With respect to community-acquired bacterial meningitis in Australia and New Zealand:

a) List two common pathogens encountered AND the empirical antimicrobial therapy of choice in EACH the following contexts:

  1.  Neonate aged < 1month
  2.  Immunocompetent adult aged 35 years
  3. Adult aged 48years on steroids
  4. Immunocompetent adult aged 85 years

(70% marks)

b) Briefly discuss the role of adjunctive corticosteroids in the management of meningitis.

(30% marks)

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College Answer

Pathogens

Neonate aged < 1 month

  • Gp B Strep (agalactiae)
  • E. coli
  • Listeria

Immunocompetent adult aged 35 years

  • Strep. pneumoniae
  • N. meningitidis

Adult aged 48 years on steroids

  • Listeria
  • Gram negative bacilli
  • [TB]

Immunocompetent adult aged 85 years

  • Strep pneumoniae
  • N meningitides
  • Listeria
  • Aerobic GNB

Antimicrobial Therapy

Neonate aged < 1month
Amoxycillin/Ampicillin + 3rd generation cephalosporin (OR Amox/Amp + aminoglycoside)

Immunocompetent adult aged 35 years
3rd generation cephalosporin + Vancomycin

Adult aged 48 years on steroids
Vancomycin + Ampicillin + either Cefepime or Meropenem

Immunocompetent adult aged 85 years
3rd generation cephalosporin + Vancomycin + Ampicillin NB Some protocols substitute Rifampicin for Vancomycin.

b)

Multiple studies and meta-analyses conflicting results with mortality and neurological sequelae. Neurological sequelae seen in up to 50% of survivors of community-acquired meningitis.

Cochrane review 2013:
Overall –

  • Trend to reduction in mortality
  • Reduced rate of hearing loss
  • Reduced rate of short-term neurological sequelae 
subgroup analyses –
  • Reduced hearing loss in children with h influenza only
  • Favourable effect on mortality with s pneumonia only
  • No effect in low income countries, except possibly for tb meningitis
 
 

Approach to use of adjunctive steroids

  • Adults in developed world – suspected or proven pneumococcus. Therefore commence steroids in all and discontinue if proven to not be pneumococcus.
  • Children – suspected or proven H influenza, although many recommendations do include steroids for suspected pneumococcal or meningococcal as well. 
Given prior to, or with first dose of antibiotics. Continued for 4 days.
  •  

Potential side-effects of steroids
 

  • Concern that steroids may reduce antibiotic penetration into CSF (esp Vancomycin) – controversial. 
  • Generic SEs – e.g. hyperglycaemia, GI bleed, immunosuppression etc.

Additional comments:
Overall  candidates  had  poor  knowledge  about  the  causative  organisms  and  appropriate antimicrobial agents in the setting of bacterial meningitis.

Discussion

a)

Pathogens of Meningitis according to Host Age and Immune Status
Host group Microbial enemies Appropriate antibiotics
(CICM model answer)
Appropriate antibiotics
(Therapeutic Guidelines)
Neonates
  • S. agalactiae
    (group B)
  • E.coli
  • L. monocytogenes

Ampicillin
+ Ceftriaxone
or + aminoglycoside

Cefotaxime
+  ampicillin
 
Adults
  • S. pneumoniae
  • L.monocytogenes
  • N. meningitidis
  • H. influenzae
Ceftriaxone
+ Vancomycin
Ceftriaxone or cefotaxime
Immunosuppressed adults
  • L.monocytogenes
  • Gram negative bacilli
  • Tuberculosis
Vancomycin
+ Ampicillin
+ Cefepime or meropenem
Ceftriaxone or cefotaxime
+ Benzylpenicillin for Listeria
+ vancomycin (most of the time)
The elderly
  • S. pneumoniae
  • L.monocytogenes
  • N. meningitidis
  • Klebsiella sp.
  • E.coli
Ceftriaxone
+ Ampicillin
+ Vancomycin
Ceftriaxone or cefotaxime
+ Benzylpenicillin for Listeria
+ vancomycin (most of the time)
 

Therapeutic Guidelines recommend slightly different drugs; benzylpenicillin is substituted for ampicillin and vancomycin is only offered to those with unidentified gram positive cocci in their CSF, or whenever an LP is not available. Aminoglycosides are not mentioned.

eTG give their references as the 2014 NSW Health guidelines, and this 2004 article by Tunkel et al from Clinical infectious diseases. It is unclear what happened to the candidates whose antibiotic choices agreed with Therapeutic Guidelines but not with the college.

The neonates get cefotaxime instead of ceftriaxone, for some reason. Dr Alistair Burns has pointed out to me that this is probably because ceftriaxone can cause worsening jaundice. Ceftriaxone clearance is around 50% biliary, leading to biliary sludge formation. Furthermore it is over 90% albumin-bound, which means it displaces bilirubin from albumin making more bilirubin bioavailable to cause havoc in the jaundiced neonate. This is supported by a review article from Furyk et al (2011), and an older article by Carla M. Odio (1995). The biliary sludging is not much of an issue, but the kernicterus is a genuine concern. The difference between these two third-gen cephalosporins becomes less important among older children, and it seems that ceftriaxone is still used on neonates in resource-poor settings (it is much cheaper) without a significant increase in adverse effects.

b)

The college are quotting this 2013 Cochrane review by Brouwer et al  was able to include 4121 participants from twenty-five trials.

  • The mortality benefit was statistically non-significant
  • Deafness was reduced (RR 0.67) as were neurological sequelae of all sorts (RR 0.83).
  • Mortality improved in the S.pneumoniae patients only
  • In children, protection against hearing loss was only seen in the H.influenzae group.
  • In third world countries, there was no benefit for anybody, except for those with tuberculosis meningitis.
  • Subgroup analysis of high quality studies did not show any effect on severe hearing loss.
  • There was an increased risk of recurrent fever, but no other side effects.

Still, the overall conclusion that corticosteroids should still be given to patients in high-income countries.

Adverse effects of corticosteroids in meningitis are mentioned in this 1996 article by Townsend et al. In brief, the only major concern is that corticosteroids may rapidly normalise the blood brain barrier function, decreasing the penetration of antibiotics into the CSF. This phenomenon is known purely from rabbit models. Might I add that in those models the decreased concentration of ampicillin in the rabit CSF was still well above MIC for the E.coli they injected into the rabbits. In the one known human study (Paris et al, 1994) with eleven meningitic children the CSF concentration of ceftriaxone was also unaffected. In short,  the evidence to feed these concerns is far from convincing.

In summary::

  • Dexamethasone should be given to all adult meningitis patients in the developed world.
  • Most guidelines recommend the same for children
  • It should be given before the first dose of antibiotics
  • It should be given for 4 days, or less if the meningitis is proven non-streptococcal (or non-Haemophilus, in the case of children)
  • The daily dose should be 0.6mg/kg.

References

References

Oh's Intensive Care manual: Chapter   54  (pp. 597)  Meningitis  and  encephalomyelitis by Angus  M  Kennedy

Van de Beek, D., et al. "Corticosteroids for acute bacterial meningitis."Cochrane Database Syst Rev 1 (2007).

Brouwer, Matthijs C., et al. "Corticosteroids for acute bacterial meningitis." Cochrane Database Syst Rev 6 (2013).

Lee, Bonita E., and H. Dele Davies. "Aseptic meningitis." Current opinion in infectious diseases 20.3 (2007): 272-277.

Beer, R., P. Lackner, and B. Pfausler. "Nosocomial ventriculitis and meningitis in neurocritical care patients." Journal of neurology 255.11 (2008): 1617-1624.

Korinek, A-M., et al. "Prevention of external ventricular drain–related ventriculitis." Acta neurochirurgica 147.1 (2005): 39-46.

NSW Health. Infants and children: acute management of bacterial meningitis: clinical practice guideline. North Sydney: NSW Ministry of Health; 2014.

Tunkel, Allan R., et al. "Practice guidelines for the management of bacterial meningitis." Clinical infectious diseases 39.9 (2004): 1267-1284.

Townsend, Gregory C., and W. Michael Scheld. "The use of corticosteroids in the management of bacterial meningitis in adults." Journal of Antimicrobial Chemotherapy 37.6 (1996): 1051-1061.

Paris, Maria M., et al. "Effect of dexamethasone on therapy of experimental penicillin-and cephalosporin-resistant pneumococcal meningitis." Antimicrobial agents and chemotherapy 38.6 (1994): 1320-1324.

Furyk, J. S., O. Swann, and E. Molyneux. "Systematic review: neonatal meningitis in the developing world." Tropical Medicine & International Health16.6 (2011): 672-679.

Odio, Carla M. "Cefotaxime for treatment of neonatal sepsis and meningitis."Diagnostic microbiology and infectious disease 22.1 (1995): 111-117.