1. Infectious diseases…
meningitis
PHCP 402
By L.K.Sarki

2. What is it?
Infectious meningitis is an inflammation of the meninges arachnoid and pia mater (subarachnoid space) associated with the presence of bacteria, viruses, fungi or protozoa in the CSF (cerebrospinal fluid)

3. What is it?
It is associated with significant mortality and risk of serious sequelae in survivors
meningitis can also be caused by
physical injury
cancer
chemical irritation
subarachnoid haemorrhage
and other conditions or certain drugs

4. Why is it important?
Every year, bacterial meningitis epidemics affect more than 400 million people living in the 21 countries of the "African meningitis belt" (from Senegal to Ethiopia).
In this area over cases were reported between 1996–2010.
Of these cases, 10% resulted in deaths, with another 10–20% developing neurological sequelae.

5. Why is it important?
During the 2010 epidemic season (weeks 1–26) 22 831 cases were recorded in 14 countries under enhanced surveillance.
Among these cases there were 2415 deaths, giving a case-fatality ratio (CFR) of 10.6%.
The highest number of cases were reported by Burkina Faso (6145 including 863 deaths) followed by Nigeria (4699 cases including 322 deaths) and Chad (3058 cases including 231 deaths).

8. epidemics
In the 2009 epidemic season, a large-scale outbreak affected the countries of the African Belt, in particular Nigeria
This year, 217 districts crossed the epidemic threshold
175 of them from Nigeria alone
In 2010, African countries were less affected by meningitis epidemics
Still, 46 districts from Burkina Faso, Chad, Cameroon, Democratic Republic of Congo, Ghana, Niger and Nigeria crossed the epidemic threshold

9. Why is it important?
Neurologic sequelae frequently associated with meningitis include
seizures, sensorineural hearing loss, and hydrocephalus
Generally, 30% – 50% of patient who survive meningitis may develop neurologic disabilities

10. Why is it important?
The risk of the development of neurologic sequelae depends on the infecting organism
At risk
Both passive and active exposures to cigarette smoke where shown to be risk factors for bacterial meningitis, especially meningococcal disease

11. Why is it important?
Although bacterial meningitis occurs in all age groups, it is predominantly a disease of the young children, with 40 – 50% of all cases occurring in the first 4 years of life
Also it is a disease of the very old

12. What causes it? Streptococcus pneumoniae (pneumococcal meningitis)
Responsible for about 75% of meningitis cases
The most common cause of bacterial meningitis in adults aged over 45 years, but almost half of all cases of pneumococcal meningitis occur in children aged under 5 years

13. What causes it? Neisseria meningitidis (meningococcal meningitis)
The most common cause of bacterial meningitis from infancy through to middle age
There are several serogroups of N. meningitidis
Serogroup A and W135 predominate in Africa
Haemophilus influenzae
Group B Streptococcus (GBS)
Listeria monocytogenes

14. What causes it? Age group Most likely organism
Neonates (< 2 months)
Group B streptococcus (S. agalactiae)
E. coli, and other G-ve bacilli (Klebsiella, Serratia species), L. monocytogenes
Infants and children (2 mo – 10 yrs)
S. pneumoniae, N. meningitidis, H. influenzae (children not vaccinated with Hib only)
Children and adults ( >10 – 30 yrs)
N. meningitidis, S. pneumoniae
Adults (30 – 60 yrs)
S. pneumoniae, N. meningitidis
Elderly ( > 60 yrs)
S. pneumoniae, N. meningitidis, E. coli, Klebsiella species, and other G-ve bacilli, L. monocytogenes

15. transmission Contagious
close or long contact with a sick person in the same household or daycare center
direct contact with a patient's oral secretions
kissing (e.g., saliva or mucus)
Listeria monocytogenes by eating contaminated food
not spread by casual contact or by simply breathing the air where a person with meningitis has been

16. Pathogenesis/pathophysiology
Meningitis develop either from
Haematogenous spread of the pathogen
The most common mechanism
Contigous spread from a parameningeal focus
E.g., sinusitis or otitis media Or
Direct inoculation as occurs with head trauma or postneurosurgery

17. Colonisation & invasion of the oropharyngeal/nasopharyngeal mucosa by the meningeal pathogens
Penetration of the Blood Brain Barrier (BBB)
Release of cell wall substances (e.g., lipopolysaccharide/endotoxin/teichoic acid
Release of inflammatory mediators (IL-1, IL-6, PGE2, TNF) by the endothelial cells and monocytes
Increased permeability of the BBB leads to influx of albumin into the subarachnoid space
Brain oedema, increased intracranial pressure, altered cerebral blood flow
Cranial nerve injury, seizures, hypoxic-ischemia brain damage, herniation

18. Clinical manifestation
Acute bacterial meningitis
Typical symptoms present abruptly (sudden-onset) and evolve quickly over a period of several hours
The ‘triad’ clinical features are the most common symptoms
Fever
Stiff neck (nuchal rigidity)
Altered mental status
When all these three features are present meningitis should be strongly suspected (may differ in infants)
Acute bacterial meningitis usually presents sudden onset of headache, neck stiffness, photophobia, fever and vomiting. On examination kernig’s sign may be positive. This is resistance to the extension of the leg when the hip is flexed, due to meningeal irritation in the lumbar area. Untreated patients with bacterial meningitis deteriorate rapidly, with development of seizures, focal cerebral signs and cranial nerve palsies. Finally obtundation and loss of conciouness heraLD DEATH

19. Clinical manifestation
Headache
Photophobia
unusual intolerance to light
A positive Brudzinski’s sign
Reflex flexion of the hip and knees produced upon flexion of the neck when lying in the recumbent position
Kernig’s sign
pain upon extension of the hamstrings when lying supine with the thighs perpendicular to the trunk

20. Clinical manifestation
Seizures
Anorexia
Nausea and vomiting
Irritability (crying)
In infants – early physical signs are usually non specific and include fever, diarrhoea, lethargy, feeding difficulties and respiratory distress

21. CSF analysis
Helpful in determining the type of organism causing the meningitis (bacterial, fungal or viral)
Lumbar puncture
It should be a clear colorless fluid which in the lumbar region of the spinal cord is at a
Pressure = 50 – 150mmH20, there may be up to 5 cells/ml, the protein concentration is up to 0.4g/L, and the glucose concentration is usually 2.2 – 4.4mmol/L (at least 60% of the blood glucose)
Gram-stained smears
CT scan
PCR

22. CSF analysis
In acute bacterial meningitis the CSF is purulent, containing numerous WBC (>500 cells/mm3 with a predominance of PMNs and often is turbid in appearance. Protein nearly always is elevated and glucose concentration is low

23. treatment
Antimicrobial therapy of meningitis requires attainment of adequate levels of bactericidal agents within the CSF
Passage of antibiotics into CSF is dependent on the degree of meningeal inflammation and integrity of the BBB and properties of the antibiotic
Lipid solubility
Protein binding
Ionic blood pH
Molecular size
Conc. of the drug in the serum

24. CSF penetration Vs antibiotics
Very good penetrators
Penetrate even when the meninges are not inflamed
CPC, metronidazole
Good penetrators
Achieve adequate penetration only when the meninges are inflamed, and given in high doses
Beta-lactams, quinolones

25. CSF penetration Vs antibiotics
Poor penetrators
Penetrate poorly under all circumstances
Aminoglycosides, erythromycin, vancomycin

26. What to give?
empirical treatment Urgent – Transfer patient to hospital If unable to transfer urgently to hospital Give broad-spectrum antibiotic Single injection – either Benzylpenicillin IV or IM 1.2g for adults and child > 10 years 600mg for Child 1 – 9 years 300mg for Infant < 1year
Initially to cover all the likely pathogens. For the purpose of selecting empiric antimicrobial therapy, patients with acute bacterial meningitis can be categorised into 4 broad groups – neonates and infants aged below 3 months; immunocompetent older infants, children and adults; immunocompromised patients and those with ventricular shunts

27. What to give? Alternatively 3rd-generation cephalosporin Or Cefotaxime
CPC

28. What to give?
Consider adjunctive treatment with dexamethasone – starting before or with first dose of antibacterial treatment
Adult - 10mg
Child – 125mcg
Usually given every 6 hours for 4 days only
Significantly reduces the rates of unfavourable outcomes, mortality, severe hearing loss and neurological sequelae
May reduce CSF penetration of antibiotics

29. Age group
1st choice
alternative
Neonates aged <8 days
Ampicillin 50mg/kg bd OR amoxicillin 25mg/kg bd AND cefotaxime 50mg/kg bd OR ceftazidime 50mg/kg bd
Benzylpenicillin 50mg bd AND ampicillin 50mg bd OR amoxicillin 25mg/kg bd AND gentamicin 2.5mg/kg bd
Neonates aged 8-28 days
Ampicillin 50mg/kg 4x/d OR amoxicillin 25mg/kg tds AND cefotaxime 50mg/kg tds OR ceftazidime 50mg/kg tds
Benzylpenicillin 50mg 3-4x/d AND ampicillin 50mg 3-4x/d OR amoxicillin 25mg/kg 3x/d AND gentamicin 2.5mg/kg 3x/d
Infants aged 1-3months
Ampicillin 50mg/kg 4x/d OR amoxicillin 25mg/kg tds AND cefotaxime 50mg/kg tds OR ceftriaxone mg/kg once daily

30. Age group 1st choice alternative
Infants and children aged >3 monthsن
Cefotaxime 50mg/kg 3x daily OR ceftriaxoneﮫ mg/kg once dailya
Ampicillin 50mg/kg 4x daily OR amoxicillin 25mg/kg 3x/d OR benzylpenicillinﻋ 30mg/kg 4-hourly and chloramphenicolﺿ mg/kg 4x daily
adults
Cefotaximeﺷ 2g 3x daily OR ceftriaxoneﮫ,ﺷ 2-4g once daily
Benzylpenicillin 2.4g 4-hourly OR ampicillin 2-3g 4x daily OR amoxicillin 2g 3x or 4x daily AND chloramphenicol mg/kg 4x daily
ن calculated doses for children should not exceed maximum recommended doses for adults
ﮫ ceftriaxone should not be administered to neonates within 24h of completion of infusions of calcium-containing solutions, causion should be exercised in older age groups
ﻋ benzylpenicillin is inactive against H. influenzae and should therefore not be used in children aged <5years
ﺿ monitoring of serum chloramphenicol level is recommended, especially in children aged ≤4years
ﺷ add ampicillin or amoxicillin to cover L. monocytogens in elderly patients or where Gram-positive bacilli seen CSF

31. epidemics
The epidemic threshold is an operational threshold established in order to differentiate the seasonal case recrudescence from epidemics.
Once the weekly attack rate reaches this pre-defined threshold within a given district, and meningococcal meningitis is confirmed, a reactive vaccination campaign should be implemented.

32. vaccination Meningococcal vaccine
Meningococcal polysaccharide A, C, W135 and Y conjugate vaccine
ACWY Vax®
Capsular polysaccharide antigens of Neisseria meningitidis

33. vaccination Pneumococcal vaccine Pneumococcal polysaccharide vaccine
pneumovax® II
Polysaccharide from each of 23 capsular types of pneumococcus
Pneumococcal polysaccharide conjugate vaccine
Prevenar 13®
Polysaccharide from each of 13 capsular types of pneumococcus

34. Prophylaxis
People who qualify as close contacts of a person with meningococcal or Haemophilus influenzae type b (Hib) meningitis are at higher risk of getting disease and may need preventive antibiotics
Close contacts of a person with meningitis caused by other bacteria, such as Streptococcus pneumoniae, do not need antibiotics

35. Chemoprophylaxis in contacts of cases of infection with N
Chemoprophylaxis in contacts of cases of infection with N. meningitidis or Hib
Persons who have slept in the same house as the patient at any time during the 7 days before the onset of symptoms
Friends of the patient
Unless treated with ceftriaxone (which reliably eliminates nasopharyngeal carriage), the index patient should also receive antibiotic prophylaxis as soon as he or she is able to take oral medication

36. Chemoprophylaxis in contacts of cases of infection with N
Chemoprophylaxis in contacts of cases of infection with N. meningitidis or Hib
Healthcare workers:
Individuals who have administered mouth-to-mouth resuscitation or had some other form of prolonged close face-to-face contact with the patient
Universities, schools, nurseries and other closed communities where two or more linked cases have occurred
Before initiating prophylaxis - Consult
Hospital infection team OR
Public health doctor

37. Chemoprophylaxis in contacts of cases of infection with N
Chemoprophylaxis in contacts of cases of infection with N. meningitidis or Hib
Meningococcal infection
Ciprofloxacin (oral)
Adults mg single dose
Child 5 – 12 yrs 250mg “
Child 1mo – 4 yrs 125mg “
Rifampicin (oral)

38. Invasive Hib
Rifampicin (oral)- given once daily for 4 days
Adults 600mg (for pregnant women obtain expert advice)
Child 1-3 months 10mg/kg
Child >3 months 20mg/kg (max. 600mg)

39. Patient care
Risk of serious toxicity when CPC is used, especially in neonates
Advice AVOID if possible
Poor CSF penetration with gentamicin in neonates, especially ‘preterms’
Advice SUBSTITUTE with, or ADD cefotaxime (better CSF penetration)- close monitoring of serum levels

40. Patient care
Treatment failures in meningitis due to penicillin resistant strains
Advice CONSIDERING one of the newer antibiotics with good activity against multiresistant G +ve bacteria
Prolonged therapy is usually required for meningitis cases due to L. monocytogens – usally 3 – 4 weeks
Up to 10% relapse rate after short courses of therapy