severe community-acquired meningitis

Severe community-acquired meningitisChristophe Boisson, Sophie Arnaud, Renaud Vialet and Claude Martin

Review R55

Addresses: Department of Anesthesia and Intensive Care, andTrauma Center, Marseilles University Hospital System, MarseillesSchool of Medicine, Marseilles, France

Correspondence: Intensive Care Unit and Trauma Center, HôpitalNord, Marseilles University Hospital System, Marseilles School ofMedicine, Marseilles, France

Received: 6 July 1999Accepted: 13 July 1999Published: 6 August 1999

Crit Care 1999, 3:R55–R65

The original version of this paper is the electronic version which canbe seen on the Internet (http://ccforum.com). The electronic versionmay contain additional information to that appearing in the paperversion.

© Current Science Ltd ISSN 1364-8535

IntroductionCommunity-acquired meningitis is associated with highmorbidity and mortality. The epidemiology of community-acquired meningitis has changed over the past 15 yearswith the use of new vaccines and with the development ofresistance to antibiotics. Bacterial meningitis would appearto be the most frequent by far, but most viral aetiologiesare very often poorly recognized. The annual incidence ofpurulent community-acquired meningitis in France wasestimated at 22 cases per million inhabitants in 1993. Ageis a major risk factor in bacterial meningitis. The mostaffected group is children under 2 years of age, in whomthe infection rate ranges from 10 to 110 cases per 100000infants per year. Such cases must be considered as anabsolute medical emergency. This review is limited tomeningitis in immunocompetent patients.

Bacterial epidemiologyFrom birth until the first month of life, Streptococcusagalactiae, Listeria monocytogenes and Enterobacteriaceae(especially Escherichia coli) are the main pathogens. From2months until 4years of age, meningitis is principally dueto Haemophilus influenzae type B (the incidence of which isdramatically decreasing because of widespread vaccina-tion), Neisseria meningitidis and Streptococcus pneumoniae. Inchildren, teenagers and young adults, N. meningitidis andS. pneumoniae represent more than 80% of the cases.Above the age of 60 years, S. pneumoniae and H. influenzaeare the most frequently isolated bacteria [1,2].

When all of these bacteria are taken together, the ele-ments that indicate a poor prognosis are as follows: age

less than 1month or greater than 45years; worsening levelof consciousness on admission; and forms with purpurafulminans [3–6]. In the absence of a specific treatment,purulent meningitis is ultimately fatal.

Pneumococcal meningitisPneumococcal meningitis is the most frequent cause ofbacterial meningitis in those older than 30 years, and wasresponsible for 20% of cases of purulent communitymeningitis in children and 60% of adult cases in France in1993. It is also more severe in terms of mortality (15–30%)and morbidity (deafness).

The increasing resistance of S. pneumoniae to penicillin (inmore than 10% of isolates) has created a problem fortherapy, which at present cannot be completely optimizedand requires a knowledge of the sensitivity phenotype ofthe bacteria in question. Penicillin-resistant pneumococci(PRP) include pneumococci with an intermediate sensi-tivity [minimum inhibitory concentration (MIC) ofbetween 0.12 and 1mg/l] and highly resistant pneumo-cocci (MIC >1mg/l).

Resistance to β-lactams is related to modifications of thegenes coding for penicillin-linked proteins (PLPs), whichare the active sites for all β-lactams, especially PLP2b andPLP2x [7]. Such genomic change is due either to agenetic transfer or to on-off mutations. The mainserotypes involved in the resistance to β-lactams are 6A,6B, 14, 19A, 19F and 23F, and 99% of the serotypes arepresent in antipneumococcal vaccine of 23 valences. Thisevolution in resistance should lead to a renewed interestin antipneumococcal vaccination.

Resistance to β-lactam antibiotics in pneumococci has beenincreasing in a disturbing manner, especially in Europe.The first strains resistant to penicillin were described inBoston in 1964 and in Chicago in 1974, and the first case ofpneumococcal meningitis resistant to ceftriaxone wasreported in 1991. The progression of resistance has beenconstant in the USA; from 1979 to 1987 the rate of resis-tance was below 10%, but since 1987 there has been anincrease of up to 30% in PRP. In Europe, Spain has a rate ofalmost 60% of PRP, followed by Bavaria with 50% resis-tance, but the rate is lower for the rest of Germany. Franceis next with 36% in children and 25% in adults in 1994. Themagnitude of resistance was high in half of the cases.

Among the cephalosporins, cefaclor, cefuroxime andcefixime are no longer active on strains resistant to

PRP = penicillin-resistant pneumococci; MIC = minimum inhibitory concentration; PLP = penicillin-linked proteins; CSF = cerebrospinal fluid;TNF = tumour necrosis factor; IL = interleukin; CT = computed tomography.

penicillin, and a direct relationship has even been notedbetween cefaclor and penicillin resistance. Of PRP strains10% are cross-resistant to macrolides: erythromycin, aswell as clarithromycin and azithromycin.

In children, the risk factors for acquiring infection withresistant S. pneumoniae are hospitalization, living in closedpopulations, β-lactam treatment in the preceding monthsand recurring otitis media. In adults the risk factors areimmunodeficiency, nosocomial infections and β-lactamtreatment in the preceding months. Limiting the spread ofS. pneumoniae resistance to antibiotics therefore dependson the following: more rational utilization of antibioticsand perhaps reduction of the systematic prophylaxis ofacute otitis media in children with recurrent otitis; evalua-tion of the optimal duration of antibiotic therapy; evalua-tion of posologies and the intake required in order to avoidlong periods with serum levels nearly at subinhibition con-centrations and favouring the selection of resistantmutants; alternating different classes of antibiotics; anddevelopment of the antipneumococcal vaccine.

Meningococcal meningitisMeningococcal meningitis occurs in endemics, with casesthat are usually sporadic causing minor endemia that arelimited in time and space, particularly in closed popula-tions of children and young adults. There is a distinct pre-ponderance of group B (60%) over group C (30%)organisms. The mean mortality rate of 10% is principallylinked to the occurrence of purpura fulminans [8].

Haemophilus influenzae meningitisWidespread vaccination is currently disrupting the epidemi-ology of H. influenzae meningitis, which is caused by type Bstrains. Approximately 50% produce β-lactamases, makingthem resistant to amino-penicillins. Despite this increase inresistance, the mortality rate has gone from 10 to 3%.

PhysiopathologyThe bacteria responsible for purulent meningitis are ofthe extracellular multiplication type, and have propertiesthat make them resistant to nonspecific defence factorsand allow them to develop in the host tissues. They alsohave specific properties that enable them to invade themeninges and cause inflammation [9,10].

Bacterial penetration in the cerebrospinal fluidThere are various arguments that support the hypothesis ofpenetration of bacteria into the cerebrospinal fluid (CSF)by the haematogenous route, with secondary penetrationthrough the haematomeningeal barrier. In the case ofexperimental infection with H. influenzae, rhinopharyngealadministration of bacteria is followed by bacteremia andthen invasion of the CSF. Similarly, intraperitoneal injec-tion of N. meningitidis in newborn rats or intravenously inmacaques causes secondary colonization of the CSF [11].

The haematomeningeal barrier is only one of the ele-ments of the haematoencephalic barrier, and pathogenicbacteria are hypothesized to invade the CSF via the bloodby two different routes: direct penetration of themeningeal capillary endothelium; or by direct penetrationat the level of the choroid plexus, which produces CSF bysecretion. The latter of these would appear to be the mostplausible hypothesis following postmortem and experi-mental observations of major and selective concentrationsof bacteria in the choroid plexus capillaries.

Inflammatory mechanisms of the subarachnoid spaceOnce the bacterium has invaded the CSF, little canprevent it from multiplying because there is almost nocomplement fractions and the immunoglobulin concentra-tion is very low. On the other hand, poor nutrition slowsbacterial multiplication.

In order to understand the cascade of events that occurs assoon as the bacterium has invaded the CSF, experimentalmeningitis models have been designed by direct injectionof bacteria into rabbit and rat cisterna magna, making itpossible to short-circuit the haematomeningeal barrier.

In-situ production of cytokinesThe most important event that follows bacterial penetra-tion into the CSF is the production of cytokines [12]. Inanimal experiments, intracisternal injection of lipopolysac-charide triggers production of tumour necrosis factor(TNF)-α, interleukin (IL)-1 and IL-6, preceding theappearance of inflammatory exudate, which can be par-tially prevented by the injection of anti-TNF-α and/oranti-IL-1 antibodies. Injection of TNF-α and IL-1 intothe cisterna magna is followed by an elevation in theprotein concentration in the CSF, an afflux of polynuclearcells and an increase in the weight of the brain, reflectingoedema. It would therefore follow that the production ofcytokines in the CSF is a prerequisite to episodes ofmeningitis. This production occurs in situ, is independentof all systemic cytokine production because the moleculescannot penetrate the haematomeningeal barrier and there-fore comes from the macrophage cells within themeninges itself [13,14].

Polynuclear affluxCytokine release allows for recruitment of polynuclearcells in the CSF by an adhesion phenomenon between theneutrophils and the endothelial cells. In fact, TNF-α andIL-1 induce the expression of adhesion molecules at thesurface of the endothelium that favours loose adhesion ofpolynuclear cells and their rolling on the endothelialsurface. Under the influence of IL-1, the endothelial cellproduces IL-8, which leads to the detachment of thepolynuclear L-selectin and interrupts polynuclear rollingbecause of the increase in integrin activity. These phe-nomena provide for even tighter adhesion between the

R56 Critical Care 1999, Vol 3 No 4

polynuclear cells and the endothelium, leading to polynu-clear extravasation in the infected tissue [15,16].

Alteration of the haematomeningeal barrierThe other consequence of cytokine production is a reduc-tion in the tightness of the hematomeningeal barrier,which is essentially related to local production of IL-1 andsynergistically assisted by TNF-α, creating a loosening ofthe tight cerebral capillary junctions.

Consequences of bacterial meningitisAll of the events that occur during an episode of bacterialmeningitis are the result of polynuclear afflux and alter-ation of the haematomeningeal barrier. The result is amixed cerebral oedema (ie both interstitial, because it islinked to the resorption of CSF at the level of the arach-noid villi, and vasogenic, because it is linked to an increasein the permeability of the haematomeningeal barrier). Inaddition, this major meningeal inflammation can lead tomajor vascular alterations of the meningeal vessels, asoccurs in vasculitis, facilitating microthromboses and par-ticipating in profound alterations in cerebral blood flowand anoxia [17].

MeningococcusN. meningitidis is a Gram-negative, oxidase-positive aerobicdiplococcus that has a polysaccharide capsule. It is a sapro-phyte, and colonizes most humans at some point in theirlives without producing any particular symptoms. Thedevelopment of disease after exposure to meningococci isthe result of a poorly known mechanism of host factorsthat have an influence on bacterial invasion of mucosalsurfaces. Among the elements that influence hostresponse, genetic control of the response to the acutestage and cytokine secretion (TNF-α, IL-1, IL-6) is ofimportance in making the prognosis. Moreover, a defi-ciency in complement predisposes the patient to ameningococcus infection with unusual serogroups (X, Y,Z, W135, 29E) [18,19].

Listeria monocytogenesL. monocytogenes is an occasional intracellular Gram-posi-tive bacteria that is capable of multiplying in themacrophages and in most of the cells of the infected hosttissue. From the sites of intracellular multiplication, L.monocytogenes can spread through the blood and reachnumerous target organs, particularly the placenta and thecentral nervous system. The bacterium first enters viadirect contact with the host cells through an 80kDaprotein called internalin, coded by chromosomal geneInlA. Internalin is a protein located at the surface of thebacterium and has a structural organization that is charac-teristic of numerous Gram-positive bacteria proteins (suchas Streptococcus and Staphylococcus spp.). Internalin interactswith receptors of unknown nature (probably integrins)located at the surface of the infected cells. After penetrat-

ing the cells, the bacteria are capable of escaping thephagosomes and of multiplying in the cytoplasm. In theinfected host, orally ingested bacteria go through theintestine via Peyer’s patches and reach the lymphatic gan-glions and the blood circulation. The principal targetorgan is the liver, where the bacteria multiply inside thehepatocytes. Hepatocyte lysis induced by the earlyrecruitment of polynuclear cells triggers a liberation ofintercellular bacteria and results in prolonged bacteraemia.At this stage, the disease is often managed well byimmunocompetent patients, who may contract an infec-tion that is often totally asymptomatic. This is probablythe most frequent scenario if the frequency of exposure toL. monocytogenes is low. However, if the inoculum ismassive, in a pregnant woman, or in patients who areimmunocompromised (patients with acquired immunode-ficiency syndrome, patients with neutropenia or who areundergoing chemotherapy) or who present with hepaticanomalies (cirrhosis, hemochromatosis), infection of thehepatocytes is not controlled and the bacteria are releasedinto the bloodstream. Metastatic localizations are possibleat this stage, particularly in the placenta or the centralnervous system [20].

Therapeutic implicationsBacterial meningitis is an infection of a defined space inwhich the host is compromised because of the absence ofcomplement fractions and the low levels of specific anti-bodies. For this reason phagocytosis is ineffective and bac-terial multiplication is rapid. Optimal antibiotic treatmentrequires that the selected antibiotic has a bactericidaleffect in the CSF.

Passage of antibiotics into the cerebrospinal fluidAntibiotics that strongly bind to proteins and those with ahigh molecular weight diffuse poorly into the cerebralparenchyma and the CSF. Meningeal inflammation par-tially improves this situation by modifying the permeabil-ity of the haematomeningeal barrier (increase in vesiculartransport, and separation of the tight junctions betweenthe endothelial cells and the meningeal vessels) [21].

Antibacterial synergy in cerebrospinal fluid in vivoIn a model of L. meningitis infection, an ampicillin–gentam-icin combination (in vitro synergy) turned out to be morerapidly bactericidal than either when used alone [22].

Antibiotic concentration in the cerebrospinal fluidSpinal concentrations of antibiotics that are equal to theminimal bacteriostatic concentration of a bacteriostaticdrug or to the MIC of a bactericidal drug should be effec-tive. This was not the case in an E. coli meningitis model,however, in which concentrations greater than 10 timesthe MIC were required to obtain the maximum elimina-tion rate for CSF bacteria. The need to obtain spinal con-centrations superior to 10 times the MIC has also been

Review Severe community-acquired meningitis Boisson et al R57

demonstrated with other bacteria and other antibiotics [9].One explanation could be that infected CSF reducesantibiotic activity. For example, the low pH of infectedCSF (between 6.7 and 7.1) reduces the activity of amino-glycosides and the increase in protein concentrationdecreases the concentration of the active drug, particularlythat of the strongly bound β-lactamase (cephalosporins).This implies the use of high doses of antibiotics, espe-cially when the MIC is elevated.

ImmunotherapyBecause of the excessive inflammation of the meningealspaces and its experimental aggravation by bacterial lysiscaused by the antibiotics, it can be useful to modify thevarious players in this immunoinflammatory cascade byattempting to inhibit the polynuclear interactions with thehaematomeningeal barrier. Inflammation, however, playsa positive role in the penetration of certain antibiotics atthe infection site. The use of methylprednisolone reducesthe spinal penetration of ampicillin and gentamicin byapproximately half.

DiagnosisClinical diagnosisThe infectious syndrome is always present. It has a brutalaspect with a high fever (>38.5°C), shivers and myalgia,sometimes accompanied by the following: pneumopathy(in cases of pneumococcus infection), purpura and septicshock. At times, it is subtle and is unfortunately diagnosedas an ear–nose–throat infection, which are often degener-ated by antibiotic therapy.

The meningeal syndrome is quasi constant. Cephalalgia isdiffuse, intense and continuous, and can radiate towardsthe nape of the neck and the back. It is increased by light,noise and coughing. Vomiting is frequent.Meningeal stiff-ness corresponds to the extension of the neck musclesduring massive flexion of the head. It is responsible forthe coiled position. It can sometimes be subtle, especiallyin an early stage or in elderly patients or in cases of coma.It can be evaluated by means of certain manoeuvres.Kernig’s sign is a symptom of meningitis that is demon-strated when patients cannot keep their legs extendedwhile sitting on a bed. In the prone position, the patientcannot raise and extend his arms because flexing occurs ata certain height. Brudzinski’s sign is a spontaneous flexionof the thighs and legs during flexion provoked by the head(when the neck is flexed from a supine position). Themeningeal syndrome can also include signs of cutaneoushyperesthesia or pyramidal irritation such as in osteoten-don hyperreflexia.

Signs of encephalitis are erratic but must be considered ashaving a poor clinical outcome; they include change inmental status that ranges from mental confusion to coma.They may also include local or generalized convulsions.

The factors that should raise suspicion of certain aetiologicdiagnoses are listed Table 1.

Biological diagnosisLumbar punctureWhen the clinical examination only reveals meningeal andinfectious signs (60–70% of cases) lumbar puncture is thefirst examination to perform [23]. If, on the other hand,onset is progressive and there appears to be signs of defi-ciency without change in mental status, followed by signsof intracranial hypertension, a cerebral computed tomogra-phy (CT) scan must be urgently performed in order toexclude the presence of an expansion process. Fundus-copic examination is completely useless.

In cases of comatose meningitis, the relationship betweenlumbar puncture and herniation is, in any case, very debat-able. Such an important examination should therefore notbe put off.

Macroscopically, the CSF has an elevated opening pres-sure, is cloudy (rice water) or purulent, confirming puru-lent meningitis and the need for subsequent antibiotictherapy (Fig. 1). Cytochemically, the CSF containsnumerous polynuclear neutrophils (≥1000/mm3); proteinconcentration is high (≥1g/l); and the CSF glucose con-centration is low or even collapsed but, in any case, is lessthan 70% of the blood glucose concentration (ie theCSF:blood glucose concentration ratio is <0.3).

Particular forms can be encountered. The CSF can haveminimal cytochemical modifications but be swarming withbacteria in cases of fulminant meningococcus meningitis,necessitating Gram’s staining in all cases with purpura,whatever the cytological results of the CSF. Moreover, an


Table 1

Aetiologic diagnoses and suggestive features

Aetiology Suggestive features and comments

Streptococcus Severe alcoholism, hypogammaglobulinemia,pneumoniae neutropenia, drepanocytic anemia, splenectomy,

polynuclear function deficiency, suppressiveimmunological therapy, acquired duramatralbreach

Neisseria Complement deficiency must be suspected.meningitidis However, there are no real risk groups.

Classically, epidemics occur in closedpopulations of young adults.

Listeria Extremes of age, pregnancy, hepatic cirrhosis, monocytogenes haemochromatosis, chronic renal failure, cellular

immunodeficiency (Hodgkin’s and non-Hodgkin’s lymphoma, chronic lymphoid leukaemia, corticotherapy, organ transplantation)

intense cellular reaction without micro-organisms ondirect examination is possible, with bacteriologic confir-mation by culture of CSF.

Lymphocytosis is possible if lumbar puncture is per-formed very early, but this condition above all indicatesListeria meningoencephalitis [24,25].

Blood culturesBlood cultures provide an indispensable diagnostic com-plement. Nonspecific examination results such as polynu-cleosis and elevated C-reactive protein may be suggestiveof a bacterial aetiology.

BacteriologyGram’s staining will provide an aetiologic diagnosis in60–90% of the cases of bacteriologic meningitis. The per-centage of positive direct examinations is highest forS. pneumoniae and H. influenzae, is lower for N. meningitidis,and is especially low for L. monocytogenes. Culturing is sys-tematic and allows for isolation and identification of thecausative bacteria. An antibiogram may be directly per-formed with the CSF if it is sufficiently rich in bacteria.The results obtained after 18–24h must always be con-firmed by classic study performed after the culture. Incases of pneumococcus infection, resistance to β-lacta-mases is sought by means of an oxacillin disk. Detection iscompleted by parallel determination of the MIC, per-formed either using classic dilution methods or using E-test with penicillin G and the β-lactams habitually usedfor the treatment of pneumococcus meningitis.

In patients with H. influenzae infection it is essential tolook for β-lactamase production. Some strains of N. menin-gitidis with reduced sensitivity to penicillin G have beenobserved in France and Spain, but without therapeuticconsequences (at the time of writing).

The interest of soluble antigen exploration has beensubject to diverse evaluations. Performed using a particleagglutination of latex sensitivity technique, it can rein-force a diagnosis when the Gram’s staining is question-able, but is of little use when the Gram’s staining isnegative [23]. Polymerase chain reaction can be a bettermeans to detect bacteria in the CSF. Intraspinal lactateconcentration alone does not have sufficient diagnosticvalue [26].

During the initial work-up, the diagnosis of bacterialmeningitis is confirmed if the bacteriologic examinationsare positive. In the case of negative results on direct exam-ination, the medical probabilities should be determined inorder to differentiate the bacterial or viral nature of anepisode of meningitis. This can be achieved by using validdecision models that take several cytological and biochem-ical parameters of the CSF into account, in addition to the

clinical data. Subsequent biological examinations are dic-tated by the clinical evolution and the initial bacterialdata. A possible second lumbar puncture is performed36–48h after treatment, enabling the clinician to judge thetherapeutic efficacy of CSF sterilization, as well as the risein glycorrhachia. The other cytological and biochemicalparameters of the CSF are of no diagnostic or prognosticvalue. In cases of therapeutic failure, an antibiotic may beadministered in the CSF.

Radiological examinationsThe indications for scanning or imaging should be verylimited when a patient with purulent meningitis is admit-ted. Performing a CT scan before the lumbar punctureexposes the patient to the risks of delaying an antibiotictherapy that has reliable results. Lumbar puncture musttherefore precede a CT scan, even in cases of coma. Thisdiagnostic approach should only be changed if there arelocalized neurological signs that suggest another diagnosisor if there is a risk of an intracranial complication, possiblymaking lumbar puncture dangerous. Haemocultures andantibiotic therapy must therefore be immediately under-taken before imaging results are obtained (Fig. 1). In an


Figure 1

Management algorithm in case of suspicion of bacterial meningitis.

Directedantibiotherapy

Suspicion of bacterial meningitisLocalized neurological deficit

Absent Present

Blood culturesBlood cultures

Lumbar puncture

Empiric antibiotic therapyPositive Gram staining

orpositive antigen test

NoYesCerebral computedtomography scan:

No lesion: lumbar punctureLesion: abscess, empyema

Empiricantibiotherapy

emergency situation, cerebral CT scan enables the clini-cian to resolve most diagnostic problems. Magnetic reso-nance imaging is more accurate than CT, but it is lessoften available and does not provide decisive supplemen-tary information.

Once antibiotic therapy has been started, the diagnosis ofintracranial complications will depend on imaging. Cere-bral CT scan is adequate for most intracranial complica-tions (hydrocephalus, abscess, empyema, cerebral infarct,haemorrhage, ventriculitis). However, in cases of cerebralthrombophlebitis CT scanning does not reveal direct signsand an angiography is required. Magnetic resonanceimaging is the examination of choice when it is availableand will provide a diagnosis of all intracranial complica-tions with sensitivity and specificity that are superior tothose of CT scanning, particularly for the diagnosis ofcerebral thrombophlebitis. In infants, transfontanel ultra-sonography is easy to perform and enables the clinician todetect abscess, ventriculitis and hydrocephalus.

A search for a portal of entry is especially justified inpneumococcal meningitis. Portals of entry are oftenear–nose–throat-related in cases of both acute and chronicpathology. Imaging relies on CT scanning, which hasbetter bone definition than MRI. It is not indicated forclinically diagnosed acute otitis. On the other hand, it isjustified when mastoiditis or an unsatisfactory evolution ofmeningitis is suspected.

Imaging is indispensable for the preoperative work-up ofall chronic pathologies and for the diagnosis of most casesof acute sinusitis.

The existence of an osteodural breach must be consideredin cases of post-traumatic pneumococcal meningitis andrecurring meningitis. In rare cases, the breach can be acongenital ear and petrosa malformation that is clearlyrevealed by CT scan, or an anterior meningoencephalo-cele or lumbosacral dermic sinus, which are betterexplored using magnetic resonance imaging. More often,the breach is secondary to a recent or old head trauma orto surgery at the base of the skull. At the level of the ear,exploration for a breach must be performed by CT scan-ning in frontal and axial millimeter sections. For the ante-rior floor, the CT scan should be used to investigate for alack of continuity, essentially at the level of the laminacribrosa and the roof of the ethmoid bone. CT scanning isthe technique of choice because it best examines thesmall bone dehiscences. Isotropic transit of the CSF is nolonger an indication [23].

Differential diagnosisAtypical cerebrospinal fluidIt can be difficult to differentiate between bacterial menin-gitis “beheaded” by an antibiotic treatment and viral

meningitis which is diagnosed early due to the context,briefness of the signs and normal glycorrhachia, reinforcedby the disappearance of polynucleosis and the appearanceof lymphocytosis in the CSF sampled 24–48h later.

In the absence of bacterial meningitis, the presence oreven the predominance of polynuclear cells in the CSFcan be encountered in several situations: bacterial patholo-gies suppurated from the brain or parameningeal spaces(subdural empyema, brain abscess), fungal infections(cryptococcosis, candidiasis, histoplasmosis, coccid-ioidomycosis), rare cases of amoebic meningitis, neoplasticmeningitis, chemical meningitis (co-trimoxazole, nons-teroidal anti-inflammatory drugs, azathioprine), systemicrecurrent aseptic puriform meningitis, disseminated lupuserythematosus, sarcoidosis, Behçet’s disease. Rupture ofan epidermoid cyst in the arachnoidea space and Mol-laret’s benign recurrent pleocytic meningitis are very rareand their diagnosis is favoured by recurrence with asudden onset, rapidly favourable evolution and the poly-morphic character of the CSF.

Acute clear cerebrospinal fluid meningitisAcute clear CSF meningitis is benign in most cases. It isdue to a great number of viruses and evolves sponta-neously towards resolution. Measles and German measlesare in very distinct decline due to systematic vaccination.

The major problem is the possibility of a herpetic aetiologyleading to emergency empiric treatment with acyclovir.The other emergency diagnostic hypothesis is Listeria neu-romeningeal infection, which also requires emergencyempiric antibiotic treatment. The possibility of a tubercu-lous infection should not be ignored, but therapy is oftenless urgent. The various diagnostic hypotheses are oftenformulated from the epidemiological data gathered fromthe context, because the microbiological results oftenarrive too late for emergency treatment [9].

Herpetic meningoencephalitisHerpetic meningitis is usually due to herpes simplex virusI. In 30% of the cases, the encephalitis is primary, but in70% it is preceded by a past history of benign herpes.Such pathology represents direct viral aggression locatedat the frontal and temporal level and leading to necrosis ofthe affected tissue. The clinical picture is not very spe-cific, but the patient will present with increasingly severemental confusion, convulsions, cranial nerve impairmentand olfactory hallucinations. However, because thesesymptoms will appear too late for effective treatment, her-petic aetiology must be presumed for encephalitis. Ifuntreated, death occurs in 60–80% of the cases with verysevere neurological sequelae in the surviving patients.

Biological diagnosis is difficult to perform: the CSF islymphocytic and serum antibodies are of little use for an


emergency diagnosis because antibody intrathecal secre-tion (estimated by comparing its level with serum level) isspecific but inconsistently detected. The electroen-cephalograph is more reliable with pseudo-periodic rhyth-micity in the frontotemporal regions. However, thisassessment is often delayed in comparison with therapy, theneed for which is urgent; its absence must not delay antivi-ral treatment. The same is true for the cerebral CT scanwith iodine injection. The images are typically hypodensezones with peripheral contrast in the temporal and frontalregions. Such images are often bilateral and symmetrical.

The currently accepted treatment for herpetic encephali-tis has considerably improved outcome: acyclovir,10mg/kg every 8h by intravenous infusions of approxi-mately 1h. The duration of treatment is classically 10days,but there have been reports in the literature of rarerelapses due to a short duration of therapy, and conse-quently 3weeks of treatment are often recommended.

Listeria meningoencephalitisListeria meningoencephalitis is certainly the most fre-quently encountered at present. The clinical signs are notvery specific. It is, however, possible to stress the frequentassociation of a straightforward meningeal syndrome andimpairment of one or several cranial nerves. Diagnosis isconfirmed by isolation of the bacterium in blood culturesand/or CSF culture. Given the small size of this Gram-positive bacillus and the low inoculum, direct examinationof the CSF is very often negative. The cytorachia is typi-cally mixed with polynuclear cells and lymphocytes, but apredominantly lymphocytic composition is observed justas fequently. Cerebral CT scan will reveal diverse featuresranging from simple oedema to necrosis. On the otherhand, a temporal lesion location is suggestive. Encephali-tis is diffuse when there are intracerebral abscesses pre-dominantly located in the rhombencephalon with multipleand necrotic abscesses. More rarely, there can be pureencephalitic forms without meningitis, which must betreated as an emergency (see the section on antibiotictherapy for L. monocytogenes, below).

Such impairment of the central nervous system is singular.Although it is frequently observed with a virus, it is rarelyencountered with pathogenic bacteria, except Mycobac-terium tuberculosis meningoencephalitis and rare neu-romeningeal infections with Nocardia asteroides, or Brucellaor Leptospira spp. Certain parasites such as Toxoplasmgondii are also capable of triggering very severe encephali-tis, especially in acquired immunodeficiency patients.

Tuberculous meningoencephalitisNeurological locations account for 0.5% of the cases oftuberculosis. It should nevertheless be considered whenthe predisposing factors suggest it (disadvantaged socialbackground, recent immigrant, tuberculosis in family

circle) or when neurological impairment is not sensitive toantibiotic or antiviral therapies. Diagnosis is difficult: theCSF reveals a mixed composition (but could be lympho-cytic), hypoglycorrhachia and hypochlorurorachia (but canbe normal), hyperproteinorachia (which only expressesthe chronic inflammatory aspect); the growth of M. tuber-culosis (Koch’s bacillus) is slow and cannot support a rapiddiagnosis; and direct examination of the CSF by Ziehlstaining is exceptionally positive. There is hope with thedetection of bacterial antigens in the CSF (using a geneamplification technique, polymerase chain reaction), butthis is still in the research stage and is not routine. Cere-bral imaging is only useful in cases with localized lesions:abscess or evolved tuberculoma, or granulomas that aredifficult to detect. Apart from these cases, the images areless specific and show inflammation: oedema or inflam-matory filling of the cisterna. More often than not, theclinician is therefore reduced to prescribing a presump-tive therapy following a series of arguments, which caneasily lead to therapeutic failure.

Evolution and prognosisIn the review by Durand et al [3] of 493 cases of bacterialmeningitis in adults the mortality rate was 25%, and in arecent study of Gram-negative meningitis 61% of the chil-dren had neurological sequelae [27]. Predisposing factorsand signs of severity for meningitis caused by several aeti-ologic agents are outlined in Table 2.

Pneumococcal meningitisPrognosis depends on the severity of both encephaliticimpairment and associated systemic signs. Mortality is high(16–33%) with otoneurological sequelae (17–29%) [10].


Table 2

Predisposing factors and signs of severity

Aetiologic agent Predisposing factors

Streptococcus Previous history of head injury, surgery at the pneumoniae base of the skull, meningitis, rhinorrhea, sudden

onset, neurological signs, otitis, sinusitis or associated pneumopathy, asplenia, human immunodeficiency virus infection

Neisseria Possible epidemic, purpurameningitidis

Listeria Immunodepression, signs of monocytogenes rhomboencephalitis, cloudy cerebrospinal fluid

with mixed composition

Haemophilus Age <5 years, absence of vaccination. influenzae

Principal signs Purpura fulminans, deep coma (Glasgow coma of severity score <8), cardiorespiratory failure

Meningococcal meningitisIn such cases severity is indicated by the infectious signsof purpura fulminans (6–13% of meningococcal infections,of which there is a 50% mortality) than to neurologicalsigns, which have a low mortality rate (3–10%) and raresequelae (6–10%) including deafness, impairment ofanother cranial nerve, hydrocephalus and epilepsy.

Listeria meningitisThe prognosis is poor, with 33% mortality and 33% sequelaeincluding upper function, tonic and deglutination disorders.

TreatmentAntibiotic therapyThere is no justification for delaying antibiotic therapy(Tables 3 and 4), because early treatment is associated withbetter outcome in cases of meningococcal and pneumococ-cal meningitis. Treatment must therefore be started imme-diately after the lumbar puncture and the initial bloodculture, and sometimes before if the CSF examination hasbeen deferred (patient far from a hospital, decision toperform a CT scan) and/or if the symptoms appear to be

fulminant (fever at 40°C, meningeal syndrome and worsen-ing level of consciousness in <24h or purpura; Fig. 1) [23].

Neisseria meningitidisN. meningitidis is sensitive to penicillins and third-genera-tion cephalosporins. Amoxicillin (200mg/kg per day),cefotaxime (200mg/kg per day), or ceftriaxone(70–100mg/kg per day) can be used for 7–10 days [28].

Listeria monocytogenesThe reference treatment for L. monocytogenes is amoxicillin(200mg/kg per day) plus gentamicin (6mg/kg per day),which, despite the weak meningeal diffusion of thesecompounds, is justified because of their in-vitro synergis-tic effect and the frequency of initial bacteraemic forms.Another excellent possibility, supported by its diffusioninto the CSF, is co-trimoxazole: 960mg every 12h intra-venously for 2–3weeks [29].

Haemophilus influenzaeH. influenzae meningitis is treated by cefotaxime(200mg/kg per day) or ceftriaxone (70–100mg/kg per day).


Table 3

Initial treatment of purulent meningitis with negative direct examination, absence of predisposing factors and signs of severity [1]

Antibiotic Posology (mg/kg per day) Administration route

Child > 3 months Cefotaxime 200–300 Four infusionsor ceftriaxone 70–100* One or two intravenous injections

Adult Amoxicillin 200 Four to six infusionsor cefotaxime 200–300 Four infusionsor ceftriaxone 70–100 One or two intravenous injections

*Maximum 4 g/day

Table 4

Initial treatment of purulent meningitis with negative direct examination, according to predisposing factors and/or signs ofseverity [1]

Patient Suspected organisms Treatment (posology)

Child Neisseria meningitidis Amoxicillin or 3-GC

Streptococcus pneumoniae 3-GC + vancomycin

Haemophilus influenzae 40–60 mg/kg per day. Four infusions > 1 h or continuous infusion(load: 15 mg/kg) 3-GC

Adult Streptococcus pneumoniae Preference 3-GC

If suspicion of penicillin-resistant 3-GC + vancomycin 40–60 mg/kg per day. Four infusions > 1 h or pneumococci and/or signs of severity continuous infusion (load: 15 mg/kg)

Listeria monocytogenes Amoxicillin is indispensable in association with gentamicin or cotrimoxazole

Neisseria meningitidis Amoxicillin or 3-GC

Child and adult Absence of predisposing factors Amoxicillin + 3-GCand signs of severity

3-GC, cefotaxime or ceftriaxone (see Table 1 for posologies).

Streptococcus pneumoniaeAntibiotic therapy for S. pneumoniae is confronted with twodifficulties: the virulence of the micro-organism andincreasing resistance to the antibiotics usually prescribedfor purulent community-acquired meningitis. The majorantibiotics that have the best in-vitro activity on PRP arecefotaxime, ceftriaxone, vancomycin, amoxicillin andimipenem. Rapid determination of the MIC for the aboveβ-lactams is indispensable in order to best adjust the treat-ment. The therapy is administered by the intravenousroute for 10–14days and is prolonged in cases of slowresponse and/or a strain with reduced sensitivity. Thechoice of antibiotic therapy is governed by the age of thepatient, the presence of signs of severity and/or risk factorsfor PRP [23,30,31].

In children under 3months of age or in adults with riskfactors for PRP and/or presenting with signs of severity,initial treatment must include a third-generationcephalosporin such as cefotaxime (300mg/kg per day infour infusions) or ceftriaxone (70–100mg/kg per day inone or two injections, maximum 4g/day), and vancomycin(60mg/kg per day either in four infusions of at least 1h orin continuous infusion with an initial load of 15mg/kg)[32]. Re-evaluation is performed at 36–48h and is basedon the clinical data and lumbar puncture.

If the evolution is favourable, further treatment willdepend on the MIC of the cephalosporin that is used. Ifthe MIC is inferior to 0.5mg/l, one can discontinue thevancomycin and possibly reduce the dosage of the third-generation cephalosporin (to 200mg/kg per day) or pre-scribe amoxicillin (150–200mg/kg per day) if theamoxicillin MIC is inferior to 0.12mg/l.

If the third-generation cephalosporin MIC is superior orequal to 0.5mg/l, initial treatment must be continued. Incase of clinical and/or microbiological failure, treatmentmust be modified by taking into account the results of thesecond lumbar puncture, the MIC of the antibiotics and theconcentration of vancomycin in the CSF [21,23]. The drugcombination should be decided with the microbiologist andchosen among a list of antibiotics for which the MIC areknown: imipenem, meropenem, rifampin and fosfomycin.

The initial treatment for an adult without a risk factor forPRP or signs of severity is cefotaxime (200–300mg/kg perday in four infusions), but amoxicillin remains an option ata dose of 200mg/kg per day in four to six infusions, espe-cially in regions where the prevalence of PRP is low. Clin-ical re-evaluation is performed at 36–48h. For subsequenttreatment, if the evolution is favourable and if the strainhas normal sensitivity to these β-lactams, one can reducethe dose of the third-generation cephalosporin or pre-scribe amoxicillin (150–200mg/kg per day). When theMIC of the third-generation cephalosporin is superior or

equal to 0.5mg/l, lumbar puncture is indispensable toconfirm an improvement in the CSF; such improvementmandates continuation of the initial treatment. In cases ofclinical and/or microbiological failure, the treatment mustbe modified by adding vancomycin to the initial treatment(see doses above).

It is recommended to treat H. influenzae and meningococ-cal meningitis for 7–10 days, but longer periods of 10–21days are required for other pathogens: 10–14 days forS. pneumoniae; 14–21 days for L. monocytogenes and group Bstreptococci; and 21 days for Gram-negative bacilli, exceptfor H. influenzae.

Empirical choice of an antibiotic therapyWhen lumbar puncture is delayed or direct examination ofthe CSF is not helpful, empiric treatment is essential. Abroad-spectrum cephalosporin (cefotaxime or ceftriaxone)is recommended for most patients, combined with ampi-cillin in children under 3 months and adults over 50 years(two populations in which S. agalactiae and L. monocytogenesare frequently found). In patients with recent head traumaor who have undergone neurosurgery, the clinician mustchoose a broad-spectrum antibiotic treatment that is activeon Gram-positive and Gram-negative bacteria, such as thecombination of ceftazidime and vancomycin. In immuno-compromised patients (chemotherapy, corticotherapy,haematologic tumours), treatment must include ampicillin(for possible listeriosis) and a cephalosporin, such as cef-tazidime, which is active on Gram-negative bacilli.

Intensive careGiven the number of cases of life-threatening secondaryor associated visceral impairment, it is important to treatrespiratory failure, septic shock, intracranial hypertensionor disseminated intravascular coagulation. As for the lattersyndrome, a recent study has demonstrated the interest ofadministering concentrated Protein C for purpura fulmi-nans in cases of meningococcemia.

Treatment of the portal of entryOtorhinologic treatment of otitis and sinusitis is an emer-gency that can be put off for a few days if the clinical evo-lution during the first few days is favourable. It can includeatticomastoidectomy, exeresis of a cholesteatoma or sinusdrainage. Detection of traumatic osteodural breaches andtheir treatment are not considered as emergencies.

ImmunotherapyCorticotherapyThe use of anti-inflammatory agents, particularly dexam-ethasone, makes it possible to reduce local inflammatoryreactions that are responsible for cerebral oedema andthereby reduce the morbidity and mortality in purulentmeningitis. Several recent studies [23,33,34], notably inchildren, have investigated neurosensory sequelae and


mortality of a short corticoid treatment administered inthe initial phase of bacterial meningitis. These studieshave demonstrated a possible reduction in mortality thathas, however, only been found in open studies performedin populations of patients whose clinical presentation wasimmediately severe with treatment often delayed. Areduction in auditory sequelae, even neuromotor seque-lae, in children treated with dexamethasone (double-blindstudies), especially in children with H. influenzae purulentmeningitis, has been noted; there is probably a similareffect for pneumococcal meningitis, but cannot be evalu-ated from the available data for meningococcal meningitis.In adults there is only partial information on the efficacyof initial corticotherapy, but there are potential disadvan-tages of corticosteroid use. Through the rapid sympto-matic modifications that they can trigger, corticosteroidscan interfere with assessment of evolution and lead to pos-sible errors in clinical interpretation. Consequently, theymust not be used for a meningitis that is insufficientlydocumented. Complications due to corticotherapy whenused in this context are very rare. On the other hand, onecan observe a return of fever when corticosteroid treat-ment is stopped. The use of dexamethasone in animalmodels has demonstrated a reduction in the penetration ofcertain antibiotics, including vancomycin, into the CSF.This could create a problem for treatment with certainantibiotics with relatively weak meningeal diffusion incases of PRP infection.

On the whole, the favourable benefit:risk ratio for earlycorticoid therapy would advocate the prescription of dex-amethasone at the beginning of treatment of purulentmeningitis in children when it is probably due to the usualcommunity bacteria. For adults, however, additional clini-cal studies will be necessary to draw conclusions on thispoint. The adults who could benefit the most are thosewho present with a high bacterial concentration in theCSF and signs of intracranial hypertension [35].

When it is used, corticotherapy must be instituted early. Itis usually administered a few minutes before the first doseof antibiotic [ie, dexamethasone intravenously (0.6mg/kgper day in two to four injections)]. The duration of treat-ment is debatable, but a 2-day treatment would appear tobe as effective as a 4-day treatment. If dexamethasone ischosen, it is better to associate it with rifampicin ratherthan vancomycin in cases of PRP.

AntimediatorsThe use of agents that block the action of polynuclearcells or cytokines has been promising in experimentalmeningitis, but has yet to be validated in humans. Arecent clinical study would seem to have found an inter-esting effect of a protein that increases bacterial perme-ability (rBPI21) in 26 children aged from 1 to 18 years andpresenting with severe meningococcaemia.

ProphylaxisPneumococcal meningitisContinuous cyclic chemoprophylaxis with penicillin G isused in certain adults (following splenectomy, osteoduralbreach victims), but is not based on well established data[36]. The emergence of resistant strains should put thispractice into question.

Vaccination is recommended for patients at risk. It is debat-able for patients aged over 65 years or under certain circum-stances for elderly or handicapped patients living in groups.Its efficacy has not been demonstrated, especially given thepoor vaccination response in groups at risk. Vaccination isineffective before the age of 2years and not advisable inpregnant women. A booster vaccination is performed after5years or earlier in immunocompromised patients.

Meningococcal meningitisIn France, a Public Health Service declaration is obligatoryonce a case has been identified. Prophylaxis involves thosein contact with the patient before diagnosis (living underthe same roof in the 10 days before hospitalization, closefriends, immediate neighbours in class, cafeteria, room) andafter curative treatment, as well as clinical staff exposed toair contamination (mouth-to-mouth resuscitation, intuba-tion). It is extended to an entire school class if several caseshave occurred in the same class, and to an entire school ifthree or more cases have occurred in different classes in lessthan a month. Casual contacts (coworkers, other studentswho were not close to the patient, health care personnel ingeneral) are not involved. Except for secondary cases, mea-sures must be taken within 8 days of the diagnosis and areorganized by the family doctor (in household cases) or, ingroup cases, by the Public Health Service and the doctorresponsible for the group. Contact subjects and contactsfrom the same group as the patient must be informed aboutthe disease and the measures to be taken. Medical observa-tion of the contact subjects must be undertaken for 2weeksafter the institution of prophylactic measures. Rhinopharyn-geal disinfection and sampling are not useful. Suspensionfrom school or isolation of the contact subjects is not recom-mended. Given the fragility of meningococcus, disinfectionor closure of an establishment, including a school, are mea-sures that are unnecessary and unjustified.

Chemoprophylaxis consists of rifampicin per os for 2 days:in adults, 600mg twice a day; in children aged 1 month to12 years, 10mg/kg three times a day; in children agedunder 1month, 5mg/kg twice a day. The wearing of softcontact lenses must be stopped during treatment due tothe risk of irreversible dyeing. Moreover, subjects takingoral contraception must be given another contraceptivesolution due to the risk of enzymatic induction.

The contraindications are pregnancy, severe hepaticdisease, porphyrias and hypersensitivity to rifampicin. In


the latter situation, use spiramycin per os for 5days: inadults, 3million IU twice a day; in children, 75000IU/kgtwice a day.

Vaccination (meningococcal vaccine A+C) is recom-mended in addition to chemoprophylaxis, beginning atthe age of 3months in the case of meningococcus A andfrom 1year of age in the case of meningococcus C. It canalso be offered to those who have stayed in a region withan epidemic: peace corps workers and members ofmedical expeditions in the sahel. Professional or academicsuspension of contact subjects and disinfection ofpremises are not useful.

Haemophilus influenzae type B meningitis The probability of contracting meningitis is markedlyincreased in children aged under 4years living in the samedomicile as an index case. Prophylaxis relies on theadministration of rifampicin (30mg/kg per day) for 4daysfrom the age of 1month. It provides an eradication rate ofapproximately 95% for carriers of H. influenzae. The emer-gence of type B strains that are resistant to rifampicin israre (0.2% in France). H. influenzae type B vaccination andprotective and immunogenic vaccines in very young chil-dren have greatly modified the epidemiology of meningi-tis in countries where these vaccines are used on a largescale. In France, according to the National ReferenceCenter data, 635 strains of H. influenzae were isolated inCSF between 1984 and 1992, 71 strains in 1993, and 34strains in 1994.

Listeria monocytogenes meningitisThe prevention of listeriosis essentially depends on foodhygiene. This applies to pregnant women, immunocom-promised subjects and the elderly.

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