neonatal infections mesfin woldesenbet, md jimma university, jimma, ethiopia houston, texas july,...
TRANSCRIPT
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
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