pediatrics 2012 polin 1006 15

CLINICAL REPORT

Management of Neonates With Suspected or ProvenEarly-Onset Bacterial Sepsis

abstractWith improved obstetrical management and evidence-based use ofintrapartum antimicrobial therapy, early-onset neonatal sepsis is be-coming less frequent. However, early-onset sepsis remains one of themost common causes of neonatal morbidity and mortality in the pre-term population. The identication of neonates at risk for early-onsetsepsis is frequently based on a constellation of perinatal risk factorsthat are neither sensitive nor specic. Furthermore, diagnostic testsfor neonatal sepsis have a poor positive predictive accuracy. As a result,clinicians often treat well-appearing infants for extended periods of time,even when bacterial cultures are negative. The optimal treatment ofinfants with suspected early-onset sepsis is broad-spectrum antimicro-bial agents (ampicillin and an aminoglycoside). Once a pathogen is iden-tied, antimicrobial therapy should be narrowed (unless synergism isneeded). Recent data suggest an association between prolonged empir-ical treatment of preterm infants (5 days) with broad-spectrum anti-biotics and higher risks of late onset sepsis, necrotizing enterocolitis,and mortality. To reduce these risks, antimicrobial therapy should bediscontinued at 48 hours in clinical situations in which the probabilityof sepsis is low. The purpose of this clinical report is to provide apractical and, when possible, evidence-based approach to the manage-ment of infants with suspected or proven early-onset sepsis. Pediatrics2012;129:10061015

INTRODUCTION

Suspected sepsis is one of the most common diagnoses made in theNICU.1 However, the signs of sepsis are nonspecic, and inammatorysyndromes 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 cliniciansare threefold: (1) identifying neonates with a high likelihood of sepsispromptly and initiating antimicrobial therapy; (2) distinguishing high-risk healthy-appearing infants or infants with clinical signs who do notrequire treatment; and (3) discontinuing antimicrobial therapy oncesepsis is deemed unlikely. The purpose of this clinical report is toprovide a practical and, when possible, evidence-based approach to thediagnosis and management of early-onset sepsis, dened by the Na-tional Institute of Child Health and Human Development and VermontOxford Networks as sepsis with onset at 3 days of age.

Richard A. Polin, MD and the COMMITTEE ON FETUS ANDNEWBORN

KEY WORDSearly-onset sepsis, antimicrobial therapy, group B streptococcus,meningitis, gastric aspirate, tracheal aspirate, chorioamnionitis,sepsis screen, blood culture, lumbar puncture, urine culture,body surface cultures, white blood count, acute phase reactants,prevention strategies

ABBREVIATIONSCFUcolony-forming unitsCRPC-reactive proteinCSFcerebrospinal uidGBSgroup B streptococciI/Timmature to total neutrophil (ratio)PMNpolymorphonuclear leukocytePPROMpreterm premature rupture of membranes

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave led conict of interest statements with the AmericanAcademy of Pediatrics. Any conicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-0541

doi:10.1542/peds.2012-0541

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

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PATHOGENESIS ANDEPIDEMIOLOGY OF EARLY-ONSETSEPSIS

Before birth, the fetus optimally ismaintained in a sterile environment.Organisms causing early-onset sepsisascend from the birth canal eitherwhen the amniotic membranes ruptureor leak before or during the course oflabor, resulting in intra-amniotic infec-tion.2 Commonly referred to as cho-rioamnionitis, intra-amniotic infectionindicates infection of the amniotic uid,membranes, placenta, and/or decidua.

Group B streptococci (GBS) can alsoenter the amniotic uid through occulttears. Chorioamnionitis is a major riskfactor for neonatal sepsis. Sepsis canbegin in utero when the fetus inhalesor swallows infected amniotic uid.The neonate can also develop sepsis inthe hours or days after birth whencolonized skin or mucosal surfaces arecompromised. The essential criterionfor the clinical diagnosis of chorio-amnionitis is maternal fever. Othercriteria are relatively insensitive. Whendening intra-amniotic infection (cho-rioamnionitis) for clinical researchstudies, the diagnosis is typically basedon the presence of maternal fever ofgreater than 38C (100.4F) and at leasttwo of the following criteria: maternalleukocytosis (greater than 15 000 cells/mm3), maternal tachycardia (greaterthan 100 beats/minute), fetal tachycar-dia (greater than 160 beats/minute),uterine tenderness, and/or foul odor ofthe amniotic uid. These thresholds areassociated with higher rates of neo-natal and maternal morbidity.

Nonetheless, the diagnosis of cho-rioamnionitis must be considered evenwhen maternal fever is the sole abnor-mal nding. Although fever is commonin women who receive epidural anes-thesia (15%20%), histologic evidenceof acute chorioamnionitis is very com-mon in women who become febrileafter an epidural (70.6%).3 Furthermore,

most of these women with histologicchorioamnionitis do not have a positiveplacental culture.3 The incidence of clin-ical chorioamnionitis varies inverselywith gestational age. In the NationalInstitute of Child Health and HumanDevelopment Neonatal Research Net-work, 14% to 28% of women deliveringpreterm infants at 22 through 28 weeksgestation exhibited signs compatiblewith chorioamnionitis.4 The major riskfactors for chorioamnionitis includelow parity, spontaneous labor, longerlength of labor and membrane rupture,multiple digital vaginal examinations(especially with ruptured membranes),meconium-stained amniotic uid, internalfetal or uterine monitoring, and pres-ence of genital tract microorganisms(eg, Mycoplasma hominis).5

At term gestation, less than 1% ofwomen with intact membranes willhave organisms cultured from amni-otic uid.6 The rate can be higher ifthe integrity of the amniotic cavity iscompromised by procedures beforebirth (eg, placement of a cerclage oramniocentesis).6 In women with pre-term labor and intact membranes, therate of microbial invasion of the amni-otic cavity is 32%, and if there is pre-term premature rupture of membranes(PPROM), the rate may be as high as75%.7 Many of the pathogens recoveredfrom amniotic uid in women with pre-term labor or PPROM (eg, Ureaplasmaspecies or Mycoplasma species) donot cause early-onset sepsis.810 How-ever, both Ureaplasma and Myco-plasma organisms can be recoveredfrom the bloodstream of infants whosebirth weight is less than 1500 g.11 Whena pathogen (eg, GBS) is recovered fromamniotic uid, the attack rate of neo-natal sepsis can be as high as 20%.12

Infants born to women with PPROMwho are colonized with GBS have anestimated attack rate of 33% to 50%when intrapartum prophylaxis is notgiven.13

The major risk factors for early-onsetneonatal sepsis are preterm birth,maternal colonization with GBS, ruptureof membranes >18 hours, and mater-nal signs or symptoms of intra-amnioticinfection.1416 Other variables includeethnicity (ie, black women are at higherrisk of being colonized with GBS), lowsocioeconomic status, male sex, andlow Apgar scores. Preterm birth/lowbirth weight is the risk factor mostclosely associated with early-onset sep-sis.17 Infant birth weight is inverselyrelated to risk of early-onset sepsis.The increased risk of early-onset sep-sis in preterm infants is also related tocomplications of labor and deliveryand immaturity of innate and adaptiveimmunity.18

DIAGNOSTIC TESTING FOR SEPSIS

The clinical diagnosis of sepsis in theneonate is difcult, because many ofthe signs of sepsis are nonspecic andare observed with other noninfectiousconditions. Although a normal physicalexamination is evidence that sepsis isnot present,19,20 bacteremia can occurin the absence of clinical signs.21 Avail-able diagnostic testing is not helpful indeciding which neonate requires em-pirical antimicrobial therapy but canassist with the decision to discontinuetreatment.22

Blood Culture

A single blood culture in a sufcientvolume is required for all neonateswith suspected sepsis. Data suggestthat 1.0 mL of blood should be theminimum volume drawn for culturewhen a single pediatric blood culturebottle is used. Dividing the specimen inhalf and inoculating aerobic and an-aerobic bottles is likely to decrease thesensitivity. Although 0.5 mL of bloodhas previously been considered ac-ceptable, in vitro data from Schelonkaet al demonstrated that 0.5 mL wouldnot reliably detect low-level bacteremia

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(4 colony-forming units [CFU]/mL orless).23 Furthermore, up to 25% ofinfants with sepsis have low colonycount bacteremia (4 CFU/mL), andtwo-thirds of infants younger than 2months of age have colony counts

Peripheral White Blood Cell Countand Differential Count

Total white blood cell counts have littlevalue in the diagnosis of early-onsetsepsis and have a poor positive pre-dictive accuracy.56,57 Many investi-gators have analyzed subcomponentsof the white blood cell count (neutrophilindices)absolute neutrophil count,absolute band count, and immature tototal neutrophil (I/T)ratioto identifyinfected infants. Like most diagnostictests for neonatal sepsis, neutrophil in-dices have proven most useful for ex-cluding infants without infection ratherthan identifying infected neonates. Neu-tropenia may be a better marker forneonatal sepsis and has better speci-city than an elevated neutrophil count,because few conditions besides sepsis(maternal pregnancy-induced hyper-tension, asphyxia, and hemolytic dis-ease) depress the neutrophil count ofneonates.58 The denitions for neutro-penia vary with gestational age,5861

type of delivery (infants born by cesar-ean delivery without labor have lowercounts than infants delivered vagi-nally),61 site of sampling (neutrophilcounts are lower in samples fromarterial blood),62 and altitude (infantsborn at elevated altitudes have highertotal neutrophil counts).63 In late pre-term and term infants, the denitionfor neutropenia most commonly usedis that suggested by Manroe et al(

concentrations to determine the dura-tion of antimicrobial therapy in an infantwith an elevated value (1.0 mg/dL).Procalcitonin concentrations increasewithin 2 hours of an infectious episode,peak at 12 hours, and normalize within2 to 3 days in healthy adult volunteers.77

A physiologic increase in procalcitoninconcentration occurs within the rst24 hours of birth, and an increase inserum concentrations can occur withnoninfectious conditions (eg, respira-tory distress syndrome).78 Procalcitoninconcentration has a modestly bettersensitivity than does CRP concentrationbut is less specic.73 Chiesa and col-leagues have published normal valuesfor procalcitonin concentrations in termand preterm infants.79 There is evidencefrom studies conducted in adult pop-ulations, the majority of which focusedon patients with sepsis in the ICU, thatsignicant reductions in use of anti-microbial agents can be achieved inpatients whose treatment is guided byprocalcitonin concentration.80

Sepsis Screening Panels

Hematologic scoring systems usingmultiple laboratory values (eg, whiteblood cell count, differential count, andplatelet count) have been recommen-ded as useful diagnostic aids. No matterwhat combination of tests is used, thepositive predictive accuracy of scoringsystems is poor unless the score isvery high. Rodwell et al described ascoring system in which a score of 1 wasassigned to 1 of 7 ndings, includingabnormalities of leukocyte count, totalneutrophil count, increased immaturepolymorphonuclear leukocyte (PMN)count, increased I/T ratio, immature tomature PMN ratio >0.3, platelet count150 000/mm3, and pronounced degen-erative changes (ie, toxic granulations)in PMNs.81 In this study, two-thirdsof preterm infants and 90% of terminfants with a hematologic score3 did not have proven sepsis.81

Furthermore, scores obtained in therst several hours after birth have beenshown to have poorer sensitivity andnegative predictive value than scoresobtained at 24 hours of age.67 Sepsisscreening panels commonly includeneutrophil indices and acute-phase re-actants (usually CRP concentration). Thepositive predictive value of the sepsisscreen in neonates is poor (99%) in small clinicalstudies.22 Sepsis screening tests might beof value in deciding which high-riskhealthy-appearing neonates do not needantimicrobial agents or whether therapycan be safely discontinued.

TREATMENT OF INFANTS WITHSUSPECTED EARLY-ONSET SEPSIS

In the United States, the most commonpathogens responsible for early-onsetneonatal sepsis are GBS and Escherichiacoli.17 A combination of ampicillin andan aminoglycoside (usually gentamicin)is generally used as initial therapy, andthis combination of antimicrobial agentsalso has synergistic activity againstGBS and Listeria monocytogenes.82,83

Third-generation cephalosporins (eg,cefotaxime) represent a reasonable al-ternative to an aminoglycoside. However,several studies have reported rapiddevelopment of resistance when cefo-taxime has been used routinely for thetreatment of early-onset neonatal sep-sis,84 and extensive/prolonged use ofthird-generation cephalosporins is a riskfactor for invasive candidiasis.85 Be-cause of its excellent CSF penetration,empirical or therapeutic use of cefo-taxime should be restricted for use ininfants with meningitis attributable toGram-negative organisms.86 Ceftriax-one is contraindicated in neonatesbecause it is highly protein boundand may displace bilirubin, leading to arisk of kernicterus. Bacteremia without anidentiable focus of infection is generallytreated for 10 days.87 Uncomplicated

meningitis attributable to GBS is trea-ted for a minimum of 14 days.88 Otherfocal infections secondary to GBS (eg,cerebritis, osteomyelitis, endocarditis)are treated for longer durations.88 Gram-negative meningitis is treated forminimum of 21 days or 14 days afterobtaining a negative culture, whicheveris longer.88 Treatment of Gram-negativemeningitis should include cefotaximeand an aminoglycoside until the resultsof susceptibility testing are known.87,88

The duration of antimicrobial therapyin infants with negative blood culturesis controversial. Many women receiveantimicrobial agents during labor asprophylaxis to prevent early-onset GBSinfections or for management of sus-pected intra-amniontic infection orPPROM. In those instances, postnatalblood cultures may be sterile (falsenegative). When considering the dura-tion of therapy in infants with negativeblood cultures, the decision shouldinclude consideration of the clinicalcourse as well as the risks associatedwith longer courses of antimicrobialagents. In a retrospective study by Cor-dero and Ayers, the average duration oftreatment in 695 infants (5 days)in infants with suspected early-onsetsepsis (and negative blood cultures)with death and necrotizing enterocoli-tis.90 Two recent papers also supportthis association.91,92

PREVENTION STRATEGIES FOREARLY-ONSET SEPSIS

The only intervention proven to decreasethe incidence of early-onset neonatalsepsis is maternal treatment withintrapartum intravenous antimicro-bial agents for the prevention of GBSinfections.93 Adequate prophylaxis isdened as penicillin (the preferredagent), ampicillin, or cefazolin given for

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4 hours before delivery. Erythromycinis no longer recommended for prophy-laxis because of high resistance rates.In parturients who have a nonseriouspenicillin allergy, cefazolin is the drugof choice. For parturients with a historyof serious penicillin allergy (anaphy-laxis, angioedema, respiratory com-promise, or urticaria), clindamycin isan acceptable alternative agent, butonly if the womans rectovaginal GBSscreening isolate has been tested anddocumented to be susceptible. If theclindamycin susceptibility is unknownor the GBS isolate is resistant to clin-damycin, vancomycin is an alternativeagent for prophylaxis. However, nei-ther clindamycin nor vancomycin hasbeen evaluated for efcacy in pre-venting early-onset GBS sepsis inneonates. Intrapartum antimicrobialagents are indicated for the followingsituations93:

1. Positive antenatal cultures or molec-ular test at admission for GBS (ex-cept for women who have a cesareandelivery without labor or membranerupture)

2. Unknown maternal colonization sta-tus with gestation 18 hours, ortemperature >100.4F (>38C)

3. GBS bacteriuria during the currentpregnancy

4. Previous infant with invasive GBSdisease

Management guidelines for the new-born infant have been published93 andare available online (http://www.cdc.gov/groupbstrep/guidelines/index.html).

CLINICAL CHALLENGES

Challenge 1: Identifying NeonatesWith Clinical Signs of Sepsis Witha High Likelihood of Early-OnsetSepsis Who Require AntimicrobialAgents Soon After Birth

Most infants with early-onset sepsisexhibit abnormal signs in the rst 24

hours of life. Approximately 1% of infantswill appear healthy at birth and thendevelop signs of infection after a vari-able time period.21 Every critically illinfant should be evaluated and receiveempirical broad-spectrum antimicrobialtherapy after cultures, even when thereare no obvious risk factors for sepsis.The greatest difculty faced by clini-cians is distinguishing neonates withearly signs of sepsis from neonateswith noninfectious conditions with rel-atively mild ndings (eg, tachypnea withor without an oxygen requirement). Inthis situation, data are insufcient toguide management. In more matureneonates without risk factors for in-fection who clinically improve over therst 6 hours of life (eg, need for oxygenis decreasing and respiratory distressis resolving), it is reasonable to with-hold antimicrobial therapy and monitorthe neonates closely. The 6-hour win-dow should not be considered absolute;however, most infants without infec-tion demonstrate some improvementover that time period. Any worsening ofthe infants condition should prompt

starting antimicrobial agents after cul-tures have been obtained.

Challenge 2: IdentifyingHealthy-Appearing Neonates Witha High Likelihood of Early-OnsetSepsis Who Require AntimicrobialAgents Soon After Birth

This category includes infants with 1 ofthe risk factors for sepsis noted pre-viously (colonization with GBS, prolongedrupture of membranes >18 hours, ormaternal chorioamnionitis). GBS is nota risk factor if the mother has receivedadequate intrapartum therapy (penicil-lin, ampicillin, or cefazolin for at least4 hours before delivery) or has a ce-sarean delivery with intact membranesin the absence of labor.93 The risk ofinfection in the newborn infant variesconsiderably with the risk factor pres-ent. The greatest risk of early-onsetsepsis occurs in infants born to womenwith chorioamnionitis who are alsocolonized with GBS and did not receiveintrapartum antimicrobial agents. Early-onset sepsis does occur in infants whoappear healthy at birth.21 Therefore,

FIGURE 1Evaluation of asymptomatic infants

some clinicians use diagnostic testswith a high negative predictive accuracyas reassurance that infection is notpresent (allowing them to withholdantimicrobial agents). The decision ofwhether to treat a high-risk infantdepends on the risk factors present,the frequency of observations, andgestational age. The threshold for

initiating antimicrobial treatment gen-erally decreases with increasing num-bers of risk factors for infection andgreater degrees of prematurity. Sug-gested algorithms for management ofhealthy-appearing, high-risk infants areshown in Figs 1, 2, and 3. Screeningblood cultures have not been shown tobe of value.21

CONCLUSIONS

The diagnosis and management of neo-nates with suspected early-onset sepsisare based on scientic principles mod-ied by the art and experience of thepractitioner. The following are well-established concepts related to neo-natal sepsis:

1. Neonatal sepsis is a major cause ofmorbidity and mortality.

2. Diagnostic tests for early-onsetsepsis (other than blood or CSF cul-tures) are useful for identifying in-fants with a low probability of sepsisbut not at identifying infants likely tobe infected.

3. One milliliter of blood drawn beforeinitiating antimicrobial therapy isneeded to adequately detect bacter-emia if a pediatric blood culture bot-tle is used.

4. Cultures of supercial body sites,gastric aspirates, and urine are ofno value in the diagnosis of early-onset sepsis.

5. Lumbar puncture is not needed inall infants with suspected sepsis (es-pecially those who appear healthy)but should be performed for infantswith signs of sepsis who can safelyundergo the procedure, for infantswith a positive blood culture, for in-fants likely to be bacteremic (on thebasis of laboratory data), and infantswho do not respond to antimicrobialtherapy in the expected manner.

6. The optimal treatment of infants withsuspected early-onset sepsis isbroad-spectrum antimicrobial agents(ampicillin and an aminoglycoside).Once the pathogen is identied,antimicrobial therapy should benarrowed (unless synergism isneeded).

7. Antimicrobial therapy should bediscontinued at 48 hours in clinicalsituations in which the probabilityof sepsis is low.

FIGURE 2Evaluation of asymptomatic infants 37 weeks gestation with risk factors for sepsis. aThe diagnosisof chorioamnionitis is problematic and has important implications for the management of thenewborn infant. Therefore, pediatric providers are encouraged to speak with their obstetricalcolleagues 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-sponse to treatment, and laboratory results. WBC, white blood cell; Diff, differential white blood cellcount.

FIGURE 3Evaluation of asymptomatic infants 37 weeks gestation with risk factors for sepsis (nochorioamnionitis). aInadequate treatment: Dened as the use of an antibiotic other than penicillin,ampicillin, or cefazolin or if the duration of antibiotics before delivery was

LEAD AUTHORRichard A. Polin, MD

COMMITTEE ON FETUS ANDNEWBORN, 20112012Lu-Ann Papile, MD, ChairpersonJill E. Baley, MDWilliam Benitz, MDWaldemar A. Carlo, MDJames Cummings, MDPraveen Kumar, MDRichard A. Polin, MD

Rosemarie C. Tan, MD, PhDKasper S. Wang, MDKristi L. Watterberg, MD

FORMER COMMITTEE MEMBERVinod K. Bhutani, MD

LIAISONSCAPT Wanda Denise Bareld, MD, MPH Centersfor Disease Control and PreventionGeorge Macones, MD American College ofObstetricians and Gynecologists

Ann L. Jefferies, MD Canadian Paediatric SocietyRosalie O. Mainous, PhD, RNC, NNP NationalAssociation of Neonatal NursesTonse N. K. Raju, MD, DCH National Institutesof Health

FORMER LIAISONWilliam Barth, Jr, MD American College ofObstetricians and Gynecologists

STAFFJim Couto, MA

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DOI: 10.1542/peds.2012-0541; originally published online April 30, 2012; 2012;129;1006Pediatrics

Richard A. Polin and the COMMITTEE ON FETUS AND NEWBORNSepsis

Management of Neonates With Suspected or Proven Early-Onset Bacterial

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Richard A. Polin and the COMMITTEE ON FETUS AND NEWBORNSepsis

Management of Neonates With Suspected or Proven Early-Onset Bacterial

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