Adverse short- and long-term outcomes among infants with mild neonatal encephalopathy.

BACKGROUND: Studies in newborns with mild neonatal encephalopathy (mNE) demonstrated normal outcomes, but recent literature suggests otherwise. METHODS: This retrospective cohort study examined inborn infants between 2014 and 2017. Biochemical and clinical characteristics determined the presence of NE and an encephalopathy score categorized infants as Definite or Possible mNE. An Unexposed control group consisted of newborns not meeting the inclusion criteria. Long-term outcomes assessed included cerebral palsy, seizures, developmental disorder, and motor and speech delay. The association of mNE with seizure disorder by 3 years of age was assessed with logistic regression and developmental disorders with Cox proportional hazards models. RESULTS: Of the 156,501 births, we identified 130 with Definite mNE and 445 with Possible mNE (0.8 and 2.8 per 1000 births, respectively). Both groups had significantly higher rates of any developmental disorder and motor and speech delay when compared to the Unexposed (p < 0.05, except for p = 0.07 for motor delay in the Possible NE group). The Definite mNE group had higher rates of developmental disorder and motor and speech delay when compared to the Unexposed with hazard ratios (95% CI) 2.0 (1.2-3.2), 3.7 (1.5-8.8), and 2.1 (1.3-3.5), respectively. CONCLUSIONS: An estimate of short- and long-term consequences of mNE suggests that there may be a higher risk of adverse outcome. IMPACT: Infants with mild NE are at significant risk for adverse short- and long-term outcomes. The risk of having an abnormal long-term outcome at 3 years of age were doubled in the mild NE group compared to the Unexposed group. Randomized clinical trials are needed as neuroprotective strategies may mitigate these.

A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma.

T-cell-mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and multiple myeloma (MM) remains an incurable disease. G-protein-coupled receptor class 5 member D (GPRC5D) is expressed in MM and smoldering MM patient plasma cells. Here, we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T-cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models, which coincide with T-cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow, which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy, and JNJ-64407564 is currently being evaluated in a phase 1 clinical trial in patients with relapsed or refractory MM (NCT03399799).

A simplified CD34+ based preharvest prediction tool for HPC(A) collection.

BACKGROUND: Hematopoietic stem cell transplantation is an important treatment that is dependent on the collection of sufficient CD34+ hematopoietic progenitor cells. The peripheral blood CD34 count (PB CD34+ counts) measured by flow cytometry can be used in predicting CD34+ stem cell yields hours before the completion of collection. Previously described formulas to predict the yield have used many different variables. As such, there is currently no consensus on an industry-standard algorithm or formula. STUDY DESIGN AND METHODS: Retrospective reviews of same-day PB CD34+ counts and the ensuing absolute CD34+ yields of mobilized donors (allogeneic and autologous) were used to develop and validate a formula using regression analysis to predict the CD34+ stem cell yield. A metric of prediction correlation, using root mean square error (RMSE), was used to assess the robustness of our prediction formula in addition to comparisons with two other published formulas, as well as subset analysis. RESULTS: A formula in the form of y = mxb with r = 0.95 and 95% confidence intervals was generated and validated. The ratio of actual to predicted yield demonstrated a high correlation coefficient (r = 0.96) with linear regression and overall RMSE of 228.4, which was lower than the two prior studies (calculated RMSE = 330.8 and 405.2). Subset analyses indicated male patients, lymphoma patients, and patients >60 years of age demonstrated lower RMSEs. CONCLUSION: We have demonstrated a simple yet robust formula that can be used prospectively to accurately predict the CD34+ stem cell yield in both autologous and allogeneic donors, which also accounts for recipient weight.

Evaluation of peripheral blood mononuclear cell collection by leukapheresis.

BACKGROUND: Adoptive immunotherapy using engineered lymphocytes has shown promising results in treating cancers even in patients who have failed other treatments. As the first essential step, the number of peripheral mononuclear cell (MNC) collection procedures is rapidly increasing. In this retrospective study, we reviewed the collection results to determine factors that affect MNC collection. STUDY DESIGN AND METHODS: We reviewed 184 collections that were performed on 169 adult allogenic donors and patients with acute lymphoid leukemia, chronic lymphoid leukemia, lymphoma, multiple myeloma, or solid-organ tumors. All the leukapheresis procedures were performed after a complete cell count with differential was obtained. Total blood volume (TBV) was defined as processed blood volume divided by patient blood volume. RESULTS: There was a significant association between the precollection MNC count (pre-MNC) and the MNC yields normalized by TBV (r = 0.926; p < 0.001) and a regression formula was created to predict MNC yields. Multiple regression analyses showed that pre-MNC, TBV, and precollection hemoglobin were strongly associated with MNC yield (R 2 = 0.866; F (3180) = 388.472; p < 0.001), and pre-MNC had the greatest influence on MNC yield (ß = 0.960; p < 0.001) followed by TBV (ß = 0.302; p < 0.001), and Hgb (ß = 0.136; p < 0.001). CONCLUSION: Our results suggest that the optimal time for MNC collection can be determined based on pre-MNC and that processing volume should be determined based on collection goal and pre-MNC to optimize and personalize the harvesting procedure.

Automated early detection of obstetric complications: theoretic and methodologic considerations.

Compared with adults who are admitted to general medical-surgical wards, women who are admitted to labor and delivery services are at much lower risk of experiencing unexpected critical illness. Nonetheless, critical illness and other complications that put either the mother or fetus at risk do occur. One potential approach to prevention is to use automated early warning systems, such as those used for nonpregnant adults. Predictive models that use data extracted in real time from electronic records constitute the cornerstone of such systems. This article addresses several issues that are involved in the development of such predictive models: specification of temporal characteristics, choice of denominator, selection of outcomes for model calibration, potential uses of existing adult severity of illness scores, approaches to data processing, statistical considerations, validation, and options for instantiation. These have not been addressed explicitly in the obstetrics literature, which has focused on the use of manually assigned scores. In addition, this article provides some results from work in progress to develop 2 obstetric predictive models with the use of data from 262,071 women who were admitted to a labor and delivery service at 15 Kaiser Permanente Northern California hospitals between 2010 and 2017.

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants.

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996-2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November-March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants' protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines.

Accuracy of international classification of diseases, ninth revision, codes for postpartum hemorrhage among women undergoing cesarean delivery.

BACKGROUND: Determining the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes for postpartum hemorrhage (PPH) is vital for reaching valid conclusions about the epidemiology of PPH. Our primary objectives were to assess the performance characteristics of ICD-9 PPH codes against a reference standard using estimated blood loss (EBL) among a cohort undergoing Cesarean delivery. STUDY DESIGN AND METHODS: We analyzed maternal discharge and EBL data from women who underwent Cesarean delivery at Kaiser Permanente Northern California facilities between 2010 and 2013. We defined PPH as an EBL of at least 1000 mL. In a secondary analysis, ICD-9 performance characteristics were assessed using an EBL of at least 1500 mL to classify severe PPH. RESULTS: We identified 35,614 hospitalizations for Cesarean delivery. Using EBL of at least 1000 mL as the "gold standard," PPH codes had a sensitivity of 27.8%, specificity of 97%, positive predictive value (PPV) of 74.5%, and a negative predictive value (NPV) of 80.9%. The prevalence of a PPH code (9%) was lower than the prevalence using a blood loss of at least 1000 mL (24%). Using a reference standard of EBL of at least 1500 mL, PPH codes had a sensitivity of 61.7%, specificity of 93.8%, PPV of 34.2%, and NPV of 97.9%. CONCLUSION: PPH ICD-9 codes have high specificity, moderately high PPVs and NPVs, and low sensitivity. An EBL of at least 1500 mL as a reference standard has higher sensitivity. Our findings suggest that, for women undergoing Cesarean delivery, quality improvement efforts are needed to enhance PPH ICD-9 coding accuracy in administrative data sets.

Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV-related hospitalizations and has been associated with decreased wheezing in the first years of life. OBJECTIVE: We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma. METHODS: We conducted a retrospective cohort investigation including children born from 1996-2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma-specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]-adjusted and PS-matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. RESULTS: By using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS-matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50-0.78). CONCLUSIONS: This investigation of RSV immunoprophylaxis in high-risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high-risk children.

Patterns and predictors of severe postpartum anemia after Cesarean section.

BACKGROUND: Postpartum anemia is associated with maternal and perinatal morbidity. Population-level data may inform guideline development for postpartum anemia screening. Our objectives were to evaluate the associations between potential predictors (predelivery anemia and postpartum hemorrhage [PPH]) with severe postpartum anemia after Cesarean section. STUDY DESIGN AND METHODS: Data were collected from 70,939 hospitalizations for Cesarean section performed at Kaiser Permanente Northern California facilities between 2005 and 2013. Severe postpartum anemia was defined as a hemoglobin (Hb) level of less than 8 g/dL before hospital discharge. Using multivariable logistic regression, we assessed the associations between predelivery anemia and PPH with severe postpartum anemia. Distributions of these characteristics among women with severe postpartum anemia were evaluated. RESULTS: The overall rate of severe postpartum anemia was 7.3% (95% confidence interval [CI], 7.1%-7.4%). Severe postpartum anemia was strongly associated with a predelivery Hb level between 10 and 10.9 g/dL (adjusted odds ratio [aOR], 5.4; 95% CI, 4.89-5.91), predelivery Hb level of less than 10 g/dL (aOR, 30.6; 95% CI, 27.21-34.6), and PPH (aOR, 8.45; 95% CI, 7.8-9.16). The proportions of women with severe postpartum anemia were highest for those experiencing PPH but no predelivery anemia (12.2%; 95% CI, 11.0%-13.6%) and those who did not incur PPH nor predelivery anemia (10.7%; 95% CI, 9.6%-12.0%). CONCLUSIONS: Our findings suggest that PPH and predelivery anemia are strong independent risk factors for severe postpartum anemia. Optimization of patients' Hb before delivery may reduce the incidence of severe anemia after Cesarean section.

Prevalence and neonatal factors associated with autism spectrum disorders in preterm infants.

OBJECTIVES: To determine the prevalence of autism spectrum disorders (ASD) across gestational age, examine the risk of ASD by gestational age controlling for other risk factors, and identify potential risk factors in the neonatal intensive care unit. STUDY DESIGN: A retrospective cohort of infants born at ≥ 24 weeks between January 1, 2000, and December 31, 2007 at 11 Kaiser Permanente Northern California hospitals (n = 195,021). ASD cases were defined by a diagnosis made at a Kaiser Permanente ASD evaluation center, by a clinical specialist, or by a pediatrician. Cox proportional hazards regression models were used to evaluate the association between gestational age and ASD as well as potential risk factors in the neonatal intensive care unit and ASD. RESULTS: The prevalence of ASD in infants <37 weeks was 1.78% compared with 1.22% in infants born ≥ 37 weeks (P < .001). Compared with term infants, infants born at 24-26 weeks had an adjusted hazard ratio (HR) for a diagnosis of ASD of 2.7 (95% CI 1.5-5.0). Infants born at 27-33 weeks (adjusted HR 1.4, 95% CI 1.1-1.8) and 34-36 weeks (adjusted HR 1.3, 95% CI 1.1-1.4) were also at increased risk. High frequency ventilation and intracranial hemorrhage were associated with ASD in infants < 34 weeks. CONCLUSIONS: ASD was ~ 3 times more prevalent in infants <27 weeks compared with term infants. Each week of shorter gestation was associated with an increased risk of ASD. High frequency ventilation and intracranial hemorrhage were associated with ASD among infants <34 weeks.

Novel endosomolytic poly(amido amine) polymer conjugates for systemic delivery of siRNA to hepatocytes in rodents and nonhuman primates.

The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of, and siRNA delivery to, specific cell types. Among recently reported delivery approaches, polymers with amphipathic properties have been used to enable endosome escape and cytosolic delivery. Here, we describe a linear amphipathic poly(amido amine) polymer conjugate system for the efficient siRNA delivery in vitro and in vivo. This polymer contains a novel amine bearing bis-acrylamide monomer designed for increasing amine density, which resulted in substantial improvement in liver uptake and RNAi activity compared to our previously reported poly(amido amine disulfide) polymer.1 The activity for this liver targeted delivery system was demonstrated in rodents and nonhuman primates.

Endosomolytic bioreducible poly(amido amine disulfide) polymer conjugates for the in vivo systemic delivery of siRNA therapeutics.

Efficient siRNA delivery is dependent not only on the ability of the delivery vehicle to target a specific organ but also on its ability to enable siRNA entry into the cytoplasm of the target cells. Polymers with endosomolytic properties are increasingly being used as siRNA delivery vehicles due to their potential to facilitate endosomal escape and intracellular delivery. Addition of disulfide bonds in the backbone of these polymers was expected to provide degradability through reduction by glutathione in cytosol. This paper describes the synthesis of new endosomolytic bioreducible poly(amido amine disulfide) polymers whose lytic potential can be masked at physiological pH, but can be restored at acidic endosomal pH. These polymer conjugates gave good in vitro knockdown (KD) and did not demonstrate cytotoxicity in a MTS assay. Efficient mRNA KD for apolipoprotein B in mouse liver was observed with these polyconjugates following intravenous dosing.

Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing. METHODS: A retrospective cohort study examined children born at ≥32 weeks gestation between 1996-2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. RESULTS: The study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32-33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03-1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49-4.50). CONCLUSIONS: Laboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.

NICU Versus Mother/Baby Unit Admission for Low-Acuity Infants Born at 35 Weeks' Gestation.

OBJECTIVES: To estimate the effect of NICU admission of low-acuity infants born at 35 weeks' gestation versus care in a mother/baby unit, on inpatient and outpatient medical outcomes. METHODS: This retrospective cohort study included 5929 low-acuity infants born at 350/7 to 356/7 weeks' gestation at 13 Kaiser Permanente Northern California hospitals with level II or level III NICUs between January 1, 2011, and December 31, 2021. Exclusion criteria included congenital anomalies and early respiratory support or antibiotics. We used multivariable regression and regression discontinuity analyses to control for confounding variables. RESULTS: Infants admitted to the NICU within 2 hours of birth (n = 862, 14.5%) had a 58 hour adjusted (98-hour unadjusted) longer length of stay. NICU admission was associated with an increased probability of a length of stay ≥96 hours (67% vs 21%; adjusted odds ratio [aOR], 4.94; 95% confidence interval [CI], 3.96-6.16). Regression discontinuity results suggested a similar (57 hour) increase in length of stay. Readmission risk, primarily for jaundice, was lower for those admitted to the NICU (3% vs 6%; aOR, 0.43; 95% CI, 0.27-0.69). Infants admitted to the NICU were slightly less likely to be receiving exclusive breast milk at 6-month follow-up (15% vs 25%; aOR, 0.73; 95% CI, 0.55-0.97; adjusted marginal risk difference -5%). CONCLUSIONS: Admitting low-acuity infants born at 35 weeks' gestation to the NICU was associated with decreased readmission, but with longer length of stay and decreased exclusive breast milk feeding at 6 months. Routine NICU admission may be unnecessary for low-acuity infants born at 35 weeks' gestation.

Independent Impact of Eat, Sleep, Console Assessment on Neonatal Opioid Withdrawal Syndrome.

Compared with the Finnegan Neonatal Abstinence Scoring System (FNASS), the Eat, Sleep, Console (ESC) approach reduces pharmacotherapy and length of stay (LOS) for neonatal opioid withdrawal syndrome (NOWS) infants. The independent outcome contribution of ESC is unknown as the approach combines ESC assessment with additional management changes. Our objective was to evaluate ESC assessment's independent impact on outcomes compared with FNASS. We conducted a retrospective cohort study of in utero opioid-exposed infants ≥35 weeks gestation managed with FNASS versus ESC. Outcomes included pharmacotherapy initiation, LOS, length of pharmacotherapy, and emergency department visit/readmissions. Among 151 FNASS and 100 ESC managed infants, pharmacotherapy initiation (P = .47), LOS for all infants (P = .49), and LOS for pharmacologically treated infants (P = .68) were similar. Length of pharmacotherapy did not differ (P = .84). Emergency department evaluation/NOWS readmission was equally rare (P = .65). Using equivalent models of care, comparison of ESC and FNASS assessment tools showed no difference in NOWS outcomes.

Accuracy of diagnostic codes for prenatal opioid exposure and neonatal opioid withdrawal syndrome.

OBJECTIVE: Determine the accuracy of diagnostic codes in identifying Prenatal Opioid Exposure (POE) and Neonatal Opioid Withdrawal Syndrome (NOWS). STUDY DESIGN: A cross-sectional study of 374,222 mother-infant dyads with delivery from 01/01/2010 to 12/31/2019. We ascertained maternal diagnostic codes for opioid use during pregnancy and infant diagnostic codes for drug exposure and withdrawal. We assessed sensitivity and positive predictive value (PPV) for POE and NOWS, defined using laboratory, pharmacy, and clinical data. RESULTS: Maternal codes had low sensitivity (36.4%) and PPV (34.7%) for POE. Infant codes for drug exposure were neither sensitive for POE (14%) nor NOWS (31.6%) and had low PPV. Codes for newborn withdrawal had low sensitivity (31.6%) for detecting NOWS, but high PPV (85%). Sensitivity improved (95.1%) for NOWS requiring pharmacologic treatment. CONCLUSIONS: Diagnostic codes identify POE and NOWS poorly. Improved case identification would include pharmacy and laboratory results, and clearly defined criteria for evidence of withdrawal.

Pyridyl aminothiazoles as potent Chk1 inhibitors: optimization of cellular activity.

Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.

Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates.

Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.

Time to positivity of blood cultures in neonatal late-onset bacteraemia.

OBJECTIVE: To determine the time to positivity (TTP) of blood cultures among infants with late-onset bacteraemia and predictors of TTP >36 hours. DESIGN: Retrospective cohort study. SETTING: 16 birth centres in two healthcare systems. PATIENTS: Infants with positive blood cultures obtained >72 hours after birth. OUTCOME: The main outcome was TTP, defined as the time interval from specimen collection to when a neonatal provider was notified of culture growth. TTP analysis was restricted to the first positive culture per infant. Patient-specific and infection-specific factors were analysed for association with TTP >36 hours. RESULTS: Of 10 235 blood cultures obtained from 3808 infants, 1082 (10.6%) were positive. Restricting to bacterial pathogens and the first positive culture, the median TTP (25th-75th percentile) for 428 cultures was 23.5 hours (18.4-29.9); 364 (85.0%) resulted in 36 hours. Excluding coagulase-negative staphylococci (CoNS), 275 of 294 (93.5%) cultures were flagged positive by 36 hours. In a multivariable model, CoNS isolation and antibiotic pretreatment were significantly associated with increased odds of TTP >36 hours. Projecting a 36-hour empiric duration at one site and assuming that all negative evaluations were associated with an empiric course of antibiotics, we estimated that 1164 doses of antibiotics would be avoided in 629 infants over 10 years, while delaying a subsequent antibiotic dose in 13 infants with bacteraemia. CONCLUSIONS: Empiric antibiotic administration in late-onset infection evaluations (not targeting CoNS) can be stopped at 36 hours. Longer durations (48 hours) should be considered when there is pretreatment or antibiotic therapy is directed at CoNS.