The brain and spinal cord are surrounded by three membranes, which from the outside inwards are the dura mater, the arachnoid mater and the pia mater. Between the arachnoid mater and the pia mater, in the subarachnoid space, is found the cerebrospinal fluid (CSF) (Fig. 38.1). This fluid, of which there is ∼︀150 mL^–1 in a normal individual, is secreted by the choroid plexuses and vascular structures which are in the third, fourth and lateral ventricles. CSF passes from the ventricles via communicating apertures to the subarachnoid space, after which it flows over the surface of the brain and the spinal cord (see Fig. 38.1). The amount of CSF is controlled by resorption into the bloodstream by vascular structures in the subarachnoid space, called the arachnoid villi. Infective meningitis is an inflammation of the arachnoid and pia mater associated with the presence of bacteria, viruses, fungi or protozoa in the CSF. Meningitis is one of the most emotive of infectious diseases, and for good reason: even today, infective meningitis is associated with significant mortality and risk of serious sequelae in survivors.

Fig. 38.1 The meninges covering the brain and spinal cord and the flow of cerebrospinal fluid (arrowed)

(modified from Ross and Wilson (1981), by permission of Churchill Livingstone).

Aetiology and epidemiology

In the UK, around 1500 cases of meningitis are notified annually. However, this almost certainly under represents the true incidence of meningitis. Viruses are the most common cause of meningitis, and are often less serious than bacterial or fungal forms of the disease.

Bacterial meningitis

Although bacterial meningitis occurs in all age groups, it is predominantly a disease of young children, with 40–50% of all cases occurring in the first 4 years of life. Two bacteria, N. meningitidis and S. pneumoniae, account for about 75% of cases. However, the pattern of micro-organisms causing meningitis is related to the age of the patient and the presence of underlying disease.

N. meningitidis is the most common cause of bacterial meningitis from infancy through to middle age, with peaks of incidence in the under-5-year age group and in adolescents. There are several serogroups of N. meningitidis, including A, B, C, W135 and Y. In the late twentieth century, serogroups B and C accounted for 60–65% and 35–40% of infections in the UK, respectively. However, with the introduction of vaccination against N. meningitidis serogroup C (MenC) into the routine immunisation programme in 1999, serogroup B now accounts for well over 80% of all meningococcal disease. There is currently no vaccine available for N. meningitidis serogroup B. Serogroups A and W135 predominate in Africa and the Middle East. A quadrivalent vaccine against serogroups A, C, W135 and Y is available to protect travellers to countries of risk. S. pneumoniae is the most common cause of meningitis in adults aged over 45 years, but almost half of all cases of pneumococcal meningitis occur in children aged under 5 years. It has a poorer outcome than meningococcal meningitis. Vaccination against the most common serotypes of S. pneumoniae using a conjugate vaccine was added to the routine childhood immunisation programme in the UK in 2006: the original 7-valent vaccine was then replaced by a 13-valent vaccine in Spring 2010. A different 23-valent polysaccharide vaccine is available for certain patient groups at risk of pneumococcal infection.

Haemophilus influenzae type b (Hib) was once the major cause of bacterial meningitis in children aged 3 months to 5 years, but introduction of routine immunisation in 1992 has almost eliminated Hib disease in the UK and other developed countries.

Although patients with meningococcal or Hib meningitis are potentially infectious, most cases of meningitis due to these bacteria are acquired from individuals who are asymptomatic nasopharyngeal carriers. People living in the same household as a patient with meningococcal disease have a 500–1200-fold increased risk of developing infection if they do not receive chemoprophylaxis (see later). Susceptible young children who are household contacts of a case of Hib disease have a similarly increased risk of becoming infected. Epidemics of meningococcal disease sometimes occur. In developed countries, these take the form of clusters of cases among people living in close proximity (e.g. in schools or army camps) or in a particular geographical area. In Africa, large epidemics with many thousands of cases occur, usually during the dry season.

In the neonatal period, group B streptococci are the most common cause of bacterial meningitis. Other causes of neonatal meningitis include Escherichia coli and other Enterobacteriaceae, Listeria monocytogenes, Staphylococcus aureus and enterococci. In most cases, infection is acquired from the maternal genital tract around the time of delivery, but transmission between patients can also occur in hospitals.

L. monocytogenes is also an occasional cause of meningitis in immunocompromised patients. Meningitis can also occur as a complication of neurosurgery, especially in patients who have ventriculoatrial or ventriculoperitoneal shunts. Coagulase-negative staphylococci are the major causes of shunt-associated meningitis, but other bacteria are important, including Enterobacteriaceae and S. aureus. Meningitis due to S. aureus may also be secondary to trauma, or local or haematogenous spread from another infective focus. Meningitis may also be a feature of multisystem bacterial diseases such as syphilis, leptospirosis and Lyme disease.

The decline in the incidence of tuberculous meningitis in developed countries has mirrored the fall in the incidence of tuberculosis in these countries. Tuberculous meningitis may occur as part of the primary infection or as a result of recrudescence of a previous infection.

Viral meningitis

Human enteroviruses such as echoviruses and Coxsackie viruses account for about 70% of cases of viral meningitis in the UK. Herpes simplex and varicella zoster viruses account for most other cases. Occasional causes of viral meningitis include mumps virus and human immunodeficiency viruses.

Fungal meningitis

In Europe, fungal meningitis is rare in individuals without underlying disease. Candida species are an occasional cause of shunt-associated meningitis. Cryptococcus neoformans has emerged as an important cause of meningitis in patients with late-stage HIV infection and other severe defects of T-cell function. With greater use of fluconazole for oral candidiasis, and especially the advent of highly active antiretroviral therapy, cryptococcosis has become much less common in developed countries. However, in sub-Saharan African countries with the highest HIV prevalence, cryptococcus is the leading cause of infective meningitis. In certain other areas of the world, infections with fungi such as Coccidioides immitis and Histoplasma capsulatum are endemic.

Pathophysiology

Most cases of bacterial meningitis are preceded by nasopharyngeal colonisation by the causative organism. In most colonised individuals, infection will progress no further, but in susceptible individuals the organism invades the submucosa by circumventing host defences (e.g. physical barriers, local immunity, phagocytes) and gains access to the CNS by invasion of the bloodstream and subsequent haematogenous seeding of the CNS. Other less common routes by which micro-organisms can reach the meninges include:

• direct spread from the nasopharynx

• blood-borne spread from other foci of colonisation or infection

• abnormal communications with the skin or mucous membranes, for example skull fractures, anatomical defects or a meningocoele

• spread from an infected adjacent focus, for example brain abscess, tuberculoma, infected paranasal air sinus or infection of the middle ear.

Once in the subarachnoid space, the infection spreads widely and incites a cascade of meningeal inflammation. The cerebral tissue is not usually directly involved although cerebral abscess may complicate some types of meningitis.

The micro-organisms that most frequently cause meningitis are capable of doing so because they have a variety of virulence factors, including mechanisms for:

• attachment to host mucosal surfaces

• evasion of phagocytosis and other host defences

• meningeal invasion

• disruption of the blood–brain barrier

• induction of pathophysiological changes in the CSF space

• secondary brain damage.

Overall, the net result of infection is vascular endothelial injury and increased blood–brain barrier permeability leading to the entry of many blood components into the subarachnoid space. This contributes to cerebral oedema and elevated CSF protein levels. In response to the cytokine response, neutrophils migrate from the bloodstream into the CSF. Cerebral oedema contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate and decreases glucose concentrations. If this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.

Clinical manifestations

Acute bacterial meningitis usually presents with sudden-onset headache, neck stiffness, photophobia, fever and vomiting. On examination, Kernig’s sign may be positive. This is resistance to extension of the leg when the hip is flexed, due to meningeal irritation in the lumbar area. Where meningitis is complicated by septicaemia, there may be septic shock. The presence of a haemorrhagic skin rash is highly suggestive, but not pathognomic, of meningococcal infection. Untreated patients with bacterial meningitis deteriorate rapidly, with development of seizures, focal cerebral signs and cranial nerve palsies. Finally, obtundation and loss of consciousness herald death.

In infants with meningitis, the early physical signs are usually non-speciﬁc and include fever, diarrhoea, lethargy, feeding difficulties and respiratory distress. Focal signs such as seizures or a bulging fontanelle usually only occur at a late stage.

Viral meningitis usually presents with acute onset of low-grade fever, headache, photophobia and neck stiffness. Unless they develop encephalitis, patients usually remain alert and oriented.

Although tuberculous and fungal meningitis sometimes present acutely, these infections typically have a more indolent course. The early stages of the diseases are dominated by general symptoms such as malaise, apathy and anorexia. As they progress, symptoms and signs more typical of meningitis usually appear.

Diagnosis

The definitive diagnosis of meningitis is established by detection of the causative organism and/or demonstration of biochemical changes and a cellular response in CSF. CSF is obtained by lumbar puncture, where a needle is inserted between the posterior space of the third and fourth lumbar vertebrae into the subarachnoid space. Before performing lumbar puncture, the possibility of precipitating or aggravating existing brain herniation in patients with intracranial hypertension must be considered. A CT scan should be performed before undertaking lumbar puncture if any neurological abnormalities are present.

In health, the CSF is a clear colourless fluid which, in the lumbar region of the spinal cord, is at a pressure of 50–150 mmH₂O. There may be up to 5 cells/μL, the protein concentration is up to 0.4 g/L and the glucose concentration is at least 60% of the blood glucose (usually 2.2–4.4 mmol/L). Table 38.1 shows how the cell count and biochemical measurements can be helpful in determining the type of organism causing meningitis.

Table 38.1 Cellular and biochemical responses in different forms of infective meningitis

In bacterial and fungal meningitis, organisms may be visible in Gram-stained smears of the CSF. The common causes of bacterial meningitis are easily distinguished from each other by their Gram stain appearance. Special stains, such as the Ziehl–Neelsen method, are necessary to visualise mycobacteria. However, only small numbers of mycobacteria are present in the CSF in tuberculous meningitis and direct microscopy is often unrevealing. Although cryptococci can be visualised by Gram staining, they are often more easily seen with India ink staining, which highlights their prominent capsules.

Regardless of the microscopic findings, CSF should be cultured to try to confirm the identity of the causative organism and to facilitate further investigations such as antibiotic sensitivity testing and typing. Special cultural techniques are required for mycobacteria, fungi and viruses. Cultures of other sites are sometimes helpful. In suspected bacterial meningitis, blood for culture should always be obtained. Bacteraemia occurs in only 10% of patients with meningococcal meningitis but is more common in most other forms of meningitis. In suspected meningococcal disease, culture of a nasopharyngeal swab may be helpful because antibiotic penetration at this site is less. It increases the chances of isolating meningococci when antibiotics were administered to the patient before presentation to hospital.

Non-culture-based methods are increasingly used to investigate the aetiology of meningitis. In particular, molecular amplification techniques such as polymerase chain reaction (PCR) are now widely used to detect meningococci, pneumococci, Mycobacterium tuberculosis and various viruses, including herpes simplex viruses and enteroviruses.

Serum antibodies to N. meningitidis and various viruses may be detected, but these investigations usually depend on demonstration of seroconversion between two samples collected a week or more apart, and are therefore undertaken more for public health than clinical reasons. Patients with tuberculous meningitis may have a positive Mantoux test or an interferon-gamma release assay.

Drug treatment

Acute bacterial meningitis is a medical emergency that requires urgent administration of antibiotics. Other considerations in some forms of meningitis include the use of adjunctive therapy such as steroids, and the administration of antibiotics to prevent secondary cases.

Antimicrobial therapy

Pharmacokinetic considerations

The antimicrobial therapy of meningitis requires attainment of adequate levels of bactericidal agents within the CSF. The principal route of entry of antibiotics into CSF is by the choroid plexus; an alternative route is via the capillaries of the central nervous system into the extracellular fluid and hence into the ventricles and subarachnoid space (see Fig. 38.1). The passage of antibiotics into CSF is dependent on the degree of meningeal inflammation and integrity of the blood–brain barrier created by capillary endothelial cells, as well as the following properties of the antibiotic:

• lipid solubility (the choroidal epithelium is highly impermeable to lipid-insoluble molecules)

• ionic dissociation at blood pH

• protein binding

• molecular size

• concentration of the drug in the serum.

Antimicrobials fall into three categories according to their ability to penetrate the CSF:

• those that penetrate even when the meninges are not inflamed, for example chloramphenicol, metronidazole, isoniazid and pyrazinamide

• those that generally penetrate only when the meninges are inflamed, and used in high doses, for example most β-lactam antibiotics, the quinolones and rifampicin

• those that penetrate poorly under all circumstances, including the aminoglycosides, vancomycin and erythromycin.

Recommended regimens

Clinical urgency determines that empirical antimicrobial therapy will usually have to be prescribed before the identity of the causative organism or its antibiotic sensitivities are known. Consideration of the epidemiological features of the case, together with microscopic examination of the CSF, is often helpful in identifying the likely pathogen. However, empiric therapy is usually with broad-spectrum antimicrobial therapy to cover all likely pathogens, at least until definitive microbiological information is available. For the purpose of selecting empiric antimicrobial therapy, patients with acute bacterial meningitis can be categorised into four broad groups: neonates and infants aged below 3 months; immunocompetent older infants, children and adults; immunocompromised patients; and those with ventricular shunts.

Antibiotics for meningitis in neonates and infants aged below 3 months

The most important pathogens in neonates include group B streptococci, E. coli and other Enterobacteriaceae, L. monocytogenes. In many centres, a third-generation cephalosporin such as cefotaxime or ceftazidime, along with amoxicillin or ampicillin, is the empiric therapy of choice for neonatal meningitis (Galiza and Heath, 2009). Cephalosporins penetrate into CSF better than aminoglycosides, and their use in Gram-negative bacillary meningitis has contributed to a reduction in mortality to less than 10%. Other centres continue to use an aminoglycoside, such as gentamicin, together with benzylpenicillin, ampicillin or amoxicillin as empiric therapy. This approach remains appropriate, especially in countries such as the UK where group B streptococci are by far the predominant cause of early-onset neonatal meningitis. Whichever empiric regimen is used, therapy can be altered as appropriate once the pathogen has been identified. Suitable dosages are shown in Table 38.2.

Table 38.2 Suitable antibiotic regimens for treatment of acute bacterial meningitis in different age groups

Age group	First-choice antibiotic therapy	Alternative therapies
Neonates, aged <8 days	Ampicillin, 50 mg/kg twice daily or amoxicillin 25 mg/kg twice daily and cefotaxime 50 mg/kg twice daily or ceftazidime 50 mg/kg twice daily	Benzylpenicillin 50 mg twice daily and ampicillin 50 mg/kg twice daily or amoxicillin 25 mg/kg twice daily and gentamicin 2.5 mg/kg twice daily
Neonates, aged 8–28 days	Ampicillin 50 mg/kg four times daily or amoxicillin 25 mg/kg three times daily and cefotaxime 50 mg/kg three times daily or ceftazidime 50 mg/kg three times daily	Benzylpencillin 50 mg three or four times daily or ampicillin 50 mg/kg three or four times daily or amoxicillin 25 mg/kg three times daily and gentamicin 2.5 mg/kg three times daily
Infants, aged 1–3 months	Ampicillin 50 mg/kg four times daily or amoxicillin 25 mg/kg three times daily and cefotaxime 50 mg/kg three times daily or ceftriaxone 75–100 mg/kg once daily
Infants and children aged >3 months^a	Cefotaxime 50 mg/kg three times daily or ceftriaxone^b 75–100 mg/kg once daily	Ampicillin 50 mg/kg four times daily or amoxicillin 25 mg/kg three times daily or benzylpenicillin^c 30 mg/kg 4-hourly and chloramphenicol^d 12.5–25 mg/kg four times daily
Adults	Cefotaxime^e 2 g three times daily or ceftriaxone^b,^e 2–4 g once daily	Benzylpenicillin 2.4 g 4-hourly or ampicillin 2–3 g four times daily or amoxicillin 2 g three or four times daily and chloramphenicol^d 12.5–25 mg/kg four times daily

a Calculated doses for children should not exceed maximum recommended doses for adults.

b Ceftriaxone should not be administered to neonates within 48 h of completion of infusions of calcium-containing solutions; caution should be exercised in older age groups.

c Benzylpenicillin is inactive against H. influenzae and should therefore not be used in children aged <5 years.

d Monitoring of serum chloramphenicol levels is recommended, especially in children aged ≤4 years.

e Add ampicillin or amoxicillin to cover L. monocytogenes in elderly patients or where Gram-positive bacilli seen in CSF.

In infants outside the immediate neonatal period, the classic neonatal pathogens account for a decreasing number of cases of meningitis and the common bacteria of meningitis in childhood (see later) become increasingly important. Amoxicillin or ampicillin plus cefotaxime or ceftriaxone is the recommended treatment. Therapy with amoxicillin or ampicillin and gentamicin is unsuitable for this age group because it provides inadequate cover against H. influenzae.

Antibiotics for meningitis in older infants, children and adults

Antimicrobial therapy has to cover S. pneumoniae, N. meningitidis and, in children aged below 5 years, H. influenzae (Yogev and Guzman-Cottrill, 2005). Achievable antibiotic CSF concentrations are compared with the susceptibilities of the common agents of meningitis in Table 38.3. Third-generation cephalosporins, such as cefotaxime, are now widely used in place of the traditional agents of choice, chloramphenicol, ampicillin, amoxicillin and penicillin (see Table 38.2). This change has stemmed from concern over the rare but potentially serious adverse effects of chloramphenicol and the emergence of resistance to penicillin, ampicillin and chloramphenicol among S. pneumoniae and H. influenzae in particular. Chloramphenicol resistance and reduced susceptibility to penicillin have also been reported in N. meningitidis. The third-generation cephalosporins have a broad spectrum of activity that encompasses not only the three classic causes of bacterial meningitis but also many other bacteria that are infrequent causes of meningitis. However, cephalosporins are inactive against L. monocytogenes, and amoxicillin or ampicillin should be added where it is possible that the patient may have listeriosis, for example in elderly patients, or where Gram-positive bacilli are seen on Gram stain. Although earlier-generation cephalosporins such as cefuroxime achieve reasonable CSF penetration and are active against the agents of meningitis in vitro, they do not effectively sterilise the CSF and should not be used to treat meningitis.

Table 38.3 Achievable CSF concentrations of antibiotics in meningitis and MIC values for common central nervous system pathogens

Ceftriaxone is a third-generation cephalosporin with a spectrum of activity comparable to that of cefotaxime. However, because of the potential for calcium chelation in vivo, ceftriaxone must not be administered within 48 h of the completion of infusions of calcium-containing solutions in neonates. The risk of precipitation is much lower in patients >28 days of age. Nevertheless, caution should still be exercised when treating older age groups, especially in the early treatment of meningococcal infections (where calcium-containing products are commonly used for resuscitation).

In meningitis due to N. meningitidis and H. influenzae, prompt administration of chemoprophylaxis to eliminate nasopharyngeal carriage can reduce the risk of secondary cases in close contacts of the case.

N. meningitidis

In view of the potentially rapid clinical progression of meningococcal disease, it is recommended that treatment should begin with the emergency administration of benzylpenicillin. Primary care clinicians should give penicillin while arranging transfer of the patient to hospital. The dose is 1200 mg for adults and children aged 10 years and above, 600 mg for children aged 1–9 years and 300 mg for children aged below 1 year. Ideally, this should be given intravenously. The intramuscular route is less likely to be effective in shocked patients but can be used if venous access cannot be obtained. The only contraindication is allergy to penicillin, where cefotaxime (1 g for adults, 50 mg/kg for children aged <12 years) or chloramphenicol (1.2 g for adults, 25 mg/kg for children aged <12 years) may be given, if available. However, it is not recommended that primary care clinicians routinely carry these alternative antibiotics.

Strains of N. meningitidis with reduced sensitivity to penicillin are well known and presently account for 5–10% of isolates in Europe and the USA. In general, these cases respond to treatment with adequate doses of benzylpenicillin, and failure of penicillin treatment has rarely been reported. Nevertheless, cefotaxime and ceftriaxone are now widely used in preference to benzylpenicillin or chloramphenicol.

S. pneumoniae

Benzylpenicillin was once widely regarded as the treatment of choice for pneumococcal meningitis. However, pneumococci resistant to penicillin have emerged across the world, presenting a major therapeutic challenge in view of the severity of pneumococcal meningitis.

Although currently only about 5% of pneumococci in the UK are penicillin resistant, the frequency of resistance is increasing, and resistance rates of more than 50% have been reported in other countries, including Spain, Hungary and South Africa. Penicillin resistance in pneumococci is defined in terms of the minimum inhibitory concentration (MIC) of penicillin. Most strains have a MIC value of 0.1–2.0 mg/L and are defined as having moderate resistance; strains with an MIC value of more than 2 mg/L are considered highly resistant. This distinction is relevant for less serious infections with moderately resistant strains, which may still respond to adequate doses of some β-lactam antibiotics, such as cefotaxime, ceftriaxone or a carbapenem. However, the clinical outcome of meningitis with penicillin-resistant pneumococci treated with a β-lactam antibiotic as monotherapy is less good. For this reason, many guidelines, including those produced by the Infectious Diseases Society of America, now recommend therapy with a combination of a third-generation cephalosporin and vancomycin (McIntosh, 2005). This approach has not been adopted universally in the UK but should certainly be considered for patients who might have acquired their infection in a location where the incidence of penicillin resistance is high. Where vancomycin is given intravenously to treat meningitis, it is important to aim for trough serum levels of 15–20 mg/L because of the limited CSF penetration of vancomycin. Another problem is the emergence of pneumococci that are tolerant to vancomycin, that is, they are able to survive, but not proliferate, in the presence of vancomycin. Although such strains are uncommon, the outcome of meningitis treated with vancomycin is poor (Cottagnoud and Tauber, 2004).

Other antibiotics may be useful in treating pneumococcal meningitis. Use of rifampicin in combination with a cephalosporin and/or vancomycin is sometimes recommended, but there are few data confirming this can improve the response rate in either penicillin-sensitive or -resistant pneumococcal meningitis. The dose of rifampicin is 600 mg twice daily in adults or 10 mg/kg (maximum 600 mg) twice daily in children. Chloramphenicol is a suitable alternative to penicillin for treatment of meningitis due to penicillin-sensitive strains, for example in patients who are penicillin allergic. However, chloramphenicol is not recommended for treating penicillin-resistant pneumococcal meningitis: although isolates may appear sensitive to chloramphenicol on routine laboratory testing, bactericidal activity is often absent and the clinical response is usually poor.

Consideration of alternative antibiotics for treatment of penicillin-resistant pneumococcal meningitis is largely based on case reports rather than clinical trials. Success has been reported with meropenem as monotherapy, and in conjunction with rifampicin. Moxifloxacin is a new-generation quinolone antibiotic with enhanced activity against Gram-positive bacteria, including S. pneumoniae, which has shown promise in experimental pneumococcal meningitis. Linezolid has excellent CSF penetration but does not have bactericidal activity, and clinical experience in treating meningitis has been variable (Rupprecht and Pﬁster, 2005).

Daptomycin is an interesting option that has potent bactericidal activity against penicillin-sensitive and -resistant pneumococci, but without being bacteriolytic. This may be an advantage in that bacterial intracellular components that contribute to the inflammatory response are not liberated by bacterial killing. Indeed, in treating experimental pneumococcal meningitis, daptomycin gives a better clinical outcome than conventional treatment.

The unpredictable nature of the response to therapy of penicillin-resistant pneumococcal meningitis means that patients require close observation during treatment, for example monitoring of C-reactive protein (CRP). Repeat examination of CSF during therapy should also be considered.

In meningococcal meningitis, spread between family members and other close contacts is well recognised; these individuals should receive chemoprophylaxis as soon as possible, preferably within 24 h. Sometimes, chemoprophylaxis may be indicated for other contacts, but the decision to offer prophylaxis beyond household contacts should only be made after obtaining expert advice (Box 38.1). Of the antibiotics conventionally used to treat meningococcal infections, only ceftriaxone reliably eliminates nasopharyngeal carriage; where another antibiotic has been used for treatment, the index case also requires chemoprophylaxis. A number of antibiotics are suitable as prophylaxis (Box 38.2).

Box 38.1 Indications for chemoprophylaxis in contacts of cases of infection with N. meningitidis or H. influenzae type b

Neisseria meningitidis

Household and other close contacts: prophylaxis usually initiated as soon as possible by clinicians caring for the patient

• Persons who have slept in the same house as the patient at any time during the 7 days before the onset of symptoms

• Boy/girl 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

Healthcare workers: prophylaxis should only be initiated after consultation with hospital infection control team or public health doctor

• Individuals who have administered mouth-to-mouth resuscitation or had some other form of prolonged close face-to-face contact with the patient

• Other contacts: prophylaxis should be initiated by a public health doctor

• Schools, nurseries, universities and other closed communities where two or more linked cases have occurred

Invasive Haemophilus influenzae type b infection

Household and other close contacts: prophylaxis usually initiated as soon as possible by clinicians caring for the patient

• Indicated only where there is another child aged less than 4 years who has not been immunised in the same household as the index patient. In such circumstances, prophylaxis should be given to all household contacts aged 1 month or older, unless there are contraindications. The index patient should also receive antibiotic prophylaxis as soon as he or she is able to take oral medication

Other contacts: prophylaxis very rarely necessary and should only be initiated by a public health physician

Meningococcal infection
Ciprofloxacin^a (oral)
Children aged 1 month – 4 years Children aged 5–12 years Adults	125 mg as a single dose 250 mg as a single dose 500 mg as a single dose
Rifampicin (oral)
Children aged <1 year	5 mg/kg twice daily on 2 consecutive days
Children aged 1–12 years	10 mg/kg (max 600 mg) twice daily on 2 consecutive days
Adults	600 mg twice daily on 2 consecutive days
Azithromycin^a (oral)Pregnant women	500 mg as a single dose
Ceftriaxone^a (intramuscular)
Children aged <12 years Adults	125 mg as a single dose 250 mg as a single dose
*Invasive Haemophilus influenzae* type b infection**
Rifampicin (oral)
Children aged 1–3 months	10 mg/kg once daily for 4 days
Children aged >3 months	20 mg/kg once daily (max 600 mg) for 4 days
Adults^b	600 mg once daily for 4 days

a Not licensed for this indication.

b For pregnant women, obtain expert advice.

Ciprofloxacin is now widely recommended for contacts of all ages (including pregnant and breast-feeding women) because of the convenience of single-dose administration and, unlike rifampicin, it does not interact with oral contraceptives and is readily available in community pharmacies. Although anaphylactoid reactions have been reported to occur in individuals receiving ciprofloxacin as chemoprophylaxis, none of these reactions has been fatal. If the strain is confirmed as group C (or A, W135 or Y), vaccination is normally offered to contacts who were given prophylaxis. There is no need to vaccinate the patient. There is currently no vaccine that protects against group B disease, which accounts for about 70% of cases of meningococcal disease in Europe.

Chemoprophylaxis against Hib infection is usually only indicated where there is an unimmunised child in the vulnerable age group in the household (see Box 38.1). Only rifampicin has been proved to be effective in eliminating nasopharyngeal carriage (see Box 38.2). Unimmunised household contacts aged below 4 years should also receive Hib vaccine. The index case should also receive rifampicin in order to eliminate nasopharyngeal carriage, and should be immunised, irrespective of age.

Antibiotics for meningitis in special groups

Immunocompromised host

In the immunocompromised neutropenic patient, the meninges can become infected. Possible causes of meningitis include Enterobacteriaceae and Pseudomonas aeruginosa, as well as the classic bacterial causes of meningitis. The choice of therapy is governed by the need to attain broad-spectrum coverage, using agents with good CSF penetration. Meropenem may now be the drug of choice for meningitis in this setting, although many other regimens are also appropriate.

Patients with cellular immune dysfunction are vulnerable to meningitis due to L. monocytogenes and C. neoformans. Ampicillin or amoxicillin, along with cefotaxime or ceftriaxone, is recommended as empirical antibacterial therapy for meningitis in these patients. Definitive treatment of listeria meningitis is normally with high-dose ampicillin (3 g four times daily) or amoxicillin (2 g four times daily), with the addition of gentamicin in order to obtain a synergistic effect. The most appropriate treatment for patients who are penicillin allergic, or in the rare circumstance of infection with a strain that is ampicillin resistant, is uncertain and specialist microbiological advice should be sought. Specific therapies for cryptococcal meningitis are described in detail as follows.

Splenectomised patients are susceptible to invasive infections with encapsulated bacteria, including S. pneumoniae and Hib. Standard therapy with either cefotaxime or ceftriaxone is appropriate.

Shunt-associated meningitis

Patients who have a ventricular shunt are at increased risk of meningitis. Shunt-associated infections are classified according to the site of initial infection. Internal infections, where the lumen of the shunt is colonised, constitute the majority of cases. External shunt infections involve the tissues surrounding the shunt. Most internal shunt infections are caused by coagulase-negative staphylococci. S. aureus and Enterobacteriaceae account for most external infections. It is generally held that management of shunt infections should include shunt removal, as well as antibiotic therapy (Infection in Neurosurgery Working Party, 2000), although the need for this has been questioned (Arnell et al., 2007). Appropriate antimicrobial regimens are shown in Table 38.4.

Table 38.4 Antimicrobial regimens for treatment of shunt meningitis

Tuberculous meningitis

The outcome in tuberculous meningitis relates directly to the severity of the patient’s clinical condition on commencement of therapy. A satisfactory response demands a high degree of clinical suspicion such that appropriate chemotherapy is initiated early, even if tubercle bacilli are not demonstrated on initial microscopy. Most currently used antituberculous agents achieve effective concentrations in the CSF in tuberculous meningitis. Detailed discussion of antituberculous therapy is given in Chapter 40. Adjunctive steroid therapy is of value in patients with more severe disease, particularly those who suddenly develop cerebral oedema soon after starting treatment or who appear to be developing a spinal block. However, routine use of steroids is not recommended. They may suppress informative changes in the CSF and interfere with antibiotic penetration by restoring the blood–brain barrier. Early neurosurgical management of hydrocephalus by means of a ventriculoperitoneal or ventriculoatrial shunt is also important in improving the prospects for neurological recovery.

Cryptococcal meningitis

The standard treatment of cryptococcal meningitis is amphotericin B, given intravenously at a dose of 0.7–1.0 mg/kg/day, with or without flucytosine 100 mg/kg/day, for 6–10 weeks. Addition of flucytosine results in quicker clearance of yeasts from the CSF, although it is debatable whether this results in improved clinical outcome. Lipid formulations of amphotericin B, such as liposomal amphotericin B, at doses of 4–6 mg/kg/day have comparable efficacy to, and fewer side effects than, conventional amphotericin B at a dose of 0.7 mg/kg. As an alternative to prolonged therapy with two potentially toxic drugs, 2 weeks therapy with amphotericin B and flucytosine may be given, followed by consolidation therapy with fluconazole 400 mg/day for at least 10 weeks. Initial treatment with fluconazole 400–800 mg/day plus flucytosine is clinically inferior to amphotericin B-based regimens, and in any case is no better tolerated than amphotericin B-based regimens. Regular haematological and biochemical monitoring is recommended during treatment, along with measurement of serum concentrations of flucytosine (which should not exceed 80 mg/L).

The clinical response to treatment of cryptococcal meningitis is slow, and it often takes 2 or 3 weeks to sterilise the CSF. Monitoring of intracranial pressure is essential, with large-volume CSF drainage indicated if the opening pressure reaches 250 mmHg. Serial CSF cultures are occasionally helpful in following the response to treatment, but monitoring of cryptococcal antigen titres in serum or CSF is of little value.

Patients with HIV infection treated for cryptococcal meningitis should then receive fluconazole indefinitely, or at least until immune reconstitution occurs. The dose of fluconazole may be reduced to 200 mg/day, depending on the patient’s clinical condition (Bicanic and Harrison, 2004). Itraconazole offers less good CSF penetration than fluconazole, but is a suitable alternative as maintenance therapy at a dose of 200–400 mg/day for patients unable to tolerate fluconazole. Clinical data with newer triazoles such as voriconazole and posaconazole remain limited, but these agents may be useful, especially in the rare situation of fluconazole-resistant cryptococcal meningitis. The echinocandin class of antifungals does not possess useful activity against Cryptococcus.

Viral meningitis

None of the currently available antiviral agents has useful activity against human enteroviruses, the commonest causes of viral meningitis (Big et al., 2009). Fortunately, however, the condition is usually self-limiting. The viruses that commonly cause this condition, herpes simplex and varicella zoster meningoencephalitis, are treated with high-dose aciclovir, 10 mg/kg three times daily for at least 10 days (adults and children aged 12 years and over). For younger children, the recommended doses are 20 mg/kg three times daily for infants up to age 3 months, and 500 mg/m² three times daily for those aged 3 months to 12 years.