Antimicrobial Chemotherapy, 5th Edition

Part 4 - Therapeutic Use of Antimicrobial Agents

Chapter 26

Infections of the Central Nervous System

Infections of the central nervous system include meningitis, encephalitis, and brain abscess. These can be caused by viruses, bacteria, fungi, and protozoa; however, bacterial and viral causes predominate.

Infection is generally acquired from an exogenous source and spreads to the central nervous system via the bloodstream. Penetrating injuries and trauma, including neurological procedures can be complicated by infection. In the case of brain abscess, bloodstream or spread from adjacent infected sites (middle ear, sinuses) are also important. All infections of the central nervous system are serious. Many infections, notably meningitis and brain abscess, will prove fatal unless diagnosed and treated promptly.

Meningitis

Meningitis is an infection within the subarachnoid space resulting in inflammation of the membranes covering the brain and the spinal cord and the intervening cerebrospinal fluid (CSF). Infection is usually caused by bacteria, viruses and occasionally fungi (Table 26.1). The inflammatory process in bacterial meningitis extends throughout the subarachnoid space and often involves the ventricles; the brain itself is generally not affected in immunocompetent individuals.

Viral meningitis is usually self-limiting. In the case of bacterial meningitis, which remains a relatively common and devastating disease with a mortality of 10-30%, the outcome is dependent upon the organism, the age of the patient, the state of consciousness on admission, the speed of diagnosis and the timeliness of treatment. Long-term neurological sequelae in survivors are common especially in neonates, infants, and those infected with Streptococcus pneumoniae.

Bacterial meningitis

About 2000 cases of bacterial meningitis are notified annually in the UK; most are caused by Neisseria meningitidis, and Str. pneumoniae.The introduction of a conjugate vaccine against Haemophilus influenzae type b in 1992 has now virtually eliminated infection with this organism. N. meningitidis is now the commonest cause of acute bacterial meningitis and is likely to remain so, until a suitable vaccine becomes available for strains of serogroup B, which account for over 60% of all cases of meningococcal disease in the UK. The introduction of vaccine against serogroup C meningococci has successfully controlled such infections.

Table 26.1 Infectious causes of meningitis (UK)

Bacteria

Viruses

Fungi

Neisseria meningitidis

Enteroviruses

Cryptococcus neoformans

Streptococcus pneumoniae

Mumps

Candida albicans

Str. agalactiae (Group B)

Herpes simplex

 

Enterobacteria

HIV

 

Staphylococcus aureus

   

Coagulase-negative staphylococci

   

Listeria monocytogenes

   

Mycobacterium tuberculosis

   

Treponema pallidum

   

The incidence of occurrence of the various forms of bacterial meningitis is strikingly age related. In the past, Escherichia coli and other enterobacteria dominated as agents of neonatal meningitis, but Str. agalactiae (Group B streptococcus) is now the leading cause. Less common causes are Listeria monocytogenes, enterobacteria other than Esch. coli, Candida albicans, and Str. pneumoniae.

  1. meningitidisis an important cause of meningitis in childhood and early adult life. Household and institutional outbreaks in schools and universities occur sporadically. After the age of 40 meningitis is most commonly caused by Str. pneumoniae.Other organisms that are occasionally encountered include L. monocytogenes (especially in those with underlying diseases), Esch. coli, Staphylococcus aureus (usually post-neurosurgery), and Mycobacterium tuberculosis.

Pathogenesis and clinical features

Str. pneumoniae and N. meningitidis are found as normal upper respiratory tract commensals in a proportion of the population. Meningitis most commonly follows haematogenous spread of the micro-organism from the nasopharynx. The sequence of events is believed to be mucosal colonization, passage through the mucosal epithelium, bacteraemia, penetration of the blood-brain barrier, and multiplication within the subarachnoid space. Occasionally, haematogenous spread from the middle ear, or other infected focus, may occur. Rarely, bacteria reach the CSF by direct extension from adjacent suppurative tissues or a ruptured intracranial abscess, or may be directly implanted into the subarachnoid space from the nasopharynx through dural defects of congenital or traumatic origin. Once a pathogen is introduced into the subarachnoid space, bacteria multiply rapidly because of inadequate local defences. There follows an intense inflammatory process with marked congestion, oedema, outpouring of exudate, and raised intracranial pressure. Blood vessels and nerves may be involved in the inflammatory process leading to arteritis, infective thrombophlebitis, and cranial nerve palsies, and the thick exudate may interfere with CSF circulation and absorption leading to blockage and hydrocephalus.

The clinical picture consists of signs and symptoms of systemic illness (e.g. general malaise, fever, toxicity, poor feeding, leucocytosis) increased intracranial pressure (e.g. headache, vomiting, irritability, disturbance of consciousness, seizures), and meningeal irritation (e.g. photophobia, neck pain, positive Kernig's sign). In neonates, infants, and old people the signs and symptoms may be non-specific and subtle.

The presence of a petechial or purpuric rash, predominantly on the extremities, in a patient with meningeal signs almost always indicates meningococcal disease and requires immediate antibiotic therapy and admission to hospital.

Viral meningitis

Viral meningitis is most commonly associated with enteroviruses (Coxsackie and echoviruses) (Table 26.1) and is therefore more common in the summer months. Herpes simplex meningitis, as distinct from herpes simplex encephalitis, may or may not be linked to active infection at other body sites. In the non-vaccinated, mumps meningitis is an unpleasant complication of this infection. Primary HIV infection may manifest as acute central nervous system disease including meningitis and should be considered in those at risk of recent exposure. Most viral meningitides are self-limiting and without major neurological complications, although headaches may persist for several weeks.

 

Encephalitis

Encephalitis indicates inflammation of the brain parenchyma and is largely the result of virus infection. Some are vector borne and therefore geographically linked. However, occasionally bacteria, fungi, and protozoa are responsible (Table 26.2).

Pathogenesis and clinical features

Invasion of the brain is generally the result of bloodstream spread complicating viraemia or bacteraemia. The inflammatory reaction may be focal or generalized and is characterized by perivascular infiltration by lymphocytes and accompanying neuronal damage.

Clinically, the illness has an acute onset with fever, headache, and clouding of consciousness. Seizures may occur. The neurological findings may be either generalized or localized causing focal or global neurological deficits. The cranial nerves may also be involved.

Laboratory diagnosis

Cerebrospinal fluid examination

Examination of the CSF obtained by lumbar puncture (provided this procedure is not contraindicated; see below) is the most effective investigation for diagnosing the nature of infection of the central nervous system. In an adult at least 4-5 ml of CSF is obtained into two or three sterile bottles, which are labelled sequentially. Blood and CSF samples for the estimation of glucose are also sent for chemical assay.

Table 26.2 Selected agents responsible for acute encephalitis

Viruses

Bacteria

Fungi

Protozoa

Herpes simplex
Arbovirusesa
HIV
Varicella zoster
Echoviruses
Cytomegalovirus
Coxsackie viruses
Epstein-Barr virus
Mumps
Measles
Influenza

Listeria monocytogenes Rickettsia spp.
Treponema pallidium

Cryptococcus neoformans

Toxoplasma gondii
Naegleria fowleri
Trypanosoma brucei rhodesiense

Includes Ross River, West Nile, Japanese encephalitis and tick-borne encephalitis viruses.

 

Examination of the CSF should include total white blood cell (including differential) and red blood cell counts, and estimation of protein concentration. Careful examination of a prepared Gram-stained smear of the centrifuged deposit of CSF reveals the causative organism in most cases and guides appropriate initial therapy in the case of bacterial meningitis. Antibiotic treatment prior to CSF collection can alter the staining and morphological characteristics of some pathogens and requires caution in interpretation. Typical laboratory findings in bacterial and viral meningitis are shown in Table 26.3.

In patients with suspected acute meningitis or encephalitis a computed tomography (CT) brain scan is frequently obtained, especially where encephalitis is suspected, seizures occur or focal neurology is detected. Lumbar puncture is contraindicated in those with evidence of raised intracranial pressure to avoid subsequent and potentially fatal compression of the brainstem through the foramen magnum (‘coning’).

Other tests, such as those that detect pneumococcal capsular polysaccharide are increasingly used but rarely show diagnostic superiority over a carefully prepared Gram-stain smear and culture of CSF. In the case of viral meningitis and tuberculous meningitis (Chapter 25, p. 353) polymerase chain reaction tests are now widely used to establish a diagnosis.

Table 26.3 Typical cerebrospinal fluid changes in bacterial and viral meningitis

Property

Normal cerebrospinal fluid

Bacterial meningitisa

Viral meningitis

Appearance

Clear, colourless

Purulent or cloudy

Clear or slightly opalescent

Cell count (per µl)

0-5

100s or 1000s

10s or 100s

Main cell type

Lymphocytes

Polymorphsb

Lymphocytesc

Protein concentration

0.1-0.4g/l

May be several g/l

Normal or slightly raised

Glucose concentration

≈60% blood glucose

<40% blood glucose

Unchanged

Gram-film

Negative

Positive

Negative

Excluding tuberculous meningitis.

Exceptions: partially treated pyogenic meningitis; tuberculous, listerial, cryptococcal, or leptospiral meningitis, in which a lymphocytic response is common.

In early cases an increased polymorph count may be seen.

 

Blood cultures

Blood cultures (two sets) should be collected, ideally before antimicrobial therapy is begun, from patients with suspected meningitis, since bacteraemia is present in a high proportion of patients with meningococcal or pneumococcal disease.

Therapeutic considerations

The treatment of bacterial meningitis requires prompt initiation of treatment, started on the basis of Gram-film findings (if available) and on the appreciation of certain principles and guidelines. However, if the patient is acutely ill, with a short history suggestive of meningitis, or if the CSF appears cloudy, then empirical (based on age and clinical setting) high-dose intravenous antibiotics should be given immediately, without waiting for laboratory results, since mortality is high in these patients.

Penetration of antibiotics into cerebrospinal fluid

The CSF represents an area of impaired host defence. Hence, agents are selected that are bactericidal and also penetrate into the CSF in therapeutic concentrations. Compounds entering CSF must traverse the blood-brain barrier (a lipid membrane in the brain capillary), the epithelial layer of the choroid plexus, or both. The choroid is impermeable to lipid-insoluble molecules. The penetration of antibiotics into the CSF is enhanced by high lipid solubility, a low degree of ionization, low molecular weight, high serum concentration of the drug, low protein binding, and the presence of meningeal inflammation.

Antimicrobial agents can be divided according to their ability to penetrate into CSF:

  • those that penetrate inflamed and non-inflamed meninges in standard doses: chloramphenicol, sulphonamides, trimethoprim, metronidazole, isoniazid, pyrazinamide, and fluconazole;
  • those that penetrate in the presence of inflamed meninges, or when used in high doses: benzylpenicillin, ampicillin, flucloxacillin, cefotaxime, ceftriaxone, vancomycin, rifampicin, amphotericin B, and flucytosine;
  • those that penetrate poorly even when the meninges are inflamed: aminoglycosides, erythromycin, tetracyclines, and fusidic acid.

Choice of antimicrobial agent

The initial choice of antimicrobial agent is based on the most likely pathogen, which is determined by the age of the patient, the clinical features, the Gram-film results of the CSF, and knowledge of the local sensitivity patterns of the suspected organism. A bactericidal agent in high dose intravenously is recommended for the treatment of meningitis, since rapid killing of bacteria occurs only when the bactericidal titre of the CSF for the relevant bacteria is between 1 in 10 and 1 in 20.

Cefotaxime and ceftriaxone, exhibit excellent activity against H. influenzae, Str. pneumoniae, N. meningitidis, group B streptococci, Esch. coli, and other enterobacteria, and are agents of choice for most forms of bacterial meningitis. High-dose intravenous cefotaxime or ceftriaxone provides CSF concentrations many times those necessary to kill the organisms. Although these cephalosporins are effective in most varieties of meningitis, listerial, and staphylococcal meningitis are exceptions (see below). Chloramphenicol, which penetrates well into CSF and was formerly widely used in neonates and adults, but is now a reserve agent for the treatment of selected patients who are allergic to penicillin, owing to toxicity and lower efficacy rates.

Duration of therapy

Antibiotic treatment of meningitis varies by pathogen. Meningococcal disease responds in 5-7 days; H. influenzae is best treated for a minimum of 7-10 days to ensure complete eradication of the organism and prevent relapse. Antimicrobial treatment of pneumococcal meningitis should be continued for at least 10-14 days. In neonatal meningitis and adult meningitis due to unusual organisms, such as L. monocytogenes, more prolonged therapy may be indicated and each case should be reviewed in consultation with a microbiologist or infectious disease specialist.

Adjunctive therapy

Despite the use of appropriate, effective, bactericidal antibiotics, mortality, and morbidity in bacterial meningitis remain high. Attention has therefore focused on the possibility of modulating the complex inflammatory process within the subarachnoid space and meninges that contributes to mortality and morbidity, including sensorineural hearing loss.

Dexamethasone therapy in concert with antimicrobial agents has been shown to decrease the incidence of sensorineural hearing loss in children with H. influenzae meningitis, but there is no reduction in mortality and gastrointestinal bleeding occurs in some patients. With the declining incidence of H. influenzae meningitis in those countries that have adopted childhood immunization against this disease, the use of dexamethasone is now used selectively in the management of other forms of bacterial meningitis, such as pneumococcal meningitis where early use has reduced mortality. It should be avoided in viral meningitis and where the diagnosis of meningitis is uncertain. It is also contraindicated in patients with septic shock complicating meningitis or in those receiving immunosuppressive therapy. It is important that dexamethasone be started before the first dose of antibiotic and continued for 4 days.

Meningococcal disease

Infections caused by N. meningitidis are both endemic and epidemic. Epidemics may occur in closed institutions, such as schools, halls of residence, and military barracks. In sub-Saharan Africa epidemics occur every few years. N. meningitidis affects primarily infants, children, and young adults. The organism is carried asymptomatically in the nasopharynx of a small proportion of the population and this represents the reservoir of infection. The disease has a seasonal incidence with most cases occurring in winter and spring. Coexisting or antecedent viral infection may play a part in invasive meningococcal disease. The following broad clinical groups can be recognized in patients with meningococcal disease according to the presenting clinical features.

Septicaemia with or without meningitis

About 15-20% of cases of meningococcal disease is characterized by the rapid development over a period of 24-48 h. The symptoms include fever, rigors, myalgias, and a petechial rash. In a few patients headache, confusion, and neck stiffness may develop later, signifying the onset of meningitis. However, the onset of illness in those with fulminant meningococcal septicaemia is much more abrupt and dramatic. The duration of illness is often less than 24 h, and on admission the patient is gravely ill, shocked, and covered with a rapidly spreading purpuric rash, which may coalesce, become ecchymotic, and even proceed to tissue necrosis. Disseminated intravascular coagulation may follow and death can occur within hours. Blood cultures are invariably positive. There may be no signs of meningism, but it is not uncommon for N. meningitidis to be recovered from an otherwise normal CSF, implying the onset of early meningitis. Mortality is 20-30% in patients with septicaemic illness.

Meningitis with or without septicaemia

This is the commonest presentation with signs and symptoms of meningitis that may occur rapidly or evolve more gradually over several days. The CSF is typically cloudy with a high polymorphonuclear leucocyte count, raised protein, and low glucose concentration. A typical petechial or purpuric rash is present in about 60% of patients; occasionally the rash may be initially maculopapular. Blood cultures are positive in about 40% of cases. With appropriate treatment, mortality is 3-5%.

Rarer forms of meningococcal disease

Occasionally N. meningitidis may localize in the joints or on heart valves producing acute septic arthritis or endocarditis. Chronic meningococcal septicaemia, although uncommon, is characterized by intermittent pyrexia, rash, and arthralgia. Occasionally a diagnosis is made retrospectively because of transient positive blood cultures in children with mild, self-limiting, febrile illness. They usually recover quickly and spontaneously without the use of antibiotics.

Treatment and prophylaxis

Ceftriaxone is the drug of choice. Therapy should be started on first suspicion of meningococcal disease. Although most strains of N. meningitidis are highly sensitive to penicillin (minimum inhibitory concentration <0.16mg/l), some strains of reduced sensitivity are occasionally encountered and hence the reason why ceftriaxone is the preferred agent.

To prevent secondary cases of meningococcal disease, household and secretion (kissing) contacts are offered antibiotic prophylaxis. The standard agent for prophylaxis is oral rifampicin, twice daily for 2 days (adults 600 mg; children 10mg/kg). Rifampicin-resistant strains occur, but are presently uncommon. A single intramuscular injection of ceftriaxone (adults 250 mg; children 125mg) or a single oral dose of ciprofloxacin (adults 500mg) are alternative prophylactic regimens. Pregnant women should be offered ceftriaxone rather than rifampicin.

Pneumococcal meningitis

Meningitis caused by Str. pneumoniae may occur at any age. The mortality in children and adults is about 20 and 35% respectively. The outlook is grave in those over the age of 60 years. There is often a pre-existing focus of infection elsewhere (e.g. pneumonia, acute otitis media, or acute sinusitis), predisposing risk factor (e.g. recent or remote head trauma, recent neurosurgical procedure, CSF leak, sickle cell anaemia, an immunodeficiency state, alcoholism, or an absent spleen). Str. pneumoniae is the commonest cause of recurrent or post-traumatic meningitis. Patients who have had a splenectomy are at particular risk of developing overwhelming pneumococcal infection. The onset of pneumococcal meningitis may be sudden and the course rapid with death occurring within 12 h. Alterations of consciousness and focal neurological defects may occur and survivors often suffer significant neurological deficits.

 

Treatment

Ceftriaxone is the preferred agent to treat pneumococcal meningitis. The increasing worldwide incidence of penicillin-resistant pneumococci has eroded the efficacy of benzylpenicillin, which was formerly the drug of choice. Strains of pneumococci that are resistant to expanded-spectrum cephalosporins such as ceftriaxone are being increasingly reported from around the world but are currently rare in the UK; rifampicin or vancomycin have been used in such cases, but are less than ideal.

The duration of treatment is at least 10 days, but is extended up to 14 days in young infants or in complicated cases.

Haemophilus meningitis

Almost all cases of meningitis due to H. influenzae are caused by the capsulate type b strains. Before the introduction of the highly successful conjugate vaccine, H. influenzae meningitis affected children under 6 years of age, reflecting the absence of anticapsular antibody in this age group. The mortality was about 7%. The onset of H. influenzae meningitis is often insidious, progressing over a period of 3-5 days. In some infants the illness may be limited to fever, vomiting, and diarrhoea in the early stages, making diagnosis of meningitis difficult.

Treatment and prophylaxis

Cefotaxime or ceftriaxone, which are active against β-lactamase-producing and non-β-lactamase-producing strains of H. influenzae are the agents of choice for treatment. Rifampicin is used as prophylaxis for all household contacts when there is an unvaccinated sibling in the house aged 4 years or younger.

Neonatal meningitis

The highest risk of developing meningitis in the newborn is within the first 2 months of life, the incidence being about 0.3 per 1000 live births. Neonatal meningitis carries a high mortality. The incidence of neurological deficits in those who survive is also depressingly high. Brain abscess is a rare complication.

Predisposing factors include prematurity, low birth weight, prolonged and difficult labour, prolonged rupture of membranes, and maternal perinatal infection. Some cases complicate congenital defects of the neuraxis.

Neonatal meningitis is usually the result of vertical transfer of pathogens from the mother in utero or during delivery, leading to early-onset (occurring within 7 days of delivery) septicaemia or meningitis; less commonly they are acquired from the environment, leading to late-onset meningitis (occurring after 7 days and occasionally up to 2 months after delivery). Early-onset disease often presents as an overwhelming septicaemia with apnoea and shock. The pulmonary manifestations may be difficult to differentiate from respiratory distress syndrome. Meningitis occurs in 30% of cases. About 1 in 100 newborns colonized with group B streptococci develop early-onset disease; mortality is over 50%. Late-onset disease usually presents as meningitis and mortality is about 20%.

The early signs and symptoms are often non-specific and include fever, lethargy, and refusal of feed. A bulging fontanelle, resulting from raised intracranial pressure, is a relatively late sign. A high degree of suspicion and prompt investigation with lumbar puncture is essential. Of those who survive, about half will have evidence of neurological damage.

Treatment

Neonatal meningitis is more difficult to treat, since a wide variety of organisms may be involved and their susceptibility to antibiotics can be unpredictable. The chosen therapy should be supported by appropriate laboratory tests.

Group B haemolytic streptococci

The treatment of choice is high dose benzylpenicillin for at least 2 weeks. Some strains show enhanced killing in vitro when benzylpenicillin is combined with gentamicin, which may be given for the first 7-10 days.

Escherichia coli and other enterobacteria

The most widely used regimen is high-dose cefotaxime in combination with gentamicin to provide synergistic bactericidal activity againstEsch. coli or other enterobacteria. Ceftriaxone together with gentamicin is preferred for meningitis caused by salmonellae, and ceftazidime plus gentamicin for Pseudomonas aeruginosa. The duration of treatment should be at least 3 weeks.

Listeria monocytogenes

This is a Gram-positive bacillus that exists as a soil saprophyte in nature. Infection is probably acquired from dairy or vegetable produce contaminated from animal sources. The organism may be carried asymptomatically in the gastrointestinal or the female genital tract. The neonate may be infected transplacentally in utero or from the genital tract during delivery. Bacteraemia may occur in a pregnant woman following a flu-like illness, which might result in intrauterine infection of the fetus leading to abortion and stillbirth, or the baby may develop symptoms of disseminated infection a few days after delivery. Neonatal mortality with intrauterine listeriosis is about 30%. Most cases of late-onset infection present as meningitis in a previously normal neonate.

  1. monocytogenesalso causes meningitis in adults, particularly in the elderly, the immunocompromised, or those with an underlying disease. Occasionally the disease occurs in previously healthy adults of all ages.

The organism is sensitive to a variety of agents, but the treatment of choice is high-dose ampicillin with or without gentamicin. In adults with a history of penicillin allergy, intravenous or oral co-trimoxazole (which is bactericidal to L. monocytogenes) should be substituted, with chloramphenicol as a further alternative. Cephalosporins have no useful activity against L. monocytogenes.

The duration of therapy should be 3 weeks since cerebritis may accompany the meningitis and requires more prolonged treatment.

A summary of current recommendations for the initial therapy of the commoner forms of bacterial meningitis is outlined in Table 26.4.

Viral and parasitic encephalitis

The treatment of herpes simplex encephalitis and African trypanosomiasis are discussed in Chapters 27 and 30 respectively.

Rarer forms of meningitis

Staphylococcus aureus

Meningitis due to Staph. aureus may occur in patients with fulminating septicaemia secondary to pneumonia or endocarditis, or as a complication of penetrating head injury, recent neurosurgical procedures (including insertion of shunts), and ruptured cerebral or epidural abscess. Mortality is high and neurological sequelae are common in survivors.

Most Staph. aureus strains are resistant to penicillin. For methicillin-sensitive strains high-dose flucloxacillin (at least 12 g daily) combined with oral rifampicin (600 mg daily) is recommended in adults. In patients who are allergic to penicillin or in meningitis due to methicillin-resistant strains, treatment is even more problematic. Parenteral vancomycin (1 g every 12 h) combined with oral rifampicin is recommended. However, since penetration of vancomycin into the CSF is limited, daily intraventricular vancomycin should also be considered. Intraventricular vancomycin is also warranted in meningitis with methicillin-sensitive strains if the CSF is persistently positive despite flucloxacillin and rifampicin, and in patients with shunt-associated meningitis. The duration of treatment for Staph aureus meningitis should be at least 3 weeks.

 

 

Table 26.4 Antibiotic treatment of the common types of bacterial meningitis

Age

Cerebrospinal fluid Gram-film findings

Presumptive organism

Treatment of choice

Antibiotic(s)

Daily dose (interval)

Duration

Comments

<2 months

Gram-positive in chains

Group B streptococci

Benzylpenicillin + gentamicina

200 mg/kg (6 h)

2 weeks

In selected patients, gentamicin may be discontinued after 7-10 days

 

Gram-negative bacilli

‘Coliforms’ (usually Esch. coli)

Cefotaxime+ gentamicina

200 mg/kg (6 h)

3 weeks

Change to ceftriaxone ifSalmonella, or ceftazidime ifPs. aeruginosa

 

Gram-positive bacilli

L. monocytogenes

Ampicillin+ gentamicina

200 mg/kg (6 h)

3 weeks

Rare cause of neonatal meningitis

 

No organisms seen

Any of the above

Cefotaxime± gentamicina ± ampicillin

200 mg/kg (6 h) 200 mg/kg (6 h)

Variableb

Ampicillin added if L. monocytogenesstrongly suspected

2 months-6 years

Gram-negative diplococci

N. meningitidis

Benzylpenicillin

300 mg/kg (4 h)

7 days

Cefotaxime if allergic to penicillin

 

Gram-positive diplococci

Str. pneumoniae

Benzylpenicillin

300 mg/kg (4 h)

10 days

Cefotaxime or ceftriaxone if allergic to penicillinc; in young infants and complicated cases treatment may be extended up to2 weeks

 

Gram-negative coccobacilli

H. influenzae

Cefotaxime or ceftriaxone

200 mg/kg (6 h)
80mg/kg (24 h)

10 days

Chloramphenicol in patients with severe cephalosporin allergy

 

No organisms seen

Any of the above 3

Cefotaxime or ceftriaxone

200 mg/kg (6 h)
80mg/kg (24 h)

Variableb

Change as appropriate according to culture result

>6-40 years

Gram-negative diplococci

N. meningitidis

Benzylpenicillin

Child: as above
Adult: 14.4g (4 h)

7 days

As above

 

Gram-positive diplococci

Str. pneumoniae

Benzylpenicillin

As above

10 days

As abovec

 

No organisms seen

Either of the above 2

Ceftriaxone

80 mg/kg (24 h)

Variableb

 

>40 years

Gram-positive diplococci

Str. pneumoniae

Benzylpenicillin

14.4g (4 h)

10 days

As above

 

Gram-positive bacilli

L. monocytogenes

Ampicillin+ gentamicin

12 g (4 h)

2-3 weeks

Co-trimoxazole if the patient allergic to penicillin

 

Gram-negative bacilli

Esch. coli, etc

Cefotaxime+ gentamicin

12 g (4 h)

3 weeks

Or ceftriaxone (4 g once daily)+ gentamicin

 

No organisms seen

Pneumococci or listeria

Ampicillin

12 g (4 h)

Variableb

Add flucloxacillin for neurosurgical patients; change as appropriate according to culture result

Any age

Gram-positive cocci in clusters

Staphylococci (usually Staph. aureus)

Flucloxacillin +

Adult: 12 g (4h)
Child: 200 mg/kg (4-6 h)

3-4 weeks

If shunt-associated removal of shunt usually necessary; vancomycin instead of flucloxacillin if:
-patient penicillin allergic
-MRSA
-Staph. epidermidisisolated

     

Rifampicin (oral)

Adult: 600 mg (12 h)
Child: 20 mg/kg (12 h)

 

MRSA, methicillin resistant Staph. aureus.

In neonates with normal renal function, the unit dose is based on the body weight (usually 2.5 mg/kg) but the interval between the doses varies with the gestational age and the postnatal age (gestational age <28 weeks, 24 h; 29-35 weeks, 18 h; 36-40 weeks, 12 h; >41 weeks, 8 h).

Duration will depend on the organism isolated.

Use cefotaxime or ceftriaxone also in areas of high prevalence of pneumococci with reduced susceptibility to penicillin.

 

Shunt-associated meningitis

In patients with hydrocephalus the ventricular CSF is diverted to other compartments of the body (usually the peritoneal cavity) with a silastic catheter (shunt). Unfortunately, 15-25% of these patients develop meningitis at some point in the life of the shunt. Staph. epidermidis accounts for about half and Staph. aureus for about a quarter of shunt infections. Among many other micro-organisms associated with such infections are Propionibacterium acnes, diphtheroids, enterococci, and Gram-negative bacilli. Most infections are believed to be due to colonization of the shunt at the time of surgery; occasionally organisms may reach the CSF and shunt through the bloodstream or by retrograde spread. Examination of the CSF obtained by needle aspiration of the reservoir is essential and yields an organism in over 90% of cases. It is not unusual to isolate bacteria from an otherwise normal CSF. Blood cultures are positive only if meningitis is associated with a ventriculo-atrial shunt.

Some patients who develop meningitis due to N. meningitidis, H. influenzae, or Str. pneumoniae are treated with appropriate antibiotics, without shunt removal. However, many infections will fail to be controlled unless there is complete removal of the shunt.

Since Staph. epidermidis is commonly resistant to flucloxacillin, therapy should be commenced with parenteral vancomycin combined with oral rifampicin and daily intraventricular vancomycin. High-dose flucloxacillin should be substituted for parenteral vancomycin if the isolate proves sensitive. Treatment should be continued for 2-3 weeks before a new shunt is inserted.

Mycobacterium tuberculosis

Tuberculous meningitis can affect any age. It is uncommon in developed countries and cases can be missed unless the physician is aware of the possibility and the laboratory is willing to exclude tuberculous meningitis in all cases in which abnormal clinical or CSF findings (increased lymphocytes, raised protein, low CSF glucose) have not been satisfactorily explained. The treatment of tuberculous meningitis is described in Chapter 25.

Cryptococcal meningitis

Cryptococcus neoformans is a saprophytic encapsulated fungus commonly found in soil and pigeon droppings. It is an uncommon cause of meningitis, occurring mainly in patients who are immunocompromised due to disease or drugs. Cryptococcal meningitis is reported to occur in about 4% of AIDS patients in the UK and up to a third of African patients with AIDS. It is probably transmitted via the respiratory tract. Most patients present with features of a subacute meningitis or meningo-encephalitis.

The treatment of cryptococcal CNS disease consists of an initial 2-week induction phase with intravenous amphotericin B, with or without flucytosine (by mouth or intravenously). Flucytosine is associated with more rapid sterilization of the CSF and fewer failures or relapses. Following induction, a consolidation phase with fluconazole is adopted. Alternative agents include amphotericin B or itraconazole. The total duration of treatment is determined by clinical response, monitoring levels of cryptococcal antigen in the blood and CSF and central nervous system imaging where appropriate. In those with underlying HIV infection and low CD4 counts fluconazole is used long term as chemoprophylaxis to prevent recurrent infection.

Culture-negative pyogenic meningitis

About 40% of patients presenting with meningitis will already have received antimicrobial therapy before lumbar puncture and this may lead to failure to isolate the organism. Prior therapy does not seriously alter cell counts or protein and glucose concentrations and it is usually still possible to differentiate between bacterial and viral meningitis. In about 10% of cases the aetiology remains unknown.

Although prior therapy may confuse the clinical picture it is not detrimental to the individual patient who has as good a prognosis as those who are untreated. ‘Best guess’ therapy should be aimed at common bacterial pathogens; ceftriaxone (or cefotaxime) for 7-14 days is a reasonable choice. The duration of therapy should be determined by clinical response and repeat CSF examination where appropriate. In the presence of an obvious meningococcal rash 7 days treatment is sufficient.

All patients in whom there is no history of previous antibiotic to account for the negative results must be investigated further to exclude conditions such as tuberculous or cryptococcal meningitis, superficial brain abscess, or other parameningeal infections.

Brain abscess

Brain abscess is a localized collection of pus within the brain parenchyma. It is a life-threatening condition, although the mortality has been reduced to less than 10% by the introduction of CT and magnetic resonance imaging, leading to earlier diagnosis and more precise localization; by improvements in surgical and bacteriological techniques; and by the use of appropriate antibiotics. About four to 10 cases a year are seen in neurological units of developed countries. Brain abscess in children accounts for less than 25% of all cases and, except in neonates, it is rare in those under 2 years of age.

Pathogenesis

Brain abscesses develop most commonly by spread of infection from an adjacent cranial site (e.g. paranasal sinuses, middle ear, mastoid, or teeth), following a penetrating cranial trauma or neurosurgery, or by haematogenous spread from a distant site (e.g. lung abscess, bronchiectasis, or endocarditis). Blood-borne spread often leads to multiple abscess formation. In about 20% of cases the primary focus of infection remains unrecognized—so-called cryptogenic abscess.

The organisms isolated usually reflect those found in the primary focus of infection. With proper attention to microbiological culture techniques, the role of anaerobes and polymicrobial infection has become apparent. Brain abscess in association with sinusitis is usually located in the frontal lobe and is most commonly caused by Str. milleri with or without anaerobes. In contrast, brain abscess following chronic suppurative otitis media or mastoiditis is usually located in the temporal lobe or cerebellum. The infection is invariably polymicrobial, and the pus obtained may yield a variety of anaerobic and aerobic bacteria. Staph. aureus is usually isolated in pure culture from brain abscess that has followed trauma or neurosurgery, or is secondary to a haematogenous spread from infective endocarditis, whereas Str. milleri together with anaerobes and other respiratory pathogens should be suspected in brain abscess complicating pyogenic lung abscess. Rare causes include M. tuberculosis, L. monocytogenes, Nocardia asteroides, Toxoplasma gondii, Cryptococcus neoformans,and other fungi.

Treatment

Although some patients with early cerebritis, or small, deep, or multiple abscesses have been treated successfully with antimicrobial therapy alone, most require surgical drainage. CT-guided stereotaxic aspiration allows more accurate drainage with minimal interference to the surrounding normal brain. Lumbar puncture is unhelpful in diagnosis and may be hazardous. Blood cultures may be positive and should be taken.

Pus obtained after any of these procedures requires prompt microscopy and culture. Because mixtures of aerobic and anaerobic bacteria are likely, antimicrobial therapy should cover both possibilities. Cefotaxime or other similar agents (ceftriaxone, ceftazidime) are recommended. When used in high doses these antibiotics penetrate well into brain abscess pus, and they are bactericidal against many of the organisms commonly encountered, including Str. milleri, Actinomyces spp., and enterobacteria. However, cephalosporins are not reliably bactericidal against all anaerobes, and for this reason metronidazole should also be used. This agent is bactericidal for almost all anaerobes and therapeutic concentrations are achieved in the brain.

The initial choice of empirical antimicrobial therapy in brain abscess depends on the site of the abscess, any predisposing factors, and the results of the Gram-film examination of pus, if available. Therapy may be modified, if required, once the culture results are available.

Frontal lobe abscess of sinus origin should be treated with high (meningitic) doses of benzylpenicillin in combination with metronidazole, since Str. milleri—with or without anaerobes—is a frequent pathogen. Temporal lobe or cerebellar abscess of otogenic origin is treated with a combination of high-dose ceftriaxone and metronidazole. Gentamicin may be added to this regimen if coliform organisms are seen on the Gram-film or are grown in culture. For brain abscesses secondary to trauma or a neurosurgical procedure, or when Staph. aureus is strongly suspected or grown, high-dose flucloxacillin in combination with oral rifampicin should be used, and in the case of MRSA, vancomycin.

The duration of antimicrobial therapy remains unsettled. It is our practice to administer antibiotics parenterally for at least 3 weeks to all surgically treated patients, often followed by appropriate oral therapy for 4-6 weeks.