in EOS. Overall, since our target was 90%, the percentage of cultures positive by 24 h was not sufficiently high to recommend routine discontinuation of empiric antibiotics after only 24 h of culture incubation.
