Suhail Allaqaband Sinai Samaritan Medical Center Milwaukee, WI

DEMOGRAPHY AND EPIDEMIOLOGY

The highest incidence is among neonates, who are usually infected by bacteria found in the birth canal at the time of parturition.
Group B streptococci (Streptococcus agalactiae) account for the majority of cases; other causes include Listeria monocytogenes, E.coli, other Gram-negative bacilli, and enterococci.

From age 1 to 23 months, the most common organisms are Streptococcus pneumoniae and Neisseria meningitidis

Children from the second to the fifth year used to have a high rate of infection caused by Haemophilus influenzae type b. However the wide use of proteinpolysaccharide conjugated vaccines has dramatically reduced the incidence of this infection From age 2 through 18, N. meningitidis is the most common cause, accounting for more than one-half of cases, followed by S. pneumoniae In adults up to age 60, S. pneumoniae is most common followed by N. meningitis Over age 60, most cases are due to S. pneumoniae and less often L. monocytogenes

Etiology - in Adults

S. pneumoniae N. meningitidis H. influenzae G -ve bacilli Listeria species Streptococci Staphylococci

30-50% 10-35% 1-3% 1-10% 5% 5% 5-15%

Predisposing factors

Most cases of meningitis occur when colonization by potential pathogens is followed by mucosal invasion of the nasopharynx However, some patients develop disease by direct extension of bacteria across a skull fracture in the area of the cribriform plate Other patients develop meningitis following systemic bacteremia as with endocarditis or a urinary tract infection or pneumonia Other predisposing conditions include asplenia, complement deficiency, corticosteroid excess, and HIV infection

CLINICAL FEATURES

The overwhelming majority of patients with bacterial meningitis have fever and headache Most patients have high fevers, but a small percentage have hypothermia

CNS symptoms
Some patients will have significant photophobia and/or clouding of the sensorium Changes in mentation and level of consciousness, seizures, and focal neurologic signs tend to appear later in the course of disease

CLINICAL FEATURES

Nuchal rigidity
Passive or active flexion of the neck will usually result in an inability to touch the chin to the chest

Tests to illustrate nuchal rigidity

The Brudzinski sign refers to spontaneous flexion of the hips during attempted passive flexion of the neck The Kernig sign refers to the inability or reluctance to allow full extension of the knee when the hip is flexed 90 degrees

CLINICAL FEATURES

Other findings
Some infectious agents, particularly N. meningitidis, can also cause characteristic skin manifestations, petechiae and palpable purpura If meningitis is the sequela of an infection elsewhere in the body, there may be features of that infection still present at the time of diagnosis of meningitis eg, otitis or sinusitis

Differential Dx

Viral - 40 % of meningitis Fungal Tuberculous Spirochete Chemical / Drug induced Collagen Vascular Disease Parameningeal infection: brain abscess, epidural abscess Subarachnoid hemorrhage Neuroleptic Malignant Syndrome

LABORATORY FEATURES

Most often the WBC count is elevated with a shift toward immature forms Platelets may be reduced if disseminated intravascular coagulation is present or in the face of meningococcal bacteremia Blood cultures are often positive, and can be very useful in the event that CSF cannot be obtained before the administration of antimicrobials
At least one-half of patients with bacterial meningitis have positive blood cultures, with the lowest yield being obtained with meningococcus

LABORATORY FEATURES
CSF analysis The CSF can be diagnostic, and every patient with meningitis should have CSF obtained unless the procedure is contraindicated Chemistry and cytologic findings highly suggestive of bacterial meningitis include a CSF glucose concentration below 45 mg/dL, a protein concentration above 500 mg/dL, and a white blood cell count above 1000/mm3 A Gram stain should also be obtained The Gram stain is positive in up to 10 percent of patients with negative CSF cultures and in up to 80 percent of those with positive cultures

DX Viral

Color Normal

Opening Pressure Normal or elevated Normal or elevated Elevated

RBC 0

WBC 1001000 mostly monos 1001000 mostly monos 1001000 mostly monos

Gluc 45-85

Prot Normal or elevated > 50

Smear Neg

Cx Neg

Funga l

Normal or cloudy Normal or cloudy

< 45

Fungal smear positive AFB positive

+/-

TB

< 45

> 50

+/-

Treatment and prevention of bacterial meningitis

Suspected bacterial meningitis is a medical emergency and immediate diagnostic steps must be taken to establish the specific cause The mortality rate of untreated bacterial meningitis approaches 100 percent and, even with optimal therapy, there is a high failure rate Empiric treatment should be begun as soon as the diagnosis is suspected using bactericidal agent(s) that achieve significant levels in the CSF

Use of bactericidal agents

Bactericidal therapy is generally necessary to cure meningitis Bacteriostatic drugs, such as clindamycin and tetracycline, are inadequate for meningitis Chloramphenicol is a bacteriostatic drug for most enteric Gram negative rods; however, it is usually bactericidal for H. influenzae, N. meningitidis, and S. pneumoniae and has been extensively and successfully used to treat meningitis caused by these organisms

Choice of agent

Selected third generation cephalosporins such as cefotaxime and ceftriaxone, have emerged as the beta-lactams of choice in the empiric treatment of meningitis These drugs have potent activity against the major pathogens of bacterial meningitis with the notable exception of listeria Ceftazidime, another third generation cephalosporin, is much less active against penicillin-resistant pneumococci than cefotaxime and ceftriaxone

Treatment - Empiric

Ceftriaxone 2 gm IV q12h or Cefotaxime

2 gm IV q4-6h

plus Vancomycin 15 mg/kg q6h If > 50 years, also add Ampicillin 2 gm IV q4h (for Listeria)

THERAPY FOR SPECIFIC PATHOGENS

Streptococcus pneumoniae
The conventional approach to the treatment of pneumococcal meningitis was the administration of penicillin alone for two weeks at a dose of four million units intravenously every four hours Good results have also been obtained with third generation cephalosporins

However, the problem of treating pneumococcal meningitis has recently been compounded by the widespread and increasingly common reports of pneumococcal strains resistant to penicillin

Cefotaxime or ceftriaxone can be used if the MIC for these drugs is less than 0.5 g/mL It is recommended that vancomycin (2 g/day) should be given with cefotaxime or ceftriaxone in the initial treatment of pneumococcal meningitis if there has been beta-lactam resistance noted locally Vancomycin should be continued if there is high level penicillin resistance and an MIC >0.5 g/mL to third generation cephalosporins If corticosteroids are given, rifampin should be added as a third agent since it increases the efficacy of the other two drugs The usual duration of therapy is two weeks

Haemophilus influenzae

A third generation cephalosporin is the drug of choice for H. influenzae meningitis Patients with H. influenzae meningitis should be treated for five to seven days For adults, a dose of 2 g every six hours of cefotaxime and 2 g every 12 hours of ceftriaxone is more than adequate therapy Pharyngeal colonization persists after curative therapy and may require a short course of rifampin if there are other children in the household at risk for invasive Haemophilus infection The recommended dose is 20 mg/kg per day (to a maximum of 600 mg/day) for four days

Neisseria meningitidis

This infection is best treated with penicillin Although there are scattered case reports of N. meningitidis resistant to penicillin, such strains are still very rare A third-generation cephalosporin is an effective alternative to penicillin for meningococcal meningitis A five day duration of therapy is adequate However, when penicillin is used, there may still be pharyngeal colonization with the infecting strain. As a result, the index patient may need to take rifampin, a fluoroquinolone, or a cephalosporin

Listeria monocytogenes

Listeria has been traditionally treated with ampicillin and gentamicin, as resistance to these drugs is quite rare Ampicillin is given in typical meningitis doses (2 g intravenously every four to six hours in adults) and gentamicin is used for synergy An alternative in penicillin-allergic patients is trimethoprim-sulfamethoxazole (dose of 10/50 mg/kg per day in two or three divided doses) The usual duration of therapy is at least three weeks

Enteric Gram negative rods

Prior to the availability of third generation cephalosporins, it was often necessary to instill an aminoglycoside antibiotic such as gentamicin directly into the cerebral ventricles It is now possible to cure these infections with high doses of third generation antibiotics A repeat CSF sample should be obtained for culture two to four days into therapy to help assess the efficacy of treatment The duration of therapy should be at least three weeks

PREVENTION OF MENINGITIS Vaccines

A spectacular reduction in H. influenzae meningitis has been associated with the near universal use of a vaccine against this organism in developed countries since 1987 There has been a 94 percent reduction in H. influenzae meningitis between 1987 and 1995 Pneumococcal vaccine administered to the chronically ill and elderly is probably useful in reducing the overall incidence of pneumococcal infections. However, its role in the prevention of meningitis is as yet undetermined

Vaccines

Meningococcal vaccines are active against many strains of N. meningitidis However, the majority of meningococcal infections in the United States are caused by type b meningococcus for which there is no vaccine Vaccines for other types (notably type a) are recommended for travelers and American military personnel to countries with epidemic meningitis Immunization against meningococci is not warranted as postexposure prophylaxis

Chemoprophylaxis

There is a role for chemoprophylaxis to prevent spread of meningococcal and haemophilus meningitis but not for pneumococcal disease The use of antimicrobial therapy to eradicate pharyngeal carriage of meningococci is widely accepted to prevent development of disease in close contacts and to eradicate pharyngeal carriage Rifampin 600 mg PO every 12 h for a total of four doses is recommended Ciprofloxacin, in a single dose of 500 mg PO, is equally effective and can be used in patients over the age of 18

Role Of Steroids

The addition of antiinflammatory agents has been attempted as an adjuvant in the treatment of meningitis Early administration of corticosteroids such as dexamethasone for pediatric meningitis has shown no survival advantage, but there is a reduction in the incidence of severe neurologic complications and deafness A meta-analysis of five such studies in children showed a relative risk of bilateral deafness of 4.1 and of late neurological sequelae of 3.9 in controls compared to children treated with steroids

A second meta-analysis of trials of meningitis in children evaluated the findings according to organism For H. influenzae type b meningitis, dexamethasone therapy was associated with a significant reduction in deafness For pneumococcal meningitis, dexamethasone was effective only if given early ; in this setting, there was a significant reduction in hearing loss Two days of therapy was as effective and less toxic than longer courses of steroid administration
Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA 1997; 278:925

There is no consensus regarding the utility of corticosteroid therapy in adults The Infectious Disease Society of America considers adjuvant corticosteroids for meningitis to be unsupported for routine use in adults but supports them for H. influenzae infections in children Guidelines for the use of systemic glucocorticoids in the management of selected infections. J Infect Dis 1992; 165:1

MORTALITY RATE AND LATE SEQUELAE

The prognosis of meningitis is linked to age and the presence of underlying disease Bacterial meningitis accompanying advanced liver disease, HIV infection, or organ transplantation is likely to be associated with more morbidity and mortality In addition, the prognosis and complications differ in children and adults

The mortality rates are lowest in children A meta-analysis of prospectively enrolled cohorts of children in developed countries showed a 4.8 percent mortality from 1955 to 1993 The mortality rate varied by organism, ranging from 3.8% for H. influenzae to 7.5 percent for N. meningitidis to 15.3% for S. pneumoniae 83.6 percent of the surviving children had apparently complete recovery The most common sequelae were
Deafness 10.5 percent. Bilateral severe or profound deafness 5.1 percent. Mental retardation 4.2 percent. Spasticity and/or paresis 3.5 percent. Seizures 4.2 percent.

Complications are more common in adults A series of 86 adults with meningitis, for example, showed a mortality rate of 18.6 percent with a complication rate of 50 percent The most common problems were:
Cerebrovascular involvement 15.1 percent. Cerebral edema 14 percent. Hydrocephalus 11.6 percent. Septic shock 11.6 percent. Disseminated intravascular coagulation 8.1 percent. Acute respiratory distress syndrome 3.5 percent.

Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study. Arch Neurol 1993; 50:575

A second review of bacterial meningitis in adults from 1962 to 1988 found a mortality rate of 25 percent that did not vary during the 26 years of the study As in children, there was a higher rate of death due to S. pneumoniae (37 percent) as compared to N. meningitidis (13 percent) and listeria (10 percent)
Acute bacterial meningitis in adults. N Engl J Med 1993; 328:21.