The etiology and incidence of bacterial meningitis (BM) in resource poor settings is changing. Antibiotic resistance patterns have altered and empirical antibiotic treatment options need review. Recent studies have assessed adjuvant therapies and supportive care.
THE EFFECT OF VACCINES ON THE INCIDENCE AND ETIOLOGY OF BACTERIAL MENINGITIS
In the past decade, there have been remarkable reductions in child mortality driven largely by public health efforts. In HIV endemic countries, the role out of prophylactic cotrimoxazole and the increased availability of antiretroviral therapy has coincided with a reduction in the incidence of Streptococcus pneumoniae infections. The role out of these programs and increasing access to conjugate vaccines for Haemophilus influenzae b (Hib), pneumococci and Group A meningoccoci (MenAfriVac) are changing the epidemiology and incidence of meningitis. Hib vaccine is part of the extended program for immunization in 72 countries leading to a rapid reduction of invasive Hib infections.1
Meningococcal meningitis is the most common bacterial meningitis worldwide and Group A was the most common epidemic-causing meningococcus. In 2010, a conjugated vaccine, MenAfriVac became available that is highly efficacious even in young children and also increases herd immunity. By 2016, 26 African meningitis belt countries will have immunized their most vulnerable age groups. But there is more to be done: serogroup A disease has decreased but serogroups W135 and X have caused recent outbreaks.2,3 In the United States, the Advisory Committee on Immunisation Practices states that immunogenicity of meningococcal conjugate vaccines decreases with time, and recommends a booster dose after 5 years.4
The 13-valent pneumococcal vaccine, licensed in 2010, has been added to the extended program for immunization schedule in many countries, with the expectation of being introduced in 50 countries by 2015. This will reduce pneumococcal invasive disease by about 40–70%—depending on prevalent serotypes and incidence of HIV infection.5 In holoendemic malarial areas, BM caused by nontyphoidal salmonellae species waxed and then waned over the past decade. In some areas, this followed the mass introduction of bed nets, indoor spraying and the change from a failing first line antimalarial treatment regimen to effective artemesinin-based combination therapy.5
Examination of cerebrospinal fluid (CSF) is the gold standard diagnostic test in BM. In many resource poor settings, despite lack of laboratory support, clinicians should have a low threshold for doing a lumbar puncture. The appearance and Gram stain of CSF assist diagnosis. If there is no laboratory, a multistix urine dipstick test will identify low glucose, high protein and white cells (a positive leucocyte esterase patch) in CSF.
Children with BM are often managed with limited resources against a background of other diseases or ill health that compromise the outcome even when optimal care is provided.
EMPIRICAL FIRST LINE TREATMENT AND ANTIBIOTIC RESISTANCE
The World Health Organization (WHO) recommends ceftriaxone or cefotaxime as first line, empirical, antibiotic therapy for children with suspected BM. Cefotaxime is more expensive and requires 8 hourly injections (ceftriaxone is 12 hourly or once daily). If cephalosporins are not available, WHO recommends penicillin or ampicillin and chloramphenicol in older children, and pencillin or ampicillin and gentamicin in infants.6
S. pneumoniae susceptibility to penicillin varies worldwide; in Malawi, resistance has been stable at 16–18%.5 Falade et al7 reported no penicillin-resistant S. pneumoniae isolates in 2009 in Nigeria, and a Ugandan report showed no full resistance, but 83% intermediate penicillin resistance.8 Hib is resistant to chloramphenicol and to ampicillin in most countries. Nontyphoidal salmonellae species have become resistant to chloramphenicol, cotrimoxazole and ampicillin, leaving the options of ciprofloxacin and/or ceftriaxone. Table 1 shows the common causes of bacterial meningitis in different age groups and recommended treatment schedules.
In the non-neonatal group, S. pneumoniae is the most common etiological agent, and if penicillin susceptibility is unknown a third generation cephalosporin should be given. Empirical treatment can start with a cephalosporin and change to an appropriate narrow-spectrum antibiotic if and when the cause is identified. In Malawi, more neonatal cases were effectively treated by ceftriaxone than by penicillin + gentamicin (99.1% vs. 91.8%; P = 0.006), especially for Gram-negative isolates (95.1% vs. 86.0%; P = 0.012).9 Amikacin or parentral ciprofloxacin are effective for many Gram-negative bacterial infections (including ESBL), and can be added for Gram-negative bacteria when a third generation cephalosporin fails.
DURATION OF ANTIBIOTIC THERAPY
A large multicountry study (n = 1004) in resource poor settings compared the outcome of 5 versus 10 days of ceftriaxone for BM caused by one of the 3 most common etiological agents, S. pneumoniae, Neisseria meningitidis and Hib.10 Randomization was on day 5 and only in stable patients with no complications. Children receiving 5 days of antibiotic therapy had a similar outcome to those who received 10 days of treatment (60.4% vs. 60.8% survival without sequelae, 26% vs. 27.2% with sequelae).
Corticosteroids as adjuvant treatment in BM remain controversial. In a large study, in African children dexamethasone conferred no benefit.11 A Cochrane review of adjuvant steroid therapy found no benefit to outcome in poorly resourced centers.12
Glycerol has been used to reduce intracranial pressure. A multicountry South American study reported encouraging results; when severe neurological sequelae and death were combined, glycerol was beneficial compared with placebo (OR: 0.44; 95% CI: 0.25–0.76; P = 0.003).13 In a Malawian study in which paracetamol and glycerol were the active adjuvant therapies, there was no benefit or harm by adding glycerol or paracetamol to standard antibiotic therapy.14
Supportive care is critical and the importance of good nursing care and monitoring cannot be over-emphasized. Fluids should be monitored, seizures controlled, adequate calorie intake ensured and serum glucose and electrolytes kept within normal limits.
A Cochrane review found no evidence for fluid restriction and some evidence to support maintenance intravenous fluids in the first 48 hours in settings with high mortality rates and late presentations.15 Where children present early and mortality is lower, evidence is insufficient to guide practice.
Seizures must be controlled promptly. WHO recommends rectal diazepam and/or paraldehyde followed by phenobarbitone if convulsions continue. Intractable seizures are difficult to manage without mechanical ventilator support and loading doses of anticonvulsant drugs such as phenobarbitone have to be repeated despite the risk of respiratory failure. Neonatal seizures are usually managed with phenobarbitone.
ANAEMIA AND MALNUTRITION
Anemia and malnutrition are common comorbidities. Roine et al16 found that correcting anemia (less than 8 g/dL) with a blood transfusion reduced mortality in BM to 23% from 39% without transfusion (P = 0.003). Also, the odds for death increased by 1.98 in mild, 2.55 in moderate and 5.85 in severe malnutrition.
Case fatality rate is as high as 37% depending on the cause, age and other cofactors.13 The prognosis is worse in infants, in children with low CSF white cell counts or low glucose, low blood pressure, anemia, persistent convulsions and those who arrive late or in coma. To these are added malnutrition and immunosuppression.
Acute complications other than those mentioned already include subdural empyema or intracranial abscess. If fever does not settle an ultrasound scan of the head should be done in children with an open fontanelle. Large subdural collections and intracranial abscesses can be drained trans-fontanelle by experienced personnel. Antibiotic therapy should be prolonged. Fever may also be caused by infected injection or cannula sites, joints or chest infections.
Long-term neurological sequelae are frequent and often devastating. Some hearing loss occurs in up to 30% of survivors, especially following pneumococcal or Salmonella spp. meningitis. Hydrocephalus may present after weeks or months. Therefore, all survivors should have their hearing tested and head size monitored after discharge. Follow-up should include physical, neurological and developmental assessments.
- Monitoring of incidence and antibiotic sensitivity must continue to be able to inform empirical treatment.
- Rapid diagnostic tests to identify the causative agent would reduce the overuse of broad-spectrum antibiotics.
- Research is needed into adjuvant therapy and seizure control.
- Improved neonatal care to reduce infection rates.
2. Delrieu I, Yaro S, Tamekloé TA, et al. Emergence of epidemic Neisseria meningitidis serogroup X meningitis in Togo and Burkina Faso. PLoS One. 2011;6:e19513
3. Emergence of W135 Meningococcal Disease - libdoc.who.int …. whqlibdoc.who.int/hq/2002/WHO_CDS_CSR_GAR_2002.1.pdf
WHO/CDS/CSR/GAR/2002.1. Emergence of W135 Meningococcal Disease. Report of a WHO Consultation Geneva 17–18 September 2001. Accessed October 2014.
4. CDC. . Updated recommendation from the Advisory Committee on Immunization Practices (ACIP) for revaccination of persons at prolonged increased risk for meningococcal disease. MMWR. 2009;58:1042–1043
5. Everett DB, Mukaka M, Denis B, et al. Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimoxazole prophylaxis in Malawi. PLoS One. 2011;6:e17765
7. Falade AG, Lagunju IA, Bakare RA, et al. Invasive pneumococcal disease in children aged <5 years admitted to 3 urban hospitals in Ibadan, Nigeria. Clin Infect Dis. 2009;48(Suppl 2):S190–S196
8. Kisakye A, Makumbi I, Nansera D, et al. Surveillance for Streptococcus pneumoniae meningitis in children aged <5 years: implications for immunization in Uganda. Clin Infect Dis. 2009;48(Suppl 2):S153–S161
9. Swann O, Everett DB, Furyk JS, et al. Bacterial meningitis in Malawian infants <2 months of age: etiology and susceptibility to World Health Organization first-line antibiotics. Pediatr Infect Dis J. 2014;33:560–565
10. Molyneux E, Nizami SQ, Saha S, et al.CSF 5 Study Group. A double blind randomised study comparing 5 vs 10 days of ceftriaxone therapy for bacterial meningitis in children. The Lancet. 2011;377:1837–1845
11. Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002;360:211–218
12. Brouwer MC, McIntyre P, Prasad K, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2013;6:CD004405
13. Peltola H, Roine I, Fernández J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2007;45:1277–1286
14. Molyneux EM, Kawaza K, Phiri A, et al. Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children. Pediatr Infect Dis J. 2014;33:214–216
15. Maconochie IK, Bhaumik S. Fluid therapy for acute bacterial meningitis. Cochrane Database Syst Rev. 2014;5:CD004786
16. Roine I, Weisstaub G, Peltola HLatAm Bacterial Meningitis Study Group. . Influence of malnutrition on the course of childhood bacterial meningitis. Pediatr Infect Dis J. 2010;29:122–125