1. Neonatal Meningitis: Current Treatment Options Ma. Teresa C. Ambat, MD Neonatology-TTUHSC 7/10/2008

2. Introduction Bacterial menigitis: 0.4 neonates / 1000 LB Consequence of hematogenous disssemination of bacteria during sepsis episode –Occurs in 10-20% of infants with bacteremia Extension from infected skin VPS or reservoirs may be the primary site of infection

3. Introduction All organisms that cause neonatal infection or sepsis can result in CNS disease  severe consequences to the developing brain Early diagnosis and therapy is mandatory  improve short and long term outcomes

4. Do infants with meninigitis have positive blood cultures? Infants with meningitis with sterile blood cultures –40% of >34 wks GA –50% of VLBW –Perform LP if sepsis/meningitis is suspected Meningitis in infants admitted to the NICU with respiratory distress is very uncommon –LP is not mandatory in these infants –LP should be done if blood culture +

5. What is the treatment of meningitis in neonates? Gram negative –3 rd generation (cefotaxime) or 4 th generation (cefepime) cephalosporin or –Carbapenem (meropenem) –+ aminoglycoside until sterilization of CSF (concentration low in CSF) –Most are resistant to ampicillin, may be used in susceptible organism –Continued treatment based on in vitro susecpetibility B lactamase producing (Enterobacter, Serratia, P. aeruginosa, Citrobacter, indole + Proteus) ESBL (Enterobacteriaceae – Klebsiella, E Coli) –Carbapenem (meropenem or imepenem) + aminoglycoside

6. Treatment GBS –Ampicillin or Pen G –+ gentamicin for synergy (discontinued after CSF sterilization by rpt LP 24/48 hrs after treatment or after 1 week) Preterm in the NICU –S aureus, CONS, enterococci, multipy-resistant pathogens –Emperic treatment: Ampicillin, nafcillin or vancomycin + aminoglycoside, cefotaxime or meropenem – depending on predominant pathogens in the NICU

7. Treatment Fungal infection –Candida spp –Amphotericin B: treatment of choice, used successfully as monotherapy –Amphotericin B lipid formulation: if renal toxicity –Fluconazole: excellent CNS penetration, + ampho B if persistent fungemia or poor clinical response –Newer azoles – Voriconazole: limited experience –Echinocandins – Caspofungin, micafungin: poor CNS penetration

8. What is the duration of treatment for meningitis in neonates? Dependent on causative organism, sites of infection, clinical severity, and course –Uncomplicated bacteremia: 7 days –Sepsis/pneumonia: 7-10 days –Meningitis: 14-21 days, dependent on causative agent Gram negative bacilli –Minimum 21 days or 2 weeks after the first sterile CSF culture whichever is longer –Repeat LP after 21 days, before discontinuation of tx: determine adequacy of therapy –Abnormal CSF findings (glucose 300 or >50%PMNs) – warrant continued therapy

9. Duration of treatment GBS meningitis –Minimum of 14 days –End of therapy LP – dependent on clinical course (seizures, hypotension, prolonged + CSF cultures, abnormal neuroimaging) Other organisms: optimal duration not known –S aureus: at least 3 weeks –Carebral abscess: prolonged tx of 4-6 wks

10. Red Book Recommendation: GBS meningitis Ampicillin + aminoglycoside – initial treatment Pen G alone – GBS indentified with clinical and microbiologic responses documented GBS meningitis –Penicillin G < 7 days: 250-400K u/k/day q8 >7 days: 450-500K u.k.day q4-6 –Ampicillin <7 days: 200-300 mg/k/day q8 >7 days: 300mg/k/day q4-6

11. Red Book Recommendation: GBS meningitis Duration of treatment –Uncomplicated meningitis: 14 days –Complicated course: longer, ventriculitis - 4 wks 2 nd LP 24 to 48 hrs after initiation of therapy assists in management and prognosis Additional LP + diagnostic imaging – if response is in doubt and neurologic abnormalities persist

12. Should other therapies be considered? Gram negative bacilli meningitis –Associated with persistently + CSF cultures, median duration of 3 days –Duration of positivity correlates with long term prognosis and impacts duration of therapy –For Gram-negative bacilli: daily or every other day LP to determine occurrence and timing of CSF sterilization

13. Should other therapies be considered? Intraventricular therapy –Generally not recommended –An option in those with ventricular drain in place and persistently + CSF cultures –Parenteral vs parenteral + intrathecal (gentamicin 1 mg/day x 3 days): No difference in case fatality or neurologic sequelae –Intraventricular gentamicin 2.5mg: Higher mortality (43% vs 13%) –Greater inflammatory injury as a result of this tx

14. Should other adjunctive therapies be provided to an infant with meningitis? Dexamethesone –No studies available in neonates, use not recommended Prophylactic fluconazol –Should be considered in preterm infants (<1000g) who require prolonged broad-spectrum antimicrobial therapy –Shown to decrease incidence of candidiasis

15. What if the infant’s CSF is abnormal but routine bacterial cultures of CSF and blood are sterile? Most frequent reason: previous antimicrobial therapy IVH can result in inflammatory changes in the absence of an infectious process When sepsis/meningitis suspected –Repeat LP should be performed –Pathogens producing aseptic meningitis should be ruled out –CSF should be sent for anaerobic, mycoplasma, fungal and viral cultures, herpes/enteroviruses PCR

16. When should neuroimaging be considered and what type of examination is recommended? Cranial US –Safe, convenient, available at the bedside –Ventricular size, development of hydrocephalus –Periventricular white matter (increased PV echogenicity  PVL in ischemia) –Not identify infarct, abscess, subdural empyema CT –Abscess, subdural collections, hydrocephalus

17. When should neuroimaging be considered and what type of examination is recommended? MRI –Indication: abnormal US, seizures, persistent + CSF cultures, due to organisms (Citrobacter, fungi) –Experts recommend brain MRI be performed on every case of neonatal meningitis Hearing evaluation for all infants with meningitis

18. What is the outcome of meninigitis in neonates? PT, BW <1000g –Low (<70) mental and psychomotor indexes, CP, vision impairment and HC (<10%) Gram negative enteric menigitis –20-30% mortality –30-50% neurologic sequelae (hydrocephalus, seizure disorder, developmental delay, CP, hearing loss) GBS meningitis –25% mortality –25-30% major neurologic sequelae (spastic quadriplegia, profound MR, hemiparesis, deafness, cortical blindness) –15-20% mild-moderate sequelae –50-60% normal –Seizures during acute illness associated with poor prognosis

19. References Kaufman D, Zanelli S, Sanchez P. Neonatal meningitis: current treatment options. Neurology: Neonatology questions and controversies 210-230, 2008. Red Book 2006.