neonatal infections

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


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 MeningitisGram 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


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


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

?


Strongly suggestivehypoglycemia / hyperglycemiahypotensionmetabolic acidosisapneashockDIChepatosplenomegalybulging fontanelleseizurespetechiaehematocheziarespiratory distress


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


• 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?


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


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%


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 Symptoms1. 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

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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?


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

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