Question 11

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)

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

Discussion

a)

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.