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Neonatal Infections Mesfin Woldesenbet, MD Jimma University, Jimma, Ethiopia Houston, Texas July, 2012.

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Presentation on theme: "Neonatal Infections Mesfin Woldesenbet, MD Jimma University, Jimma, Ethiopia Houston, Texas July, 2012."— Presentation transcript:

1 Neonatal Infections Mesfin Woldesenbet, MD Jimma University, Jimma, Ethiopia Houston, Texas July, 2012

2 Questions? 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?

3 Objectives To briefly review neonatal immunology and why neonates are so susceptible to infections To 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.

5 Why are infants, especially premies, more susceptible to infections?

6 Neonatal Immune System All neonates relatively immunocompromised Immature and Ineffective: –Antibodies –Complement –Neutrophils –Skin / mucosal barriers

7 Antibody

8 Antibodies (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) Antibodies    Infectious agent Immunity

9 No contact with infectious agents = no antibody production Antibodies    Infectious agent Immunity x x

10 Remington and Klein, Sixth Edition, 2006 Maternal Transfer of Antibodies Antibody transfer increases with GA Most during 3rd trimester No guarantee maternal antibodies present to the infecting organism

11 Complement



14 Neutrophils

15 Neonatal Neutrophils Immature –  Chemotaxis –  Deformability –  Phagocytosis –  Storage pool Adults 14-fold > circulating pool Neonates only 2-fold

16 Manroe et al, J Pediatr, 1979

17 “Normal” VLBW neonates Mouzinho et al, Pediatr 94:76, 1994

18 Neonatal Barriers to Infection

19 Neonatal Anatomic Barriers Immature skin and mucosal surfaces –  layers –  junctions between cells –  secretory IgA Umbilical cord Breaches - catheters, tape

20 Invasive Fungal Dermatitis in a VLBW infant JL Rowen, Sem Perinatal 27: , 2003

21 Epidemiology

22 Incidence Mortality – 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 deaths Sepsis – 1-21/1000 world wide; US1-8/1000 live births – Culture proven 2/1000 (3-8% of infants evaluated for sepsis) – Premature <1000 g 26/ g 8-9/1000

23 Neonatal Sepsis: Incidence 2/1000 live births with culture proven sepsis –Bacterial / Viral / Fungal –80% infants develop bacterial sepsis –20% infants perinatally acquired viral infections –~ 25% of infected infants have meningitis Higher rate with preterm birth –26/1000 preterm infants with BW < 1000g –8-9/1000 preterm infants with BW g Remington and Klein, Sixth Edition, 2006

24 Neonatal Bacterial Sepsis: Disease Patterns Early Onset Neonatal Sepsis (EONS) –Fulminant, multi-system illness –< 7 days old –Obstetrical complications –Prematurity –Perinatal acquisition –High mortality, 5-50% Late Onset Neonatal Sepsis (LONS) –Sepsis and/or meningitis –7 days to 3 months old –Perinatal or postnatal acquisition –Lower mortality, 2-6%

25 Infection Timing Onset – Early Onset 1 st 24 hrs 85 % hrs5% – Late Onset 7-90 days

26 Etiologic Agents of Neonatal Sepsis Frequency(%)  Group B Streptococci 40  Escherichia coli 17 Streptococcus viridans 7 Staphylococcus aureus 6 Enterococcus spp 6 Coagulase-negative staphylococci 5 Klebsiella pneumoniae 4 Pseudomonas spp 3 Serratia marcescans 2 Others 10 *Schuchat et al, Pediatrics 105: 21-26, 2000

27 Etiologic Agents of Neonatal Meningitis Gram Positive Bacteria;Frequency (%)  Group B Streptococci 53 Listeria monocytogenes 7 Miscellaneous gram-positives 6 Gram Negative Bacteria:  Escherichia coli 19 Klebsiella species 8 Haemophilus influenzae 1 Miscellaneous gram-negatives8 Anaerobes 3 Feigen & Cherry, Fifth Edition, 2004

28 Incidence of Neonatal Group B Streptoccal Sepsis 5-35% Pregnant women colonized 1/ colonized women infant with early onset disease 1-7/1000live births in /1000live births in 1999 Remington and Klein, Sixth Edition, 2006

29 Rate of Early- and Late-onset 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 : 15-20

30 What do we know about trends in “other pathogens”? Most studies: stable rates of ‘other’ sepsis Concerns for increased rates of E. coli, all gram negatives, or amp-R infections Population-based (multicenter) studies find stable rates of total non-GBS and E. coli One 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 increasing Increases restricted to low birth weight or preterm deliveries

31 N=22, p=0.52, linear trend Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases, Full-Term Infants, ABCs, Selected Counties CA and GA, Hyde et al, Pediatrics 2002;110(4):690-5.

32 N=37, p=0.02, linear trend Ampicillin Susceptibility of E. coli from Early-Onset Sepsis Cases Preterm Infants, ABCs, Selected Counties CA and GA, Hyde et al, Pediatrics 2002;110(4):690-5.

33 Susceptibility of GBS: ABC/EIP Isolates, isolates from MN, GA, NY, OR (1173 invasive, 107 colonizing): –All susceptible to penicillin, ampicillin, cefotaxime and vancomycin –19% erythromycin resistance –11% clindamycin resistance

34 Risk Factors for Early Onset Neonatal Sepsis Primary (significant)  Prematurity or low birth weight –Preterm labor –Premature or prolonged rupture of membranes  Maternal fever / chorioamnionitis –Fetal hypoxia –Traumatic delivery Secondary –Male –Lower socioeconomic status –African-American race Remington and Klein, Sixth Edition, 2006

35 Factors associated with early-onset GBS disease: multivariable analysis Characteristic Adjusted 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 infant 5.54 ( ) Intrapartum fever5.36 ( ) Schrag et al, NEJM 2002, 347:233-9

36 Predisposing Factors Overall sepsis rate8/1000 Maternal Fever4/1000 PROM10-13/1000 Fever & PROM87/1000

37 Early 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 = adjusted RR 25% of asymptomatic infants, with culture positive sepsis, had maternal fever as the ONLY criteria for evaluation. Chen et al, J of Perinatal, 2002, 22:

38 Early Onset Neonatal Sepsis: Presentation and Diagnosis

39 Early Onset Neonatal Sepsis: Signs/Symptoms ?

40 Strongly suggestive hypoglycemia / hyperglycemia hypotension metabolic acidosis apnea shock DIC hepatosplenomegaly bulging fontanelle seizures petechiae hematochezia respiratory distress

41 Early Onset Neonatal Sepsis: Signs/Symptoms Nonspecific lethargy, irritability temperature instability -- hypothermia or fever poor feeding cyanosis tachycardia abdominal distention jaundice tachypnea

42 Early 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 infants A 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

43 Early Onset Neonatal Sepsis: Laboratory Evaluation  Cultures  Chest Radiograph Complete Blood Cell Count Glucose Bilirubin Liver Function Tests Coagulation studies C-reactive Protein (CRP)

44 RDS vs. GBS pneumonia???

45 Early 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% LONS Klein, Sem in Perinat, 5:3-8

46 Early Onset Neonatal Sepsis: Cultures -- Who and Which? CSF culture -- should always be considered Meningitis frequently accompanies sepsis % meningitis cases have + blood culture -Yield reportedly low if respiratory distress is the only major sign of infection -Specific signs & symptoms occur in less than 50% of infants with meningitis -Using “selective criteria” for obtaining CSF may result in missed or delayed diagnosis in up to 37% of infants with meningitis Wiswell et al, Pediatrics, 1995

47 Laboratory Diagnosis of Neonatal Meningitis CSF - - > 32 WBC/mm 3 > 60% PMN glucose < 50% - 75% of serum protein > 150 mg/dl organisms on gram stain

48 Early Onset Neonatal Sepsis: Complete Blood Cell Counts Is the CBC helpful as an indicator of early onset neonatal sepsis? –Thrombocytopenia frequently associated with sepsis –WBC may be high, low or “normal –Persistent low WBC more predictive of sepsis than elevated WBC (ANC < 1200) –I:T quotient unreliable

49 Early Onset Neonatal Sepsis: Complete Blood Cell Counts

50 Single or serial neutrophil values DO NOT assist in the diagnosis of EONS or determining the duration of therapy 99% of asymptomatic, culture-negative neonates > 35 weeks GA had 1 or more “abnormal” WBC values

51 Early Onset Neonatal Sepsis: C-Reactive Protein Measure of inflammation -- NOT specific for infection Elevated CRP, > 10 mg/L (>1 mg/dl), highly associated with sepsis --- but NOT diagnostic Limited by lack of “normal” reference values for <24 hours old or preterm infants Trend with multiple samplings correlates with infection as takes time to rise -- two samples ~24 hours apart useful Potentially useful when maternal antibiotics given - pretreatment interferes with cultures

52 Early Onset Neonatal Sepsis: C-reactive Protein CRP levels 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.

53 Treatment Prevention – vaccines, GBS prophylaxis, HAND- WASHING Supportive – respiratory, metabolic, thermal, nutrition, monitoring drug levels/toxicity Specific – antimicrobials, immune globulins Non-specific – IVIG, NO inhibitors & inflammatory mediators

54 Early Onset Neonatal Sepsis: Empiric Treatment Initial: Ampicillin and Gentamicin IV (Cefotaxime discouraged) Duration: “Rule out sepsis” hours Pneumonia5 - 7 days Sepsis days Meningitis days Primarily determined by etiologic organism cultured Secondarily determined by clinical course/response ?CRP-guided determination of duration? Remington and Klein, Sixth Edition, 2006

55 Early Onset Neonatal Sepsis: Supportive Therapy Ventilation BP support - fluids, Dopamine/Dobutamine/HCTZ TPN FFP - clotting factors, C3, antibodies G-CSF - stimulate WBC production/release Steroids not indicated as anti-inflammatory Remington and Klein, Sixth Edition, 2006

56 Treatment 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 days Meningitis14 days minimum

57 Indications for GBS Intrapartum Prophylaxis AAP Redbook, 2006 Report of the Committee on Infectious Diseases

58 * 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 suspected chorioamnionitis? Duration of IAP before delivery < 4 hours # Full diagnostic evaluation * Empiric therapy++ Limited evaluation $ & Observe ≥ 48 hours If sepsis is suspected, full diagnostic evaluation and empiric therapy ++ Gestational age <35 weeks? No evaluation No therapy Observe ≥ 48 hours** Maternal Rx for GBS? Signs of neonatal sepsis? Algorithm for Neonate whose Mother Received Intrapartum Antibiotics

59 Treatment of E. Coli Infections Ampicillin and an Aminoglycoside IV With confirmation of diagnosis /sensitivities: - drop Amp - substitute a third generation cephalosporin Duration (from first negative culture) Uncomplicated sepsis days Meningitis21 days minimum

60 Treatment of Listeria Monocytogenes Infections Ampicillin and an Aminoglycoside IV Duration (from first negative culture) Uncomplicated sepsis days Meningitis 14 days minimum

61 Prognosis Neonatal Sepsis Mortality % overall - highest in premature infants Morbidity ?? 25% ?? Neonatal Bacterial Meningitis Mortality % - - 5% if infant survives the first 24 hr Morbidity up to 50% % mild to moderate neurologic sequelae % severe neurologic impairment

62 Early Onset Neonatal Sepsis: Prognosis - Prematurity Organism Mortality for BW <1500g Mortality for BW g Mortality for BW >2500g Group B Streptococci 73%20%10% Escherichia coli73%42%13% Staphylococcus aureus 44%15%5% Other67%33%13% Total67%28%10% Remington and Klein, Sixth Edition, 2006

63 Early Onset Neonatal Sepsis: Summary GBS is still the predominant organism isolated in EONS Our efforts at IAP have reduced, but not eliminated, early onset GBS sepsis Obstetrical risk factors, including premature/near-term delivery and maternal intrapartum fever, help to identify the infants at highest risk for EONS Ancillary laboratory evaluations, including the CRP value, may assist in determination of the most appropriate length of therapy

64 Late Onset Neonatal Sepsis

65 Perinatal acquisition with later onset –Term or preterm –Bacterial: GBS, Chlamydia –Viral: HSV, CMV, HepB, HIV –Fungal: Candida Nosocomial acquisition –Health care associated infections –Preterm or sick term infant

66 Late Onset GBS Transmission - Perinatally or postnatally -- intrapartum prophylaxis or neonatal treatment of early onset disease does not decrease risk of late onset disease Symptoms - 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.

67 Herpes Simplex Virus (HSV) Incidence 1/ ,000 live births 1/200 pregnant women > 75% asymptomatic Enveloped DS-DNA 75% HSV II  HSVI Transmission 5-8% transplacental (congenital) 85-90% perinatally Primary infection (risk 30-50%) Secondary infection (risk <5% 5-10% postnatally Parent, caregiver Usually non-genital - hand, mouth Nosocomial spread from other infants via hands of health care professionals

68 HSV Specific Symptoms 1.Disseminated Disease Multi-organ involvement Sepsis syndrome, DIC Liver, CNS, lung predominance Severe liver & CNS dysfunction common Wide temp variations characteristic 2.Localized Central Nervous System Disease Seizures common 3.Disease localized to the skin, eye and mouth Vesicles, cloudy cornea. conjunctivitis, ulcers Onset 1-4 weeks of age Clinical overlap exists Skin lesions absent or appear late with disseminated/CNS disease

69 HSV Diagnosis High index of suspicion – History – Age (1-4 weeks) – Sepsis Syndrome unresponsive to antibiotic therapy PE - classic vesicular lesions Culture - readily grows within 1-3 days – Mouth, nasopharynx, conjunctivae rectum – swabs after hours of age – Skin vesicles, urine, stool, blood and CSF YPCR - diagnostic method of choice - best on CSF, other fluids –CSF pleocytosis (especially monos) and elevated protein –Coagulopathy/DIC, thrombocytopenia, liver dysfunction –EEG


71 Imaging Classic CT/MRI - temporal lobe lesion but may have many presentations to include hydrocephalus

72 HSV Therapy - Prognosis Acyclovir IV – 21 days for disseminated or CNS – 14 days for skin, eye and mouth Mimimal toxicity - primarily liver - large volume IV Decreases 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

73 Neonatal Nosocomial Infections

74 Risk Factors for Neonatal Nosocomial Sepsis Prematurity ELBW > VLBW Increased LOS Abdominal surgery / NEC Hyperalimentaion / Intralipids / IV fluid Neutropenia, Thrombocytopenia Catheters –UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc

75 Umbilical Arterial and Venous Catheters Life-saving tools on the NICU Necessary evil Increased of infections –Minimally at 7 days –Significantly at days or when clot present UVC > UAC –Stasis, hyperal/IL, thrombin formation

76 Umbilical Arterial and Venous Catheters Require strict protocols regarding use and care to reduce infection rates Remove: –when no longer needed –when evidence of infection or clot formation Replace when required >14 days –PICC / broviac / percutaneous a-line

77 Neonatal Nosocomial Infections: Microbiology Skin flora YCoagulase negative Staphylococcus YCandida spp Methicillin-resistant Staphylococcus aureus –Source: infant, care-givers, parents Gram-negative bacteria YEnterococcus spp, Enterobacter spp, E. coli Pseudomonas spp, Klebsiella spp, Seratia spp –Source: Infant GI tract Person-to-person transmission from Nursery personnel Nursery environmental sites: sinks, multiple use solutions, countertops, respiratory therapy equipment…

78 Late Onset Neonatal Sepsis: Empiric Treatment Initial: Vancomycin and Aminoglycoside IV (Cefotaxime discouraged) Duration (from first negative culture) : “Rule out sepsis” hours Pneumonia5 - 7 days Sepsis days Meningitis days Primarily determined by etiologic organism cultured Secondarily determined by clinical course/response ?CRP-guided determination of duration? Remington and Klein, Sixth Edition, 2006

79 Concerns for Antibiotic- resistant organisms Vancomycin- resistant enterococcus (VRE) –Theoretic risk on NICU –  risk with multiple course of vanco –Strict contact isolation Methicillin-resistant Staphylococcus aureus (MRSA) –Real risk on NICU –Community / maternal acquired –Vanco use required –Strict contact isolation

80 Treatment of Coagulase Negative Staphylococcal Infections Vancomycin IV (± Rifampin if difficult to clear) Duration (from first negative culture) Uncomplicated sepsis days Meningitis days Removal of indwelling intravascular catheters

81 Treatment of Gram-Negative Infections Aminoglycoside IV + Cefotaxime or Cefepime Duration (from first negative culture) Uncomplicated sepsis days Meningitis days Removal of indwelling intravascular catheters

82 Prognosis Dependent upon organism and early initiation of appropriate therapy LOS increased in all cases Morbidity also variable dependent upon organ involvement - worse with meningitis

83 Gentamicin PMA (weeks) Postnatal Age ( Days) Dose (mg/kg/dose) Interval (hours) ≤ 29* ≥ ≥ ≥ 35ALL424 * Significant asphyxia, use of indomethaciDo Gentamicin level around the 3 rd dose


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