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6/24/2013
Baby Be Cool: Evaluation and Management of the Febrile Neonate
12th Annual Update in Acute and Emergency Care Pediatric (TN EMSC / TN AAP) Conference
John V. Williams, MD
Associate Professor
Pediatric Infectious Diseases
Financial disclosures
• Scientific Advisory Board of Quidel
– Makes rapid antigen tests for strep, RSV, and flu and PCR tests for RSV, metapneumovirus, and flu
• No discussion of off‐label use of drugs
Objectives
• Name the most common pathogens in febrile neonates
• Describe the appropriate evaluation of febrile neonates
• Know empiric therapy for febrile neonates
• Be familiar with recent changes in the approach to febrile neonates 1
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Notes
• This presentation focuses on management of well appearing infant without clinical focus
• The overriding challenge in this population is to NOT MISS serious bacterial infection (SBI)
• Clinical appearance does not exclude SBI
• “Everybody looks good…until they look bad.” Case #1
• A full term, three‐week‐old female infant presents with a rectal temperature of 101.5. The baby has been feeding well and is not ill appearing. The appropriate next step is to: A. Observe as an outpatient. B. Obtain a CBC in the office.
C. Treat with amoxicillin.
D.Obtain a full sepsis evaluation including LP and admit to the hospital for observation.
E. Full sepsis workup, admit, and administer empiric ampicillin and gentamicin. Case 1 Labs
• CBC: WBC 8,000 (65% neutrophils)
• CSF: RBC 25, WBC 800
– 65% polys, 25% lymphs, 10% monos
– Protein 65, Glucose 35
– Gram stain: no organisms
• Urinalysis: normal
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Age‐Related Causes of Serious Infection in Young Infants
Bacteremia/Meningitis
<1 month
1–3 months
Group B streptococcus
Enteroviruses
E. coli (and other enteric gram‐negatives)
Herpes simplex virus (HSV)
Staph aureus (MRSA/MSSA)
Streptococcus pneumoniae
Listeria monocytogenes
Salmonella
Neisseria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae
Group B streptococcus
Enteroviruses
Staph aureus (MRSA/MSSA)
Neisseria meningitidis
Salmonella
H. influenzae
Listeria monocytogenes
Meningitis incidence is highest during the first 2 months of life
Thigpen et al NEJM 2011
GBS remains most common < 2 months
Thigpen et al NEJM 2011
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Group B Streptococcus (GBS, S. agalactiae)
• ~40% of women of childbearing age are colonized with GBS
– ~50% of all humans have GI colonization
• 50% of infants born to colonized women will be infected
• Approximately 1% of colonized infants will develop invasive disease
Early vs. Late‐Onset GBS
• Early‐onset: < 7 days
– Sepsis and pneumonia
– ~2200 cases annually in US • Late‐onset: 7 days to 3 months
– Meningitis
– 1400 cases annually in US • 140 deaths/year; significant morbidity
Intrapartum prophylaxis decreases incidence of invasive GBS
• Screening or risk‐based approach
• IV antibiotics intrapartum
• Intrapartum antibiotics reduce early‐
onset, but not late‐onset disease
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Case 1 Labs
• CBC: WBC 8,000 (65% neutrophils)
• CSF: RBC 25, WBC 800
– 65% polys, 25% lymphs, 10% monos
– Protein 65, Glucose 35
– Gram stain: no organisms
• Urinalysis: normal
“Aseptic” meningitis in the young infant
• Enterovirus most common (summer)
– Occasionally hepatitis, myocarditis, sepsis
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Herpes simplex less common but SEVERE
Early bacterial meningitis
Parameningeal focus (brain abscess)
Rare: CMV, syphilis, TB
Neonatal HSV infections
• <6 weeks of age
– Most occur in mothers w/o history of HSV
• Skin, eye, and mucous membrane (SEM)
– 70% progress if untreated
• CNS disease: encephalitis
– Devastating
• Disseminated infection: sepsis, hepatitis, pneumonitis, DIC ± CNS disease
– May lack CNS disease (CSF HSV PCR negative)
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Neonatal SEM HSV
Other Age‐Related Causes of Serious Infection in Young Infants
Urinary tract infection
0‐3 months
E. coli
Other enteric gram‐negatives
Enterococcus
Osteoarticular infections
<1 month
1‐3 months
Group B streptococcus
Staph aureus (MRSA/MSSA)
Staph aureus (MRSA/MSSA)
Group B streptococcus
Streptococcus pneumoniae
Case #2
A full term, six‐week‐old male infant presents with a rectal temperature of 101.3. The baby has been feeding well and is not ill appearing. A full septic evaluation, including LP, is unremarkable. The appropriate next step is to: A. Admit and administer empiric ampicillin and gentamicin.
B. Treat with amoxicillin.
C. Administer ceftriaxone and discharge home with next‐
day follow up in the office.
D. Discharge home with next‐day follow up in the office. 6
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Management of the well appearing febrile young infant
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Driven by desire to not miss serious infections
Heavily informed by laboratory data
Discordant approaches in ED vs. practice
Continues to evolve
Historical low risk criteria
ROCHESTER
CBC: WBC 5,000‐15,000; absolute band count ≤1500/mm3
Urine: <10 WBC/HPF at 40×
Stool: <5 WBC/HPF if diarrhea
BOSTON
CBC: WBC <20,000
Urine: negative leukocyte esterase
CSF: leukocyte count less than 10 × 106/L,
PHILADELPHIA CBC: WBC <15,000; band: total neutrophil ratio <0.2
Urine: <10 WBC/HPF; no bacteria on Gram stain
CSF: <8 WBC/mm3; no bacteria on Gram stain
Chest radiograph: no infiltrate
Stool: no RBC; few to no WBC
NOTE: All assume well appearing, normal exam, good follow up
What is the risk of SBI in infants < 3 months?
• High risk group
– 24.3% SBI
– 12.8% bacteremia
– 3.9% meningitis
• Low risk group
– 2.6% SBI
– 1.3% bacteremia
– 0.6% meningitis Meta‐analysis
Baraff et al Ped Infect Dis J 1992
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What about private practice?
• PROS study of 219 practices (573 clinicians)
• 3066 febrile infants <3 months
– 1975 (64%) not hospitalized
– Under one month more likely to have workup
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83% CBC/blood culture
55% LP
68% Antibiotics
60% hospitalized
Pantell et al JAMA 2004
How did private practice do?
• Bacteremia in 54 (1.8%)
• Bacterial meningitis in 14 (0.5%)
• Well appearing infants >25 days old ≤38.6°C
– 0.4% bacteremia/bacterial meningitis
• 61/63 cases of bacteremia/bacterial meningitis received antibiotics at first visit
– 2 infants diagnosed next day with GBS bacteremia or pneumococcal meningitis
Pantell et al JAMA 2004
UTI most common bacterial infection in PROS study
• 5.4% of 3066 infants
• 9.7% in 1666 with initial testing
• Other studies have found UTI rates of 10‐20% in similar populations
Pantell et al JAMA 2004
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How well did different models predict bacteremia/bacterial meningitis?
Pantell et al JAMA 2004
What do Pediatric ED docs do?
• PEM fellowship directors phone survey
– 53/64 (83%) response
• ED with policies more consistent (81% vs. 19%)
• Mandatory sepsis W/U?
– 45% if <28 days (next most common was 60 days)
– 92% at temp >100.4
• Admission rates varied
Schneider et al Ped Emerg Care 2012
Can an academic health center improve their approach?
• Evidence‐based care process model (EB‐CPM)
• Included guidelines for outpatient evaluation and inpatient management
– High and low risk criteria
– Discharge at 24‐36 hours based on criteria
• Compared 3‐year baseline with 1‐year implementation
Byington et al Pediatrics 2012
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EB‐CPM Results
• 8044 infants with 8431 febrile episodes
– ~2400 <28 days
• Overall 735 (9%) SBI
– UTI 617 (9%)
– Bacteremia 172 (2%)
– Bacterial meningitis 23 (0.2%)
Byington et al Pediatrics 2012
EB‐CPM Outcomes
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Increased diagnosis of UTI
More enterovirus PCR testing
No missed cases of meningitis
Reduced length of stay and admission costs
– Offset increased costs of initial testing
Byington et al Pediatrics 2012
Risk criteria perform poorly during first month of life
• Rate of SBI consistent by week in 449 neonates
– 22% week 1, 26% week 2, 18% week 3, 12% week 4
– SBI 6% even in “low risk” neonates
• SBI in 3.5% of low risk vs. 31% of high risk among 465 neonates
Schwartz et al Arch Dis Child 2008; Bilavsky et al Scand J Inf Dis 2011; 10
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Initial Evaluation and Treatment of the Febrile Infant < 29 Days
Preliminary Vanderbilt Guidelines
Inclusion Criteria
‐Infant < 29 days
‐Any reliably taken temperature > than 38.0C (100.4F)
Febrile infant < 29 days
Ill
Appearing
Yes
Full Sepsis Evaluation &
HSV Evaluation
No
1
1
Full Sepsis Evaluation
2
Risk of HSV based on HSV Checklist
Ampicillin
Gentamicin
Acyclovir
3
Any Yes
HSV Evaluation
2
No
Ampicillin
Gentamicin
Admit
Ampicillin
Gentamicin
Acyclovir
Admit
Admit
1
Full Sepsis Evaluation
‐Blood culture
‐CBC/plt/diff
‐AST/ALT
‐Urine culture
‐Urinalysis with micro
‐CSF gram stain and culture
‐CSF cell counts, glucose, protein (Enterovirus PCR with pleocytosis anytime or without pleocytosis during season)
‐Consider CXR for respiratory symptoms and exam not consistent with bronchiolitis
‐Consider stool guaiac, leukocytes, and culture for diarrhea
Empiric Treatment
‐Ampicillin
<7 days: 100 mg/kg/dose q8h
>7 days: 100 mg/kg/dose q6h
‐Gentamicin
‐Cefotaxime
Add cefotaxime 100mg/kg/dose q8h for gram negative rods seen on gram stain 2
Herpes Simplex Virus (HSV) Checklist
‐Hypothermia (<96.5F/35.8C) or respiratory distress
‐History of seizures or seizure during evaluation
‐Vesicles on exam (including scalp)
‐CSF pleocytosis for age (>19 nucleated cells/hpf)
‐Elevated transaminases (>2x upper limit of normal)
** If any of these are present, testing and treatment is recommended
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HSV Evaluation
‐Serum HSV PCR
‐CSF HSV PCR
‐Eye/nasopharyngeal/rectal swabs for HSV culture
‐Swabs of vesicles for HSV DFA, HSV PCR, and HSV culture
Empiric Treatment
‐Acyclovir 20mg/kg/dose every 8 hours
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Initial Evaluation and Management of the Febrile Infant 29‐60 days
Preliminary Vanderbilt Guidelines
‐Infant 29‐60 days
‐Any reliably taken temperature >38.0C (100.4F)
**For infants who are test positive for flu or RSV, obtaining U/A with micro, urine culture, blood culture and monitoring off antibiotics is recommended unless workup is concerning for bacterial. If starting antibiotics, a lumbar puncture is recommended prior to initiation.
Febrile Infant 29‐60 days
3
Full Sepsis Evaluation High Risk
Low 3
Risk
Seizures or vesicles concerning for HSV
Ceftriaxone
* Add vancomycin for CSF pleocytosis 4
Discharge home if meets discharge criteria. +/‐
Ceftriaxone dose
Yes
Admit
Ceftriaxone and Acyclovir
•Add vancomycin for CSF pleocytosis Full Sepsis Evaluation
‐Blood culture
‐CBC/plt/diff
‐Urine culture
‐Urinalysis with micro
‐CSF gram stain and culture
‐CSF cell counts, glucose, protein (Enterovirus PCR with pleocytosis anytime or with no pleocytosis during season)
‐Consider CXR for severe respiratory symptoms
‐Consider stool gram stain and culture for diarrhea
Empiric Treatment
Meningitis
‐ Ceftriaxone (50mg/kg/dose q12h) + Vancomycin (15mg/kg/dose q6h)
2
HSV Evaluation
1
Bacteremia/UTI
‐ Ceftriaxone (50mg/kg/dose q24h)
HSV Evaluation ‐Serum HSV PCR
‐CSF HSV PCR
‐Eye/nasopharyngeal/rectal swabs for HSV culture
‐Swabs of vesicles for HSV DFA, HSV PCR, and HSV culture
Empiric Treatment
‐Acyclovir 20mg/kg/dose q8 hours
2
Classified as Low Risk Infant if each is true. Classified as High Risk Infant if any one is not true.
‐>37 weeks gestational age ‐No congenital medical and/or surgical comorbidities
‐No previous antibiotic use within the last 7 days
‐Urinalysis with neg nitrites, LE, and < 10 WBC/hpf
‐CBC with 5K‐15K WBC, <1500 ANC
‐CSF with <10 Nucleated cells/hpf
‐CXR (if obtained) without focal infiltrates
ED Discharge Criteria
‐Classified as low risk (meets ALL criteria)
‐Family understanding of diagnosis and plan
‐Contact with PCP and PCP who agrees with plan and will follow up next day
‐Adequate transportation for follow up appointment or return to ED
‐Working phone with documentation of reachable number 3
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Inpatient Management
Preliminary Vanderbilt Guidelines
Inpatient Management ‐ High risk infants
• Serious Bacterial infection
– Treat accordingly; review sensitivities and adjust antibiotics accordingly; consult Infectious Disease specialist for all meningitis
• HSV infection
– Continue acyclovir and consult Infectious Disease specialist
• Bacterial workup negative, enterovirus testing positive
– Stop antibiotics, consider discharge at 24 hours if meets discharge criteria
• Bacterial workup negative, virus testing negative
– If well appearing, stop antibiotics and consider discharge at 36 hours if meets discharge criteria; urine culture is completed and negative or is reviewed is confirmed negative by review at 36 hours
Inpatient Management ‐ Low Risk Infants
• Serious Bacterial Infection positive
– Treat accordingly; review culture results and sensitivities and adjust accordingly
• Bacterial Infection negative, viral infection negative or positive
– Stop antibiotics and consider discharge at 24 hours if meets discharge criteria; urine culture is final negative or reviewed and negative at 24 hours; blood culture is negative at 24 hours; and CSF is reviewed and negative at 24 hours 13
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Inpatient Minimal Discharge Criteria
Serious Bacterial Infection
UTI or Bacteremia:
• Tolerating po
• Afebrile
• Completed appropriate parenteral therapy or home antibiotics arranged
• Follow up arranged including discussion with PCP
No Serious Bacterial Infection
No HSV risk or HSV Ruled out:
• Tolerating po
• Follow up arranged including discussion with PCP Bacterial Meningitis:
• Plan for full inpatient course of antibiotics unless otherwise recommended by Infectious Disease specialist
Future directions
• Point‐of‐care viral PCR testing
• Biomarkers for SBI (CRP, procalcitonin, secretory phospholipase A2, etc.)
• GBS or HSV vaccines?
Key points I
• Management of the febrile infant is evolving
• Urine studies are most forgotten piece
• Risk stratification must be a part of any strategy or guideline
• For well appearing <1 month, recommend full sepsis workup, admit, and empiric antibiotics
– Earlier discharge may be possible if virus testing positive and/or blood, urine, and CSF cultures negative at 24‐36 hours
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Key points II
• For well appearing 1‐2 months, outpatient management may be appropriate
– Limited evaluation if RSV or flu positive
– Always include urine studies
• Strongly recommend LP if giving antibiotics
• Close follow up critical for all outpatients
Febrile Neonate Working Group
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Carrie Lind, MD
Sarah Parker, MD
Natasha Halasa, MD
Jim Gay, MD
Aida Yared, MD
Laurie Lawrence, MD
Matt Locklair, MD
Lauren McClain, MD
Melissa Gervase, Pharm.D.
Jason Kastner, MD
Baby Be Cool: Evaluation and Management of the Febrile Neonate
12th Annual Update in Acute and Emergency Care Pediatric (TN EMSC / TN AAP) Conference
John V. Williams, MD
Associate Professor, Pediatric Infectious Diseases
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Empiric Antibiotics for Infants <29 days:
Empiric Antibiotics for Infants >29 days:
‐Meningitis (CSF pleocytosis)
‐Meningitis (CSF pleocytosis)
Ampicillin: <7 days: 100 mg/kg/dose q8h
Vancomycin: 15mg/kg/dose q6h
(If renal impairment, contact pharmacy)
>7 days: 100 mg/kg/dose q6h
Ceftriaxone: 50mg/kg/dose q12h
Gentamicin: TBD
Acyclovir: 20mg/kg/dose q8h
‐Bacteremia/UTI
*Add cefotaxime 100mg/kg/dose q8h for Gram Negative Rods seen on gram stain Ceftriaxone: 50mg/kg/dose q24h
‐Bacteremia/UTI
Ampicillin: <7 days: 100 mg/kg/dose q12h
>7 days: 50 mg/kg/dose q6h
Gentamicin: TBD
‐Concern/Testing for HSV Infection
Acyclovir: 20mg/kg/dose q8h
*If on acyclovir and/or other nephrotoxic medications, strongly consider IVF
‐Concern/Testing for HSV Infection
Acyclovir: 20 mg/kg/dose q8h
*If on acyclovir and/or other nephrotoxic
medications, strongly consider IVF
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