Neonatal Infections

Mesfin Woldesenbet, MDJimma University, Jimma, Ethiopia

Houston, TexasJuly, 2012

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?

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

“Prematurity is an infectious disease.”- James Todd, M.D.

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

Neonatal Immune System

• All neonates relatively immunocompromised

• Immature and Ineffective:

– Antibodies

– Complement

– Neutrophils

– Skin / mucosal barriers

Antibody

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

No contact with infectious agents = no antibody production

Antibodies

Infectious agent

Immunity

x x

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

Complement

Neutrophils

Neonatal Neutrophils

• Immature– Chemotaxis– Deformability– Phagocytosis– Storage pool

• Adults 14-fold > circulating pool

• Neonates only 2-fold

Manroe et al, J Pediatr, 1979

“Normal” VLBW neonates

Mouzinho et al, Pediatr 94:76, 1994

Neonatal Barriers to Infection

Neonatal Anatomic Barriers

• Immature skin and mucosal surfaces– layers– junctions between cells– secretory IgA

• Umbilical cord• Breaches - catheters, tape

Invasive Fungal Dermatitis in a VLBW infant

JL Rowen, Sem Perinatal 27:406-413, 2003

Epidemiology

Incidence• Mortality

– 13-69% world wide– 13-15% of all neonatal deaths (US)

• Meningitis– 0.4-2.8/1000 live births (US 0.2-0.4/1000)– 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

26/1000 1000- 2000 g

8-9/1000

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 1000-2000g

Remington and Klein, Sixth Edition, 2006

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%

Infection

Timing

• Onset– Early Onset 1st 24 hrs 85 %

24-48 hrs5%

– Late Onset 7-90 days

Etiologic Agents of Neonatal Sepsis

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

Etiologic Agents of Neonatal Meningitis

Gram Positive Bacteria; Frequency (%) Group B Streptococci 53Listeria monocytogenes 7Miscellaneous gram-positives 6

Gram Negative Bacteria: Escherichia coli 19Klebsiella species 8Haemophilus influenzae 1Miscellaneous gram-negatives 8

Anaerobes 3

Feigen & Cherry, Fifth Edition, 2004

Incidence of Neonatal Group B Streptoccal Sepsis

• 5-35% Pregnant women colonized

• 1/100-200 colonized women

• infant with early onset disease

• 1-7/1000 live births in 1993

• 0.44/1000 live births in 1999

Remington and Klein, Sixth Edition, 2006

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 2000 342: 15-20

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

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, 1998-2000

Hyde et al, Pediatrics 2002;110(4):690-5.

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, 1998-2000

Hyde et al, Pediatrics 2002;110(4):690-5.

Susceptibility 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

vancomycin

– 19% erythromycin resistance

– 11% clindamycin resistance

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

Factors associated with early-onset GBS disease: multivariable analysis

Characteristic Adjusted RR (95% CI)

GBS screening 0.46 (0.36-0.60)

Prolonged ROM (> 18 h) 1.41 (0.97-2.06)

Pre-term delivery 1.50 (1.07-2.10)

Black race 1.87 (1.45-2.43)

Maternal age <20 y 2.22 (1.59-3.11)

Previous GBS infant 5.54 (1.71-17.94)

Intrapartum fever 5.36 (3.60-7.99)

Schrag et al, NEJM 2002, 347:233-9

Predisposing Factors

Overall sepsis rate 8/1000

Maternal Fever 4/1000

PROM 10-13/1000

Fever & PROM 87/1000

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.

• 5.36 = 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, 22:653-657

Early Onset Neonatal Sepsis:Presentation and Diagnosis

Early Onset Neonatal Sepsis:Signs/Symptoms

?

Early Onset Neonatal Sepsis:Signs/Symptoms

Strongly suggestivehypoglycemia / hyperglycemiahypotensionmetabolic acidosisapneashockDIChepatosplenomegalybulging fontanelleseizurespetechiaehematocheziarespiratory distress

Early Onset Neonatal Sepsis:Signs/Symptoms

Nonspecificlethargy, irritabilitytemperature instability -- hypothermia or feverpoor feedingcyanosistachycardiaabdominal distentionjaundicetachypnea

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

Early Onset Neonatal Sepsis:Laboratory Evaluation

• Cultures

• Chest Radiograph

• Complete Blood Cell Count

• Glucose

• Bilirubin

• Liver Function Tests

• Coagulation studies

• C-reactive Protein (CRP)

RDS vs. GBS pneumonia???

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

Early Onset Neonatal Sepsis:Cultures -- Who and Which?

• CSF culture -- should always be considered Meningitis frequently accompanies sepsis

- 50-85% 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

Laboratory Diagnosis of Neonatal Meningitis

CSF - - > 32 WBC/mm3

> 60% PMN

glucose < 50% - 75% of serum

protein > 150 mg/dl

organisms on gram stain

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

Early Onset Neonatal Sepsis:Complete Blood Cell Counts

Early 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 therapy

• 99% of asymptomatic, culture-negative neonates > 35 weeks GA had 1 or more “abnormal” WBC values

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

Early 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.

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

Early Onset Neonatal Sepsis: Empiric Treatment

Initial:Ampicillin and Gentamicin IV(Cefotaxime discouraged)

Duration: “Rule out sepsis” 48 - 72 hours

Pneumonia 5 - 7 daysSepsis 7 - 10 daysMeningitis 14 - 21 days

Primarily determined by etiologic organism culturedSecondarily determined by clinical course/response?CRP-guided determination of duration?

Remington and Klein, Sixth Edition, 2006

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

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 10 - 14 daysMeningitis 14 days minimum

Indications for GBS Intrapartum Prophylaxis

AAP Redbook, 2006 Report of the Committee on Infectious Diseases

* 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

Treatment of E. Coli Infections

Ampicillin and an Aminoglycoside IVWith confirmation of diagnosis /sensitivities:- drop Amp- substitute a third generation cephalosporin

Duration (from first negative culture)Uncomplicated sepsis 10 -14 daysMeningitis 21 days minimum

Treatment of Listeria Monocytogenes Infections

Ampicillin and an Aminoglycoside IV

Duration (from first negative culture)Uncomplicated sepsis 10 -14 daysMeningitis 14

days minimum

Prognosis

Neonatal SepsisMortality 20 - 30% overall - highest in premature infantsMorbidity ?? 25% ??

Neonatal Bacterial MeningitisMortality 15 - 30% - - 5% if infant survives the first 24 hr Morbidity up to 50%30 - 35% mild to moderate neurologic sequelae5 - 10% severe neurologic impairment

Early Onset Neonatal Sepsis:Prognosis - Prematurity

Organism Mortality for BW <1500g

Mortality for BW 1500-2500g

Mortality for BW >2500g

Group B Streptococci

73% 20% 10%

Escherichia coli 73% 42% 13%

Staphylococcus aureus

44% 15% 5%

Other 67% 33% 13%

Total 67% 28% 10%

Remington and Klein, Sixth Edition, 2006

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

Late Onset Neonatal Sepsis

Late Onset Neonatal Sepsis

• 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

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.

Herpes Simplex Virus (HSV)

• Incidence• 1/3000-20,000 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

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

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 24-48 hours of age

– Skin vesicles, urine, stool, blood and CSF PCR - diagnostic method of choice - best on CSF, other fluids

– CSF pleocytosis (especially monos) and elevated protein

– Coagulopathy/DIC, thrombocytopenia, liver dysfunction

– EEG

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cped%5Cimages%5CLarge%5C1588ped0995-04.jpg&template=izoom2

Imaging

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

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

Neonatal Nosocomial Infections

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

Umbilical Arterial and Venous Catheters

• Life-saving tools on the NICU• Necessary evil• Increased of infections

– Minimally at 7 days– Significantly at 10-14 days or when clot present

• UVC > UAC– Stasis, hyperal/IL, thrombin formation

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

Neonatal Nosocomial Infections: Microbiology

• Skin floraCoagulase negative StaphylococcusCandida spp• Methicillin-resistant Staphylococcus aureus

– Source: infant, care-givers, parents• Gram-negative bacteria

Enterococcus 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…

Late Onset Neonatal Sepsis: Empiric Treatment

Initial:Vancomycin and Aminoglycoside IV(Cefotaxime discouraged)

Duration (from first negative culture): “Rule out sepsis” 48 - 72 hours

Pneumonia 5 - 7 daysSepsis 10 -14 daysMeningitis 14 - 21 days

Primarily determined by etiologic organism culturedSecondarily determined by clinical course/response?CRP-guided determination of duration?

Remington and Klein, Sixth Edition, 2006

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

Treatment of Coagulase Negative Staphylococcal Infections

Vancomycin IV (± Rifampin if difficult to clear)

Duration (from first negative culture)Uncomplicated sepsis 10 -14 daysMeningitis 14 -

21 days

Removal of indwelling intravascular catheters

Treatment of Gram-Negative Infections

Aminoglycoside IV + Cefotaxime or Cefepime

Duration (from first negative culture)Uncomplicated sepsis 10 -14 daysMeningitis 14 - 21

days

Removal of indwelling intravascular catheters

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

GentamicinPMA (weeks)

Postnatal Age ( Days)

Dose (mg/kg/dose)

Interval (hours)

≤ 29* 0-7 8-28≥ 29

544

483624

30-34 0-7≥ 8

4.54

3624

≥ 35 ALL 4 24

* Significant asphyxia, use of indomethaci Do Gentamicin level around the 3rd dose