2Questions?Why are infants, especially premies, more susceptible to infections?What are the clinical manifestations of neonatal infections?Bacterial?HSV?How to prevent infections?Antibiotics - indications, contraindications, cautions, resistance, etc.How to interpret labs?Any precautions with lines?
3ObjectivesTo briefly review neonatal immunology and why neonates are so susceptible to infectionsTo review the epidemiology, clinical presentation, diagnosis and treatment of the most common bacterial and HSV neonatal infections.To review modes of infection prevention.To differentiate between preterm and term infants in all these areas
4“Prematurity is an infectious disease.” - James Todd, M.D.
5Why are infants, especially premies, more susceptible to infections?
6Neonatal Immune System All neonates relatively immunocompromisedImmature and Ineffective:AntibodiesComplementNeutrophilsSkin / mucosal barriers
8AntibodiesInfectious agentImmunityAntibodies (anti- foreign bodies) are produced by host white cells on contact with the invading micro-organism which is acting as an antigen (e.g. generates antibodies). The individual may then be immune to further attacks.(Modified From: Roitt, I: Essential Immunology, 4th edition, Blackwell Scientific Publications, 1980)
9No contact with infectious agents = no antibody production AntibodiesInfectious agentImmunityxxNo contact with infectious agents = no antibody production
10Maternal Transfer of Antibodies Antibody transfer increases with GAMost during 3rd trimesterNo guarantee maternal antibodies present to the infecting organismRemington and Klein, Sixth Edition, 2006
19Neonatal Anatomic Barriers Immature skin and mucosal surfaceslayersjunctions between cellssecretory IgAUmbilical cordBreaches - catheters, tape
20Invasive Fungal Dermatitis in a VLBW infant Figure 1. Invasive fungal dermatitis in an extremely low birth weight infant. Note the erosions and crusts. Blood cultures were also positive.Figure 2. Skin biopsy from a neonate with invasive fungal dermatitis. Gomori methenamine silver stain shows a cluster of hyphal forms in the dermiJL Rowen, Sem Perinatal 27: , 2003
22Incidence Mortality Meningitis Sepsis 13-69% world wide 13-15% of all neonatal deaths (US)Meningitis/1000 live births (US /1000)Mortality 13-59%; US 4% of all neonatal deathsSepsis1-21/1000 world wide; US1-8/1000 live birthsCulture proven 2/1000 (3-8% of infants evaluated for sepsis)Premature <1000 g /1000g /1000
23Neonatal Sepsis: Incidence 2/1000 live births with culture proven sepsisBacterial / Viral / Fungal80% infants develop bacterial sepsis20% infants perinatally acquired viral infections~ 25% of infected infants have meningitisHigher rate with preterm birth26/1000 preterm infants with BW < 1000g8-9/1000 preterm infants with BW gRemington and Klein, Sixth Edition, 2006
24Neonatal Bacterial Sepsis: Disease Patterns Early Onset Neonatal Sepsis (EONS)Fulminant, multi-system illness< 7 days oldObstetrical complicationsPrematurityPerinatal acquisitionHigh mortality, 5-50%Late Onset Neonatal Sepsis (LONS)Sepsis and/or meningitis7 days to 3 months oldPerinatal or postnatal acquisitionLower mortality, 2-6%
25Infection Timing Onset Early Onset 1st 24 hrs 85 % 24-48 hrs 5% Late Onset days
26Etiologic Agents of Neonatal Sepsis Frequency(%) Group B Streptococci Escherichia coliStreptococcus viridansStaphylococcus aureusEnterococcus sppCoagulase-negative staphylococciKlebsiella pneumoniaePseudomonas sppSerratia marcescansOthers*Schuchat et al, Pediatrics 105: 21-26, 2000
27Etiologic Agents of Neonatal Meningitis Gram Positive Bacteria; Frequency (%) Group B StreptococciListeria monocytogenesMiscellaneous gram-positivesGram Negative Bacteria: Escherichia coliKlebsiella speciesHaemophilus influenzaeMiscellaneous gram-negatives 8AnaerobesFeigen & Cherry, Fifth Edition, 2004
28Incidence of Neonatal Group B Streptoccal Sepsis 5-35% Pregnant women colonized1/ colonized womeninfant with early onset disease1-7/1000 live births in 19930.44/1000 live births in 1999Remington and Klein, Sixth Edition, 2006
29Rate of Early- and Late-onset GBS Disease in the 1990s, U.S. Group B Strep Association formed1st ACOG & AAPstatementsCDC draftguidelines publishedConsensusguidelinesRATE OF EARLY- AND LATE-ONSET GBS DISEASE IN THE 1990s, U.S.More important than changes in policies are changes in disease incidence.This slide shows a graph plotting the incidence of early-and late-onset GBS disease in the ABCs areas from 1989 to 2000.Late-onset disease is represented by the blue line in this graph.Even with the implementation of guidelines recommending GBS prophylaxis, late-onset disease rates remain stable during the 1990s at approximately 0.3 cases per 1000 live births.The white line represents early-onset disease.The incidence of early-onset GBS disease in the United States since 1993 has declined 70% (from 1.7 cases per 1000 live births in 1993 to 0.45 cases per 1000 live births in 1999) , coinciding with increased prevention activities.As of 2000, the graph shows that the rates have plateaued at 0.5 cases per 1000 live births.This graph was originally published by Schrag in New England Journal of Medicine, 2000, 342:Schrag, New Engl J Med : 15-20
30What do we know about trends in “other pathogens”? Most studies: stable rates of ‘other’ sepsisConcerns for increased rates of E. coli, all gram negatives, or amp-R infectionsPopulation-based (multicenter) studies find stable rates of total non-GBS and E. coliOne multicenter study of very LBW infants found a decrease in GBS by 4.2 /1,000, but an increase in E coli rates of 3.6/1,000 (Stoll et al, NEJM, 2002, 347:240-7)% of E. coli sepsis w/ amp resistance may be increasingIncreases restricted to low birth weight or preterm deliveriesWHAT DO WE KNOW ABOUT TRENDS IN “OTHER PATHOGENS”?Most studies find stable rates of sepsis caused by other pathogensA few single hospitals found increased rates or case counts of E coli, all gram negatives, or of amp R pathogens; one multicenter study of very low birth weight infants found an increased incidence of E. coli in the 1990s (Stoll et al., NEJM 347:240-7)Other population-based (multicenter) studies find stable rates of total nonGBS and E coliProportion of E. coli neonatal sepsis with amp resistance may be increasingIncreases restricted to low birth weight or preterm deliveries; increases may not be related to GBS prophylaxisSee CDC’s revised GBS guidelines (MMWR Aug. 16,2002 (RR-11)) for a detailed review of these studies that includes references
31Ampicillin Susceptibility of E Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases, Full-Term Infants, ABCs, Selected Counties CA and GA,Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases, Full-Term Infants, ABCs, Selected Counties CA and GA,This bar chart shows a stable trend (P=0.52) in the number of ampicillin resistant E. coli early onset sepsis infections among full term infants in selected counties of CA and GA from These data are from T. Hyde et al., Pediatrics 2002;110(4):690-5.In 1998 surveillance detected 8 cases, 4 were ampicillin resistantIn 1999 surveillance detected 8 cases, 3 were ampicillin resistantIn 2000 surveillance detected 6 cases, 2 were ampicillin resistantN=22, p=0.52, linear trendHyde et al, Pediatrics 2002;110(4):690-5.
32Ampicillin Susceptibility of E Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases Preterm Infants, ABCs, Selected Counties CA and GA,Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases Preterm Infants, ABCs, Selected Counties CA and GA,This bar chart shows a significantly increasing trend (P=0.02) in the number of ampicillin resistant E. coli early onset sepsis infections among preterm infants in Pediatrics 2002;110(4):690-5.selected counties of CA and GA from These data are from T. Hyde et al., In 1998 surveillance detected 6 cases, 1 was ampicillin resistantIn 1999 surveillance detected 12 cases, 10 were ampicillin resistantIn 2000 surveillance detected 18 cases, 15 were ampicillin resistantN=37, p=0.02, linear trendHyde et al, Pediatrics 2002;110(4):690-5.
33Susceptibility of GBS: ABC/EIP Isolates, 1995-2000 1280 isolates from MN, GA, NY, OR (1173 invasive, 107 colonizing):All susceptible to penicillin, ampicillin, cefotaxime and vancomycin19% erythromycin resistance11% clindamycin resistanceSUSCEPTIBILITY OF GBS: Isolates from the ABCs,1280 isolates from MN, GA, NY, OR (1173 invasive, 107 colonizing)All susceptible to penicillin, ampicillin, cefotazime and vancomycin19% erythromycin resistance11% clindamycin resistance
34Risk Factors for Early Onset Neonatal Sepsis Primary (significant)Prematurity or low birth weightPreterm laborPremature or prolonged rupture of membranesMaternal fever / chorioamnionitisFetal hypoxiaTraumatic deliverySecondaryMaleLower socioeconomic statusAfrican-American raceRemington and Klein, Sixth Edition, 2006
35Factors associated with early-onset GBS disease: multivariable analysis CharacteristicAdjusted RR (95% CI)GBS screening0.46 ( )Prolonged ROM (> 18 h)1.41 ( )Pre-term delivery1.50 ( )Black race1.87 ( )Maternal age <20 y2.22 ( )Previous GBS infant5.54 ( )Intrapartum fever5.36 ( )FACTORS ASSOCIATED WITH EARLY-ONSET GBS DISEASE: MULTIVARIABLE ANALYSISThis table shows the factors significantly associated with early-onset GBS disease in multivariable analysis, as reported by Schrag et al, NEJM 2002, 347:233-9Prenatal GBS screening was significantly protective.The relative risk associated with screening was 0.46 (95% CI: )A number of other factors were associated with increased risk of early-onset diseaseThe relative risk associated with prolonged rupture of membranes (ROM) was 1.41 (95% CI: )The relative risk associated with pre-term delivery was 1.50 (95% CI: )The relative risk associated with Black race was 1.87 (95% CI: )The relative risk associated with maternal age less than 20 was 2.22 (95% CI: )The relative risk associated with previous GBS infant was 5.54 (95% CI: )The relative risk associated with intrapartum fever was 5.36 (95% CI: )Schrag et al, NEJM 2002, 347:233-9
37Early Onset Neonatal Sepsis: Risk Factors - Maternal Fever Maternal fever is a significant risk factor for EONS and may add in the identification of infected but initially asymptomatic infant.5.36 = adjusted RR25% of asymptomatic infants, with culture positive sepsis, had maternal fever as the ONLY criteria for evaluation.Chen et al, J of Perinatal, 2002, 22:
38Early Onset Neonatal Sepsis: Presentation and Diagnosis
42Early Onset Neonatal Sepsis: Signs/Symptoms - Fever The infant with sepsis may have an elevated, depressed or normal temperature.Fever is seen in up to 50% of infected infants.Fever is more common in term infants, while hypothermia is more common in preterm infantsA single elevated temperature reading or fever as an isolated finding is infrequently associated with sepsis.Persistent fever for greater than 1 hour is more frequently associated with infection.Fever occurs more frequently with LONS or with viral, rather than bacterial, sepsis.Klein, Sem in Perinat, 5:3-8
43Early Onset Neonatal Sepsis: Laboratory Evaluation Cultures Chest RadiographComplete Blood Cell CountGlucoseBilirubinLiver Function TestsCoagulation studiesC-reactive Protein (CRP)
45Early Onset Neonatal Sepsis: Cultures -- Who and Which? Blood culture -- indicated in ALL infants with suspected sepsis. Repeat cultures indicated if initial culture positive.Urine culture -- low yield in EONS+ in 1.6% EONS compared to 7.47% LONSKlein, Sem in Perinat, 5:3-8
46Early Onset Neonatal Sepsis: Cultures -- Who and Which? CSF culture -- should always be considered Meningitis frequently accompanies sepsis50-85% meningitis cases have + blood cultureYield reportedly low if respiratory distress is the only major sign of infectionSpecific signs & symptoms occur in less than 50% of infants with meningitisUsing “selective criteria” for obtaining CSF may result in missed or delayed diagnosis in up to 37% of infants with meningitisWiswell et al, Pediatrics, 1995
47Laboratory Diagnosis of Neonatal Meningitis CSF > 32 WBC/mm3> 60% PMNglucose < 50% - 75% of serumprotein > 150 mg/dlorganisms on gram stain
48Early Onset Neonatal Sepsis: Complete Blood Cell Counts Is the CBC helpful as an indicator of early onset neonatal sepsis?Thrombocytopenia frequently associated with sepsisWBC may be high, low or “normalPersistent low WBC more predictive of sepsis than elevated WBC (ANC < 1200)I:T quotient unreliable
50Early Onset Neonatal Sepsis: Complete Blood Cell Counts Single or serial neutrophil values DO NOT assist in the diagnosis of EONS or determining the duration of therapy99% of asymptomatic, culture-negative neonates > 35 weeks GA had 1 or more “abnormal” WBC values
51Early Onset Neonatal Sepsis: C-Reactive Protein Measure of inflammation -- NOT specific for infectionElevated CRP, > 10 mg/L (>1 mg/dl), highly associated with sepsis --- but NOT diagnosticLimited by lack of “normal” reference values for <24 hours old or preterm infantsTrend with multiple samplings correlates with infection as takes time to rise -- two samples ~24 hours apart usefulPotentially useful when maternal antibiotics given - pretreatment interferes with cultures
52Early Onset Neonatal Sepsis: C-reactive Protein CRP levels <10mg/L, determined >24 hours after beginning therapy correctly identified 99% of infants not needing further therapy.May be useful in determining end-point for “rule-out sepsis” evaluations, especially with maternal antibiotic treatment.CRP-guided determination of length of therapy, shortened the treatment course for most infected infants without increasing the rate of relapse.Limitations: no studies evaluating meningitis or infections other than bacterial sepsis.
54Early Onset Neonatal Sepsis: Empiric Treatment Initial:Ampicillin and Gentamicin IV(Cefotaxime discouraged)Duration:“Rule out sepsis” hoursPneumonia daysSepsis daysMeningitis daysPrimarily determined by etiologic organism culturedSecondarily determined by clinical course/response?CRP-guided determination of duration?Remington and Klein, Sixth Edition, 2006
55Early Onset Neonatal Sepsis: Supportive Therapy VentilationBP support - fluids, Dopamine/Dobutamine/HCTZTPNFFP - clotting factors, C3, antibodiesG-CSF - stimulate WBC production/releaseSteroids not indicated as anti-inflammatoryRemington and Klein, Sixth Edition, 2006
56Treatment of GBS Infections Initial- Ampicillin and Gentamycin IV(Gent synergy for first 3 days)- May switch to Penicillin G IV(with confirmation of diagnosis/sensitivities)Duration (from first negative culture)Uncomplicated sepsis daysMeningitis days minimum
57Indications for GBS Intrapartum Prophylaxis AAP Redbook, 2006 Report of the Committee on Infectious Diseases
58Algorithm for Neonate whose Mother Received Intrapartum Antibiotics Maternal antibioticsfor suspectedchorioamnionitis?Duration of IAPbefore delivery< 4 hours #Full diagnostic evaluation *Empiric therapy++Limited evaluation$ &Observe ≥ 48 hoursIf sepsis is suspected, fulldiagnostic evaluation andempiric therapy ++Gestational age<35 weeks?No evaluationNo therapyObserve ≥ 48 hours**Maternal Rx for GBS?Signs of neonatal sepsis?YESYESYESNOYESNOYESNO* 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.
59Treatment of E. Coli Infections Ampicillin and an Aminoglycoside IVWith confirmation of diagnosis /sensitivities:- drop Amp- substitute a third generation cephalosporinDuration (from first negative culture)Uncomplicated sepsis daysMeningitis days minimum
60Treatment of Listeria Monocytogenes Infections Ampicillin and an Aminoglycoside IVDuration (from first negative culture)Uncomplicated sepsis daysMeningitis days minimum
61Prognosis Neonatal Sepsis Mortality % overall - highest in premature infantsMorbidity ?? 25% ??Neonatal Bacterial MeningitisMortality % - - 5% if infant survives the first 24 hrMorbidity up to 50%% mild to moderate neurologic sequelae5 - 10% severe neurologic impairment
62Early Onset Neonatal Sepsis: Prognosis - Prematurity OrganismMortality for BW <1500gMortality for BW gMortality for BW >2500gGroup BStreptococci73%20%10%Escherichia coli42%13%Staphylococcus aureus44%15%5%Other67%33%Total28%Remington and Klein, Sixth Edition, 2006
63Early Onset Neonatal Sepsis: Summary GBS is still the predominant organism isolated in EONSOur efforts at IAP have reduced, but not eliminated, early onset GBS sepsisObstetrical risk factors, including premature/near-term delivery and maternal intrapartum fever, help to identify the infants at highest risk for EONSAncillary laboratory evaluations, including the CRP value, may assist in determination of the most appropriate length of therapy
65Late Onset Neonatal Sepsis Perinatal acquisition with later onsetTerm or pretermBacterial: GBS, ChlamydiaViral: HSV, CMV, HepB, HIVFungal: CandidaNosocomial acquisitionHealth care associated infectionsPreterm or sick term infant
66Late Onset GBSTransmission - Perinatally or postnatally -- intrapartum prophylaxis or neonatal treatment of early onset disease does not decrease risk of late onset diseaseSymptoms - 7days - 3 months. Typically 3-4 weeks old.Occult bacteremia or meningitis most common. However, focal infections (pneumonia, UTI, cellulitis, osteomylelitis, septic arthritis) may occur.Diagnosis - Culture of blood, CSF, sputum, urine, abscess or other body fluid.Treatment - Penicillin, as with early onset disease.
67Herpes Simplex Virus (HSV) Incidence1/ ,000 live births1/200 pregnant women> 75% asymptomaticEnveloped DS-DNA75% HSV IIHSVITransmission5-8% transplacental (congenital)85-90% perinatallyPrimary infection (risk 30-50%)Secondary infection (risk <5%5-10% postnatallyParent, caregiverUsually non-genital - hand, mouthNosocomial spread from other infants via hands of health care professionals
68HSV Specific Symptoms Disseminated Disease Multi-organ involvement Sepsis syndrome, DICLiver, CNS, lung predominanceSevere liver & CNS dysfunction commonWide temp variations characteristicLocalized Central Nervous System DiseaseSeizures commonDisease localized to the skin, eye and mouthVesicles, cloudy cornea. conjunctivitis, ulcersOnset 1-4 weeks of ageClinical overlap existsSkin lesions absent or appear late withdisseminated/CNS disease
69HSV Diagnosis High index of suspicion History Age (1-4 weeks) Sepsis Syndrome unresponsive to antibiotic therapyPE - classic vesicular lesionsCulture - readily grows within 1-3 daysMouth, nasopharynx, conjunctivae rectum – swabs after hours of ageSkin vesicles, urine, stool, blood and CSFPCR - diagnostic method of choice - best on CSF, other fluidsCSF pleocytosis (especially monos) and elevated proteinCoagulopathy/DIC, thrombocytopenia, liver dysfunctionEEG
71ImagingClassic CT/MRI - temporal lobe lesion but may have many presentations to include hydrocephalus
72HSV Therapy - Prognosis Acyclovir IV21 days for disseminated or CNS14 days for skin, eye and mouthMimimal toxicity - primarily liver - large volume IVDecreases mortality with disseminated disease from ~75% to 25-40%Decreases morbidity from 90% to 65%Improvements in both mortality and morbidity dependent upon early initiation of Acyclovir
74Risk Factors for Neonatal Nosocomial Sepsis PrematurityELBW > VLBWIncreased LOSAbdominal surgery / NECHyperalimentaion / Intralipids / IV fluidNeutropenia, ThrombocytopeniaCathetersUAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
75Umbilical Arterial and Venous Catheters Life-saving tools on the NICUNecessary evilIncreased of infectionsMinimally at 7 daysSignificantly at days or when clot presentUVC > UACStasis, hyperal/IL, thrombin formation
76Umbilical Arterial and Venous Catheters Require strict protocols regarding use and care to reduce infection ratesRemove:when no longer neededwhen evidence of infection or clot formationReplace when required >14 daysPICC / broviac / percutaneous a-line
78Late Onset Neonatal Sepsis: Empiric Treatment Initial:Vancomycin and Aminoglycoside IV(Cefotaxime discouraged)Duration (from first negative culture):“Rule out sepsis” hoursPneumonia daysSepsis daysMeningitis daysPrimarily determined by etiologic organism culturedSecondarily determined by clinical course/response?CRP-guided determination of duration?Remington and Klein, Sixth Edition, 2006
79Concerns for Antibiotic-resistant organisms Vancomycin- resistant enterococcus (VRE)Theoretic risk on NICU risk with multiple course of vancoStrict contact isolationMethicillin-resistant Staphylococcus aureus (MRSA)Real risk on NICUCommunity / maternal acquiredVanco use requiredStrict contact isolation
80Treatment of Coagulase Negative Staphylococcal Infections Vancomycin IV(± Rifampin if difficult to clear)Duration (from first negative culture)Uncomplicated sepsis daysMeningitis daysRemoval of indwelling intravascular catheters
81Treatment of Gram-Negative Infections Aminoglycoside IV + Cefotaxime or CefepimeDuration (from first negative culture)Uncomplicated sepsis daysMeningitis daysRemoval of indwelling intravascular catheters
82Prognosis Dependent upon organism and early initiation of appropriate therapyLOS increased in all casesMorbidity also variable dependent upon organinvolvement - worse with meningitis
83Gentamicin PMA (weeks) Postnatal Age ( Days) Dose (mg/kg/dose) Interval(hours)≤ 29*0-78-28≥ 295448362430-34≥ 84.5≥ 35ALL* Significant asphyxia, use of indomethaciDo Gentamicin level around the 3rd dose