The findings, which were published today in Pediatrics, could help clinicians tailor the use of early antibiotics in newborns. Only those deemed at risk for infection should receive antibiotics, thereby reducing unnecessary use.
“Given the risks associated with early-onset sepsis in infants, it isn’t surprising that newborns are often administered antibiotics immediately after birth,” said first author Dustin D. Flannery, DO, MSCE, an attending neonatologist and clinical researcher at Children’s Hospital of Philadelphia.
“However, our study shows that it is safe to withhold antibiotics in infants, including those born preterm, with low-risk delivery characteristics. Such infants are unlikely to be infected at birth, and can be spared the potential complications of systemic antibiotic exposure.”
Predicting which infants will develop EOS, however, is challenging. This has led to an order of magnitude higher rate of antibiotic use compared to the rate of infants with confirmed infection.
Prolonged antibiotic use among newborns is associated with serious adverse outcomes among preterm infants and potential longstanding complications among full term infants, underscoring the need for a better way to assess infection risk.
Since the primary way a newborn is exposed to bacteria is through the delivery process, the researchers decided to analyze delivery characteristics to see if they could help providers identify infants at lowest risk of EOS. In a retrospective study, they assessed all infants born between 2009 and 2014 at two Philadelphia birth hospitals who had a blood or cerebrospinal fluid culture obtained within 72 hours after birth.
The researchers also included infants born across the gestational age spectrum. Prior studies have assessed EOS risk in both extremely preterm (less than 28 weeks’ gestation) and full term (37 weeks or more) infants, but few have analyzed the risk among late and moderately preterm infants (28-36 weeks’ gestation), despite the fact that these infants make up the bulk of neonatal intensive care unit (NICU) admissions.
Overall, 7,549 infants had a culture drawn and were included in the study. Of these, 1,121 (14.8%) were born in a low-risk delivery setting and 6,428 (85.2%) were not. A total of 41 infants had confirmed cases of EOS; none of the infected patients were born in the setting of a low-risk delivery.
Even though no infants born in a low-risk delivery setting developed EOS, 80% of them were empirically treated with antibiotics. There was no difference between the low risk and non-low risk groups in the proportion of infants who received prolonged antibiotics, suggesting that clinicians did not appreciate or account for the lower risk of infection and stop antibiotics in the absence of confirmed infection.
“In the United States, an estimated 400,000 uninfected term infants receive empirical antibiotics at birth every year, and upwards of 90% of extremely preterm infants receive antibiotics,” Dr. Flannery said.
In most high-income countries, the incidence of culture-confirmed early-onset sepsis (EOS) has decreased to 0.4–0.8 cases per 1000 live-born term infants over the last years; the overall incidence has reached about 1–2 cases per 1000 live newborns [1, 2]. This result has been achieved through a continuous update of current evidence [3–9].
As the incidence of EOS has decreased over the last two decades, clinicians raised concerns about antibiotic exposure among uninfected newborns: according to Group B Streptococcus (GBS) EOS prevention guidelines, approximately 10% of the total neonatal population are exposed to antibiotics in the first postnatal days, and almost 100% of the extremely preterm population are exposed to ampicillin and an aminoglycoside [10].
Early antibiotic exposure is associated with the emergence of antibiotic-resistant pathogenic microorganisms and with the decrease of intestinal microbial diversity, which can cause very difficult to treat infections [10]. Antibiotics administration in the neonatal period has also been linked with late onset sepsis, necrotizing enterocolitis, increased mortality and long term health outcomes such as childhood asthma, obesity, inflammatory bowel disease, celiac disease and type 1 diabetes [10].
Furthermore, administration of antibiotics to neonates often results in admission to intensive care unit, decreased breastfeeding, invasive procedures and increased hospital costs [11].
For all these reasons, it is important to avoid unnecessary antibiotics administration to patients during the early post-natal period [11]. However, the clinical diagnosis of sepsis is challenging for neonatologists because many signs of sepsis are nonspecific and are observed with other non-infectious conditions [7].
On the other side, low-level bacteremia (4 colony-forming units/mL or less), inadequate blood specimens (less than 1 mL) or maternal antibiotic treatment before or during delivery may result in negative blood cultures [1, 7]. It has been estimated that the incidence of culture-negative EOS is 6 to 16 times higher than that of culture-confirmed EOS [1]. Total white blood cell (WBC) count with its subcomponents and platelet count have also shown a poor predictive accuracy, and the specificity and selectivity of genetic biomarkers are yet to be fully evaluated [7, 12].
Protein biomarkers demonstrate high specificity and sensitivity and include C-reactive protein (CRP) and Procalcitonin (PCT), which are the most commonly used protein biomarkers for the diagnosis of sepsis and monitoring of antibiotic therapy [12–15]. Both CRP and PCT have a physiologic increase over the first 24–48 h of life; baseline concentrations of both markers are mainly affected by birth weight and gestational age (GA) [16]. On these basis, different attempts have been done to establish the appropriate cut-off values of both PCT and CRP [17–19]. Umbilical blood PCT and CRP have also been tested for EOS diagnosis; cut-off values were different among studies (0.5–2 ng/ml for PCT and 1–10 mg/l for CRP) [20].
After June 2005, several studies have assessed the safety of monitoring neonates at risk for EOS with serial physical examinations: this approach resulted in less laboratory exams and antibiotics exposure without missing any case of EOS [21–23].
In December 2012 the Kaiser Permanente EOS calculator has been developed with the purpose of avoiding antibiotic overtreatment [24]. The EOS calculator is based on a multivariate predictive risk model which allows clinicians to estimate a newborn’s individual risk for EOS given objective maternal risk factors and the infant’s clinical presentation [24]. This model permits to overcome some disadvantages of the CDC algorithm, such as the dichotomization of the continuous variables and the inclusion of maternal chorioamnionitis (CAM) as an impactful risk factor for starting antibiotic therapy [24].
A vast majority of studies about the EOS calculator demonstrates its efficacy in reducing antibiotic overtreatment, laboratory testing, painful procedures and NICU admission with increased opportunities for mother-child bonding and breastfeeding (Table 1) [11, 25–50].
Table 1
Summary of main articles about EOS calculator included for review
| Reference | Patient population | Results |
|---|---|---|
| Escobar et al., 2014 [25] | ≥ 34 weeks’ GA | According to 2010 CDC guidelines, 11% of infants were treated with empirical antibiotics, although only 0.04% had blood culture-confirmed sepsis. Using a risk stratification scheme based on maternal and neonatal data, 4% of infants would have been treated with empirical antibiotics |
| Shakib et al., 2015 [26] | ≥ 34 weeks’ GA well-appearing infants exposed to maternal CAM | Reduction of patients with testing/initial antibiotics by at least 80% if using the EOS calculator compared with 2010 CDC guidelines |
| Kuzniewicz et al., 2017 [27] | ≥ 35 weeks’ GA | Reduction of blood culture use from 14.5% (2010 CDC guidelines) to 4.9% (EOS calculator). Reduction of empiric antibiotic administration in the first 24 h from 5.0% (2010 CDC guidelines) to 2.6% (EOS calculator) with subsequent decrease of antibiotic days per 100 births from 16.0 to 8.5 days |
| Money et al., 2017 [28] | ≥ 37 weeks’ GA well-appearing infants exposed to maternal CAM | Reduction of empiric antibiotic treatment from 99.7% (2010 CDC guidelines) to 2.5% (EOS calculator). One patient with culture-positive EOS would not have received antibiotics based on the EOS calculator |
| Warren et al., 2017 [29] | ≥ 34 weeks’ GA infants who received antibiotics at birth for suspected EOS | Reduction of empiric antibiotic treatment from 93% (2010 CDC guidelines) to 23% (EOS calculator). Both 2010 CDC guidelines and the EOS calculator recommended treatment for 7 patients with culture-negative EOS |
| Beavers et al., 2018 [30] | ≥ 34 weeks’ GA exposed to maternal CAM | NICU admissions rates decreased from 91 to 37%, the number of blood cultures decreased from 92 to 50% and antibiotic administration rates decreased from 94 to 37% when 2010 CDC guidelines were replaced with EOS calculator recommendations |
| Carola et al., 2018 [31] | ≥ 35 weeks’ GA infants exposed to maternal CAM | Only 0.43% of neonates born to mothers with CAM had culture-proven EOS. Empiric antibiotics would have been recommended in 23.5% of the patients according to EOS calculator (76.5% reduction in empirical antibiotic administration compared with 2010 CDC guidelines). Blood culture only was recommended for 8.9% of the neonates; treatment with antibiotics would have been recommended for 3 of the 5 neonates with positive blood culture. All 5 neonates with positive blood cultures had abnormal CBC and CRP values at 6–12 h |
| Dhudasia et al., 2018 [32] | ≥ 36 weeks’ GA | Reduction in antibiotics administration from 6.3 to 3.7% when current CDC guidelines were compared to EOS calculator. There was also a reduction in use of laboratory tests for suspected EOS from 26.9 to 4.9% |
| Gievers et al., 2018 [33] | ≥ 35 weeks’ GA infants exposed to maternal CAM | Compared to the 2010 CDC guidelines, EOS calculator yields a reduction of antibiotic exposure from 95 to 9%, laboratory evaluation from 96 to 22% and NICU observation from 73 to 10% |
| Klingaman et al., 2018 [34] | ≥ 35 weeks’ GA | Compared to the 2010 CDC guidelines, EOS calculator yields a reduction in CBCs by 88%, blood cultures by 94%, and antibiotic administration by 78% |
| Strunk et al., 2018 [35] | ≥ 35 weeks’ GA infants requiring evaluation and/or treatment for suspected EOS | Reduction of patients admitted to NICU from 24.2 to 21.2%, decrease of blood culture sampling from 15.2 to 11.1% and reduction of empiric antibiotic administration from 12.0 to 7.6% when using EOS calculator and not local guidelines based on AAP recommendations |
| Akangire et al., 2019 [36] | ≥ 34 weeks’ GA | Compared to current CDC/AAP guidelines, the EOS calculator-based approach yields a reduction of empiric antibiotic administration from 11.0 to 5.0% and blood culture use from 14.8 to 7.6% |
| Arora et al., 2019 [37] | ≥ 34 weeks’ GA infants admitted to NICU | Significant reduction in the rate of both antibiotic prescriptions (70.3% vs. 49.6%) and sepsis evaluations (90.9% vs. 68.8%) after implementation of the EOS calculator. 92% overlap in blood culture recommendations and 95% overlap between antibiotic recommendations when current CDC guidelines were compared to EOS calculator |
| Benaim et al., 2019 [11] | ≥ 34 weeks’ GA | Over the period of study, antibiotic administration decreased by 38.0% with updated local EOS guidelines. Reduction of antibiotic administration would have been 31.0% (for an EOS incidence of 0.6/1000) and 1.0% (for an EOS incidence of 2/1000) with the EOS calculator |
| Bridges et al., 2019 [38] | ≥ 37 weeks’ GA infants exposed to maternal CAM | Compared with 2010 CDC guidelines, 93.0% of patients were not admitted to the NICU and only 11.0% required laboratory evaluation; rates of exclusive breastfeeding increased from less than 10.0% to greater than 50.0% after implementation of the EOS calculator. The length of the NICU stay decreased from an average of 138 to 12 days with no negative consequences |
| Eason et al., 2019 [39] | ≥ 37 weeks’ GA infants with risk factors for EOS or suspected EOS | The percentage of infants screened with a suspected infection receiving 5 days of antibiotics reduced from 31.0% with NICE guidelines to 5.0% with EOS calculator. Clinically well infants with risk factors alone receiving 36 h of antibiotics, reduced from 63.0% with NICE guidelines to 3.0% with EOS calculator |
| Fowler et al., 2019 [40] | ≥ 34 weeks’ GA | 6 patients with culture-positive EOS were identified in the study period and recommendations from the calculator were in alignment with current CDC/AAP guidelines |
| Goel et al., 2019 [41] | ≥ 34 weeks’ GA | 16% of infants were started on antibiotics as per NICE recommendations compared with 4.3% with EOS calculator. There were seven positive blood cultures (three infants were recommended antibiotics by both, three were not identified in the asymptomatic stage by either; one was a contaminant) |
| Gong et al., 2019 [42] | ≥ 34 weeks’ GA infants exposed to maternal intrapartum fever | Compared to the CDC/AAP guidelines, the EOS calculator-based approach yields a net monetary benefit (3998 $ per infant), largely by preventing unnecessary antibiotic treatment (67.4% decrease in antibiotic use in the calculator arm) |
| Hershkovich-Shporen et al., 2019 [43] | ≥ 35 weeks’ GA newborns with the following inclusion criteria: treated with antibiotic, born to mothers with risk factors for EOS, born to mothers with clinical CAM or that received IAP | 15.0% of the patients received antibiotic treatment according to 2010 CDC recommendations; 8.0% of the patients would have received antibiotic treatment according to EOS calculator. Only 2/89 (2.25%) newborns treated for maternal clinical CAM according to 2010 CDC guidelines, had proven EOS. Three of the mothers whose newborn developed EOS, had no risk factors so there was no need for the EOS calculator |
| Joshi et al., 2019 [44] | ≥ 34 weeks’ GA well-appearing newborns exposed to maternal CAM | Compared to the CDC/AAP guidelines, the usage of the EOS calculator yields a reduction of empirical antibiotics administration from 100% of patients to 8.9% |
| Leonardi et al., 2019 [45] | ≥ 35 weeks’ GA newborns exposed to maternal CAM and/or intrapartum fever | 228/312 (73.1%) infants did not require admission to the NICU based on their risk assessment using the EOS calculator; according to local guidelines, all infants would have been admitted to the NICU for evaluation and treatment of presumed sepsis, regardless of clinical appearance. Breastfeeding rates at discharge were 89.0% for infants remaining with their mothers in the newborn nursery, and 37.0% for infants admitted to the NICU |
| Stipelman et al., 2019 [46] | ≥ 34 weeks’ GA infants exposed to maternal CAM | Reduction in antibiotics administration from 7.0% (according to CDC/AAP guidelines) to 1.0% after implementation of the EOS calculator. 2 missed cases of culture-positive EOS with EOS calculator |
| Benincasa et al., 2020 [47] | ≥ 34 weeks’ GA neonates who received EOS antibiotics according to the hospital’s current practice | 219/384 (57.0%) patients received antibiotics by EOS calculator and 64/384 (16.7%) by evaluation of clinical signs. All patients with positive blood culture were detected by both EOS calculator and clinical signs surveillance. Estimated costs were US$ 415.576 for EOS calculator and US$ 314.353 for evaluation of clinical signs |
| Morris et al., 2020 [48] | ≥ 34 weeks’ GA infants with EOS confirmed on blood or cerebrospinal fluid culture | Within 4 h of birth, antibiotics were recommended for 39/70 (55.7%) infants with NICE guidelines, compared with 27/70 (38.6%) with the EOS calculator. The 12 infants advised early treatment only by NICE guidelines remained well, only one showing mild symptoms after 4 h. Another 4 babies received antibiotics by 4 h outside NICE and EOS calculator guidance. The remaining 27 infants (38.6%) received antibiotics when symptomatic after 4 h. Only one infant who was unwell from birth, died. Both NICE guidelines and EOS calculator were poor in identifying EOS within 4 h; NICE guidelines were superior to the EOS calculator in identifying asymptomatic cases |
| Perez et al., 2020 [49] | ≥ 35 weeks’ GA | Compared to the current AAP guidelines, the usage of the EOS calculator yields 54.0% reduction in the number of infants undergoing sepsis workup evaluations and 51.0% decrease in the number of infants receiving antibiotics |
| van der Weijden et al., 2020 [50] | ≥ 34 weeks’ GA neonates at risk for EOS | Dutch guidelines recommended antibiotic treatment for 363/890 (40.8%) neonates versus 101/890 (11.3%) with EOS calculator (p < 0.01). Antibiotic treatment was recommended by both methods for 90/890 (10.1%) neonates, including 2 patients with positive blood culture |
CAM Chorioamnionitis, CBC Cell blood count, CRP C-reactive protein, EOS Early-onset sepsis, GA Gestational age, IAP Intrapartum antibiotic prophylaxis
The objective of our study was to compare the administration of antibiotics based on our local EOS guidelines derived from current evidence with the calculator’s recommendations in neonates born at ≥34 weeks’ GA.
reference link :https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7992929/
More information: Dustin D. Flannery et al, Delivery Characteristics and the Risk of Early-Onset Neonatal Sepsis, Pediatrics (2022). DOI: 10.1542/peds.2021-052900
