TREATMENT AND OUTCOME

1. Bacterial meningitis in the neonate:
treatment and outcome
Collected by
Tarek S Kotb
MBBCH
MRCPCH.UK

2. Introduction
 bacterial meningitis is more common in the first month than at any
other time of life . Despite advances in infant intensive care ,neonatal
meningitis remains a devastating disease.
 The mortality rate has declined from almost 50% in 1970s to
contemporary rates of less than 10% . However morbidity from
neonatal meningitis is relatively unchanged . Survivors remain at high
risk for neurologic sequelae and lifelong impairment .
Neonatal meningitis in England and Wales: sequelae at 5 years of age.
de Louvois J, Halket S, Harvey D
Eur J Pediatr. 2005;164(12):730.
http://www.uptodate.com/contents/bacterial-meningitis-in-the-neonate-treatment-and-outcome/abstract/3,5#

3. Supportive care
 Supportive care for neonates with meningitis may
include :
 Fluid maintenance
 Prevention of hypoglycemia
 Control of seizures
 Provision of O2 and mechanical ventilator support
 Nutritional support (TPN)
Saez-Llorens X, McCracken GH Jr. Krugman's Infectious Diseases of Children. In: Krugman's Infectious Diseases of
Children, 11th ed, Greshon AA, Hotez PJ, Katz SL (Eds), Mosby, Philadelphia 2004. p.373.

4. Antimicrobial therapy
 Overview :
 Appropriate broad-spectrum antimicrobial therapy
with agents that have adequate CSF penetration is
indicated if the initial csf evaluation is suggestive of
bacterial meningitis :
 Organism present in gram stain
 Increased CSF white blood cells
 Increased CSF proteins
 Decreased CSF glucose
antibiotics should be initiated as soon as possible

5. Empirical therapy
 Empirical therapy for nonbacterial infections also
can be indicated for some neonates pending
definitive evaluation eg . Acyclovir for herpes
simplex virus in neonates who have mucocutaneous
vesicles or clinical or CSF finding suggesting HSV

6. Empirical therapy
 The initial choice of antimicrobials for suspected
bacterial meningitis in neonates is based on :-
 Infant age
 Likely pathogens
 The susceptibility pattern of gram negative
organisms causing late onset infections in infants
with continuous care in a particular nursery.

7. Common pathogens
 In neonates 0 – 3 days of agethe most common
bacterial pathogens are:
 group B streptococcus (GBS)
 E.coli
 other enteric bacilli
 Listeria monocytogenes.
 Uncommon pathogens include other streptococci
including groups A,C or G ,viridans streptococci and
enterococci , non-typeable H. influenzae ,N
meningitidis and strept. Pneumoniae.

8. Common pathogens
 in neonates 4 days of age or older the gram negative
organisms must be considered in addition to GBS
,E.coli and other enterics including serratia
marcescens ,Pseudomonas aeruginosa and
citroobacter koseri as well as L.monocytogenes
 In continiously hospitalized neonates 7 days of age
or older a wide range of potential gram positive
organisms must be considered in addition to
antimicrobial resistent gram negative organisms
such as Acinetobacter ,stenotrophomonas ,MDR
klebsiella and other enterics

9. Common pathogens
 in neonates admitted from the community meningitis
due to staphylococcus aureus is not a concern , in
hospitalized VLBW neonates late onset S.aureus
has been documented albeit rarely.
IEvaluation and treatment of community-acquired Staphylococcus aureus infections in term and late-preterm
previously healthy neonates.
Fortunov RM, Hulten KG, Hammerman WA, Mason EO Jr, Kaplan SL
Pediatrics. 2007;120(5):937.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

10. Early onset sepsis
 Initial empirical therapy for suspected bacterial meningitis
within the 1st 3 – 6 days of age is ampicillin and an
aminoglycoside usually gentamycin
 an alternative regimen of ampicillin and an expanded spectrum
3rd generation cephalosporin such as cefotaxaime can be used
if L.monocytogenes or enterococci are unlikely. Adding
cefotaxaime to the regimen broadens emperical coverage fore
grame –ve organisms
 High rates of ampicillin resistance among E.coli isolated and
the link between maternal intrapartum ampicillin and E.coli
resistance has been reported in VLBW infants <1500 g but not
near term or term infant.
Neonatal early onset Escherichia coli sepsis: trends in incidence and antimicrobial resistance in the era of intrapartum
antimicrobial prophylaxis.
AUAlarcon A, Peña P, Salas S, Sancha M, Omeñaca F
SOPediatr Infect Dis J. 2004;23(4):295. Division of Neonatology, Department of Pediatrics, Hospital Universitario La Paz,
Paseo de la Castellana 261, 28046 Madrid, Spain. luisiana12@terra.es

11. Important note
 in NICU setting cephalosporin use should be
restricted to neonates with suspected bacterial
meningitis based on CSF and/or clinical findings .
When use of cefotaxime is routine eg. For all
neonates treated to R/O sepsis rapid emergence of
cephalosporin –resistent strains esp. Enterobacter
cloacae ,Klebsiella and Serratia can occur.
American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia and meningitis in
neonates). In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American
Academy of Pediatrics, Elk Grove Village, IL 2015. p.340.

12. Early onset
 If meningitis resulting from a gram –ve organism is
strongly suspected eg. When the CSF Gram stain
reveals gram –ve bacilli the empirical regimen of
ampicillin and an an aminoglycoside should be
expanded to include cefotaxime . If cefotaxime is not
available meropenem may be substituted.

13. Late onset
 Initial empirical therapy for suspected bacterial
meningitis after the 1st week of life depend on :
 the preliminary CSF finding
 and whether the neonates remain hospitalised since
birth or has been discharged from birth hospital and
is admitted from the community.

14. Late onset neonates admitted from the
community
 Who are strongly suspected to have bacterial
meningitis based on CSF study and/or clinical
findings the initial empiric regimen consists of
ampicillin PLUS an aminoglycoside (usually genta)
PLUS cefotaxime
 Antibiotic coverage should generally not be narrowed
on the Gram stain results because they are subject to
observer misinterpretation .
 Empiric therapy should be continued tell bending
confirmation of the organism and susceptibility
results .
Practice guidelines for the management of bacterial meningitis.
Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ
Clin Infect Dis. 2004;39(9):1267.
Drexel University College of Medicine, Philadelphia, PA 19129, USA. allan.tunkel@drexel.edu

15. Late onset : neonates hospitalized since
birth
 for infants hospitalized since birth late onset sepsis without
meningitis is initially treated with vancomycin and an
aminoglycoside . When LP suggests meningitis cefotaxime should
be added to provide an extended spectrum for Gram –ve enterics
and for optimal activity in the CSF against pneumococcci .
 Cefotaxime also should be added when LP can not be performed
due to clinical instability.
 Ampicillin should be added to vancomycin-aminoglycoside regemin
if L.monocytogenes is suspected in basis of Gram stain because
vancomycin concentration in the CSF are not bactericidal for these
organisms
PubMed
Is lumbar puncture necessary to exclude meningitis in neonates and young infants: lessons from the group B streptococcus
cellulitis- adenitis syndrome.
Albanyan EA, Baker CJ
Pediatrics. 1998;102(4 Pt 1):985.
Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

16. Important note
 If cefotaxime is not available or if there is concern for
infection due to MDR gram-ve organism meropenem
rather than cefotaxime is preferred choice for
empirical therapy .
 The determination of whether to provide empiric
therapy for MDR gram-ve is based upon susceptibility
patterns of gram-ve organisms at particular NICU.
Extended-Spectrumβ-Lactamase-Producing and Third-Generation Cephalosporin-Resistant Enterobacteriaceae in Children:
Trends in the United States, 1999-2011.
AULogan LK, Braykov NP, Weinstein RA, Laxminarayan R, CDC Epicenters Prevention Program
SOJ Pediatric Infect Dis Soc. 2014 Dec;3(4):320-8. Epub 2014 Mar 19.
Departments of Pediatrics Section of Pediatric Infectious Diseases, Rush Medical College, Rush University Medical Center,
Chicago, Illinois John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois.

17. Specific therapy
 Once the causative organism and the in vitro
antimicrobial susceptibility results are known
empirical antimicrobial therapy should be altered
accordingly

18. GBS
 GBS is uniformly susceptible to penicillin and
ampicillin
 The combination of penicillin + an aminoglycoside
can be employed until sterility of the blood stream
and CSF has been documented
Synergy between penicillins and low concentrations of gentamicin in the killing of group B streptococci.
Swingle HM, Bucciarelli RL, Ayoub EM
J Infect Dis. 1985;152(3):515.

19. Gram –ve enteric bacteria
 Ampicillin is the antimicrobial of choice for neonatal
meningitis resulting from ampiciliin susceptible strain of
E.coli .
 Ampicillin-resistent E.coli and other gram-ve organisms
usually are treated with combination of an expanded-
spectrum cephalosporin ,generally cefotaxime (or
ceftazidime in case of Pseudomonas ) in combination with
an aminoglycoside usually gentamycin .
 Once sterility of the CSF is documented the
aminoglycoside can be discontinued and the appropriate
B-lactam continued to complete a minimum of 21 days or
14 days of theraby after the CSF is sterile .
 Meropenem is recommended for treatment of MDR enteric
organisms

20. Listeria
 The combination of ampicillin and gentamycin is
more effective than ampicillin alone and it is
appropriate for initial therapy.
 When the CSF has been sterilized and the patient
improved clinically a 14 – 21 day course of treatment
cab be completed with ampicillin monotherapy.

21. CONS
 Vancomycin is the drug of choice for proven
meningitis caused by CONS . These organisms
rarely invade the meninges except as a complication
of bacteremia accompanying IVH in VLBW <1500 g
or as a result of surgical manipulations or placement
of V-P shunt.
 Sterilization of the CSF usually is achieved promptly
after initiation of vancomycin if the CSF is peristently
positive consideration should be given to adding
rifampicin 5 mg/kg every 12 hours to vancomycin for
synergy

22. Duration of therapy
Positive CSF culture :-
 Depend on causative organism
 A 14 days course is sufficient for neonates with
uncomplicated meningitis caused by GBS or other
gram+ve organisms such as Listeria or
Enterococcus
 A longer course of therapy is required for neonates
with GBS who have a complicated course
 A 21 days course is the minimum for neonates with
meningitis resulting from E.coli or gram-ve
pathogens
American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia and meningitis in
neonates). In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American
Academy of Pediatrics, Elk Grove Village, IL 2015. p.340.

23. Duration of therapy
negative CSF culture
 Must be determined on an individual clinical basis:
 For neonates with clinically suspected bacterial
meningitis(with or without pleocytosis) but with
negative blood and CSF cultures (obtained before
antibiotic therapy) the author suggest
discontinuation of antimicrobial after 48-72 hours of
–ve cultures .
 For neonates with CSF pleocytosis and bacteremia
but a –ve CSF culture we usually continue
meningeal doses of antimicrobial therapy for 10 days
for gram +ve and 14 days for gram-ve bacteremia

24. Duration of therapy
LP delayed
 The total duration of therapy depend on CSF
evaluation and blood culture result:
 Those who have a CSF pleocytosis and +ve blood c/s
are treated for 10 days for gram +ve and 14 days for
gram-ve bacteremia
 For those who have a CSF pleocytosis and a –ve
blood c/s we individualized the doses of meningitic
doses based on clinical parameters whether thhere is
a noninfectious explanation for the pleocytosis eg.
IVH
 For those who have a normal CSF and –ve csf and
blood c/s antibiotics will be D/C after 48 -72 hours

25. Duration of therapy
antibiotic exposure prior to evaluation
 Exposure through maternal antrapartum antibiotic
prophylaxis (IAP) or antibiotics given to the neonate
for any reason may influence the interpretation of
the results;
 Maternal IAP neonates whose mothers received IAP
and have a clinical course suggesting sepsis or
meningitis are treated in the same manner as infants
with proven sepsis or meningitis
 Neonates receiving antibiotics for other reasons eg.
For VUR are treated in the same manner as infants in
whom CSF was delayed .

26. Dexamethasone
 The effect of dexamethasone to diminish the risk of
neurologic sequelae in neonatal meningitis was
evaluated in small randomized trial that didn’t have a
placebo arm , the administration of dexa didn’t
significantly affect mortality or neurologic outcome
at two years of age and dexamethasone therapy is
not currentlly recommended
Lack of effectiveness of dexamethasone in neonatal bacterial meningitis.
AUDaoud AS, Batieha A, Al-Sheyyab M, Abuekteish F, Obeidat A, Mahafza T
SOEur J Pediatr. 1999;158(3):230.
Department of Pediatrics, Jordan University of Science&Technology, Faculty of Medicine, Irbid. daoud@just.edu.jo

27. Monitoring response to therapy
 Ongoing evaluation : monitoring development of
complication . CSF evaluation ,neuroimaging and
blood c/s should be performed to document sterility
in the blood stream.

28. Repeat LP
 Should be repeated routinely at 24 -48 hours after
initiation of antimicrobial therapy to document CSF
sterilization
 Gram +ve usually clear rapidly within 24 hours
whereas gram –ve may persist for several days in
severe cases
The rate of bacteriologic response to antimicrobial therapy in neonatal meningitis.
AUMcCracken GH Jr
SOAm J Dis Child. 1972;123(6):547.

29. Why reevaluation of the CSF is important
 Reevaluation of the CSF 24 – 48 hours is important for several
reasons
 Delayed sterilization of the CSF is associated with increased risk
of developing neurologic sequelae .
 The persistent identification of the organism on a Gram stain
may be an early identification of inadequacy of antimicrobial
therapy
 Persistence of viable organisms more than 48 hours after
initiation of theraby is an indication for diagnostic neuroimaging
because it can indicate a purulent focus (ventriculitis, small
vessel thrombi)
 Sterilization of the CSF is a criterion for D/C combination therapy
for some pathogens
J Pediatr. 1993;122(1):15.
J Paediatr Child Health. 1990;26(4):212.

30. Neuroimaging
 Indicated to assist in defining the potential
complication of neonatal meningitis andd typically is
performed late in the course of therapy to provide
the best prognostic information
Cranial sonography in pyogenic meningitis in neonates and infants.
AURaju VS, Rao MN, Rao VS
SOJ Trop Pediatr. 1995;41(2):68.

31. outcome
• Outcomes vary according to the causative organism
and the infant birth wt
 Gram +ve infections:
Early outcomes of group B streptococcal meningitis in the 21st century.
AULevent F, Baker CJ, Rench MA, Edwards MS
SOPediatr Infect Dis J. 2010;29(11):1009.
CONCLUSIONS: Despite advances in intensive care, 26% of term and near-term infants with
GBS meningitis die or have neurologic impairment at hospital discharge. Additional strategies
to prevent GBS meningitis are needed.
ADDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas
 Gram-ve infections:
Gram-negative enteric bacillary meningitis: a twenty-one-year experience.
AUUnhanand M, Mustafa MM, McCracken GH Jr, Nelson JD
SOJ Pediatr. 1993;122(1):15.
The case-fatality rate was 17%, and 61% of survivors had long-term sequelae that included
seizure disorders, hydrocephalus, physical disability, developmental delay, and hearing loss.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.

32. Factors predective of death or serious adverse
sequelae from bacterial meningitis
 LBW<2500 g or preterm < 37 weeks
 History of symptoms for > 24 hours before
hospitalisation
 Leucopenia WBC< 5000 and neutropenia at
presentation
 Seizures occur > 72 hours after hospitalization
 Focal neurologic defects
 Requirement for mechanical ventilation or inotropes.
 Delayed sterilization of the CSF.
J Perinatol. 2011;31(6):425.
Pediatrics. 2000;106(3):477.

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