Management of Neonates with Suspected Or Proven Early-Onset Bacterial Sepsis

Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis

Richard A. Polin, MD and the COMMITTEE ON FETUS AND abstract NEWBORN With improved obstetrical management and evidence-based use of KEY WORDS intrapartum antimicrobial therapy, early-onset neonatal sepsis is be- early-onset sepsis, antimicrobial therapy, group B streptococcus, meningitis, gastric aspirate, tracheal aspirate, chorioamnionitis, coming less frequent. However, early-onset sepsis remains one of the sepsis screen, blood culture, lumbar puncture, urine culture, most common causes of neonatal morbidity and mortality in the pre- body surface cultures, white blood count, acute phase reactants, term population. The identification of neonates at risk for early-onset prevention strategies sepsis is frequently based on a constellation of perinatal risk factors ABBREVIATIONS fi CFU—colony-forming units that are neither sensitive nor speci c. Furthermore, diagnostic tests CRP—C-reactive protein for neonatal sepsis have a poor positive predictive accuracy. As a result, CSF—cerebrospinal fluid clinicians often treat well-appearing infants for extended periods of time, GBS—group B streptococci — even when bacterial cultures are negative. The optimal treatment of I/T immature to total neutrophil (ratio) PMN—polymorphonuclear leukocyte infants with suspected early-onset sepsis is broad-spectrum antimicro- PPROM—preterm premature rupture of membranes bial agents (ampicillin and an aminoglycoside). Once a pathogen is iden- This document is copyrighted and is property of the American tified, antimicrobial therapy should be narrowed (unless synergism is Academy of Pediatrics and its Board of Directors. All authors needed). Recent data suggest an association between prolonged empir- have filed conflict of interest statements with the American ≥ Academy of Pediatrics. Any conflicts have been resolved through ical treatment of preterm infants ( 5 days) with broad-spectrum anti- a process approved by the Board of Directors. The American biotics and higher risks of late onset sepsis, necrotizing enterocolitis, Academy of Pediatrics has neither solicited nor accepted any and mortality. To reduce these risks, antimicrobial therapy should be commercial involvement in the development of the content of discontinued at 48 hours in clinical situations in which the probability this publication. of sepsis is low. The purpose of this clinical report is to provide a The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. practical and, when possible, evidence-based approach to the manage- Variations, taking into account individual circumstances, may be ment of infants with suspected or proven early-onset sepsis. Pediatrics appropriate. 2012;129:1006–1015

INTRODUCTION “Suspected sepsis” is one of the most common diagnoses made in the NICU.1 However, the signs of sepsis are nonspecific, and inflammatory syndromes of noninfectious origin mimic those of neonatal sepsis. Most infants with suspected sepsis recover with supportive care (with or without initiation of antimicrobial therapy). The challenges for clinicians www.pediatrics.org/cgi/doi/10.1542/peds.2012-0541 are threefold: (1) identifying neonates with a high likelihood of sepsis doi:10.1542/peds.2012-0541 promptly and initiating antimicrobial therapy; (2) distinguishing “high- All clinical reports from the American Academy of Pediatrics risk” healthy-appearing infants or infants with clinical signs who do not automatically expire 5 years after publication unless reaffirmed, require treatment; and (3) discontinuing antimicrobial therapy once revised, or retired at or before that time. sepsis is deemed unlikely. The purpose of this clinical report is to PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). provide a practical and, when possible, evidence-based approach to the Copyright © 2012 by the American Academy of Pediatrics diagnosis and management of early-onset sepsis, defined by the Na- tional Institute of Child Health and Human Development and Vermont Oxford Networks as sepsis with onset at ≤3daysofage.

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PATHOGENESIS AND most of these women with histologic The major risk factors for early-onset EPIDEMIOLOGY OF EARLY-ONSET chorioamnionitis do not have a positive neonatal sepsis are preterm birth, SEPSIS placental culture.3 The incidence of clin- maternal colonization with GBS, rupture of membranes >18 hours, and mater- Before birth, the fetus optimally is ical chorioamnionitis varies inversely nal signs or symptoms of intra-amniotic maintained in a sterile environment. with gestational age. In the National infection.14–16 Other variables include Organisms causing early-onset sepsis Institute of Child Health and Human ethnicity (ie, black women are at higher ascend from the birth canal either Development Neonatal Research Net- risk of being colonized with GBS), low when the amniotic membranes rupture work, 14% to 28% of women delivering ’ socioeconomic status, male sex, and or leak before or during the course of preterm infants at 22 through 28 weeks low Apgar scores. Preterm birth/low labor, resulting in intra-amniotic infec- gestation exhibited signs compatible 4 birth weight is the risk factor most tion.2 Commonly referred to as “cho- with chorioamnionitis. The major risk closely associated with early-onset sep- rioamnionitis,” intra-amniotic infection factors for chorioamnionitis include sis.17 Infant birth weight is inversely indicates infection of the amniotic fluid, low parity, spontaneous labor, longer related to risk of early-onset sepsis. membranes, placenta, and/or decidua. length of labor and membrane rupture, multiple digital vaginal examinations The increased risk of early-onset sep- Group B streptococci (GBS) can also (especially with ruptured membranes), sis in preterm infants is also related to enter the amniotic fluid through occult meconium-stained amniotic fluid, internal complications of labor and delivery tears. Chorioamnionitis is a major risk fetal or uterine monitoring, and pres- and immaturity of innate and adaptive factor for neonatal sepsis. Sepsis can immunity.18 begin in utero when the fetus inhales ence of genital tract microorganisms 5 or swallows infected amniotic fluid. (eg, Mycoplasma hominis). The neonate can also develop sepsis in At term gestation, less than 1% of DIAGNOSTIC TESTING FOR SEPSIS the hours or days after birth when women with intact membranes will The clinical diagnosis of sepsis in the colonized skin or mucosal surfaces are have organisms cultured from amni- neonate is difficult, because many of compromised. The essential criterion otic fluid.6 The rate can be higher if the signs of sepsis are nonspecific and for the clinical diagnosis of chorio- the integrity of the amniotic cavity is are observed with other noninfectious amnionitis is maternal fever. Other compromised by procedures before conditions. Although a normal physical criteria are relatively insensitive. When birth (eg, placement of a cerclage or examination is evidence that sepsis is defining intra-amniotic infection (cho- amniocentesis).6 Inwomenwithpre- not present,19,20 bacteremia can occur rioamnionitis) for clinical research term labor and intact membranes, the in the absence of clinical signs.21 Avail- studies, the diagnosis is typically based rate of microbial invasion of the amni- able diagnostic testing is not helpful in on the presence of maternal fever of otic cavity is 32%, and if there is pre- deciding which neonate requires em- greater than 38°C (100.4°F) and at least term premature rupture of membranes pirical antimicrobial therapy but can two of the following criteria: maternal (PPROM), the rate may be as high as assist with the decision to discontinue leukocytosis (greater than 15 000 cells/ 75%.7 Many of the pathogens recovered treatment.22 mm3), maternal tachycardia (greater from amniotic fluidinwomenwithpre- than 100 beats/minute), fetal tachycar- term labor or PPROM (eg, Ureaplasma Blood Culture dia (greater than 160 beats/minute), species or Mycoplasma species) do A single blood culture in a sufficient uterine tenderness, and/or foul odor of not cause early-onset sepsis.8–10 How- volume is required for all neonates the amniotic fluid. These thresholds are ever, both Ureaplasma and Myco- with suspected sepsis. Data suggest associated with higher rates of neo- plasma organisms can be recovered that 1.0 mL of blood should be the natal and maternal morbidity. from the bloodstream of infants whose minimum volume drawn for culture Nonetheless, the diagnosis of cho- birth weight is less than 1500 g.11 When when a single pediatric blood culture rioamnionitis must be considered even a pathogen (eg, GBS) is recovered from bottle is used. Dividing the specimen in when maternal fever is the sole abnor- amniotic fluid, the attack rate of neo- half and inoculating aerobic and an- mal finding. Although fever is common natal sepsis can be as high as 20%.12 aerobic bottles is likely to decrease the in women who receive epidural anes- Infants born to women with PPROM sensitivity. Although 0.5 mL of blood thesia (15%–20%), histologic evidence who are colonized with GBS have an has previously been considered ac- of acute chorioamnionitis is very com- estimated attack rate of 33% to 50% ceptable, in vitro data from Schelonka mon in women who become febrile when intrapartum prophylaxis is not et al demonstrated that 0.5 mL would after an epidural (70.6%).3 Furthermore, given.13 not reliably detect low-level bacteremia

PEDIATRICS Volume 129, Number 5, May 2012 1007 Downloaded from by Craig Traugott on March 24, 2016 (4 colony-forming units [CFU]/mL or Body Surface Cultures infants with “traumatic taps” (or 23 less). Furthermore, up to 25% of Bacterial cultures of the axilla, groin, nonbacterial illnesses), the mean infants with sepsis have low colony and the external ear canal have a poor number of white blood cells in un- ≤ count bacteremia ( 4CFU/mL),and positive predictive accuracy. They are infected preterm or term infants was 3 – two-thirds of infants younger than 2 expensive and add little to the evalu- consistently <10 cells/mm .44 50 Cell < months of age have colony counts 10 ation of an infant with possible bac- counts 2 standard deviations from the 24,25 CFU/mL. Neal et al demonstrated terial sepsis.34,35 mean were generally less than 20 that more than half of blood specimens cells/mm3.46 In a study by Garges et al, inoculated into the aerobic bottle were Tracheal Aspirates the median number of white blood cells less than 0.5 mL.26 A study by Connell in infants who were born at greater Cultures and Gram stains of tracheal et al indicated that blood cultures with than 34 weeks’ gestation and had aspirate specimens may be of value if an adequate volume were twice as bacterial meningitis was 477/mm3.43 obtained immediately after endotra- likely to yield a positive result.27 Ablood In contrast, the median number of white cheal tube placement.36 Once an infant culture obtained through an umbilical has been intubated for several days, blood cells in infants who were born at artery catheter shortly after placement ’ tracheal aspirates are of no value in less than 34 weeks gestation and had for other clinical indications is an ac- 3 51 the evaluation of sepsis.37 meningitis was 110/mm . Infants with ceptable alternative to a culture drawn meningitis attributable to Gram-negative from a peripheral vein.28 Theriskof Lumbar Puncture pathogens typically have higher CSF recovering a contaminant is greater white blood cell counts than do infants The decision to perform a lumbar punc- with a blood culture drawn from an with meningitis attributable to Gram- 29 ture in a neonate with suspected early- umbilical vein. There are, however, positive pathogens.52 Adjusting the onset sepsis remains controversial. In data to suggest that a blood culture CSF white blood cell count for the the high-risk, healthy-appearing in- drawn from the umbilical vein at the number of red blood cells does not fant, data suggest that the likelihood time of delivery using a doubly clam- improve the diagnostic utility (loss of of meningitis is extremely low.38 In the ped and adequately prepared segment sensitivity with marginal gain in speci- of the cord is a reliable alternative to infant with clinical signs that are thought ficity).53 In addition, the number of bands a culture obtained peripherally.30 to be attributable to a noninfectious condition, such as respiratory distress in a CSF specimen does not predict 54 syndrome, the likelihood of meningitis meningitis. With a delay in analysis Urine Culture > is also low.39 However, in bacteremic ( 2 hours), white blood cell counts A urine culture should not be part of the infants, the incidence of meningitis may and glucose concentrations decrease fi 55 sepsis workup in an infant with suspected be as high as 23%.40,41 Blood culture signi cantly. 31 early-onset sepsis. Unlike urinary tract alonecannotbeusedtodecidewho Protein concentrations in uninfected, infections in older infants (which are needs a lumbar puncture, because term newborn infants are <100 mg/ usually ascending infections), urinary blood cultures can be negative in up dL.44–50 Preterm infants have CSF pro- tract infections in newborn infants are to 38% of infants with meningitis.42,43 tein concentrations that vary inversely attributable to seeding of the kidney The lumbar puncture should be per- with gestational age. In the normogly- during an episode of bacteremia. formed in any infant with a positive cemic newborn infant, glucose con- blood culture, infants whose clinical centrations in CSF are similar to those Gastric Aspirates course or laboratory data strongly in older infants and children (70%–80% Thefetusswallows500to1000mLof suggest bacterial sepsis, and infants of a simultaneously obtained blood amniotic fluideachday.Therefore,if who initially worsen with antimicro- specimen). A low glucose concentration there are white blood cells present in bial therapy. For any infant who is is the CSF variable with the greatest amniotic fluid, they will be present in critically ill and likely to have cardio- specificity for the diagnosis of menin- gastric aspirate specimens at birth. vascular or respiratory compromise gitis.43,51 Protein concentrations are However, these cells represent the ma- from the procedure, the lumbar punc- higher and glucose concentrations are ternal response to inflammation and ture can be deferred until the infant is lowerintermthaninpreterminfants have a poor correlation with neonatal more stable. with meningitis. However, meningitis sepsis.32 Gram stains of gastric aspirates Cerebrospinal fluid (CSF) values indic- occurs in infants with normal CSF to identify bacteria are of limited value ative of neonatal meningitis are con- values, and some of these infants have and are not routinely recommended.33 troversial. In studies that have excluded high bacterial inocula.43,51

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Peripheral White Blood Cell Count 28 through 36 weeks’ gestation, and Counts obtained 6 to 12 hours after and Differential Count 500/mm3 in infants born at <28 weeks’ birth are more likely to be abnormal Total white blood cell counts have little gestation. Peak values occurred at 6 to than are counts obtained at birth, be- value in the diagnosis of early-onset 8 hours after birth; the lower limits of cause alterations in the numbers (and 3 sepsis and have a poor positive pre- normal at that time were 7500/mm , ratios) of mature and immature neutro- 3 3 fl dictive accuracy.56,57 Many investi- 3500/mm , and 1500/mm for infants phils require an established in ammatory > ’ gators have analyzed subcomponents born at 36 weeks gestation, 28 to response. Therefore, once the decision is ’ < ’ of the white blood cell count (neutrophil 36 weeks gestation, and 28 weeks made to start antimicrobial therapy indices)—absolute neutrophil count, gestation, respectively.61 It is notewor- soon after birth, it is worth waiting 6 to absolute band count, and immature to thy that the study by Schmutz et al was 12 hours before ordering a white blood 68,69 total neutrophil (I/T)ratio—to identify performed at 4800 feet above sea level, cell count and differential count. whereas that of Manroe et al was per- infected infants. Like most diagnostic Platelet Counts tests for neonatal sepsis, neutrophil in- formed at 500 feet above sea level. dices have proven most useful for ex- The absolute immature neutrophil count Despite the frequency of low platelet counts in infected infants, they are a cluding infants without infection rather follows a similar pattern to the absolute nonspecific, insensitive, and late indica- than identifying infected neonates. Neu- neutrophil count and peaks at approx- tor of sepsis.70,71 Moreover, platelet tropenia may be a better marker for imately 12 hours of life. The number of counts are not useful to follow clinical neonatal sepsis and has better speci- immature neutrophils increases from a 3 response to antimicrobial agents, be- ficity than an elevated neutrophil count, maximal value of 1100 cells/mm at 3 cause they often remain depressed for because few conditions besides sepsis birth to 1500 cells/mm at 12 hours of days to weeks after a sepsis episode. (maternal pregnancy-induced hyper- age.58 Absolute immature counts have tension, asphyxia, and hemolytic dis- a poor sensitivity and positive predic- Acute-Phase Reactants ease) depress the neutrophil count of tive accuracy for early-onset sepsis.22 A wide variety of acute-phase reactants neonates.58 The definitions for neutro- Furthermore, if exhaustion of bone mar- have been evaluated in neonates with 58–61 row reserves occurs, the number of im- penia vary with gestational age, suspected bacterial sepsis. However, only mature forms will remain depressed.64 type of delivery (infants born by cesar- C-reactive protein (CRP) and procalcito- ean delivery without labor have lower The I/T ratio has the best sensitivity of nin concentrations have been investiga- counts than infants delivered vagi- any of the neutrophil indices. However, tedinsufficiently large studies.72,73 CRP 61 nally), site of sampling (neutrophil with manual counts, there are wide concentration increases within 6 to 8 counts are lower in samples from interreader differences in band neu- hours of an infectious episode in neo- 62 fi 65 arterial blood), and altitude (infants trophil identi cation. The I/T ratio is nates and peaks at 24 hours.74,75 The < born at elevated altitudes have higher 0.22 in 96% of healthy preterm infants sensitivity of a CRP determination is 63 < ’ 66 total neutrophil counts). In late pre- born at 32 weeks gestational age. low at birth, because it requires an term and term infants, the definition Unlike the absolute neutrophil count inflammatory response (with release for neutropenia most commonly used and the absolute band count, maximum of interleukin-6) to increase CRP con- is that suggested by Manroe et al normal values for the I/T ratio occur at centrations.76 The sensitivity improves 3 3 (<1800/mm at birth and <7800/mm birth (0.16) and decline with increasing dramatically if the first determination at 12–14 hours of age).58 Schmutz et al postnatal age to a minimum value of ismade6to12hoursafterbirth.Benitz reinvestigated these reference ranges 0.12.58 In healthy term infants, the 90th et al have demonstrated that excluding using modern cell-counting instrumen- percentile for the I/T ratio is 0.27.59 a value at birth, 2 normal CRP deter- tation in 30 254 infants born at 23 to 42 A single determination of the I/T ratio minations (8–24 hours after birth and weeks’ gestation.61 Infants with diagnoses has a poor positive predictive accuracy 24 hours later) have a negative pre- known to affect neutrophil counts (eg, (approximately 25%) but a very high dictive accuracy of 99.7% and a nega- those born to women with pregnancy- negative predictive accuracy (99%).66 tive likelihood ratio of 0.15 for proven induced hypertension or those with The I/T ratio may be elevated in 25% to neonatal sepsis.76 If CRP determina- early-onset sepsis) were excluded. In 50% of uninfected infants.67 tions remain persistently normal, it is this study, the lower limits of normal Exhaustion of bone marrow reserves strong evidence that bacterial sepsis is for neutrophil values at birth were will result in low band counts and lead unlikely, and antimicrobial agents can be 3500/mm3 in infants born at >36 weeks’ to falsely low ratios. The timing of the safely discontinued. Data are insufficient gestation, 1000/mm3 in infants born at white blood cell count is critical.68 to recommend following sequential CRP

PEDIATRICS Volume 129, Number 5, May 2012 1009 Downloaded from by Craig Traugott on March 24, 2016 concentrations to determine the dura- Furthermore, scores obtained in the meningitis attributable to GBS is trea- tion of antimicrobial therapy in an infant first several hours after birth have been ted for a minimum of 14 days.88 Other with an elevated value (≥1.0 mg/dL). shown to have poorer sensitivity and focal infections secondary to GBS (eg, Procalcitonin concentrations increase negative predictive value than scores cerebritis, osteomyelitis, endocarditis) within 2 hours of an infectious episode, obtained at 24 hours of age.67 Sepsis are treated for longer durations.88 Gram- peak at 12 hours, and normalize within screening panels commonly include negative meningitis is treated for 2 to 3 days in healthy adult volunteers.77 neutrophil indices and acute-phase re- minimum of 21 days or 14 days after A physiologic increase in procalcitonin actants (usually CRP concentration). The obtaining a negative culture, whichever concentration occurs within the first positive predictive value of the sepsis is longer.88 Treatment of Gram-negative 24 hours of birth, and an increase in screen in neonates is poor (<30%); meningitis should include cefotaxime serum concentrations can occur with however, the negative predictive accuracy and an aminoglycoside until the results noninfectious conditions (eg, respira- has been high (>99%) in small clinical of susceptibility testing are known.87,88 tory distress syndrome).78 Procalcitonin studies.22 Sepsis screening tests might be The duration of antimicrobial therapy concentration has a modestly better of value in deciding which “high-risk” in infants with negative blood cultures sensitivity than does CRP concentration healthy-appearing neonates do not need is controversial. Many women receive but is less specific.73 Chiesa and col- antimicrobial agents or whether therapy antimicrobial agents during labor as leagues have published normal values can be safely discontinued. prophylaxis to prevent early-onset GBS for procalcitonin concentrations in term infections or for management of sus- 79 and preterm infants. There is evidence TREATMENT OF INFANTS WITH pected intra-amniontic infection or from studies conducted in adult pop- SUSPECTED EARLY-ONSET SEPSIS PPROM. In those instances, postnatal ulations, the majority of which focused blood cultures may be sterile (false on patients with sepsis in the ICU, that In the United States, the most common negative). When considering the dura- significant reductions in use of anti- pathogens responsible for early-onset tion of therapy in infants with negative microbial agents can be achieved in neonatal sepsis are GBS and Escherichia blood cultures, the decision should patients whose treatment is guided by coli.17 A combination of ampicillin and include consideration of the clinical procalcitonin concentration.80 an aminoglycoside (usually gentamicin) course as well as the risks associated is generally used as initial therapy, and with longer courses of antimicrobial this combination of antimicrobial agents agents. In a retrospective study by Cor- Sepsis Screening Panels also has synergistic activity against dero and Ayers, the average duration of Hematologic scoring systems using GBS and Listeria monocytogenes.82,83 treatment in 695 infants (<1000 g) multiple laboratory values (eg, white Third-generation cephalosporins (eg, with negative blood cultures was 5 ± blood cell count, differential count, and cefotaxime) represent a reasonable al- 3days.89 Cotten et al have suggested platelet count) have been recommen- ternative to an aminoglycoside. However, an association with prolonged adminis- ded as useful diagnostic aids. No matter several studies have reported rapid tration of antimicrobial agents (>5days) what combination of tests is used, the development of resistance when cefo- in infants with suspected early-onset positive predictive accuracy of scoring taxime has been used routinely for the sepsis (and negative blood cultures) systems is poor unless the score is treatment of early-onset neonatal sep- with death and necrotizing enterocoli- very high. Rodwell et al described a sis,84 and extensive/prolonged use of tis.90 Two recent papers also support scoring system in which a score of 1 was third-generation cephalosporins is a risk this association.91,92 assigned to 1 of 7 findings, including factor for invasive candidiasis.85 Be- abnormalities of leukocyte count, total cause of its excellent CSF penetration, neutrophil count, increased immature empirical or therapeutic use of cefo- PREVENTION STRATEGIES FOR polymorphonuclear leukocyte (PMN) taxime should be restricted for use in EARLY-ONSET SEPSIS count, increased I/T ratio, immature to infants with meningitis attributable to The only intervention proven to decrease mature PMN ratio >0.3, platelet count Gram-negative organisms.86 Ceftriax- the incidence of early-onset neonatal ≤150 000/mm3, and pronounced degen- one is contraindicated in neonates sepsis is maternal treatment with erative changes (ie, toxic granulations) because it is highly protein bound intrapartum intravenous antimicro- in PMNs.81 In this study, two-thirds and may displace bilirubin, leading to a bial agents for the prevention of GBS of preterm infants and 90% of term risk of kernicterus. Bacteremia without an infections.93 Adequate prophylaxis is infants with a hematologic score identifiable focus of infection is generally defined as penicillin (the preferred ≥3 did not have proven sepsis.81 treated for 10 days.87 Uncomplicated agent), ampicillin, or cefazolin given for

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≥4 hours before delivery. Erythromycin hours of life. Approximately 1% of infants starting antimicrobial agents after cul- is no longer recommended for prophy- will appear healthy at birth and then tures have been obtained. laxis because of high resistance rates. develop signs of infection after a vari- In parturients who have a nonserious able time period.21 Every critically ill Challenge 2: Identifying penicillin allergy, cefazolin is the drug infant should be evaluated and receive Healthy-Appearing Neonates With of choice. For parturients with a history empirical broad-spectrum antimicrobial a “High Likelihood” of Early-Onset of serious penicillin allergy (anaphy- therapy after cultures, even when there Sepsis Who Require Antimicrobial laxis, angioedema, respiratory com- are no obvious risk factors for sepsis. Agents Soon After Birth promise, or urticaria), clindamycin is The greatest difficulty faced by clini- This category includes infants with 1 of an acceptable alternative agent, but cians is distinguishing neonates with the risk factors for sepsis noted pre- only if the woman’s rectovaginal GBS early signs of sepsis from neonates viously (colonization with GBS, prolonged screening isolate has been tested and with noninfectious conditions with rel- rupture of membranes >18 hours, or documented to be susceptible. If the atively mild findings (eg, tachypnea with maternal chorioamnionitis). GBS is not clindamycin susceptibility is unknown or without an oxygen requirement). In a risk factor if the mother has received or the GBS isolate is resistant to clin- this situation, data are insufficient to adequate intrapartum therapy (penicil- damycin, vancomycin is an alternative guide management. In more mature lin, ampicillin, or cefazolin for at least agent for prophylaxis. However, nei- neonates without risk factors for in- 4 hours before delivery) or has a ce- ther clindamycin nor vancomycin has fection who clinically improve over the sarean delivery with intact membranes been evaluated for efficacy in pre- first 6 hours of life (eg, need for oxygen in the absence of labor.93 Theriskof venting early-onset GBS sepsis in is decreasing and respiratory distress infectioninthenewborninfantvaries neonates. Intrapartum antimicrobial is resolving), it is reasonable to with- considerably with the risk factor pres- agents are indicated for the following hold antimicrobial therapy and monitor ent. The greatest risk of early-onset situations93: the neonates closely. The 6-hour win- sepsis occurs in infants born to women 1. Positive antenatal cultures or molec- dow should not be considered absolute; with chorioamnionitis who are also ular test at admission for GBS (ex- however, most infants without infec- colonized with GBS and did not receive cept for women who have a cesarean tion demonstrate some improvement intrapartum antimicrobial agents. Early- delivery without labor or membrane over that time period. Any worsening of onset sepsis does occur in infants who rupture) the infant’s condition should prompt appear healthy at birth.21 Therefore, 2. Unknown maternal colonization status with gestation <37 weeks, rupture of membranes >18 hours, or temperature >100.4°F (>38°C) 3. GBS bacteriuria during the current pregnancy 4. Previous infant with invasive GBS disease Management guidelines for the newborn infant have been published93 and are available online (http://www.cdc. gov/groupbstrep/guidelines/index.html).

CLINICAL CHALLENGES Challenge 1: Identifying Neonates With Clinical Signs of Sepsis With FIGURE 1 a “High Likelihood” of Early-Onset Evaluation of asymptomatic infants <37 weeks’ gestation with risk factors for sepsis. aThe diagnosis of chorioamnionitis is problematic and has important implications for the management of the Sepsis Who Require Antimicrobial newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical Agents Soon After Birth colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, re- Most infants with early-onset sepsis sponse to treatment, and laboratory results. IAP, intrapartum antimicrobial prophylaxis; WBC, white exhibit abnormal signs in the ﬁrst 24 blood cell; Diff, differential white blood cell count.

PEDIATRICS Volume 129, Number 5, May 2012 1011 Downloaded from by Craig Traugott on March 24, 2016 some clinicians use diagnostic tests initiating antimicrobial treatment gen- CONCLUSIONS with a high negative predictive accuracy erally decreases with increasing num- The diagnosis and management of neo- as reassurance that infection is not bers of risk factors for infection and nates with suspected early-onset sepsis present (allowing them to withhold greater degrees of prematurity. Sug- are based on scientificprinciplesmod- antimicrobial agents). The decision of gested algorithms for management of ified by the “art and experience” of the whether to treat a high-risk infant healthy-appearing, high-risk infants are practitioner. The following are well- depends on the risk factors present, shown in Figs 1, 2, and 3. Screening established concepts related to neo- the frequency of observations, and blood cultures have not been shown to natal sepsis: gestational age. The threshold for be of value.21 1. Neonatal sepsis is a major cause of morbidity and mortality. 2. Diagnostic tests for early-onset sepsis (other than blood or CSF cultures) are useful for identifying infants with a low probability of sepsis but not at identifying infants likely to be infected. 3. One milliliter of blood drawn before initiating antimicrobial therapy is needed to adequately detect bacteremia if a pediatric blood culture bottle is used. 4. Cultures of superficial body sites, FIGURE 2 gastric aspirates, and urine are of Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis. aThe diagnosis of chorioamnionitis is problematic and has important implications for the management of the no value in the diagnosis of early- newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical onset sepsis. colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, re- 5. Lumbar puncture is not needed in sponse to treatment, and laboratory results. WBC, white blood cell; Diff, differential white blood cell all infants with suspected sepsis (es- count. pecially those who appear healthy) but should be performed for infants with signs of sepsis who can safely undergo the procedure, for infants with a positive blood culture, for infants likely to be bacteremic (on the basis of laboratory data), and infants who do not respond to antimicrobial therapy in the expected manner. 6. The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once the pathogen is identified, antimicrobial therapy should be FIGURE 3 Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis (no narrowed (unless synergism is chorioamnionitis). aInadequate treatment: Defined as the use of an antibiotic other than penicillin, needed). ampicillin, or cefazolin or if the duration of antibiotics before delivery was <4h.bDischarge at 24 h is acceptable if other discharge criteria have been met, access to medical care is readily accessible, 7. Antimicrobial therapy should be and a person who is able to comply fully with instructions for home observation will be present. If discontinued at 48 hours in clinical any of these conditions is not met, the infant should be observed in the hospital for at least 48 h and until discharge criteria are achieved. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood situations in which the probability cell; Diff, differential white blood cell count. of sepsis is low.

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LEAD AUTHOR Rosemarie C. Tan, MD, PhD AnnL.Jefferies,MD– Canadian Paediatric Society Richard A. Polin, MD Kasper S. Wang, MD Rosalie O. Mainous, PhD, RNC, NNP – National Kristi L. Watterberg, MD Association of Neonatal Nurses COMMITTEE ON FETUS AND Tonse N. K. Raju, MD, DCH – National Institutes NEWBORN, 2011–2012 FORMER COMMITTEE MEMBER of Health Lu-Ann Papile, MD, Chairperson Vinod K. Bhutani, MD Jill E. Baley, MD FORMER LIAISON William Benitz, MD LIAISONS William Barth, Jr, MD – American College of Waldemar A. Carlo, MD CAPT Wanda Denise Barﬁeld, MD, MPH – Centers Obstetricians and Gynecologists James Cummings, MD for Disease Control and Prevention Praveen Kumar, MD George Macones, MD – American College of STAFF Richard A. Polin, MD Obstetricians and Gynecologists Jim Couto, MA

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Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis Richard A. Polin and the COMMITTEE ON FETUS AND NEWBORN Pediatrics 2012;129;1006; originally published online April 30, 2012; DOI: 10.1542/peds.2012-0541 Updated Information & including high resolution figures, can be found at: Services /content/129/5/1006.full.html References This article cites 90 articles, 30 of which can be accessed free at: /content/129/5/1006.full.html#ref-list-1 Citations This article has been cited by 30 HighWire-hosted articles: /content/129/5/1006.full.html#related-urls

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