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    • Guidance for the Clinician in Rendering Pediatric CareCLINICAL REPORTManagement of Neonates With Suspected or ProvenEarly-Onset Bacterial Sepsisabstract Richard A. Polin, MD and the COMMITTEE ON FETUS AND NEWBORNWith improved obstetrical management and evidence-based use of KEY WORDS early-onset sepsis, antimicrobial therapy, group B streptococcus,intrapartum antimicrobial therapy, early-onset neonatal sepsis is be- 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 strategiessepsis is frequently based on a constellation of perinatal risk factors ABBREVIATIONS CFU—colony-forming unitsthat are neither sensitive nor specific. Furthermore, diagnostic tests CRP—C-reactive proteinfor neonatal sepsis have a poor positive predictive accuracy. As a result, CSF—cerebrospinal fluidclinicians often treat well-appearing infants for extended periods of time, GBS—group B streptococci I/T—immature to total neutrophil (ratio)even when bacterial cultures are negative. The optimal treatment of PMN—polymorphonuclear leukocyteinfants with suspected early-onset sepsis is broad-spectrum antimicro- PPROM—preterm premature rupture of membranesbial agents (ampicillin and an aminoglycoside). Once a pathogen is iden- This document is copyrighted and is property of the Americantified, antimicrobial therapy should be narrowed (unless synergism is Academy of Pediatrics and its Board of Directors. All authorsneeded). 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 throughical treatment of preterm infants (≥5 days) with broad-spectrum anti- a process approved by the Board of Directors. The Americanbiotics and higher risks of late onset sepsis, necrotizing enterocolitis, Academy of Pediatrics has neither solicited nor accepted anyand mortality. To reduce these risks, antimicrobial therapy should be commercial involvement in the development of the content of this publication.discontinued at 48 hours in clinical situations in which the probabilityof 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 bement of infants with suspected or proven early-onset sepsis. Pediatrics appropriate.2012;129:1006–1015INTRODUCTION“Suspected sepsis” is one of the most common diagnoses made in theNICU.1 However, the signs of sepsis are nonspecific, and inflammatorysyndromes of noninfectious origin mimic those of neonatal sepsis. Mostinfants with suspected sepsis recover with supportive care (with orwithout initiation of antimicrobial therapy). The challenges for clinicians www.pediatrics.org/cgi/doi/10.1542/peds.2012-0541are threefold: (1) identifying neonates with a high likelihood of sepsis doi:10.1542/peds.2012-0541promptly and initiating antimicrobial therapy; (2) distinguishing “high- All clinical reports from the American Academy of Pediatricsrisk” 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 Pediatricsdiagnosis and management of early-onset sepsis, defined by the Na-tional Institute of Child Health and Human Development and VermontOxford Networks as sepsis with onset at ≤3 days of age.1006 FROM THE AMERICAN ACADEMY OF PEDIATRICS
    • FROM THE AMERICAN ACADEMY OF PEDIATRICSPATHOGENESIS AND most of these women with histologic The major risk factors for early-onsetEPIDEMIOLOGY 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 ical chorioamnionitis varies inversely of membranes >18 hours, and mater-Before birth, the fetus optimally is with gestational age. In the National nal signs or symptoms of intra-amnioticmaintained in a sterile environment. Institute of Child Health and Human infection.14–16 Other variables includeOrganisms causing early-onset sepsis Development Neonatal Research Net- ethnicity (ie, black women are at higherascend from the birth canal either work, 14% to 28% of women delivering risk of being colonized with GBS), lowwhen the amniotic membranes rupture preterm infants at 22 through 28 weeks’ socioeconomic status, male sex, andor leak before or during the course of gestation exhibited signs compatible low Apgar scores. Preterm birth/lowlabor, resulting in intra-amniotic infec- with chorioamnionitis.4 The major risk birth weight is the risk factor mosttion.2 Commonly referred to as “cho- factors for chorioamnionitis include closely associated with early-onset sep-rioamnionitis,” intra-amniotic infection low parity, spontaneous labor, longer sis.17 Infant birth weight is inverselyindicates infection of the amniotic fluid, length of labor and membrane rupture, related to risk of early-onset sepsis.membranes, placenta, and/or decidua. multiple digital vaginal examinations The increased risk of early-onset sep-Group B streptococci (GBS) can also sis in preterm infants is also related to (especially with ruptured membranes),enter the amniotic fluid through occult complications of labor and delivery meconium-stained amniotic fluid, internaltears. Chorioamnionitis is a major risk and immaturity of innate and adaptive fetal or uterine monitoring, and pres-factor for neonatal sepsis. Sepsis can immunity.18begin in utero when the fetus inhales ence of genital tract microorganismsor swallows infected amniotic fluid. (eg, Mycoplasma hominis).5The neonate can also develop sepsis in At term gestation, less than 1% of DIAGNOSTIC TESTING FOR SEPSISthe hours or days after birth when women with intact membranes will The clinical diagnosis of sepsis in thecolonized skin or mucosal surfaces are have organisms cultured from amni- neonate is difficult, because many ofcompromised. The essential criterion otic fluid.6 The rate can be higher if the signs of sepsis are nonspecific andfor the clinical diagnosis of chorio- the integrity of the amniotic cavity is are observed with other noninfectiousamnionitis is maternal fever. Other compromised by procedures before conditions. Although a normal physicalcriteria are relatively insensitive. When birth (eg, placement of a cerclage or examination is evidence that sepsis isdefining intra-amniotic infection (cho- amniocentesis).6 In women with pre- not present,19,20 bacteremia can occurrioamnionitis) 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 inon 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 cantwo of the following criteria: maternal (PPROM), the rate may be as high as assist with the decision to discontinueleukocytosis (greater than 15 000 cells/ 75%.7 Many of the pathogens recovered treatment.22mm3), maternal tachycardia (greater from amniotic fluid in women with pre-than 100 beats/minute), fetal tachycar- term labor or PPROM (eg, Ureaplasma Blood Culturedia (greater than 160 beats/minute), species or Mycoplasma species) do A single blood culture in a sufficientuterine tenderness, and/or foul odor of not cause early-onset sepsis.8–10 How- volume is required for all neonatesthe amniotic fluid. These thresholds are ever, both Ureaplasma and Myco- with suspected sepsis. Data suggestassociated with higher rates of neo- plasma organisms can be recovered that 1.0 mL of blood should be thenatal and maternal morbidity. from the bloodstream of infants whose minimum volume drawn for cultureNonetheless, the diagnosis of cho- birth weight is less than 1500 g.11 When when a single pediatric blood culturerioamnionitis must be considered even a pathogen (eg, GBS) is recovered from bottle is used. Dividing the specimen inwhen 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 thein women who receive epidural anes- Infants born to women with PPROM sensitivity. Although 0.5 mL of bloodthesia (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 Schelonkamon in women who become febrile when intrapartum prophylaxis is not et al demonstrated that 0.5 mL wouldafter an epidural (70.6%).3 Furthermore, given.13 not reliably detect low-level bacteremiaPEDIATRICS Volume 129, Number 5, May 2012 1007
    • (4 colony-forming units [CFU]/mL or Body Surface Cultures infants with “traumatic taps” (orless). 23 Furthermore, up to 25% of Bacterial cultures of the axilla, groin, nonbacterial illnesses), the meaninfants with sepsis have low colony and the external ear canal have a poor number of white blood cells in un-count bacteremia (≤4 CFU/mL), and positive predictive accuracy. They are infected preterm or term infants wastwo-thirds of infants younger than 2 expensive and add little to the evalu- consistently <10 cells/mm3.44–50 Cellmonths of age have colony counts <10 ation of an infant with possible bac- counts 2 standard deviations from theCFU/mL.24,25 Neal et al demonstrated terial sepsis.34,35 mean were generally less than 20that 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 cellsless than 0.5 mL.26 A study by Connell in infants who were born at greater Cultures and Gram stains of trachealet al indicated that blood cultures with than 34 weeks’ gestation and had aspirate specimens may be of value ifan adequate volume were twice as bacterial meningitis was 477/mm3.43 obtained immediately after endotra-likely to yield a positive result.27 A blood In contrast, the median number of white cheal tube placement.36 Once an infantculture obtained through an umbilical blood cells in infants who were born at has been intubated for several days,artery catheter shortly after placement less than 34 weeks’ gestation and had tracheal aspirates are of no value infor other clinical indications is an ac- meningitis was 110/mm3.51 Infants with the evaluation of sepsis.37ceptable alternative to a culture drawn meningitis attributable to Gram-negativefrom a peripheral vein.28 The risk of pathogens typically have higher CSF Lumbar Puncturerecovering a contaminant is greater white blood cell counts than do infantswith a blood culture drawn from an The decision to perform a lumbar punc- with meningitis attributable to Gram-umbilical vein.29 There are, however, ture in a neonate with suspected early- positive pathogens.52 Adjusting thedata to suggest that a blood culture onset sepsis remains controversial. In CSF white blood cell count for thedrawn from the umbilical vein at the the high-risk, healthy-appearing in- number of red blood cells does nottime of delivery using a doubly clam- fant, data suggest that the likelihood of meningitis is extremely low.38 In the improve the diagnostic utility (loss ofped 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 to be attributable to a noninfectious ficity).53 In addition, the number of bandsa culture obtained peripherally.30 condition, such as respiratory distress in a CSF specimen does not predict syndrome, the likelihood of meningitis meningitis.54 With a delay in analysisUrine Culture (>2 hours), white blood cell counts is also low.39 However, in bacteremicA urine culture should not be part of the infants, the incidence of meningitis may and glucose concentrations decreasesepsis workup in an infant with suspected be as high as 23%.40,41 Blood culture significantly.55early-onset sepsis.31 Unlike urinary tract alone cannot be used to decide who 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 inverselyattributable 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 thoseGastric Aspirates course or laboratory data strongly in older infants and children (70%–80%The fetus swallows 500 to 1000 mL of suggest bacterial sepsis, and infants of a simultaneously obtained bloodamniotic fluid each day. Therefore, if who initially worsen with antimicro- specimen). A low glucose concentrationthere are white blood cells present in bial therapy. For any infant who is is the CSF variable with the greatestamniotic 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 areHowever, these cells represent the ma- from the procedure, the lumbar punc- higher and glucose concentrations areternal response to inflammation and ture can be deferred until the infant is lower in term than in preterm infantshave a poor correlation with neonatal more stable. with meningitis. However, meningitissepsis.32 Gram stains of gastric aspirates Cerebrospinal fluid (CSF) values indic- occurs in infants with normal CSFto identify bacteria are of limited value ative of neonatal meningitis are con- values, and some of these infants haveand are not routinely recommended.33 troversial. In studies that have excluded high bacterial inocula.43,511008 FROM THE AMERICAN ACADEMY OF PEDIATRICS
    • FROM THE AMERICAN ACADEMY OF PEDIATRICSPeripheral White Blood Cell Count 28 through 36 weeks’ gestation, and Counts obtained 6 to 12 hours afterand Differential Count 500/mm3 in infants born at <28 weeks’ birth are more likely to be abnormalTotal 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 (andsepsis and have a poor positive pre- normal at that time were 7500/mm3, ratios) of mature and immature neutro-dictive accuracy. 56,57 Many investi- 3500/mm3, and 1500/mm3 for infants phils require an established inflammatorygators have analyzed subcomponents born at >36 weeks’ gestation, 28 to response. Therefore, once the decision isof the white blood cell count (neutrophil 36 weeks’ gestation, and <28 weeks’ made to start antimicrobial therapyindices)—absolute neutrophil count, gestation, respectively.61 It is notewor- soon after birth, it is worth waiting 6 toabsolute band count, and immature to thy that the study by Schmutz et al was 12 hours before ordering a white bloodtotal neutrophil (I/T)ratio—to identify performed at 4800 feet above sea level, cell count and differential count.68,69infected infants. Like most diagnostic whereas that of Manroe et al was per- formed at 500 feet above sea level. Platelet Countstests for neonatal sepsis, neutrophil in-dices have proven most useful for ex- The absolute immature neutrophil count Despite the frequency of low platelet follows a similar pattern to the absolute counts in infected infants, they are acluding infants without infection rather neutrophil count and peaks at approx- nonspecific, insensitive, and late indica-than identifying infected neonates. Neu- imately 12 hours of life. The number of tor of sepsis.70,71 Moreover, platelettropenia may be a better marker for immature neutrophils increases from a counts are not useful to follow clinicalneonatal sepsis and has better speci- maximal value of 1100 cells/mm3 at response to antimicrobial agents, be-ficity than an elevated neutrophil count, birth to 1500 cells/mm3 at 12 hours of cause they often remain depressed forbecause few conditions besides sepsis age.58 Absolute immature counts have days to weeks after a sepsis episode.(maternal pregnancy-induced hyper-tension, asphyxia, and hemolytic dis- a poor sensitivity and positive predic- Acute-Phase Reactantsease) depress the neutrophil count of tive accuracy for early-onset sepsis.22 Furthermore, if exhaustion of bone mar- A wide variety of acute-phase reactantsneonates.58 The definitions for neutro- row reserves occurs, the number of im- have been evaluated in neonates withpenia vary with gestational age,58–61 suspected bacterial sepsis. However, onlytype of delivery (infants born by cesar- mature forms will remain depressed.64 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, ted in sufficiently large studies.72,73 CRPnally),61 site of sampling (neutrophil with manual counts, there are wide concentration increases within 6 to 8counts are lower in samples from interreader differences in band neu- hours of an infectious episode in neo-arterial blood),62 and altitude (infants trophil identification.65 The I/T ratio is nates and peaks at 24 hours.74,75 Theborn at elevated altitudes have higher <0.22 in 96% of healthy preterm infants sensitivity of a CRP determination istotal neutrophil counts).63 In late pre- born at <32 weeks’ gestational age.66 low at birth, because it requires anterm and term infants, the definition Unlike the absolute neutrophil count inflammatory response (with releasefor 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(<1800/mm3 at birth and <7800/mm3 birth (0.16) and decline with increasing dramatically if the first determinationat 12–14 hours of age).58 Schmutz et al postnatal age to a minimum value of is made 6 to 12 hours after birth. Benitzreinvestigated these reference ranges 0.12.58 In healthy term infants, the 90th et al have demonstrated that excludingusing 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 andweeks’ 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 proveninduced 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 isthis study, the lower limits of normal Exhaustion of bone marrow reserves strong evidence that bacterial sepsis isfor neutrophil values at birth were will result in low band counts and lead unlikely, and antimicrobial agents can be3500/mm3 in infants born at >36 weeks’ to falsely low ratios. The timing of the safely discontinued. Data are insufficientgestation, 1000/mm3 in infants born at white blood cell count is critical. 68 to recommend following sequential CRPPEDIATRICS Volume 129, Number 5, May 2012 1009
    • 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 Otherwith 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 for2 to 3 days in healthy adult volunteers.77 neutrophil indices and acute-phase re- minimum of 21 days or 14 days afterA physiologic increase in procalcitonin actants (usually CRP concentration). The obtaining a negative culture, whicheverconcentration occurs within the first positive predictive value of the sepsis is longer.88 Treatment of Gram-negative24 hours of birth, and an increase in screen in neonates is poor (<30%); meningitis should include cefotaximeserum concentrations can occur with however, the negative predictive accuracy and an aminoglycoside until the resultsnoninfectious conditions (eg, respira- has been high (>99%) in small clinical of susceptibility testing are known.87,88tory distress syndrome).78 Procalcitonin studies.22 Sepsis screening tests might be The duration of antimicrobial therapyconcentration has a modestly better of value in deciding which “high-risk” in infants with negative blood culturessensitivity than does CRP concentration healthy-appearing neonates do not need is controversial. Many women receivebut is less specific.73 Chiesa and col- antimicrobial agents or whether therapy antimicrobial agents during labor asleagues have published normal values can be safely discontinued. prophylaxis to prevent early-onset GBSfor procalcitonin concentrations in term infections or for management of sus-and preterm infants.79 There is evidence TREATMENT OF INFANTS WITH pected intra-amniontic infection orfrom studies conducted in adult pop- SUSPECTED EARLY-ONSET SEPSIS PPROM. In those instances, postnatalulations, the majority of which focused blood cultures may be sterile (falseon 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 negativemicrobial agents can be achieved in neonatal sepsis are GBS and Escherichia blood cultures, the decision shouldpatients whose treatment is guided by coli.17 A combination of ampicillin and include consideration of the clinicalprocalcitonin 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 ofHematologic 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- 3 days.89 Cotten et al have suggestedplatelet 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 (>5 days)what combination of tests is used, the development of resistance when cefo- in infants with suspected early-onsetpositive 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 supportscoring system in which a score of 1 was third-generation cephalosporins is a risk this association.91,92assigned 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 FORpolymorphonuclear leukocyte (PMN) taxime should be restricted for use in EARLY-ONSET SEPSIScount, increased I/T ratio, immature to infants with meningitis attributable to The only intervention proven to decreasemature 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 witherative 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 GBSof preterm infants and 90% of term risk of kernicterus. Bacteremia without an infections.93 Adequate prophylaxis isinfants 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 for1010 FROM THE AMERICAN ACADEMY OF PEDIATRICS
    • FROM THE AMERICAN ACADEMY OF PEDIATRICS≥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: Identifyingpenicillin allergy, cefazolin is the drug infant should be evaluated and receive Healthy-Appearing Neonates Withof choice. For parturients with a history empirical broad-spectrum antimicrobial a “High Likelihood” of Early-Onsetof serious penicillin allergy (anaphy- therapy after cultures, even when there Sepsis Who Require Antimicrobiallaxis, angioedema, respiratory com- are no obvious risk factors for sepsis. Agents Soon After Birthpromise, or urticaria), clindamycin is The greatest difficulty faced by clini- This category includes infants with 1 ofan 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, prolongedscreening isolate has been tested and with noninfectious conditions with rel- rupture of membranes >18 hours, ordocumented to be susceptible. If the atively mild findings (eg, tachypnea with maternal chorioamnionitis). GBS is notclindamycin susceptibility is unknown or without an oxygen requirement). In a risk factor if the mother has receivedor 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 leastagent 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 membranesbeen evaluated for efficacy in pre- first 6 hours of life (eg, need for oxygen in the absence of labor.93 The risk ofventing early-onset GBS sepsis in is decreasing and respiratory distress infection in the newborn infant variesneonates. 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-onsetsituations93: the neonates closely. The 6-hour win- sepsis occurs in infants born to women1. 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 sta- tus with gestation <37 weeks, rup- ture of membranes >18 hours, or temperature >100.4°F (>38°C)3. GBS bacteriuria during the current pregnancy4. Previous infant with invasive GBS diseaseManagement guidelines for the new-born infant have been published93 andare available online (http://www.cdc.gov/groupbstrep/guidelines/index.html).CLINICAL CHALLENGESChallenge 1: Identifying NeonatesWith Clinical Signs of Sepsis With FIGURE 1a “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 theSepsis Who Require Antimicrobial newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetricalAgents 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, whiteexhibit abnormal signs in the first 24 blood cell; Diff, differential white blood cell count.PEDIATRICS Volume 129, Number 5, May 2012 1011
    • some clinicians use diagnostic tests initiating antimicrobial treatment gen- CONCLUSIONSwith 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 sepsispresent (allowing them to withhold greater degrees of prematurity. Sug- are based on scientific principles mod-antimicrobial agents). The decision of gested algorithms for management of ified by the “art and experience” of thewhether 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 cul- tures) are useful for identifying in- fants 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 bacter- emia if a pediatric blood culture bot- tle is used. 4. Cultures of superficial body sites,FIGURE 2Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis. The diagnosis a gastric aspirates, and urine are ofof 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 witha positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, re- 5. Lumbar puncture is not needed insponse 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 in- fants 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 beFIGURE 3Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis (no narrowed (unless synergism ischorioamnionitis). 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 <4 h. bDischarge at 24 his acceptable if other discharge criteria have been met, access to medical care is readily accessible, 7. Antimicrobial therapy should beand a person who is able to comply fully with instructions for home observation will be present. If discontinued at 48 hours in clinicalany of these conditions is not met, the infant should be observed in the hospital for at least 48 h anduntil discharge criteria are achieved. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood situations in which the probabilitycell; Diff, differential white blood cell count. of sepsis is low.1012 FROM THE AMERICAN ACADEMY OF PEDIATRICS
    • FROM THE AMERICAN ACADEMY OF PEDIATRICSLEAD AUTHOR Rosemarie C. Tan, MD, PhD Ann L. Jefferies, MD – Canadian Paediatric SocietyRichard A. Polin, MD Kasper S. Wang, MD Rosalie O. Mainous, PhD, RNC, NNP – National Kristi L. Watterberg, MD Association of Neonatal NursesCOMMITTEE ON FETUS AND Tonse N. K. Raju, MD, DCH – National InstitutesNEWBORN, 2011–2012 FORMER COMMITTEE MEMBER of HealthLu-Ann Papile, MD, Chairperson Vinod K. Bhutani, MDJill E. Baley, MD FORMER LIAISONWilliam Benitz, MD LIAISONS William Barth, Jr, MD – American College ofWaldemar A. Carlo, MD CAPT Wanda Denise Barfield, MD, MPH – Centers Obstetricians and GynecologistsJames Cummings, MD for Disease Control and PreventionPraveen Kumar, MD George Macones, MD – American College of STAFFRichard A. Polin, MD Obstetricians and Gynecologists Jim Couto, MAREFERENCES 1. Escobar GJ. The neonatal “sepsis work-up”: 11. Goldenberg RL, Andrews WW, Goepfert AR, grams at birth: A population-based study. personal reflections on the development of et al The Alabama Preterm Birth Study: Pediatrics. 2000;106(2 pt 1):256–263 an evidence-based approach toward newborn umbilical cord blood Ureaplasma ure- 20. Buckler B, Bell J, Sams R, et al. Unnecessary infections in a managed care organization. alyticum and Mycoplasma hominis cul- workup of asymptomatic neonates in the Pediatrics. 1999;103(1, suppl E):360–373 tures in very preterm newborn infants. era of group B streptococcus prophylaxis 2. Polin RA, St Geme JW III. Neonatal sepsis. Am J Obstet Gynecol. 2008;198(1):43.e1–43. [published online ahead of print August 22, Adv Pediatr Infect Dis. 1992;7:25–61 e5 2010]. Infect Dis Obstet Gynecol. doi: 3. Riley LE, Celi AC, Onderdonk AB, et al. Asso- 12. Benitz WE, Gould JB, Druzin ML. Risk factors 21. Ottolini MC, Lundgren K, Mirkinson LJ, ciation of epidural-related fever and non- for early-onset group B streptococcal sep- Cason S, Ottolini MG. Utility of complete infectious inflammation in term labor. Obstet sis: estimation of odds ratios by critical blood count and blood culture screening to Gynecol. 2011;117(3):588–595 literature review. Pediatrics. 1999;103(6). diagnose neonatal sepsis in the asymp- 4. Stoll BJ, Hansen NI, Bell EF, et al; Eunice Available at: www.pediatrics.org/cgi/content/ tomatic at risk newborn. Pediatr Infect Dis Kennedy Shriver National Institute of Child full/103/6/e77 J. 2003;22(5):430–434 Health and Human Development Neonatal 13. Newton ER, Clark M. Group B streptococcus 22. Gerdes JS. Clinicopathologic approach to Research Network. Neonatal outcomes of and preterm rupture of membranes. Obstet the diagnosis of neonatal sepsis. Clin Per- extremely preterm infants from the NICHD Gynecol. 1988;71(2):198–202 inatol. 1991;18(2):361–381 Neonatal Research Network. Pediatrics. 14. Schuchat A, Zywicki SS, Dinsmoor MJ, et al. 23. Schelonka RL, Chai MK, Yoder BA, Hensley D, 2010;126(3):443–456 Risk factors and opportunities for preven- Brockett RM, Ascher DP. Volume of blood 5. Tita AT, Andrews WW. Diagnosis and man- tion of early-onset neonatal sepsis: a multi- required to detect common neonatal patho- agement of clinical chorioamnionitis. Clin center case-control study. Pediatrics. 2000; gens. J Pediatr. 1996;129(2):275–278 Perinatol. 2010;37(2):339–354 105(1 pt 1):21–26 24. Dietzman DE, Fischer GW, Schoenknecht FD. 6. Gibbs RS, Duff P. Progress in pathogenesis 15. Schrag SJ, Hadler JL, Arnold KE, Martell- Neonatal Escherichia coli septicemia— and management of clinical intraamniotic Cleary P, Reingold A, Schuchat A. Risk fac- bacterial counts in blood. J Pediatr. 1974; infection. Am J Obstet Gynecol. 1991;164(5 tors for invasive, early-onset Escherichia 85(1):128–130 pt 1):1317–1326 coli infections in the era of widespread 25. Kellogg JA, Ferrentino FL, Goodstein MH, 7. Romero R, Quintero R, Oyarzun E, et al. intrapartum antibiotic use. Pediatrics. 2006; Liss J, Shapiro SL, Bankert DA. Frequency of Intraamniotic infection and the onset of 118(2):570–576 low level bacteremia in infants from birth labor in preterm premature rupture of the 16. Martius JA, Roos T, Gora B, et al. Risk fac- to two months of age. Pediatr Infect Dis J. membranes. Am J Obstet Gynecol. 1988;159 tors associated with early-onset sepsis in 1997;16(4):381–385 (3):661–666 premature infants. Eur J Obstet Gynecol 26. Neal PR, Kleiman MB, Reynolds JK, Allen SD, 8. DiGiulio DB, Romero R, Kusanovic JP, et al. Reprod Biol. 1999;85(2):151–158 Lemons JA, Yu PL. Volume of blood sub- Prevalence and diversity of microbes in the 17. Stoll BJ, Hansen NI, Sánchez PJ, et al; mitted for culture from neonates. J Clin amniotic fluid, the fetal inflammatory response, Eunice Kennedy Shriver National Institute of Microbiol. 1986;24(3):353–356 and pregnancy outcome in women with pre- Child Health and Human Development Neo- 27. Connell TG, Rele M, Cowley D, Buttery JP, term pre-labor rupture of membranes. Am J natal Research Network. Early onset neonatal Curtis N. How reliable is a negative blood Reprod Immunol. 2010;64(1):38–57 sepsis: the burden of group B Streptococcal culture result? Volume of blood submitted 9. DiGiulio DB, Romero R, Amogan HP, et al. and E. coli disease continues. Pediatrics. for culture in routine practice in a children’s Microbial prevalence, diversity and abun- 2011;127(5):817–826 hospital. Pediatrics. 2007;119(5):891–896 dance in amniotic fluid during preterm 18. Wynn JL, Levy O. Role of innate host 28. Pourcyrous M, Korones SB, Bada HS, Patter- labor: a molecular and culture-based in- defenses in susceptibility to early-onset son T, Baselski V. Indwelling umbilical arte- vestigation. PLoS ONE. 2008;3(8):e3056 neonatal sepsis. Clin Perinatol. 2010;37 rial catheter: a preferred sampling site for10. Viscardi RM. Ureaplasma species: role in (2):307–337 blood culture. Pediatrics. 1988;81(6):821–825 diseases of prematurity. Clin Perinatol. 19. Escobar GJ, Li DK, Armstrong MA, et al. 29. Anagnostakis D, Kamba A, Petrochilou V, 2010;37(2):393–409 Neonatal sepsis workups in infants >/=2000 Arseni A, Matsaniotis N. Risk of infectionPEDIATRICS Volume 129, Number 5, May 2012 1013
    • associated with umbilical vein catheterization. 42. Stoll BJ, Hansen N, Fanaroff AA, et al. To tap at: www.pediatrics.org/cgi/content/full/123/ A prospective study in 75 newborn infants. or not to tap: high likelihood of meningitis 6/e967 J Pediatr. 1975;86(5):759–765 without sepsis among very low birth weight 55. Rajesh NT, Dutta S, Prasad R, Narang A. Effect30. Polin JI, Knox I, Baumgart S, Campman E, infants. Pediatrics. 2004;113(5):1181–1186 of delay in analysis on neonatal cerebrospinal Mennuti MT, Polin RA. Use of umbilical cord 43. Garges HP, Moody MA, Cotten CM, et al. fluid parameters. Arch Dis Child Fetal blood culture for detection of neonatal bac- Neonatal meningitis: what is the correlation Neonatal Ed. 2010;95(1):F25–F29 teremia. Obstet Gynecol. 1981;57(2):233–237 among cerebrospinal fluid cultures, blood 56. Christensen RD, Rothstein G, Hill HR, Hall RT.31. Visser VE, Hall RT. Urine culture in the cultures, and cerebrospinal fluid parame- Fatal early onset group B streptococcal evaluation of suspected neonatal sepsis. ters? Pediatrics. 2006;117(4):1094–1100 sepsis with normal leukocyte counts. J Pediatr. 1979;94(4):635–638 44. Shah SS, Ebberson J, Kestenbaum LA, Hodinka Pediatr Infect Dis. 1985;4(3):242–24532. Vasan U, Lim DM, Greenstein RM, Raye JR. RL, Zorc JJ. Age-specific reference values for 57. Engle WD, Rosenfeld CR. Neutropenia in Origin of gastric aspirate polymorphonuclear cerebrospinal fluid protein concentration in high-risk neonates. J Pediatr. 1984;105(6): leukocytes in infants born after prolonged neonates and young infants. J Hosp Med. 982–986 rupture of membranes. J Pediatr. 1977;91(1): 2011;6(1):22–27 58. Manroe BL, Weinberg AG, Rosenfeld CR, 69–72 45. Byington CL, Kendrick J, Sheng X. Normative Browne R. The neonatal blood count in33. Mims LC, Medawar MS, Perkins JR, Grubb cerebrospinal fluid profiles in febrile in- health and disease. I. Reference values for WR. Predicting neonatal infections by evalu- fants. J Pediatr. 2011;158(1):130–134 neutrophilic cells. J Pediatr. 1979;95(1):89–98 ation of the gastric aspirate: a study in two 46. Ahmed A, Hickey SM, Ehrett S, et al. Cere- 59. Schelonka RL, Yoder BA, desJardins SE, Hall hundred and seven patients. Am J Obstet brospinal fluid values in the term neonate. RB, Butler J. Peripheral leukocyte count Gynecol. 1972;114(2):232–238 Pediatr Infect Dis J. 1996;15(4):298–303 and leukocyte indexes in healthy newborn34. Choi Y, Saha SK, Ahmed AS, et al. Routine 47. Bonadio WA, Stanco L, Bruce R, Barry D, Smith term infants. J Pediatr. 1994;125(4):603–606 skin cultures in predicting sepsis pathogens D. Reference values of normal cerebrospinal 60. Mouzinho A, Rosenfeld CR, Sánchez PJ, Risser among hospitalized preterm neonates in fluid composition in infants ages 0 to 8 weeks. R. Revised reference ranges for circulating Bangladesh. Neonatology. 2008;94(2):123– Pediatr Infect Dis J. 1992;11(7):589–591 neutrophils in very-low-birth-weight neonates. 131 48. Nascimento-Carvalho CM, Moreno-Carvalho Pediatrics. 1994;94(1):76–8235. Evans ME, Schaffner W, Federspiel CF, Cotton OA. Normal cerebrospinal fluid values in 61. Schmutz N, Henry E, Jopling J, Christensen RB, McKee KT, Jr, Stratton CW. Sensitivity, full-term gestation and premature neo- RD. Expected ranges for blood neutrophil specificity, and predictive value of body nates. Arq Neuropsiquiatr. 1998;56(3A): concentrations of neonates: the Manroe surface cultures in a neonatal intensive 375–380 and Mouzinho charts revisited. J Perinatol. care unit. JAMA. 1988;259(2):248–252 49. Martín-Ancel A, García-Alix A, Salas S, Del 2008;28(4):275–28136. Sherman MP, Goetzman BW, Ahlfors CE, Castillo F, Cabañas F, Quero J. Cerebrospi- 62. Christensen RD, Rothstein G. Pitfalls in the Wennberg RP. Tracheal asiration and its nal fluid leucocyte counts in healthy neo- interpretation of leukocyte counts of newborn clinical correlates in the diagnosis of nates. Arch Dis Child Fetal Neonatal Ed. infants. Am J Clin Pathol. 1979;72(4):608–611 congenital pneumonia. Pediatrics. 1980;65 2006;91(5):F357–F358 63. Lambert RM, Baer VL, Wiedmeier SE, Henry (2):258–263 50. Kestenbaum LA, Ebberson J, Zorc JJ, Hodinka E, Burnett J, Christensen RD. Isolated ele-37. Srinivasan HB, Vidyasagar D. Endotracheal RL, Shah SS. Defining cerebrospinal fluid vated blood neutrophil concentration at aspirate cultures in predicting sepsis in white blood cell count reference values in altitude does not require NICU admission if ventilated neonates. Indian J Pediatr. 1998; neonates and young infants. Pediatrics. 2010; appropriate reference ranges are used. 65(1):79–84 125(2):257–264 J Perinatol. 2009;29(12):822–82538. Johnson CE, Whitwell JK, Pethe K, Saxena K, 51. Smith PB, Garges HP, Cotton CM, Walsh TJ, 64. Christensen RD, Rothstein G. Exhaustion of Super DM. Term newborns who are at risk Clark RH, Benjamin DK Jr. Meningitis in mature marrow neutrophils in neonates for sepsis: are lumbar punctures necessary? preterm neonates: importance of cerebro- with sepsis. J Pediatr. 1980;96(2):316–318 Pediatrics. 1997;99(4). Available at: www. spinal fluid parameters. Am J Perinatol. pediatrics.org/cgi/content/full/99/4/e10 2008;25(7):421–426 65. Schelonka RL, Yoder BA, Hall RB, et al. Dif- ferentiation of segmented and band neu-39. Eldadah M, Frenkel LD, Hiatt IM, Hegyi T. 52. Smith PB, Cotten CM, Garges HP, et al. A trophils during the early newborn period. Evaluation of routine lumbar punctures in comparison of neonatal Gram-negative rod J Pediatr. 1995;127(2):298–300 newborn infants with respiratory distress and Gram-positive cocci meningitis. J Per- syndrome. Pediatr Infect Dis J. 1987;6(3): inatol. 2006;26(2):111–114 66. Lloyd BW, Oto A. Normal values for mature 243–246 53. Greenberg RG, Smith PB, Cotten CM, Moody and immature neutrophils in very preterm40. Isaacs D, Barfield CP, Grimwood K, McPhee MA, Clark RH, Benjamin DK Jr. Traumatic babies. Arch Dis Child. 1982;57(3):233–235 AJ, Minutillo C, Tudehope DI; Australian Study lumbar punctures in neonates: test per- 67. Gerdes JS, Polin RA. Sepsis screen in neo- Group for Neonatal Infections. Systemic formance of the cerebrospinal fluid white nates with evaluation of plasma fibronec- bacterial and fungal infections in infants blood cell count. Pediatr Infect Dis J. 2008; tin. Pediatr Infect Dis J. 1987;6(5):443–446 in Australian neonatal units. Med J Aust. 27(12):1047–1051 68. Newman TB, Puopolo KM, Wi S, Draper D, 1995;162(4):198–201 54. Kanegaye JT, Nigrovic LE, Malley R, et al; Escobar GJ. Interpreting complete blood41. May M, Daley AJ, Donath S, Isaacs D; Aus- American Academy of Pediatrics, Pediatric counts soon after birth in newborns at risk tralasian Study Group for Neonatal Infec- Emergency Medicine Collaborative Research for sepsis. Pediatrics. 2010;126(5):903–909 tions. Early onset neonatal meningitis in Committee. Diagnostic value of immature 69. Rozycki HJ, Stahl GE, Baumgart S. Impaired Australia and New Zealand, 1992–2002. Arch neutrophils (bands) in the cerebrospinal sensitivity of a single early leukocyte count Dis Child Fetal Neonatal Ed. 2005;90(4):F324– fluid of children with cerebrospinal fluid in screening for neonatal sepsis. Pediatr F327 pleocytosis. Pediatrics. 2009;123(6). Available Infect Dis J. 1987;6(5):440–4421014 FROM THE AMERICAN ACADEMY OF PEDIATRICS
    • FROM THE AMERICAN ACADEMY OF PEDIATRICS70. Manzoni P, Mostert M, Galletto P, et al. Is 79. Chiesa C, Natale F, Pascone R, et al. C re- 87. Nizet V, Klein JO. Bacterial sepsis and men- thrombocytopenia suggestive of organism- active protein and procalcitonin: reference ingitis. In: Remington JS, Klein JO, Wilson specific response in neonatal sepsis? intervals for preterm and term newborns Christopher B, Nizet V, eds. Infectious Dis- Pediatr Int. 2009;51(2):206–210 during the early neonatal period. Clin Chim eases of the Fetus and Newborn Infant. 7th71. Guida JD, Kunig AM, Leef KH, McKenzie SE, Acta. 2011;412(11-12):1053–1059 ed. Philadelphia, PA: Saunders; 2010:222–275 Paul DA. Platelet count and sepsis in very low 80. Hayashi Y, Paterson DL. Strategies for re- 88. Pickering LK, Baker CJ, Kimberlin DW, Long birth weight neonates: is there an organism- duction in duration of antibiotic use in SS, eds. Red Book: 2009 Report of the specific response? Pediatrics. 2003;111(6 pt hospitalized patients. Clin Infect Dis. 2011; Committee on Infectious Diseases. 28th ed. 1):1411–1415 52(10):1232–1240 Elk Grove Village, IL: American Academy of72. Vouloumanou EK, Plessa E, Karageorgopoulos 81. Rodwell RL, Leslie AL, Tudehope DI. Early Pediatrics; 2009 DE, Mantadakis E, Falagas ME. Serum diagnosis of neonatal sepsis using a he- 89. Cordero L, Ayers LW. Duration of empiric procalcitonin as a diagnostic marker for matologic scoring system. J Pediatr. 1988; antibiotics for suspected early-onset sep- neonatal sepsis: a systematic review and 112(5):761–767 sis in extremely low birth weight infants. meta-analysis. Intensive Care Med. 2011;37 82. Baker CN, Thornsberry C, Facklam RR. Syn- Infect Control Hosp Epidemiol. 2003;24(9): (5):747–762 ergism, killing kinetics, and antimicrobial 662–66673. Benitz WE. Adjunct laboratory tests in the susceptibility of group A and B streptococci. 90. Cotten CM, Taylor S, Stoll B, et al; NICHD diagnosis of early-onset neonatal sepsis. Antimicrob Agents Chemother. 1981;19(5): Neonatal Research Network. Prolonged du- Clin Perinatol. 2010;37(2):421–438 716–725 ration of initial empirical antibiotic treat-74. Gabay C, Kushner I. Acute-phase proteins and 83. MacGowan A, Wootton M, Bowker K, Holt ment is associated with increased rates of other systemic responses to inflammation. HA, Reeves D. Ampicillin-aminoglycoside in- necrotizing enterocolitis and death for N Engl J Med. 1999;340(6):448–454 teraction studies using Listeria monocy- extremely low birth weight infants. Pedi-75. Philip AG. Response of C-reactive protein togenes. J Antimicrob Chemother. 1998;41 atrics. 2009;123(1):58–66 in neonatal Group B streptococcal in- (3):417–418 91. Kuppala VS, Meinzen-Derr J, Morrow AL, fection. Pediatr Infect Dis. 1985;4(2):145– 148 84. Bryan CS, John JF, Jr, Pai MS, Austin TL. Schibler KR. Prolonged initial empirical Gentamicin vs cefotaxime for therapy of neo- antibiotic treatment is associated with ad-76. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in natal sepsis. Relationship to drug resistance. verse outcomes in premature infants. the diagnosis of neonatal infection. Pedi- Am J Dis Child. 1985;139(11):1086–1089 J Pediatr. 2011;159(5):720–725 atrics. 1998;102(4). Available at: www.pedi- 85. Manzoni P, Farina D, Leonessa M, et al. Risk 92. Alexander VN, Northrup V, Bizzarro MJ. atrics.org/cgi/content/full/102/4/e41 factors for progression to invasive fungal Antibiotic exposure in the newborn in-77. Dandona P, Nix D, Wilson MF, et al. Procalci- infection in preterm neonates with fungal tensive care unit and the risk of necrotiz- tonin increase after endotoxin injection in colonization. Pediatrics. 2006;118(6):2359– ing enterocolitis. J Pediatr. 2011;159(3): normal subjects. J Clin Endocrinol Metab. 2364 392–397 1994;79(6):1605–1608 86. Bégué P, Floret D, Mallet E, et al. Pharma- 93. Centers for Disease Control and Prevention.78. Lapillonne A, Basson E, Monneret G, Bienvenu cokinetics and clinical evaluation of cefo- Prevention of perinatal group B strepto- J, Salle BL. Lack of specificity of procalcitonin taxime in children suffering with purulent coccal disease—revised guidelines from for sepsis diagnosis in premature infants. meningitis. J Antimicrob Chemother. 1984; CDC, 2010. MMWR Recomm Rep. 2010;59 Lancet. 1998;351(9110):1211–1212 14(suppl B):161–165 (RR-10):1–36PEDIATRICS Volume 129, Number 5, May 2012 1015