Time to Positive Blood and Cerebrospinal Fluid Cultures in Hypothermic Young Infants

We performed a secondary analysis of a retrospective cohort study including 9 children’s hospitals. Infants ≤90 days of age presenting to the emergency department or inpatient setting with hypothermia (temperature ≤36.0°C) from September 1, 2017, to May 5, 2021, were identified by International Classification of Diseases, versions 9 and 10 diagnosis codes, or hypothermia on initial vital signs as previously described.³  Included patients had documented or reported hypothermia and positive blood and/or CSF cultures. We excluded patients with fever within 48 hours of initial presentation, central venous catheters, trauma or cardiac arrest, unavailable culture results, and inability to see the treating physician’s management.

Team members manually extracted deidentified data from the electronic medical record into a central REDCap database. Demographic data included age, sex, medical complexity, and gestational age. Clinical characteristics included vital signs on presentation, repeat temperature instability, medical complexity, maternal history of β-hemolytic Streptococcus group B (GBS) infection, ill appearance, antibiotic exposure, and death.

Repeated temperature instability was defined as more than 1 hypothermic temperature in a 24-hour period. Ill appearance was defined as the following terms documented on physical examination: ill appearance, toxic, limp, unresponsive, gray, cyanotic, apnea, weak cry, poorly perfused, grunting, listless, lethargic, or irritable.^3,16,17  Feudtner’s complex chronic conditions were used as the measure for medical complexity and defined as a severe medical condition expected to last ≥12 months and requiring subspecialty care or involving multiple organ systems.¹⁸ 

Similar to previous TTP articles, pathogenic bacteria were defined as organisms from a blood or CSF culture that received a treatment course of antibiotics for bacteremia and/or meningitis as documented by the treating physician and did not include empirical antibiotic therapy.^12,13  Contaminant bacteria in blood or CSF cultures were defined as those not receiving antibiotic treatment courses; these infants often received 1 to 2 days of empirical antibiotics while awaiting culture results. TTP was defined as the difference between the time the culture was obtained and when it first resulted positive using time-stamped data from the electronic medical record. Patient charts were manually reviewed to ensure all inclusion and exclusion criteria had been met. The study protocol was approved by the institutional review board at each participating site.

Descriptive statistics were calculated to summarize patient demographics, clinical characteristics, and primary outcomes for positive cultures. Continuous variables are reported as the mean ± SD, the median (interquartile range [IQR]), and the range (min, max). Differences in continuous variables between the pathogenic organism and contaminant groups were tested using a 2-sample t test and 95% confidence intervals for the mean differences were reported. Differences between categorical variables were assessed using a χ² test or Fisher’s exact test. Significance was established at a P value < .05. All data analyses were completed using R statistical software (version 4.1.0).

Of the 1098 young infants with hypothermia, 77 (7.0%) had bacteria isolated on either the blood and/or CSF culture (Fig 1). Of 71 positive blood cultures, 20 (28.2%) were treated as pathogenic organisms. Five (50%) of the 10 positive CSF cultures were treated as pathogenic. Four (5.2%) infants had bacteria isolated from both blood and CSF cultures, 3 of which were treated as pathogenic. Of the 20 infants with pathogenic positive blood cultures, 14 (70%) were ≤28 days old, 12 (60%) had premature gestation, 19 (95%) were not medically complex, and 11 (55%) were ill-appearing. Of the 5 infants with pathogenic positive CSF cultures, 2 (40%) were ≤28 days old, 4 (80%) had premature gestation, 4 (80%) were not medically complex, and 2 (40%) were ill-appearing. Additional patient demographics of infants with positive blood and CSF cultures are found in Tables 1 and 2.

The most common pathogenic organisms isolated from the blood were GBS and Staphylococcus aureus, accounting for 30% of isolated pathogenic organisms. Coagulase-negative Staphylococcus and/or viridans group streptococci accounted for 86% of contaminant blood culture organisms. GBS accounted for 40% of pathogenic organisms isolated from the CSF, whereas coagulase-negative Staphylococcus accounted for 60% of CSF contaminant organisms. Of the positive cultures treated as contaminant organisms, 6 infants were readmitted within 30 days of initial evaluation and none had IBI. A list of pathogenic and contaminant organisms is found in Supplemental Fig 3.

The median (IQR) TTP for pathogenic blood cultures was 16.8 (IQR 12.7–19.2) hours compared with 26.1 (IQR 20.5–48.1) hours for contaminant organisms (P < .001). The median TTP for pathogenic organisms on CSF cultures was 34.3 (IQR 2.0–53.7) hours, compared with 58.1 (IQR 52–72) hours for contaminant CSF organisms (P < .186). Eighteen (90%) pathogenic organisms from blood were positive <24 hours from collection, and all 20 were positive by 36 hours from collection. Two (40%) pathogenic CSF organisms were positive by 24 hours after collection, and 3 (60%) were positive by 36 hours (Fig 2).

Our study is the first to compare the TTP of blood and CSF cultures between pathogenic and contaminant bacteria in hypothermic young infants. All pathogenic blood cultures were positive within 36 hours of collection. Of the 5 pathogenic CSF cultures, 3 were positive in that time frame.

Because differences in LOS of young infants admitted for hypothermia have been recently reported,^15,19  knowledge of when blood cultures are likely to be positive may influence clinical decision-making for infants at low risk of bacteremia. The measured TTP of pathogenic blood cultures was similar to that reported for febrile infants, with positivity expected within 24 hours.^11–14  This observation may allow safe reductions in LOS for well-appearing infants with hypothermia, similar to how understanding TTP has contributed to decreased LOS for febrile infants.¹⁰ 

The measured TTP of pathogenic CSF cultures in hypothermic infants was longer than the 14.0 hours¹¹  and 28.9 hours¹²  reported in previous studies of febrile infants evaluated for SBI. This study highlights potential differences in the clinical course of infants presenting with hypothermia versus fever, despite similar rates of meningitis. It is unclear if these differences in CSF TTP are the result of alterations in the inflammatory cascade resulting in hypothermia as a presenting symptom of infants with sepsis.²⁰ 

Similar to previous studies, we did not study TTP differences between well- and ill-appearing infants.^12,13  Although there were no differences in clinical appearance between pathogenic and contaminant cultures, 55% of pathogenic blood cultures and 40% of pathogenic CSF cultures were in ill-appearing infants. Aronson and colleagues found no significant difference in TTP of blood and CSF cultures based off of clinical appearance.¹⁴ 

Our study has several limitations. Because of its retrospective design, our study was limited by a lack of standardized procedures for obtaining and processing cultures. Reliance on clinician decision-to-treat for defining pathogens may result in misclassification of pathogenic bacteria and/or contaminant bacteria. No patients with blood or CSF cultures treated as contaminant bacteria were readmitted to the hospital within 30 days for IBI, making misclassification of contaminant bacteria less likely. Small sample size limited the precision of our TTP estimates. Our low number of pathogenic CSF cultures and potential for misclassification limit TTP estimates.

Our study is the first to compare the TTP of blood and CSF cultures between pathogenic and contaminant bacteria in hypothermic young infants. Larger studies validating our findings could direct efforts to safely shorten LOS for hypothermic infants undergoing investigation for IBI.

All members who have contributed to the Hypothermic Young Infant Research Collaborative, including Alex Ewing, PhD; Meghan Gray, MD; Noah Hellermann, MD; Elizabeth Rinaldi, MD; Melissa Burns, MD; Amber Domako, MD; Rachael Mullin, DO; Hania Adib, MD; Evan Ingram, MD; Emma Schwendeman, MD; and Ali Sawani, DO.