Management of Neonates Born at ≤34 6/7 Weeks' Gestation with Suspected Or Proven Early-Onset Bacterial Sepsis Karen M

CLINICAL REPORT

Guidance for the Clinician in Rendering Pediatric Care

≤ ’ Management of Neonates Born at 34 Karen M. Puopolo, MD, PhD, FAAP,a,b William E. Benitz, MD, FAAP,c Theoklis E. Zaoutis, MD, MSCE, FAAP,a, d COMMITTEE6/7 ONWeeks FETUS AND NEWBORN, GestationCOMMITTEE ON INFECTIOUS DISEASES With Suspected or Proven Early-Onset Bacterial Sepsis Early-onset sepsis (EOS) remains a serious and often fatal illness among abstract infants born preterm, particularly among newborn infants of the lowest gestational age. Currently, most preterm infants with very low birth weight are treated empirically with antibiotics for risk of EOS, often for prolonged aDepartment of Pediatrics, Perelman School of Medicine, University periods, in the absence of a culture-confirmed infection. Retrospective of Pennsylvania, Philadelphia, Pennsylvania; bChildren’s Hospital of studies have revealed that antibiotic exposures after birth are associated Philadelphia, and dRoberts Center for Pediatric Research, Philadelphia, Pennsylvania; and cDivision of Neonatal and Developmental Medicine, with multiple subsequent poor outcomes among preterm infants, making the Department of Pediatrics, School of Medicine, Stanford University, Palo risk/benefit balance of these antibiotic treatments uncertain. Gestational Alto, California age is the strongest single predictor of EOS, and the majority of preterm This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have births occur in the setting of other factors associated with risk of EOS, filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process making it difficult to apply risk stratification strategies to preterm infants. approved by the Board of Directors. The American Academy of Laboratory tests alone have a poor predictive value in preterm EOS. Delivery Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. characteristics of extremely preterm infants present an opportunity to Clinical reports from the American Academy of Pediatrics benefit from identify those with a lower risk of EOS and may inform decisions to initiate expertise and resources of liaisons and internal (AAP) and external or extend antibiotic therapies. Our purpose for this clinical report is to reviewers. However, clinical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations provide a summary of the current epidemiology of preterm neonatal sepsis or government agencies that they represent. and provide guidance for the development of evidence-based approaches to The guidance in this report does not indicate an exclusive course of sepsis risk assessment among preterm newborn infants. treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

DOI: https://doi.org/10.1542/peds.2018-2896 Antibiotics are administered shortly after birth to nearly all preterm Address correspondence to Karen M. Puopolo, MD, PhD, FAAP. E-mail: – [email protected] infants with very low birth weight (VLBW) (birth weight <1500 g) 1 4 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). because of the risk of early-onset sepsis (EOS).‍ ‍ ‍ Physicians are often reluctant to discontinue antibiotics once initiated for many reasons, including the relatively high risk of EOS among preterm infants and the To cite: Puopolo KM, Benitz WE, Zaoutis TE, AAP COMMITTEE relatively high rate of mortality attributable to infection.‍ Particularly ON FETUS AND NEWBORN, AAP COMMITTEE ON INFECTIOUS DISEASES. Management of Neonates Born at ≤34 6/7 Weeks’ among infants with VLBW, neonatal clinicians must determine which Gestation With Suspected or Proven Early-Onset Bacterial infants are most likely to have EOS when nearly all have some degree Sepsis. Pediatrics. 2018;142(6):e20182896 of respiratory or systemic instability.‍ Poor predictive performance of common laboratory tests and concerns regarding the unreliability Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 6, December 2018:e20182896 FROM THE AMERICAN ACADEMY OF PEDIATRICS of blood cultures add to the whereas studies from the early 1990s when these occur at the lowest difficulty in discriminating at-risk revealed10, rates11 of 19 to 32 per 1000 gestational ages; evidence suggests infants.‍ Because gestational age infants.‍ ‍ Improvements among that microbial-induced maternal is the strongest predictor of EOS VLBW incidence may be limited to inflammation –can initiate parturition and approximately two-thirds of those born at older gestational ages.‍ and elicit fetal inflammatory 5,15 18 preterm births are associated with No significant change over time responses.‍ ‍ ‍ Organisms isolated preterm labor, premature rupture was observed in a study of 34636 from the intrauterine compartment ’ of membranes (PROM),5 or clinical infants born from 1993 to 2012 at of women with preterm labor, PROM, chorioamnionitis, risk stratification 22 to 28 weeks gestation, with the or both are primarilyUreaplasma vaginal in strategies cannot be applied to reported incidence ranging8 from 20.‍5 origin and include low-virulence preterm newborn infants in the same to 24.‍4 per 1000 infants.‍ Morbidity species, such as , as manner as for term neonates.‍ and mortality from EOS remain well as anaerobicEscherichia species coli and well- PATHOGENESIS AND CURRENT substantial: 95% of preterm infants recognizedStreptococcus neonatal pathogens,– EPIDEMIOLOGY OF PRETERM with EOS require neonatal intensive such as 16 and18 group NEONATAL EOS care for respiratory distress and/or B Listeria (GBS).‍ monocytogenes‍ The blood pressure support, and 75% of isolation of maternal oral flora and,

deaths from6, EOS10 occur among infants more rarely, – , Preterm EOS is defined as a blood with VLBW.‍ ‍ The mortality rate suggests a transplacental16,18 20 pathway or cerebrospinal fluid (CSF) culture among those with EOS is an order of for some IAIs.‍ ‍ ‍ Inflammation obtained within 72 hours after birth magnitude higher among preterm inciting parturition may not, compared with term infants, whether however, always be attributable to that is growing a pathogenic bacterial ≥ – measured by gestational age (1.‍6% IAI.‍ Inflammation resulting from species.‍ This microbiological – definition stands in contrast to at 37 weeks, 30% at 25 28 weeks, immune-mediated rejection of the and approximately 50% at 22 24 fetal or placental compartment (from the functional definitions of sepsis 7,8, 10 ≥ used in pediatric and adult patients, weeks) ‍ ‍ or birth weight (3.‍5% maternal extrauterine infection), as for whom the definition is used to among those born at 15006 g vs 35% well as that incited by reproductive specify a series of time-sensitive for those born at <1500 g).‍ or nonreproductive microbiota, may interventions.‍ The current overall all contribute to the pathogenesis incidence of EOS in the United States The pathogenesis of preterm of preterm labor and PROM, is approximately 0.‍8 cases per 1000 EOS is complex.‍ EOS primarily complicating the interpretation of 6 “ 15,20 live births.‍ A disproportionate begins in utero and was originally placental pathology.‍ ‍ ” number of cases occur among infants described as the amniotic 12,13 RISK FACTORS FOR PRETERM EOS born preterm in a manner that is infection syndrome.‍ ‍ ‍ Among inversely proportional to gestational term infants, EOS pathogenesis age at birth.‍ The incidence of EOS is most commonly develops during ≥ ’ approximately 0.‍5 cases per 1000 labor and involves ascending Multiple clinical risk factors have ≤ infants born at 37 weeks gestation, colonization and infection of the been used to assess the risk of EOS ’ compared with approximately 1 case uterine compartment with maternal among infants born at 34 6/7 ’ per 1000 infants born at 34 to 36 gastrointestinal and genitourinary weeks gestation.‍ Univariate analyses ’ weeks gestation, 6 cases per 1000 flora, with subsequent colonization of risk factors for EOS among infants born at <34 weeks gestation, and invasive infection of the fetus preterm infants have been used to ’ 20 cases per 1000 infants born at <29 and/or fetal aspiration of infected identify gestational age, birth weight, ’ weeks gestation,– and 32 cases per amniotic fluid.‍ This intrapartum PROM and prolonged rupture of

1000 infants6 10 born at 22 to 24 weeks sequence may be responsible for EOS membranes (ROM), preterm onset gestation.‍ ‍‍ The incidence of EOS that develops after PROM or during of labor, maternal age and race, has declined among term infants over preterm labor that is induced for maternal intrapartum fever, mode the past 25 years, a change attributed maternal indications.‍ However, the of delivery, and administration to the implementation of evidence- pathogenesis of preterm EOS likely of intrapartum antibiotics to be based intrapartum antimicrobial begins before the onset of labor in associated with risk of EOS; however, therapy.‍ The impact of such therapies many cases of preterm labor and/or the independent contribution of any on preterm infants is less clear.‍ PROM.‍ Intraamniotic infection (IAI) specific factor other than gestational

Authors of the most recent studies may cause stillbirth14 in the second and age has been difficult to quantify.‍ For report an EOS incidence among third trimesters.‍ In approximately example, among term infants, there infants with VLBW ranging from 9 to 25% of cases, IAI is the cause of is a linear relationship between the 9 11 cases per 1000 infants with VLBW, preterm labor and PROM, particularly duration of ROM and the risk of EOS.‍ Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS

’ In contrast, the relationship between risk for EOS.‍ In a study of 15318 enterocolitis (NEC) before hospital PROM and the risk of EOS is not infants born at 22 to 28 weeks discharge were significantly more simply described by its occurrence or gestation, those born by cesarean likely to have received prolonged duration but modified by gestational delivery with membrane rupture empirical antibiotic therapy1 in the age as well as by the additional at delivery and without clinical first week after birth.‍ The authors presence of clinical chorioamnionitis– chorioamnionitis were significantly of the study estimated that the and the administration of latency17,21 24 less likely to have4 EOS or die before risk of NEC increased by 7% for and intrapartum antibiotics.‍ ‍ ‍‍ 12 hours of age.‍ The number needed each additional day of antibiotics These observations are likely related to treat for infants born in these administered in the absence of to uncertainty regarding the role of circumstances was approximately culture-confirmed EOS.‍ Authors of intrauterine infection and cervical 200; with the additional absence a single-center study of infants with structural defects in the24, pathogenesis25 of histologic chorioamnionitis, VLBW estimated that the risk of NEC of spontaneous PROM.‍ ‍ the number needed4 to treat is increased by 20% for each additional approximately 380.‍ Another study day of antibiotics administered in of 109 cases of EOS occurring among the absence of a culture-confirmed The clinical diagnosis of 31 chorioamnionitis has been used as 5313 infants with VLBW over a infection.‍ Authors of another study a primary risk factor for identifying 25-year period revealed that 97% of of 11669 infants with VLBW assessed infants at risk for EOS.‍ Most preterm– cases occurred in infants born with the overall rate of antibiotic use and infants with EOS are born to4,26 women29 some combination of PROM,29 preterm found that higher rates during the with this clinical diagnosis.‍ ‍ ‍ The labor, or concern for IAI.‍ In that first week after birth or during the American College of Obstetricians report, 2 cases of listeriosis occurred entire hospitalization were both and Gynecologists (ACOG) recently in the context of unexplained fetal associated with increased mortality, “ ” advocated for using the term distress in otherwise uncomplicated even when adjusted for multiple

intraamniotic infection rather pregnancies.‍ predictors33 of neonatal morbidity and than chorioamnionitis (which is ANTIBIOTIC STEWARDSHIP IN mortality.‍ One concern in each of primarily a histologic diagnosis) PRETERM EOS MANAGEMENT these studies is that some infants and published guidance for its30 categorized as uninfected may in fact have suffered from EOS.‍ Yet, diagnosis and management.‍ A ’ confirmed diagnosis of IAI is made Currently, most premature infants even among 5640 infants born at by a positive result on an amniotic with VLBW are treated empirically 22 to 28 weeks gestation at a lower fluid Gram-stain, culture, or placental with antibiotics for risk of EOS, risk for EOS, those who received histopathology.‍ Suspected IAI is often for prolonged periods, even in prolonged empirical antibiotic diagnosed by maternal intrapartum the absence of a culture-confirmed therapy during the first week after fever (either a single documented infection.‍ Prolonged empirical birth had higher rates of death and ≥ ° 4 maternal intrapartum temperature antibiotics are administered to bronchopulmonary dysplasia.‍ – ° of 39.‍0 C or a temperature of approximately 35% to 50% of Several explanations are possible 38.‍0 38.‍9 C that persists for >30 infants with– a low gestational age, for all of these findings, including minutes) and 1 or more of the with significant1 4 center-specific simply that physicians administer following: (1) maternal leukocytosis, variation.‍ ‍‍ Antibiotic drugs are the most antibiotics to the sickest (2) purulent cervical drainage, and administered for many reasons, infants.‍ Other potential mechanisms (3) fetal tachycardia.‍ The ACOG including the relatively high include the role of antibiotics in recommends that intrapartum incidence of EOS among preterm promoting dysbiosis of the gut, skin, antibiotics be administered infants, the relatively high rate of and respiratory tract, affecting the whenever IAI is diagnosed or mortality attributable to infection, interactions between colonizing flora suspected and when otherwise and the frequency of clinical in maintaining health and promoting unexplained maternal fever occurs instability after birth.‍ Empirical immunity; it is also possible during labor.‍ Chorioamnionitis or antibiotics administered to very that antibiotics and dysbiosis

IAI is strongly associated with EOS preterm infants in the first days after function as modulators34,35 of vascular in preterm infants, with a number– birth have been– associated with an development.‍ Although the full needed to treat of only 6 to4, 4026 29infants increased 1,risk4, 31 of33 subsequent poor relationship between early neonatal per case of confirmed EOS.‍ ‍ ‍‍ outcomes.‍ ‍ ‍ ‍ ‍ One multicenter antibiotic exposures and subsequent Conversely, the absence of clinical study of 4039 infants born from 1998 childhood health remains to be and histologic chorioamnionitis to 2001 with a birth weight of <1000 defined, current evidence suggests may be used to identify a group of g revealed that those infants who that such exposures do affect preterm preterm infants who are at a lower died or had a diagnosis of necrotizing infants.‍ Physicians should consider Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 6, December 2018 3 the risk/benefit balance of initiating who have severe systemic instability, sepsis evaluations performed at <72 antibiotic therapy for risk of EOS the administration of empirical hours of age.‍ Modern blood culture as well as for continuing empirical antibiotics may be reasonable but is systems use optimized enriched antibiotic therapy in the absence of a not mandatory.‍ culture media with antimicrobial culture-confirmed infection.‍ Infants in this category who are born neutralization properties, RISK CATEGORIZATION FOR PRETERM by vaginal or cesarean delivery after continuous-read detection systems, INFANTS efforts to induce labor and/or ROM and specialized pediatric culture before delivery are subject to factors bottles.‍ Although concerns have associated with the pathogenesis of been raised regarding incomplete Perhaps the greatest contributor EOS during delivery.‍ If any concern detection of low-level bacteremia to the nearly universal practice of for infection arises during the and the effects of intrapartum27,37 empirical antibiotic administration process of delivery, the infant should antibiotic administration, ‍ to preterm infants is the uncertainty be managed as recommended below these systems reliably detect in EOS risk assessment.‍ Because for preterm infants at a higher risk bacteremia at a level of 1 to 10 gestational age is the strongest for EOS.‍ Otherwise, an acceptable colony-forming units if a minimum predictor of EOS, and two-thirds of approach to these infants is to of 1 mL of blood is inoculated; preterm births are associated with obtain a blood culture and to initiate authors of several studies– report preterm labor, PROM, or clinical 5 antibiotic therapy for infants with no effect of intrapartum38 42 antibiotics concern for intrauterine infection, respiratory and/or cardiovascular on time to positivity.‍ ‍ ‍ Culture media containing antimicrobial risk stratification strategies cannot instabilityPreterm Infants after birth at Higher.‍ Risk for β be applied to preterm infants in the EOS neutralization elements efficiently same manner as for term neonates.‍ In neutralize -lactam39 antibiotics particular, the Neonatal Early-Onset and gentamicin.‍ A median blood ’ Sepsis Risk Calculator does not apply Infants born preterm because of culture time to positivity <24 hours is to infants 36born before 34 0/7 weeks cervical incompetence, preterm reported among– VLBW infants when gestation.‍ The objective of EOS risk labor, PROM, chorioamnionitis or using contemporary29,43 46 blood culture assessment among preterm infants is, IAI, and/or acute and otherwise techniques.‍ ‍ ‍ Pediatric blood therefore, to determine which infants unexplained onset of nonreassuring culture bottles generally require are at the lowest risk for infection fetal status are at the highest risk for a minimum of 1 mL of blood for47, 48 and who, despite clinical instability, EOS.‍ In these cases, IAI may be the optimal recovery of organisms.‍ may be spared administration cause of preterm birth or a secondary The use of 2 separate bottles of empirical antibiotics.‍ The complication of PROM and cervical may provide the opportunity to circumstances of preterm birth may dilatation.‍ IAI may also be the determine if commensal species are provide the best current approach to cause of unexplained fetal distress.‍ true infections49,50 by comparing growth EOSPreterm management Infants at for Lower preterm Risk infants for .‍ The most reasonable approach in the two.‍ ‍ Use of 1 aerobic EOS to these infants is to perform a and 1 anaerobic culture bottle may blood culture and start empirical optimizeE coli organism recovery.‍ Most antibiotic treatment.‍ Obtaining CSF Staphylococcusneonatal pathogens, Staphylococcusincluding Criteria for preterm infants to be for culture before the administration aureusGBS, , coagulase-negative considered at a lower risk for EOS of antibiotics should be considered if , and include the following: (1) obstetric the infant will tolerate the procedure , will grow in anaerobic indications for preterm birth (such and if it will not delay the initiation of conditions.‍ One study revealed that as maternal preeclampsia or other antibiotic therapy.‍ with routine use of both pediatric noninfectious medical illness or LABORATORY TESTING aerobic andBacteroides adult anaerobic fragilis blood placental insufficiency), (2) birth by cultures, strict anaerobic species cesarean delivery, and (3) absence Blood Culture (primarily ) of labor, attempts to induce labor, or were isolated in 16% of EOS cases29 any ROM before delivery.‍ Acceptable in preterm infants with VLBW.‍ An initial approaches to these infants In the absence of validated, clinically anaerobic blood culture is routinely might include (1) no laboratory available molecular diagnostic tests, a performed among adult patients evaluation and no empirical blood culture remains the diagnostic at risk for infection and can be antibiotic therapy, or (2) a blood standard for EOS.‍ Newborn surface used for neonatal blood cultures.‍ culture and clinical monitoring.‍ For cultures and gastric aspirate analysis Individual centers may benefit infants who do not improve after cannot be used to diagnose EOS, and from collaborative discussion with initial stabilization and/or those a urine culture is not indicated in the laboratory where cultures Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS are processed to optimize local of infection.‍ Most studies in which absence of a culture-confirmed CSFprocesses Culture.‍ the performance characteristics of infection.‍ the complete blood cell (CBC) count TREATMENT OF PRETERM EOS in predicting infection is addressed have been focused on term infants.‍ The incidence of meningitis is In 1 large multicenter study, the higher among preterm infants The microbiology of EOS in the – ’ authors assessed the relationship (approximately 0.‍7 cases per United States is largely unchanged between the WBC count and culture- 1000 live births at 22 28 weeks over the past 10 years.‍ Authors of 4 confirmed EOS and analyzed data E coli gestation) compared with the ’ national surveillance studies continue – separately for infants born at <34 incidence in the overall birth 56 to identify as the most common weeks gestation.‍ They found that population (approximately 0.‍02 0.‍04 bacteria isolated in EOS cases that 6,10 all components of the CBC count cases per 1000 live births).‍ ‍ In the occur among preterm infants, lacked sensitivity for predicting study of differential EOS risk among whether defined by a gestational age EOS.‍ The highest likelihood ratios E coli very preterm infants, meningitis did of <34 weeks or by a birth weight (LRs) for EOS were associated with not occur at all among lower-risk of <1500 g.‍ Overall, is isolated 4 extreme values.‍ A positive LR of >3 preterm infants.‍ The true incidence in approximately 50%, and GBS is (ie, a likelihood of infection at least 3 of meningitis among preterm infants ’ isolated in approximately 20% of all times higher than the entire group of ’ may be underestimated because of EOS cases occurring among infants infants born at <34 weeks gestation) 6 the common practice of performing a μ born at <34 weeks gestation.‍ was associated with a WBC count lumbar puncture after the initiation Fungal organisms are isolated in of <1000 cells per L, an absolute of empirical antibiotic therapy.‍ <1% of cases.‍ Approximately 10% neutrophil count of <1000, and an Although most preterm infants of cases are caused by other Gram- immature-to-total neutrophil ratio of with culture-confirmed early-onset μ positive organisms (predominantly >0.‍25.‍ A total WBC count of >50000 meningitis grow the same organism viridans group streptococci and cells per L (LR, 2.‍3) and a platelet from blood cultures, the concordance enterococci), and approximately count of <50000 (LR, 2.‍2) had a S aureus is not 100%, and CSF cell count 20% of cases are caused by other modest relationship to EOS.‍ – L parameters51 may not always identify Other Inflammatory Markers monocytogenesGram-negative organisms.‍ meningitis.‍ If a CSF culture has not (approximately 1% 2%) and been obtained before the initiation (approximately 1%) of empirical antibiotics, physicians are uncommon causes of preterm Other markers of inflammation, 4,6, 11 should balance the physiologic EOS.‍ ‍ ‍ If an anaerobic culture is including C-reactive protein (CRP), stability of the infant, the risk of EOS, routinely performed, strict anaerobic procalcitonin, interleukins (soluble and the potential harms associated bacteria are isolated in up to 15% interleukin 2 receptor, interleukin 6, B fragilis with prolonged antibiotic therapy α of EOS cases among preterm infants and interleukin 8), tumor necrosis when making the decision to perform – with VLBW, with being factor , and CD64 are addressed a lumbar puncture in preterm infants 57 60 the predominant anaerobic species in multiple studies.‍ ‍ ‍ Both CRP 29 who are critically ill.‍ isolated.‍ White Blood Cell Count and procalcitonin concentrations increase in newborn infants in Ampicillin and gentamicin are the response to a variety of inflammatory first choice for empirical therapy The white blood cell (WBC) count, stimuli, including infection, asphyxia, for EOS.‍ This combination will be differential (immature-to-total and pneumothorax.‍ Procalcitonin effective againstL monocytogenes GBS, most other neutrophil ratio), and absolute concentrations also increase streptococcal and enterococcalE coli neutrophil count are commonly naturally over the60 first 24 to 36 species, and .‍ used to assess risk of EOS.‍ Multiple hours after birth.‍ Single values of Although two-thirds of EOS clinical factors can affect the WBC CRP or procalcitonin obtained after isolates and most other Gram- count and differential,– including birth to assess the risk of EOS are negative EOS isolates are resistant gestational age at birth, sex, and neither sufficiently sensitive nor to ampicillin, the majority remain 52 55 β 6 mode of delivery.‍ ‍‍ Fetal bone specific to guide EOS care decisions.‍ sensitive to gentamicin.‍ Extended- marrow depression attributable to Consistently normal values of CRP spectrum, -lactamase-producing maternal preeclampsia or placental and procalcitonin over the first 48 organisms are only rarely reported insufficiency, as well as prolonged hours of age are associated with the among EOS cases in the United States.‍ exposure to inflammatory signals absence of EOS, but serial abnormal Therefore, the routine empirical use

(such as PROM), frequently result values alone should not be used of broader-spectrum antibiotics is 61 in abnormal values in the absence to extend antibiotic therapy in the not warranted and may be harmful.‍ Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number 6, December 2018 5 E coli

Nonetheless, 1% to 2% of cases maternal obstetric conditions known or placental insufficiency in the were resistant to both ampicillin and to affect fetal hematopoiesis.‍ absence of labor, attempts to gentamicin in recent surveillanceB fragilis PREVENTION STRATEGIES induce labor, or ROM before studies by the Centers for Disease delivery are at a relatively low Control and Prevention, and risk for EOS.‍ Depending on the is not uniformly6,62 sensitive to these The only proven preventive clinical condition of the neonate, medications.‍ ‍ Therefore, among strategy for EOS is the appropriate physicians should consider preterm infants who are severely administration of maternal the risk/benefit balance of an ill and at the highest risk for Gram- intrapartum antibiotic prophylaxis.‍ EOS evaluation and empirical negative EOS (such as infants with The most current recommendations ⚬⚬antibiotic therapy.‍ VLBW born after prolonged PROM from national organizations, Infants born preterm because of and infants exposed to prolonged – such as the AAP, ACOG, and maternal cervical incompetence, courses of antepartum antibiotic 63 65 Centers for Disease Control and preterm labor, PROM, clinical therapy ‍‍ ), the empirical addition Prevention, should be followed concern for IAI, or acute onset of broader-spectrum antibiotic for the administration of GBS of unexplained nonreassuring therapy may be considered until intrapartum prophylaxis as well as fetal status are at the highest risk culture results are available.‍ for the administration of intrapartum for EOS.‍ Such neonates should The choice of additional therapy antibiotic therapy when there undergo EOS evaluation with should be guided by local antibiotic is suspected or confirmed IAI.‍ a blood culture and empirical resistance data.‍ Neonatal practices are focused on the ⚬⚬antibiotic treatment.‍ When EOS is confirmed by a blood identification and empirical antibiotic treatment of preterm neonates Obstetric and neonatal care culture, a lumbar puncture should providers should communicate be performed if not previously done.‍ at risk for EOS; these practices cannot prevent EOS.‍ The empirical and document the circumstances Antibiotic therapy should use the of preterm birth to facilitate EOS narrowest spectrum of appropriate administration of intramuscular penicillin to all newborn infants to risk assessment among preterm agents once antimicrobial infants.‍ sensitivities are known.‍ The duration prevent neonatal, GBS-specific EOS is not justified and is not endorsed 3.‍ Clinical centers should consider of therapy should be guided byRed by the AAP.‍ Neither GBS intrapartum the development of locally Book:expert Report references of the (eg, Committee the American on antibiotic prophylaxis nor any appropriate written guidelines InfectiousAcademy ofDiseases Pediatrics [AAP] neonatal EOS practice will prevent for preterm EOS risk assessment ) and informed late-onset GBS infection or any other and clinical management.‍ After by the results of a CSF analysis and form of late-onset bacterial infection.‍ guidelines are implemented, the achievement of sterile blood Preterm infants are particularly ongoing surveillance, designed to and CSF cultures.‍ Consultation with susceptible to late-onset GBS identify low-frequency adverse infection, with approximately 40% infectious disease specialists should ≤ events and affirm efficacy, is of late-onset GBS cases occurring be considered for cases complicated ’ recommended.‍ among infants born at 34 6/7 by meningitis or other site-specific 66,67 4.‍ The diagnosis of EOS is made by a weeks gestation.‍ ‍ infections and for cases with complex blood or CSF culture.‍ EOS cannot SUMMARY POINTS antibiotic resistance patterns.‍ be diagnosed by laboratory tests alone, such as CBC count or CRP When initial blood culture results are levels.‍ negative, antibiotic therapy should 1.‍ The epidemiology, microbiology, be discontinued by 36 to 48 hours of and pathogenesis of EOS differ 5.‍ The combination of ampicillin incubation, unless there is evidence substantially between term infants and gentamicin is the most of site-specific infection.‍ Persistent and preterm infants≤ with VLBW’ .‍ appropriate empirical antibiotic cardiorespiratory instability is regimen for infants at risk for common among infants with VLBW 2.‍ Infants born at 34 6/7 weeks EOS.‍ Empirical administration and is not alone an indication for gestation can be categorized of additional broad-spectrum prolonged empirical antibiotic by level of risk for EOS by the antibiotics may be indicated in circumstances of their preterm administration.‍ Continuing empirical ⚬⚬ preterm infants who are severely antibiotic administration in response birth.‍ ill and at a high risk for EOS, to laboratory test abnormalities alone Infants born preterm by particularly after prolonged is rarely justified, particularly among cesarean delivery because of antepartum maternal antibiotic preterm infants born in the setting of maternal noninfectious illness treatment.‍ Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS Wanda Barfield, MD, MPH, CAPT USPHS– Centers Karen M. Farizo, MD – US Food and Drug for Disease Control and Prevention Administration 6.‍ When blood cultures are sterile, Erin Keels, MS, APRN, NNP-BC – National Marc Fischer, MD, FAAP – Centers for Disease antibiotic therapy should be Association of Neonatal Nurses Control and Prevention Natasha Halasa, MD, MPH, FAAP Pediatric discontinued by 36 to 48 hours of – STAFF Infectious Diseases Society incubation, unless there is clear Nicole Le Saux, MD – Canadian Pediatric Society Jim Couto, MA evidence of site-specific infection.‍ Scot Moore, MD, FAAP – Committee on Practice Persistent cardiorespiratory Ambulatory Medicine COMMITTEE ON INFECTIOUS DISEASES, instability is common among Angela K. Shen, ScD, MPH – National Vaccine 2017–2018 Program Office preterm infants with VLBW and is Carrie L. Byington, MD, FAAP, Chairperson Neil S. Silverman, MD – American College of not alone an indication for prolonged Yvonne A. Maldonado, MD, FAAP, Vice Chairperson Obstetricians and Gynecologists empirical antibiotic administration.‍ Ritu Banerjee, MD, PhD, FAAP James J. Stevermer, MD, MSPH, FAAFP – American Laboratory test abnormalities Elizabeth D. Barnett, MD, FAAP Academy of Family Physicians alone rarely justify prolonged James D. Campbell, MD, MS, FAAP Jeffrey R. Starke, MD, FAAP – American Thoracic Society empirical antibiotic administration, Jeffrey S. Gerber, MD, PhD, FAAP Ruth Lynfield, MD, FAAP Kay M. Tomashek, MD, MPH, DTM – National particularly among preterm infants Flor M. Munoz, MD, MSc, FAAP Institutes of Health at a lower risk for EOS.‍ LEAD AUTHORS Dawn Nolt, MD, MPH, FAAP STAFF Ann-Christine Nyquist, MD, MSPH, FAAP Karen M. Puopolo, MD, PhD, FAAP Sean T. O Leary, MD, MPH, FAAP Jennifer M. Frantz, MPH William E. Benitz, MD, FAAP ’ Mobeen H. Rathore, MD, FAAP Theoklis E. Zaoutis, MD, MSCE, FAAP Mark H. Sawyer, MD, FAAP ABBREVIATIONS COMMITTEE ON FETUS AND NEWBORN, William J. Steinbach, MD, FAAP Tina Q. Tan, MD, FAAP 2017 2018 – Theoklis E. Zaoutis, MD, MSCE, FAAP James Cummings, MD, Chairperson AAP: American Academy of Sandra Juul, MD EX OFFICIO Ivan Hand, MD Pediatrics Eric Eichenwald, MD David W. Kimberlin, MD, FAAP – Red Book Editor ACOG: American College of Brenda Poindexter, MD Michael T. Brady, MD, FAAP – Red Book Associate Obstetricians and Editor Dan L. Stewart, MD Gynecologists Mary Anne Jackson, MD, FAAP – Red Book Susan W. Aucott, MD CBC: complete blood cell Karen M. Puopolo, MD, PhD, FAAP Associate Editor Jay P. Goldsmith, MD Sarah S. Long, MD, FAAP – Red Book Associate CRP: C-reactive protein Kristi Watterberg, MD, Immediate Past Editor CSF: cerebrospinal Streptococcus fluid Chairperson Henry H. Bernstein, DO, MHCM, FAAP – Red Book EOS: early-onset sepsis Online Associate Editor GBS: group B LIAISONS H. Cody Meissner, MD, FAAP – Visual Red Book Associate Editor IAI: intraamniotic infection Kasper S. Wang, MD – American Academy of LR: likelihood ratio Pediatrics Section on Surgery NEC: necrotizing enterocolitis Thierry Lacaze, MD Canadian Paediatric Society LIAISONS – PROM: premature rupture of Joseph Wax, MD – American College of Amanda C. Cohn, MD, FAAP – Centers for Disease Obstetricians and Gynecologists Control and Prevention membranes Tonse N.K. Raju, MD, DCH – National Institutes of Jamie Deseda-Tous, MD – Sociedad ROM: rupture of membranes Health Latinoamericana de Infectología Pediátrica VLBW: very low birth weight WBC: white blood cell

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics. or g/cgi/doi/10. 1542/peds.2018-2894.

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