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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 6/24/2013 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 2 6/24/2013 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 3 6/24/2013 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 4 6/24/2013 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 • • • • 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) 5 6/24/2013 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 6/24/2013 Management of the well appearing febrile young infant • • • • 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 7 6/24/2013 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 • • • • 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 8 6/24/2013 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 9 6/24/2013 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 • • • • 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 6/24/2013 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 3 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 11 6/24/2013 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 4 12 6/24/2013 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 6/24/2013 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 14 6/24/2013 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 • • • • • • • • • • 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 15 6/24/2013 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 16