1. Fever in the Infant Gina Lowell July 5th, 2005

2. Defining the problem Infants <60 days old –T > 38ºC (100.4ºF) –Physical exam findings unreliable –Immunologic status shifting Maternal antibodies wane Infant antibodies still developing –T cell/B cell function diminished –Immunizations not yet received Premature infants at greater disadvantage –Transplacental IgG received in 3rd trimester

3. Serum IgG levels in the first five years of life ©2005 UpToDate®

4. Etiology Viral causes –Most common (presumed vs. confirmed) –Adenoviruses, Enteroviruses, Influenza, RSV, Parainfluenza, etc. –HSV: uncommon but worrisome Bacterial causes –Less common 7.2-8.5% of febrile infants <90 days old will have a serious bacterial infection (SBI) A greater proportion of these occur during the first month of life

5. Serious Bacterial Infection Bacteremia Meningitis Urinary tract infection Soft tissue infection Bone/joint infection Endocarditis Pneumonia Gastroenteritis

6. Pathogens The first month –GBS (Streptococcus agalactiae) –E. coli –Listeria monocytogenes The second month: All of the above, plus… –Streptococcus pneumoniae –Hemophilus influenza type b Incidence has decreased to fewer than 1 case per 100,000 children less than 5 years old

7. Group B Streptococcus (GBS) Gram positive diplococcus; 9 serotypes Range of infection: EOD versus LOD –EOD: Presents 1st week after birth Vertical transmission Risk factors –Delivery <37wks gestation –Maternal chorioamnionitis (T>38°C) –Prolonged rupture of membranes (>18 hours) –Previous infant with invasive GBS disease Prevented by appropriate intrapartum antibiotics (IPA) –2 doses of Ampicillin prior to delivery –LOD: Presents 1-4 weeks after birth Can present up to 3-6 months after birth Horizontal transmission IPA does not prevent LOD

8. GBS: Treatment Empiric treatment for suspected GBS –EOD: Ampicillin and an aminoglycoside (Gentamicin) –LOD: Ampicillin and a 3rd generation cephalosporin (Cefotaxime or Ceftriaxone) Await culture and sensitivities –Uniformly sensitive to penicillin –While GBS are susceptible to cephalosporins and other antibiotics, none of these are superior to ampicillin or penicillin Length of treatment –Bacteremia: 10 days –Meningitis: 14-21 days –Osteomyelitis or Endocarditis: 4 weeks

9. Escherichia coli Gram negative bacillus Lengthy range of infection: from birth to several weeks old Risk factors –Intrapartum Delivery <37wks gestation Maternal chorioamnionitis (T>38°C) Prolonged rupture of membranes (>18 hours) Low birth weight Traumatic delivery –Metabolic Galactosemia Acidosis –Skin defects Myelomeningocele

10. E. coli: Treatment Empiric treatment for suspected E. coli –Ampicillin and an aminoglycoside (Gentamicin) or –Ampicillin and a 3rd generation cephalosporin (Cefotaxime or Ceftriaxone) CAUTION! Emergence of gram negative bacilli with ESBL can occur with routine use of cephalosporins (Klebsiella, Enterobacter, Serratia sp.) Await culture and sensitivities –Ampicillin or 3rd generation cephalosporin with an aminoglycoside Length of treatment –Bacteremia: 10-14 days –Meningitis: 21 days

11. Listeria monocytogenes Gram positive bacillus Rare: 124/10^6 births Foodborne transmission –Unpasteurized milk, soft cheeses, prepared meats, unwashed raw vegetables Similar range of infection to GBS –EOD: days after birth Moms may have flu-like illness days prior to delivery In utero transmission (while mom bacteremic) –LOD: several days to weeks after birth Mom asymptomatic Postpartum transmission

12. Listeria: Treatment Empiric treatment for suspected Listeria –Ampicillin and Gentamicin Await culture and sensitivities –Ampicillin: bacteriostatic –Gentamicin: bactericidal –Bactrim is preferred in PCN allergic patients –Cephalosporins are not active against Listeria Length of treatment –Bacteremia: 10-14 days –Meningitis: 14-21 days

13. Streptococcus pneumoniae Gram positive diplococcus; 90 serotypes SPIN: S. pneumoniae infections in the neonate –Accounts for 1-11% of septicemia in the infant <30 days old –2-3 weeks old at presentation –Patients were ill with bacteremia, meningitis, pneumonia, and otitis media Incidence rises during the second month of life Predominates from the 3rd month of life onward

14. S. pneumoniae: Treatment Empiric treatment for suspected S. pneumoniae –3rd generation cephalosporin 50% of isolates are resistant to penicillin 50% of PCN-resistant strains are also resistant to cephalosporins –If bacterial meningitis is suspected, add Vancomycin Await culture and sensitivities –3rd generation cephalosporins –If resistant to cephalosporins, consult ID Length of treatment –Bacteremia: 10-14 days –Meningitis: 14-21 days

15. Herpes Simplex Virus Two serotypes: HSV-1 and HSV-2 –75% of neonatal infections are due to HSV-2 Incidence: 1 in 3,000-20,000 live births –Infection occurs in 33-50% of infants born vaginally to mothers with primary HSV infection –More than 75% of these moms had no signs or symptoms of infection before or during pregnancy Range of presentation: Birth to 4 weeks old Pattern of presentation –SEM: 40% –CNS: 35% –Disseminated: 25%

16. HSV: Treatment Empiric treatment for suspected HSV –Acyclovir IV Await diagnostic results –Tzanck preparation (skin scraping) –Culture (eyes, nasopharynx, skin, rectal) –PCR (CSF) –EEG, MRI (temporal lobe abnormalities) Length of treatment –14 days for SEM –21 days for CNS and disseminated disease

17. Lab investigation of the febrile infant Blood –CBC, culture –LFT’s if suspicious for HSV Urine –UA, culture CSF –Cell count, protein, glucose, culture, HSV PCR when suspicious Stool –Culture if suspicious for bacterial gastroenteritis CXR –If patient has one or more respiratory symptoms

18. Empiric treatment of the febrile infant Ampicillin: 1st and 2nd month –GBS –E. coli –Listeria Gentamicin: 1st month –E. coli –Listeria Ceftriaxone/Cefotaxime: 2nd month –S. pneumoniae –E. coli Vancomycin: 2nd month –Only if strongly suspicious of bacterial meningitis Acyclovir: 1st month –Only if strongly suspicious of HSV

19. Admission and Antibiotics: Who needs it? Defining Low Risk Infants Rochester criteria Boston criteria Philadelphia criteria Age Gestation 0-60 days >37 wks 28-89 days N/S 29-60 days N/S Temp Appearance >38°C Well >38°C Well >38.2°C Well Labs (Not complete) WBC 5-15 Bands<1.5 WBC<20 CSF WBC<10 WBC<15 CSF WBC<8 Treatment Follow up Not defined Reliable CTX IM 24 hours None 24 hours Low risk infants Outcome 47% NPV 98.9% Not defined 5.4% of low risk infants had SBI 19% NPV 99.7%

20. Troubleshooting LP –Dry –Traumatic Confirmed viral infection: Risk of concomitant SBI –Infants with confirmed viral infection (e.g. RSV+) are at lower risk for SBI than those without an identified viral infection Predisposition to SBI can vary among viruses Preterm infants or infants<30 days generally should receive the full sepsis evaluation and treatment even if viral infection is confirmed ABX received prior to lab evaluation –At risk for partially treated meningitis –Full sepsis evaluation and treatment –If negative, close observation off of antibiotics is warranted In all of these scenarios, follow your clinical judgement

21. Sources Baraff LJ, Bass JW, Fleisher, GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22:1198-1210 Baskin, MN. The prevalence of serious bacterial infection by age in febrile infants during the first 3 months of life. Pediatr Ann. 1993;22:462. Behrman RE, Kliegman RM. Nelson Essentials of Pediatrics, 3rd Edition. Immunology and Allergy: Physiologic Immunodeficiency in the Neonate. 1998;8:269 Byington CL et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics. 2004;113(6):1662-1666 Byington CL et al. Ampicillin-resistant pathogens in febrile infants. Pediatrics. 2003;111(5):964-968. Durbin WJ. Pneumococcal Infections. Pediatrics in Review. 2004;25(12):418-423. Gotoff SP. Group B Streptococcal Infections. Pediatrics in Review. 2002;23(11):381-385. Hoffman JA et al. Streptococcus pneumoniae infections in the neonate. Pediatrics. 2003;112(5):1095-1102. Posfay-Barbe KM, Wald ER. Listeriosis. Pediatrics in Review. 2004;25(5):151-156. Waggoner-Fountain LA, Grossman LB. Herpes Simplex Virus. Pediatrics in Review. 2004;25(3):86-92.