Management of Management of Neonatal SepsisNeonatal Sepsis

Niki Kosmetatos, MDNiki Kosmetatos, MD

Anthony Piazza, MDAnthony Piazza, MD

Ira Adams-Chapman, MDIra Adams-Chapman, MD

J. Devn Cornish, MDJ. Devn Cornish, MD

Emory UniversityEmory University

Department of PediatricsDepartment of Pediatrics

Note: Dr. Cornish does not have any financial relationships to disclose nor will he discuss any non-approved drug or device uses.

Babies and Bacteria…Babies and Bacteria…

Gram positive bacteria (anthrax)

Gram negative bacteria (pseudomonas)

……Don’t mix!Don’t mix!

IncidenceIncidence MortalityMortality

– 13-69% world wide13-69% world wide– 13-15% of all neonatal deaths (US) (813-15% of all neonatal deaths (US) (8thth cause) cause)

MeningitisMeningitis– 0.4-2.8/1000 live births (US 0.2-0.4/1000)0.4-2.8/1000 live births (US 0.2-0.4/1000)– Mortality 13-59%; US 4% of all neonatal deathsMortality 13-59%; US 4% of all neonatal deaths

SepsisSepsis– 1-21/1000 world wide; US,1-2/1000 live births1-21/1000 world wide; US,1-2/1000 live births– Culture proven 2/1000 (3-8% of infants Culture proven 2/1000 (3-8% of infants

evaluated for sepsis); 10-20/1000 VLBWevaluated for sepsis); 10-20/1000 VLBW– Prematures Prematures <1000 g <1000 g 26/1000 26/1000

1000 - 2000 g 1000 - 2000 g 8-9/10008-9/1000

Predisposing FactorsPredisposing FactorsGeneral Host FactorsGeneral Host Factors Prematurity (OR 25 if < 1,000 gms)Prematurity (OR 25 if < 1,000 gms) Race – GBS sepsis blacks>whites (x4)Race – GBS sepsis blacks>whites (x4) Sex – sepsis & meningitis more common Sex – sepsis & meningitis more common

in males, esp. gram negative infectionsin males, esp. gram negative infections Birth asphyxia, meconium staining, stressBirth asphyxia, meconium staining, stress Breaks in skin & mucous membrane Breaks in skin & mucous membrane

integrity integrity (e.g. omphalocoele, meningomyelocoele)(e.g. omphalocoele, meningomyelocoele)

Environmental exposureEnvironmental exposure Procedures Procedures (e.g. lines, ET-tubes)(e.g. lines, ET-tubes)

Predisposing FactorsPredisposing Factors Maternal/Obstetrical FactorsMaternal/Obstetrical Factors

GeneralGeneral – – socioeconomic status, poor prenatal socioeconomic status, poor prenatal care, vaginal flora, maternal substance abuse, care, vaginal flora, maternal substance abuse, known exposures, known exposures, prematurityprematurity, twins, twins

Maternal infectionsMaternal infections – –chorioamnionitis (1-10% of chorioamnionitis (1-10% of pregnancies), fever (>38° C/100.4° F), sustained pregnancies), fever (>38° C/100.4° F), sustained fetal tachycardia, venereal diseases, fetal tachycardia, venereal diseases, UTI/bacteriuria, foul smelling lochia, GBS+ (OR 204), UTI/bacteriuria, foul smelling lochia, GBS+ (OR 204), other infectionsother infections

Obstetrical manipulationObstetrical manipulation – – amniocentesis, amniocentesis, amnioinfusion, prolonged labor, fetal monitoring, amnioinfusion, prolonged labor, fetal monitoring, digital exams, previa/abruption?digital exams, previa/abruption?

Premature & Prolonged ROM, preterm laborPremature & Prolonged ROM, preterm labor

Predisposing FactorsPredisposing Factors

Overall sepsis rateOverall sepsis rate 2/10002/1000

Maternal FeverMaternal Fever 4/10004/1000

PROMPROM 10-13/100010-13/1000

Fever & PROMFever & PROM 87/100087/1000

Preterm Labor/PROMPreterm Labor/PROM

Prematurity Prematurity (~10%) 15-25% due to (~10%) 15-25% due to maternal infectionmaternal infection

>18-24h term; >12-18h preterm>18-24h term; >12-18h preterm Bacterial infectionBacterial infection

synthesis of PGsynthesis of PG– Macrophage TNF/IL stimulate PG Macrophage TNF/IL stimulate PG

synthesis, cytokine releasesynthesis, cytokine release****– Release of collagenase & elastase Release of collagenase & elastase

ROMROM + Amniotic fluid cultures 15% + Amniotic fluid cultures 15% (with (with

intact membranes)intact membranes)

SSEPSISEPSISORGANISMSORGANISMS (all babies) (all babies) Group B strep Group B strep (most common G+)(most common G+) 41%41%

Other strep Other strep 23%23%

Coliforms Coliforms (E. coli most common G-)(E. coli most common G-) 17%17%

Staph aureusStaph aureus 4% 4%

ListeriaListeria 2%2%

Nosocomial infectionsNosocomial infections CandidaCandida Note: 73% G+ and 27% G-Note: 73% G+ and 27% G-

SSEPSISEPSISORGANISMSORGANISMS (VLBW) (VLBW) Group B strep Group B strep (most common G+)(most common G+) 12%12%

Other strep Other strep 9% 9%

Coliforms Coliforms (E. coli most common G-)(E. coli most common G-) 41%41%

CONSCONS 15%15%

ListeriaListeria 2%2%

Nosocomial infectionsNosocomial infections CandidaCandida 2%2%

Note: 45% G+ and 53% G-Note: 45% G+ and 53% G-Source: Stoll et al Ped Inf Dis 2005, 24:635Source: Stoll et al Ped Inf Dis 2005, 24:635

Routes of InfectionRoutes of Infection

Transplacental/HematogenousTransplacental/Hematogenous Ascending/Birth CanalAscending/Birth Canal AspirationAspiration Device Associated InfectionDevice Associated Infection NosocomialNosocomial EpidemicEpidemic

Transplacental/Transplacental/HematogenousHematogenous Organisms (Not just “TORCHS”)Organisms (Not just “TORCHS”)

Toxoplasmosis Toxoplasmosis ParvovirusParvovirusRubella Rubella GonorrheaGonorrheaCytomegalovirus Cytomegalovirus MumpsMumpsHerpes* Herpes* TBTBSyphilis Syphilis VaricellaVaricellaAcute VirusesAcute Viruses HIVHIV

CoxsackieCoxsackie PolioPolioAdenovirusAdenovirus GBSGBSEchoEcho MalariaMalariaEnterovirusEnterovirus LymeLyme

Ascending/Birth CanalAscending/Birth Canal

Organisms - GI/GU flora, Organisms - GI/GU flora, Cervical/BloodCervical/Blood

E. Coli E. Coli HerpesHerpes

GBSGBS CandidaCandida

ChlamydiaChlamydia HIVHIV

UreaplasmaUreaplasma MycoplasmaMycoplasma

ListeriaListeria HepatitisHepatitis

EnterococcusEnterococcus AnaerobesAnaerobes

GonorrheaGonorrhea SyphilisSyphilis

HPVHPV

NosocomialNosocomial Organisms – Organisms –

Skin Flora, Equipment/Environment Skin Flora, Equipment/Environment Staphylococcus – Coagulase neg & posStaphylococcus – Coagulase neg & posMRSAMRSAKlebsiellaKlebsiellaPseudomonasPseudomonasProteusProteusEnterobacterEnterobacterSerratiaSerratiaRotavirusRotavirusClostridium – C dificileClostridium – C dificileFungiFungi

InfectionInfection

TimingTiming

OnsetOnset– Early OnsetEarly Onset 1 1stst 24 hrs 24 hrs 85 %85 %

24-48 hrs24-48 hrs5%5%

– Late OnsetLate Onset 7-90 days 7-90 days

SymptomsSymptoms Non-specific/Common Non-specific/Common

– Respiratory distress Respiratory distress (90%)(90%) - - RR, apnea RR, apnea (55%), (55%),

hypoxia/vent need hypoxia/vent need (36%), (36%), flaring/gruntingflaring/grunting

– Temperature instability, feeding problemsTemperature instability, feeding problems– Lethargy-irritability Lethargy-irritability (23%)(23%)

– Gastrointestinal – Gastrointestinal – poor feeding, vomiting, poor feeding, vomiting, abdominal distention, ileus, diarrheaabdominal distention, ileus, diarrhea

– Color—Color—Jaundice, pallor, mottlingJaundice, pallor, mottling

– Hypo- or hyperglycemiaHypo- or hyperglycemia– Cardiovascular – Cardiovascular – HypotensionHypotension (5%), (5%),

hypoperfusion, tachycardiahypoperfusion, tachycardia– Metabolic acidosisMetabolic acidosis NICHD dataNICHD data

SymptomsSymptoms Less commonLess common

– SeizuresSeizures– DICDIC– PetechiaePetechiae– HepatosplenomegalyHepatosplenomegaly– ScleremaSclerema

Meningitis symptomsMeningitis symptoms– Irritability, lethargy, poorly responsiveIrritability, lethargy, poorly responsive– Changes in muscle tone, etc.Changes in muscle tone, etc.

EvaluationEvaluation Non-specific Non-specific

– CBC/diff, platelets – ANC, I/T ratioCBC/diff, platelets – ANC, I/T ratio– RadiographsRadiographs– CRPCRP– Fluid analysis – LP, Fluid analysis – LP, U/A U/A – Glucose, lytes, gasesGlucose, lytes, gases

Specific – Cultures, stainsSpecific – Cultures, stains Other – immunoassays, PCR, DNA Other – immunoassays, PCR, DNA

microarraymicroarray

Results “Trigger Results “Trigger Points” Points” CBCCBC

– WBC <5.0, abs neutro <WBC <5.0, abs neutro <1,7501,750, bands >2.0, bands >2.0– I/T ratio > I/T ratio > 0.2*0.2*– Platelets < 100,000Platelets < 100,000

CRP > 1.0 mg/dlCRP > 1.0 mg/dl CSF > 20 WBC’s with few or no RBC’s CSF > 20 WBC’s with few or no RBC’s Radiographs: infiltrates on CXR, ileus Radiographs: infiltrates on CXR, ileus

on KUB, periosteal elevation, etc.on KUB, periosteal elevation, etc.

TreatmentTreatment PreventionPrevention – vaccines, GBS – vaccines, GBS

prophylaxis, HAND-WASHINGprophylaxis, HAND-WASHING SupportiveSupportive – respiratory, metabolic, – respiratory, metabolic,

thermal, nutrition, monitoring drug thermal, nutrition, monitoring drug levels/toxicitylevels/toxicity

SpecificSpecific – antimicrobials, immune – antimicrobials, immune globulinsglobulins

Non-specificNon-specific – IVIG, NO inhibitors & – IVIG, NO inhibitors & inflammatory mediatorsinflammatory mediators

Neonatal Sepsis:Neonatal Sepsis:the special case ofthe special case of

Group B Strep Group B Strep SepsisSepsis

Mother to Infant Mother to Infant TransmissionTransmission

GBS colonized mother (20-30% in US)

Non-colonized newborn

Colonized newborn

AsymptomaticEarly-onset sepsis, pneumonia, meningitis

50% 50%

98% 2%

RISK FACTORSRISK FACTORS Previous GBS-infected babyPrevious GBS-infected baby Gestational age <37 wksGestational age <37 wks Maternal disease (esp. GBS UTI)Maternal disease (esp. GBS UTI) Ruptured membranes > 18 hoursRuptured membranes > 18 hours Location of delivery (e.g., home)Location of delivery (e.g., home) Infant/Fetal symptommatologyInfant/Fetal symptommatology Clinical suspicionClinical suspicionNote: incidence has fallen 80% since CDC prevention guidelines Note: incidence has fallen 80% since CDC prevention guidelines

were published in 1996were published in 1996

GBS SGBS SEPSISEPSIS

Mothers in labor or Mothers in labor or with ROM with ROM should be should be treated treated if:if: ChorioamnionitisChorioamnionitis History of previous GBS+ baby History of previous GBS+ baby Mother GBS+ or GBS-UTI this preg.Mother GBS+ or GBS-UTI this preg. Mother’s GBS status unknown and:Mother’s GBS status unknown and:

– < 37 wks gestation< 37 wks gestation– ROM ROM ≥≥ 18 hrs 18 hrs– Maternal temp Maternal temp ≥≥ 38 38o o (100.4(100.4ooF)F)

0

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2.5

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Year

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Early-onset Late-onset

Rate of Early- and Late-onset Rate of Early- and Late-onset GBS Disease in the 1990s, U.S.GBS Disease in the 1990s, U.S.

Consensus guidelines

1st ACOG & AAP statements

Group B Strep Association formed

CDC draft guidelines published

Schrag, New Engl J Med 2000 342: 15-20

INFANTS TO BE SCREENEDINFANTS TO BE SCREENED Maternal “chorioamnionitis”Maternal “chorioamnionitis” Maternal illness Maternal illness (i.e. UTI, pneumonia)(i.e. UTI, pneumonia) Maternal peripartum fever > 38Maternal peripartum fever > 38oo

(100.4(100.4ooF)F) Prolonged ROM Prolonged ROM ≥≥ 18 hrs ( 18 hrs (≥≥ 12 hrs 12 hrs

preterm)preterm) Mother GBS+ with inadequate Mother GBS+ with inadequate

treatment (treatment (< 4 hrs< 4 hrs))– No screening necessary if C-section delivery No screening necessary if C-section delivery

with intact membraneswith intact membranes

GBS SGBS SEPSISEPSIS

INFANTS TO BE SCREENEDINFANTS TO BE SCREENED Prolonged labor (> 20 hrs)Prolonged labor (> 20 hrs) Home or contaminated deliveryHome or contaminated delivery ““Chocolate-colored”/foul smelling Chocolate-colored”/foul smelling

amniotic fluidamniotic fluid Persistent fetal tachycardiaPersistent fetal tachycardia SYMPTOMATIC INFANTSYMPTOMATIC INFANT

– treat immediately (in DR if possible)treat immediately (in DR if possible)

GBS SGBS SEPSISEPSIS

SEPSIS SCREENSEPSIS SCREEN CBC with differentialCBC with differential Platelet countPlatelet count Blood culture x 1-2 (ideally 1 ml)Blood culture x 1-2 (ideally 1 ml) Chest X-ray &/or LP if Chest X-ray &/or LP if

symptommaticsymptommatic Close observation and frequent Close observation and frequent

clinical evaluationclinical evaluation Role of CRPRole of CRP

GBS SGBS SEPSISEPSIS

* CBC, blood cx, & CXR if resp sx. If ill consider LP.++ Duration of therapy may be 48 hrs if no sx.$ CBC with differential and blood culture# Applies only to penicillin, Ampicillin, or cefazolin. ** If healthy & ≥ 38 wks & mother got ≥ 4 hours IAP, may D/C at 24 hrs.

Maternal antibiotics for suspectedchorioamnionitis?

Duration of IAPbefore delivery

< 4 hours #

Full diagnostic evaluation *Empiric therapy++

Limited evaluation$ & Observe ≥ 48 hoursIf sepsis is suspected, full diagnostic evaluation and empiric therapy ++

Gestational age

<35 weeks?

No evaluation No therapyObserve ≥ 48 hours**

Maternal Rx for GBS?

Signs of neonatal sepsis?

Algorithm for Neonate whose Mother Received Intrapartum Antibiotics

Careful Observation&

Immediate Antibiotics

Careful Observation pending review of

screen

• Symptomatic INFANT• Maternal intrapartum fever > 38.6o

• “Chocolate” or foul smelling fluid• Ill mother

• Fetal tachycardia • Home delivery• Maternal fever < 38.6o

• PROM • Mat GBS with < 2 dose abx

(-) Screen (+) Screen (-) Screen (+) Screend/c abx; careful obs and monit bld cx until d/c

Cont abx until bld cx neg for 48o if asympt. Use clini-cal judgement for cessation of abx if pt is/was sympt

Careful obs and monit bld cx until d/c

Initiate abx & cont until bl cx (-) for 48o. Clinical judgement for cessation of abx if pt sympt

Initiate, resume or continue abx therapy and treat for 7-10 days for gram pos organism or longer if gram neg organism cultured. LP may be performed at the discretion of

attending, especially in seriously symptomatic pt

Blood Culture Positive

SSEPSISEPSIS

SIGNS and SYMPTOMSSIGNS and SYMPTOMS temp instabilitytemp instability • lethargy • lethargy poor feeding/residualspoor feeding/residuals • resp distress • resp distress glucose instabilityglucose instability • poor • poor

perfusionperfusion hypotensionhypotension • bloody stools • bloody stools abdominal distentionabdominal distention • bilious • bilious

emesisemesis apneaapnea • tachycardia • tachycardia skin/joint findingsskin/joint findings

LABORATORY EVALUATIONLABORATORY EVALUATION Provide added value when results are normalProvide added value when results are normal

– high negative predictive valuehigh negative predictive value– low positive predictive valuelow positive predictive value

abnl results could be due to other reasons and abnl results could be due to other reasons and not infectionnot infection

IT < 0.3, ANC > 1,500 (normal) do not start IT < 0.3, ANC > 1,500 (normal) do not start abx, or d/c abx if started, if pt remains abx, or d/c abx if started, if pt remains clinically stableclinically stable

IT IT >> 0.3, ANC < 1,500 consider initiation of 0.3, ANC < 1,500 consider initiation of abx pending bld cx in “at-risk” pt who was not abx pending bld cx in “at-risk” pt who was not already begun on antibiotics for other factorsalready begun on antibiotics for other factors

SSEPSISEPSIS

LABORATORY EVALUATIONLABORATORY EVALUATION Positive screenPositive screen

– total WBC total WBC << 5,000 5,000 – – I/T I/T >> 0.3 0.3– ANC ANC << 1,500 1,500 – platelets < 100,000– platelets < 100,000

Additional work-upAdditional work-up– CXR, urine cx, and LP as clinically indicatedCXR, urine cx, and LP as clinically indicated

CRPCRP– no added value for diagnosis of early onset no added value for diagnosis of early onset

sepsissepsis– best for best for negativenegative predicativepredicative valuevalue or when or when

used seriallyused serially– notnot to be used to decide about rx, duration of to be used to decide about rx, duration of

rx or need for LPrx or need for LP– positive results for a single value obtained at positive results for a single value obtained at

24 hrs ranges > 4.0 - 10.0 mg/dL24 hrs ranges > 4.0 - 10.0 mg/dL

SSEPSISEPSIS

SSEPSISEPSISTREATMENTTREATMENT Review protocolReview protocol AntibioticsAntibiotics

– Ampicillin 100 mg/kg/dose IV q 12 hoursAmpicillin 100 mg/kg/dose IV q 12 hours– Gentamicin 4 mg/kg/dose IV q 24 hoursGentamicin 4 mg/kg/dose IV q 24 hours

IM route may be used in asymptomatic pt on IM route may be used in asymptomatic pt on whom abx are initiated for maternal risk factors whom abx are initiated for maternal risk factors or or to avoid delays to avoid delays when there is difficulty when there is difficulty obtaining IVobtaining IV

– For meningitis: Ampicillin 200-300 mg/kg/dFor meningitis: Ampicillin 200-300 mg/kg/d Symptomatic managementSymptomatic management

– respiratory, cardiovascular, fluid supportrespiratory, cardiovascular, fluid support

PrognosisPrognosis

Fatality rate 2-4 times higher in Fatality rate 2-4 times higher in LBW than in term neonatesLBW than in term neonates

Overall mortality rate 15-40%Overall mortality rate 15-40% Survival less likely if also Survival less likely if also

granulocytopenic (I:T > 0.80 granulocytopenic (I:T > 0.80 correlates with death and may correlates with death and may justify granulocyte transfusion).justify granulocyte transfusion).

Infection and OutcomeInfection and Outcome Leviton, et al, Ped Res 1999Leviton, et al, Ped Res 1999 1078 infants <1500 grams and/or <32 1078 infants <1500 grams and/or <32

wks wks Infants with IUI were more likely to Infants with IUI were more likely to

have PVLhave PVL Chorioamnionitis was associated with Chorioamnionitis was associated with

a 4-fold increased risk of CP (17% vs. a 4-fold increased risk of CP (17% vs. 3%)3%)

Nelson, et al reported increased Nelson, et al reported increased cytokine response in population based cytokine response in population based study of term but not preterm infantsstudy of term but not preterm infants

Infection and ND Infection and ND OutcomeOutcome IUI and postnatal infection both IUI and postnatal infection both

appear to increase the risk for appear to increase the risk for adverse ND outcomeadverse ND outcome

Role of inflammatory mediators/SIRS Role of inflammatory mediators/SIRS in brain injury in the preterm infantin brain injury in the preterm infant– Pressure passive CNS circulationPressure passive CNS circulation– Direct cytotoxicity to the developing brainDirect cytotoxicity to the developing brain– Inherent vulnerability of the Inherent vulnerability of the

oligodendrocyte precursoroligodendrocyte precursor

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Sepsis+Meningitis (N=152)

Sepsis+NEC (N=252)

Sepsis Alone (N=1740)

Clinical Infection (N=1415)

Adjusted Odds Ratios and 95% CIsStoll, JAMA 2004

Postnatal Infection and ND Outcome: PDI < 70 Infection Groups Compared to Uninfected by Logistic

Regression

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Sepsis+Meningitis (N=152)

Sepsis+NEC (N=252)

Sepsis Alone (N=1740)

Clinical Infection (N=1415)

Postnatal Infection and ND Outcome: Cerebral Palsy

Adjusted Odds Ratios and 95% CIsStoll, JAMA 2004

Infection Groups Compared to Uninfected by Logistic Regression

Late Onset InfectionLate Onset Infection Majority of ELBW infants will develop Majority of ELBW infants will develop

late onset sepsislate onset sepsis Significant associated morbidity and Significant associated morbidity and

mortalitymortality CONS still the most common pathogenCONS still the most common pathogen Gram-negative pathogens increasing Gram-negative pathogens increasing

in prevelance and are associated with in prevelance and are associated with higher mortality ratehigher mortality rate

Neonatal Infection and Neonatal Infection and OutcomeOutcome Increased risk of adverse ND Increased risk of adverse ND

outcome in ELBW infants with LOSoutcome in ELBW infants with LOS Increased risk of poor growth at 18 Increased risk of poor growth at 18

months AA in ELBW with LOSmonths AA in ELBW with LOS Poor outcome associated with NECPoor outcome associated with NEC ?Role of cytokines and inflammatory ?Role of cytokines and inflammatory

mediators in CNSmediators in CNS

Prevention of Nosocomial Prevention of Nosocomial InfectionsInfections

HANDWASHINGHANDWASHING HANDWASHINGHANDWASHING Universal precautionsUniversal precautions Limit use devices and cathetersLimit use devices and catheters Minimize catheter manipulationMinimize catheter manipulation Nursery designNursery design Meticulous skin careMeticulous skin care EducationEducation

Thank You!!Thank You!!