Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
Meningitis and brain abscess
- G. Finch
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 or viruses. The inflammatory process in bacterial meningitis extends throughout the subarachnoid space and often involves the ventricles; the brain itself is generally not affected.
Viral meningitis is usually self-limiting, but bacterial meningitis remains a relatively common and devastating disease with a mortality of 10–30 per cent. The outcome is dependent upon the organism, the age of the patient, the state of consciousness and clinical presentation on admission, and the speed of diagnosis and treatment. Long-term neurological sequelae in survivors is high especially in neonates, infants, and those with Streptococcus pneumoniae meningitis. Early diagnosis and appropriate antimicrobial therapy are the keys to reducing mortality and sequelae of this most serious infection.
About 2000 cases of bacterial meningitis are notified annually in the UK; most are caused by Neisseria meningitidis, Haemophilus influenzaetype b, and Str. pneumoniae. Since the introduction of a conjugate vaccine against Haemophilus influenzae type b in 1992, invasive disease with this organism has been virtually eliminated. 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 per cent of all cases of meningococcal disease in the UK.
The frequency of occurrence of the various forms of bacterial meningitis is strikingly age related (Table 27.1). In the past Escherichia coliand other enterobacteria dominated as agents of neonatal meningitis, but group B haemolytic streptococci
(Str. agalactiae) are now the leading cause. These pathogens account for about 5 per cent of meningitis in the neonatal period and can occasionally occur beyond 28 weeks of age. Less common causes are Listeria monocytogenes, enterobacteria other than Esch. coli, Candida albicans, and Str. pneumoniae.
Table 27.1 Distribution of organisms in different age groups in 617 cases of bacterial and fungal meningitis
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), andMycobacterium tuberculosis.
Pathogenesis and clinical features
Str. pneumoniae and N. meningitidis are found as normal commensals in a propor- tion 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 subarach-noid space, bacteria multiply rapidly because of inadequate local defences. There follows an intense inflammatory process with marked congestion, oedema and outpouring of exudate. Blood vessels and nerves may be involved in the inflam-matory 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 and leucocytosis) increased intracranial pressure (e.g. headache, vomiting, irritability, disturbance of consciousness and seizure) and meningeal irritation (e.g. photophobia, neck pain and 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.
Lumbar puncture should be performed promptly (unless contra-indicated; see below) and the CSF sent to the laboratory without delay. 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.
Examination of the CSF in the microbiology laboratory includes total white blood cell (including differential) and red blood cell counts, and estimation of protein. The most critical investigation is the examination of a carefully prepared Gram-stained smear of the centrifuged deposit of CSF. Diligent examination of the Gram-film reveals the causative organism in most cases and the appropriate therapy is based on this result. Considerable caution should be exercised in the interpretation of the Gram-film, especially when the CSF has been obtained after antibiotic therapy, since Gram-positive organisms may decolorize easily, and cocci may elongate and assume bacillary forms. Typical laboratory findings in bacterial and viral meningitis are shown in Table 27.2.
Table 27.2 Typical CSF changes in bacterial and viral meningitis
Other tests, such as those that detect pneumococcal capsular polysaccharide (e.g. countercurrent electrophoresis or latex particle agglutination) rarely show diagnostic superiority over a carefully prepared Gram-stain smear and culture of CSF.
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. Mortality in these patients is high, and a delay of 30–60 min may worsen the prognosis.
Since bacteraemia is present in a high proportion of patients and organisms may occasionally be isolated only from blood cultures (e.g. in patients with meningo-coccal disease who have not yet developed meningitis) at least two sets of blood cultures are taken before antimicrobial therapy is begun. Furthermore, when patients have to receive antibiotics before lumbar puncture, either because the patient is acutely ill, or when lumbar puncture is contraindicated until a tomography (CT) scan has been performed (e.g. in the presence of focal neurological signs or papilloedema), blood culture may be the only investigation to yield the causative agent.
Success in the treatment of bacterial meningitis rests on prompt initiation of treatment, started on the basis of Gram-film findings and on the appreciation of certain principles and guidelines.
Penetration of antibiotics into CSF
The CSF represents an area of impaired host defence. Hence, it is imperative to ensure that the antimicrobial agent selected is bactericidal to the invading organism and able to penetrate into the CSF in therapeutic concentration. 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 epithelium is highly impermeable to lipid-insoluble molecules. All β-lactam antibiotics penetrate the normal blood-brain barrier poorly (about 0.5–2 per cent of the peak serum concentration). 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.
The commonly used antimicrobial agents can be divided into three broad groups according to their ability to penetrate into CSF.
- Those that penetrate inflamed and non-inflamed meninges, even when used in standard doses. These include chloramphenicol, sulphonamides, trimetho- prim, metronidazole, the antituberculosis agents isoniazid and pyrazinamide, and the antifungal agent fluconazole.
- Those that penetrate when the meninges are inflamed, or when used in high doses. These include benzylpenicillin, ampicillin, flucloxacillin, extended-spectrum cephalosporins (cefotaxime, ceftriaxone), vancomycin, rifampicin and the antifungal agents, amphotericin B, and flucytosine.
- Those that penetrate poorly even when the meninges are inflamed. These include aminoglycosides, the earlier cephalosporins, erythromycin and other macrolides, tetracyclines, and fusidic acid.
Choice of antimicrobial agent
The initial choice of antimicrobial agent is based on the age of the patient, the clinical setting, the Gram-film results of the CSF, and prior knowledge of the local sensitivity patterns of the suspected organism. Since the CSF lacks intrinsic opsonic and bactericidal activity and, in the early stages of meningitis, the density of organism may reach high levels, a bactericidal rather than a bacteristatic agent is recommended for the treatment of meningitis. Rapid killing of bacteria occurs only when the bactericidal titre of the CSF for the relevant bacteria is between in 10 and 1 in 20.
The availability of safe, broad-spectrum agents, notably cephalosporins like cefotaxime and ceftriaxone, has revolutionized the treatment of meningitis. These agents exhibit excellent activity in vitro against H. influenzae, Str. pneumoniae, N. meningitidis, group B streptococci,Esch. coli, and other enterobacteria. Intra- venous therapy with high doses of cefotaxime or ceftriaxone usually provides CSF concentrations many times those necessary to kill the organisms. They are effective in most varieties of meningitis with the notable exception of infection caused by L. monocytogenes. Chloramphenicol, which penetrates well into CSF and was formerly widely used in neonates and adults, has become a reserve agent for the treatment of selected patients who are allergic to penicillin. It is no longer recommended for meningitis caused by Gram-negative bacilli.
Route and mode of administration
Intravenous administration of antibiotics is essential. Since β-lactam antibiotics enter CSF poorly, these antibiotics should be given parenterally in frequent high bolus doses rather than by continuous administration, to ensure adequate concentrations in the CSF. The dosage interval is dependent upon the half-life of the drug used; for cefotaxime the interval is usually 4–6 h, but for ceftriaxone, a 12–24 h interval is sufficient.
Chloramphenicol is unusual in that the oral route can be used after the initial acute stages of illness. Oral penicillin V or amoxycillin have no place in the treatment of bacterial meningitis.
Duration of therapy
Antibiotic treatment of meningococcal meningitis need last only 5 days, although in practice, it is usually 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 days for most patients, and up to 2 weeks in young infants or in complicated cases. In neonatal meningitis and adult meningitis due to unusual organisms, more prolonged therapy may be indicated and each case should be reviewed in consultation with a microbiologist or infectious disease specialist.
Despite the use of appropriate, effective, bactericidal antibiotics, mortality and morbidity in bacterial meningitis remain high. In an attempt to improve response to conventional antimicrobial therapy, attention has 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 is associated with a decreased 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, use of dexamethasone remains controversial.
Meningococcal disease, which represents a spectrum of illness caused by N. meningitidis, is a worldwide problem. It occurs in epidemics across the ‘meningitis belt’ in sub-Saharan Africa every 7–10 years, and high or increased levels of endemic meningococcal disease have been reported from many other parts of the world. N. meningitidis primarily affects 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: almost two-thirds of cases occur between December and May (winter and spring) and a co-existing or antecedent viral infection may play a part in invasive meningococcal disease.
The clinical presentation can vary widely and recognizing the symptoms can mean the difference between life and death. It is still not widely appreciated that life-threatening meningococcal disease does not present primarily as meningitis! The following broad clinical groups can be recognized in patients with meningo-coccal disease according to the presenting clinical features.
Septicaemia with or without meningitis
In about 15–20 per cent of cases of meningococcal disease features of septicaemia predominate, characterized by the rapid development of a systemic illness over a period of 24–48 h. The symptoms include fever, rigors, myalgias and a widespread 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 in parts and become ecchymotic. Disseminated intravascular coagulation may soon 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 per cent in patients with septicaemic illness.
‘Classic' meningitis with or without septicaemia
This is by far the commonest presentation. The clinical picture is usually dominated by signs and symptoms of meningitis which may occur rapidly or evolve more gradually over several days. The CSF is typically cloudy with pleocytosis, raised protein and low glucose concentration. A typical petechial or purpuric rash is present in about 60 per cent of patients, but occasionally the rash may be maculopapular initially. Blood cultures are positive in about 40 per cent of cases and probably reflects secondary bacteraemia resulting from the local suppurative process within the subarachnoid space, rather than the ongoing primary bacteraemia following nasopharyngeal colonization. Mortality is 3–5 per cent.
Rarer forms of meningococcal disease
Occasionally N. meningitidis may localize in the joints or heart valves producing acute septic arthritis or endocarditis, or the septicaemic illness may become chronic and indolent, producing chronic meningococcal septicaemia, which is characterized by intermittent pyrexia, rash and arthralgias.
Occasionally diagnosis is made retrospectively because of 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
Benzylpenicillin in high (meningitic) doses is the drug of choice. Therapy should be started on first suspicion of meningococcal disease. Most strains of N. menin-gitidis are highly sensitive to penicillin (MIC <0.16 mg/l), but strains of reduced sensitivity are occasionally encountered. Patients with isolates for which the MIC of penicillin exceeds 0.32 mg/ml, or those who are allergic to penicillin, are best treated with either cefotaxime or ceftriaxone. Since N. meningitidis can no longer be assumed to be sensitive to penicillin, all isolates must be tested for susceptibility.
Before benzylpenicillin became widely available, sulphonamides (principally sulphadiazine) were used for the treatment of meningococcal meningitis. They were also used for prophylaxis, since, unlike other agents used for treatment, such as benzylpenicillin or chloramphenicol, they are effective in eradicating N. meningitidis from the throat. However, sulphonamide-resistant strains are now common and these drugs can no longer be used for treatment or prophylaxis unless it is known that the isolate is sensitive.
The standard agent now used as prophylaxis for meningococcal disease is oral rifampicin, twice daily for 2 days (adults 600 mg; children 10 mg/kg). Rifampicin-resistant strains occur, but are presently uncommon. A single intramuscular injection of ceftriaxone (adults 250 mg; children 125 mg) or a single oral dose of ciprofloxacin (adults 500 mg) are alternative prophylactic regimens. Pregnant women should be offered ceftriaxone rather than rifampicin.
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 per cent. 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
In the UK about 28 per cent of strains are ampicillin-resistant, usually, but not always, owing to the production of β-lactamase. Chloramphenicol resistance is rare in the UK, but in some parts of the world resistance to ampicillin and chloramphenicol is common.
Cefotaxime or ceftriaxone, which are active against β-lactamase-producing and non-β-lactamase-producing strains of H. influenzae are the preferred agents for treatment. In patients with a firm history of cephalosporin allergy, chloram-phenicol can be used. Rifampicin is used as prophylaxis for close contacts when there is a sibling in the house aged 4 years or younger.
As a cause of meningitis Str. pneumoniae is a threat throughout life. The mortality in children and adults is about 20 and 35 per cent respectively. The outlook is grave in those over the age of 60 years.
In contrast to meningococcal or haemophilus meningitis, there is often a pre-existing focus of infection elsewhere (e.g. pneumonia, acute otitis media, or acute sinusitis) or the presence of an associated 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, when organisms may reach the meninges via abnormal communications between the nasopharynx and the subarachnoid space. Patients who have had a splenectomy are at risk of developing overwhelming pneumococcal infection. The onset may be sudden and the course rapid with death within 12 h. Alterations of consciousness and focal neurological defects may occur and survivors often suffer significant neurological deficits.
In places where penicillin-resistant strains of Str. pneumoniae are rare, benzylpenicillin remains the drug of choice. Elsewhere, antimicrobial therapy in patients with suspected or proven pneumococcal meningitis should be commenced with cefotaxime or ceftriaxone and changed to benzylpenicillin only if the strain isolated is subsequently confirmed to be sensitive. Penicillin-resistant strains of Str. pneumoniae have been reported from many countries of the world, including the US and the UK, and penicillin sensitivity tests should now be a routine procedure on all clinical isolates. Strains of pneumococci that are resistant to expanded-spectrum cephalosporins are being increasingly reported; 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.
The neonate is at the highest risk of developing meningitis within the first 2 months of life, the incidence being about 0.3 per 1000 live births. Neonatal meningitis carries a high mortality and the incidence of neurological deficits in
those who survive is depressingly high. Brain abscess is a rare complication, but it should be considered in meningitis caused by Gram-negative bacilli, particularly Citrobacter diversus.
Predisposing factors include prematurity, low birth weight, prolonged and diffi-cult labour, prolonged rupture of membranes, and maternal perinatal infection. Some cases complicate congenital neurological defects.
The organisms responsible are varied. They are usually acquired by vertical transfer 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 per cent of cases. About 1 in 100 newborns colonized with group B streptococci develop early-onset disease; mortality is over 50 per cent. Late-onset disease usually presents as meningitis and mortality is around 20 per cent.
The early signs and symptoms of are often non-specific: lethargy, refusal of feeds, and fever. A bulging fontanelle 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 of neonatal meningitis
Neonatal meningitis is particularly difficult to treat, since a wide variety of organisms may be involved and the susceptibility of the organisms (see below) involved is unpredictable. The chosen therapy should be backed up by appropriate laboratory tests.
Group B haemolytic streptococci
These are less sensitive to penicillin and are killed more slowly than group A haemolytic streptococci. Penicillin and gentamicin act synergistically, causing accelerated killing in vitro. The treatment of choice is high dose benzylpenicillin for at least 2 weeks, together with gentamicin for the first 7–10 days.
Esch. 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 aerug-inosa. The duration of treatment should be at least 3 weeks.
This is a Gram-positive bacillus that exists as a soil saprophyte in nature. Infection is probably acquired from dairy or vegetable produce contaminated with listeria from animal sources. The organism may be carried asymptomatically in the
gastrointestinal or the female genital tract. The neonate may be infected trans-placentally in utero or from the female 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 per cent. Most cases of late-onset infection present as meningitis in a previously normal neonate.
- 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 gentamicin, which have a synergistic bactericidal effect. In adults with a history of penicillin allergy, intravenous or oral co-trimox-azole (which is bactericidal to L. monocytogenes), is the best alternative. Cephalosporins have no useful activity against L. monocytogenes.
The duration of therapy should be 3 weeks for neonates or those who are immunocompromised and at least 2 weeks in normal hosts.
A summary of current recommendations for the initial therapy of the commoner forms of bacterial meningitis is outlined in Table 27.3.
Table 27.3 Antibiotic treatment of the common types of bacterial meningitis
Rarer forms of meningitis
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.
The vast majority of Staph. aureus strains are resistant to penicillin, so the choice of antibiotics is limited; for methicillin-sensitive strains high-dose flucloxacillin (at least 12 g daily) combined with oral rifampicin (600 mg daily) is recommended. In patients who are allergic to penicillin or in meningitis due to methicillin-resistant strains, treatment is even more problematic. Parenteral vancomycin (1 g every12 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.
In patients with hydrocephalus the ventricular CSF is diverted to other compartments of the body (usually the peritoneal cavity or the right atrium) with a
silastic catheter (shunt). Unfortunately, 15–25 per cent of these patients develop meningitis at some point in the life of the shunt. Staph. epidermidis accounts for about 50 per cent and Staph. aureus for 25 per cent 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 yields an organism in over 90 per cent 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.
Most cases are treated by complete removal of the shunt system followed by appropriate antibiotics. However, patients who develop meningitis due to N. meningitidis, H. influenzae or Str. pneumoniae are treated with appropriate antibiotics, without shunt removal.
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.
In addition to group B streptococci, other streptococci may cause meningitis following head injury, neurosurgical procedures, or rupture of cerebral abscess. High-dose benzylpenicillin is the drug of choice. Metronidazole should be added if meningitis is secondary to rupture of an intracranial abscess because of the possibility of a mixed anaerobic and aerobic infection.
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 per cent 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 sub-acute meningitis or meningo-encephalitis.
Fluconazole (200–400 mg daily) is the agent of choice, since it is relatively non-toxic, penetrates well into CSF, and is well absorbed by the oral route. In the few patients unresponsive to fluconazole, amphotericin B (0.6–1.0 mg/kg daily up to a total dose of 2–3 g) is used. Addition of the less toxic flucytosine (150 mg/kg daily) allows a lower dose of amphotericin B (0.3 mg/kg daily) to be used, with less risk of nephrotoxicity. Moreover, the combination sterilizes CSF more rapidly, and is associated with fewer failures and relapses. The duration
of treatment is usually 6 weeks. Flucytosine should not be used alone, since resistance may emerge during therapy.
In about 50 per cent of AIDS patients treated with fluconazole, relapse occurs and primary therapy with amphotericin B and flucytosine is recommended before the commencement of long-term maintenance therapy with fluconazole. Flucytosine is often associated with bone marrow suppression in patients with AIDS and in these patients a lower dose (75–100 mg/kg daily) is given over a shorter period (2–4 weeks); frequent monitoring of serum levels is recommended.
Tuberculous meningitis can affect any age after the neonatal period. It is uncommon in developed countries, but cases can be missed unless the physician is aware of the possibility and the laboratory is keen 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 26.
Culture-negative pyogenic meningitis
About 40 per cent 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 per cent 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; cefotaxime (or ceftriaxone) for 7–10 days is a reasonable choice, unless there is an obvious meningococcal rash, when benzylpenicillin would be more appropriate.
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 para-meningeal infections.
Brain abscess is a localized collection of pus within the brain parenchyma. It is a life-threatening condition which used to carry a mortality of 40 per cent. This has been reduced to less than 10 per cent by the introduction of computed tomography (CT) and magnetic resonance imaging (MRI), leading to earlier diagnosis and more precise localization; by improvements in surgical and bacteriological
techniques; and by the use of appropriate antibiotics. About 4–10 cases a year are seen in neurological units of developed countries. Brain abscess in children accounts for less than 25 per cent of all cases and, except in neonates, it is rare in those under 2 years of age.
Brain abscesses develop most commonly by spread of infection from an adjacent area (e.g. paranasal sinuses, middle ear, mastoid, or dental site), 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 cause multiple abscess formation. In about 20 per cent of cases the primary focus of infection remains unrecognized—so-called cryptogenic abscess. However, as imaging techniques become more widely available, there may be further reduction in the prevalence of cryptogenic abscess.
The organisms isolated usually reflect those found in the primary focus of infection. With proper attention to technique, the role of anaerobes and polymi-crobial 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 which 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.
Lumbar puncture is unhelpful in diagnosis and may be hazardous, but blood cultures may be positive and should be taken.
Although some patients with early cerebritis, or small, deep, or multiple abscesses have been treated successfully with antimicrobial therapy alone, most require surgical drainage after burr-hole placement or complete surgical excision after craniotomy. CT-guided stereotaxic aspiration allows more accurate drainage with minimal interference to the surrounding normal brain.
Pus obtained after any of these procedures should be sent to the laboratory immediately for urgent 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 even after oral administration.
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 cefotaxime 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.
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.