Neisseria meningitidis

Authors: Keith A.V. Cartwright MA BM FRCP FRCPath FFPH

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MICROBIOLOGY

Neisseria meningitidis (the meningococcus) is a fastidious Gram-negative diplococcus that colonizes and invades only man. In genetic terms, its closest relative is the gonococcus, Neisseria gonorrhoeae. The entire genetic sequences of a serogroup A and a serogroup B meningococcus have been published. The normal habitat of the meningococcus is the posterior nasopharynx. Carriage is rare in infants and young children, rises to a peak of about 25-30% in late teen years and then declines slowly in older age groups; overall carriage rates are about 10% (12). Carriage may be of long duration, more than a year. Perhaps surprisingly, most meningococci are not very infectious; transmission from person to person is by the respiratory route and generally only results from prolonged close contact. Once having colonized a new susceptible individual in a very small proportion of cases the organisms may breach the nasopharyngeal mucosal barrier, usually shortly after colonization, to cause invasive disease. Transmissibility, invasiveness and virulence vary enormously between strains. Most strains are incapable of causing disease in immunocompetent individuals and most older children and adults are immune to systemic infection.

Meningococci are divided into serogroups on the basis of structural differences in the capsular polysaccharide, a major virulence factor; only well capsulated strains have the potential to invade immunocompetent individuals. Strains are further classified into types and subtypes based on variations in the class 2/3 and class 1 outer membrane proteins, respectively. A typing scheme based on direct sequencing of DNA fragments (~ 500 base pairs) of seven housekeeping genes (multi-locus sequence typing, or MLST) (31) has gained wide acceptance and has permitted the unambiguous assignment of meningococci to specific clonal groupings. An important consequent finding is that most cases of invasive disease are caused by a small number of hypervirulent lineages (26). A further finding of great clinical and epidemiological importance has been the discovery that meningococci that are otherwise genetically virtually identical, may acquire through transformation genes that permit the expression of different capsular polysaccharides (52). Since meningococcal vaccines (with the exception of serogroup B vaccines) are all currently based on capsular polysaccharides, this raises the possibility of serogroup shift within specific clones, and thus the possibility of vaccine escape mutants. It is clear that detailed ongoing microbiological surveillance will be required to support population-wide deployment of meningococcal vaccines.

EPIDEMIOLOGY

Globally, the great majority of meningococcal disease in immunocompetent individuals is caused by strains of three serogroups - A, B and C. Serogroup A disease dominates in the "meningitis belt" of sub-Saharan Africa, in the Middle East, Asia and in some other tropical countries. In higher-latitude countries including the North American continent, Europe and Australasia, serogroups B and C predominate. In the United States, strains of serogroup Y cause approximately one third of cases, with unusual predilections for older adults and for causing lower respiratory tract infection.

Attack rates vary widely by region, by country and over time. Overall disease rates in higher-latitude countries are often about 1-2 per 10⁵ population, but higher rates are not uncommon from time to time. In the U.S.A., attack rates have been less than 1 per 10⁵ population for some years (3, 14). Meningococci can cause clusters of cases in families, schools universities and military training establishments. They can also cause more diffuse, community-wide outbreaks which are usually due to strains of a single clonal type. For some years in the 1990s there were outbreaks of serogroup W disease amongst Muslims visiting Saudi Arabia while undertaking Haj or Umrah pilgrimage. The outbreaks were controlled by the introduction of compulsory vaccination for visiting pilgrims.

Overall, attack rates are highest in the very young, peaking at about age 7 months then falling steadily to age 10 years, followed by a second and smaller peak in those in their late teens (33). The disease incidence in adults is low. The sex ratio of cases usually shows a small male preponderance.

Infants, among whom the prevalence of protective antibodies is low, only rarely acquire meningococci; when they do, the chances of invasive disease are high. The second disease peak in teenagers and young adults may be associated with to the peak of carriage, and more importantly, the peak of acquisition that occurs around this age.

Massive pancontinental epidemics due to serogroup A strains occur in sub-Saharan Africa (the so-called "meningitis belt") at intervals of about 5-10 years with attack rates of 100 or more per 10⁵ population. These are due to the introduction and dissemination of new meningococcal clones within susceptible populations (2).

CLINICAL MANIFESTATIONS

The two main clinical manifestations of invasive meningococcal disease are meningitis (75% - 80%) and septicemia (15% - 20%). Occasionally, meningococci causes other infections including pneumonia, pericarditis, conjunctivitis, endophthalmitis, septic arthritis, pelvic infection or a chronic low-grade septicaemia. They may also cause brief, self-limited bacteraemic episodes that resolve without antibiotic treatment.

The onset of invasive meningococcal disease is normally rapid, particularly in the septicaemic form of the disease. Most patients become progressively ill within 24 to 48 hours, though in a few cases the disease progresses so rapidly that the patient becomes moribund or dies within a few hours of the onset of infection.

Early symptoms are normally nonspecific, resembling those of influenza. Fever, malaise, lassitude, nausea, shivers, tachycardia, and mild headache are all common early features (65). As the illness progresses, headache may become more pronounced, accompanied by photophobia, confusion and vomiting (due to raised intracranial pressure), going on to coma if untreated. Infants are grizzly, listless, and off their food. They may have a cold periphery despite fever. Meningitis should be suspected in any febrile, apathetic infant with pallor, a cold periphery despite fever, and/or an inability to make and maintain eye contact.

In both meningococcal meningitis and septicemia, a very common (but not invariable) feature of the illness is the development of a vasculitic (non-blanching) skin rash. This may manifest itself initially as tiny spots (petechiae), but if untreated can progress, sometimes astonishingly rapidly, to much larger areas of ecchymosis (purpura). Since the rash is caused by damage to capillaries and small blood vessels with consequent bleeding into the skin, the vasculitic rash of meningococcal disease will not blanch on pressure. Parents can test the nature of a suspicious rash in a child by pressing a glass tumbler firmly on a spot or group of spots to see if they fade. The test may need to be repeated because an early, rather nondescript morbilliform pale pink blanching rash can also occur in up to 25% of cases. After a few hours this rash may resemble the more classical and familiar petechial or purpuric rash. In the absence of an alternative credible diagnosis the combination of fever and a non-blanching rash should be treated as probable meningococcal infection until proved otherwise. Empirical intravenous antibiotics should be started without delay and the patient referred urgently to a hospital. About 5% of patients do not develop a rash.

The mortality in promptly treated meningococcal meningitis is about 2-4%, whereas mortality in septicemia without meningitis is 20-40%. Most deaths occur within the first 24 to 48 hours. The higher case fatality rates reported in the the U.S.A. may reflect differences in case definitions or less complete ascertainment of surviving cases rather than any true difference in the fatality rate.

LABORATORY DIAGNOSIS

A diagnosis of invasive meningococcal disease is usually established by isolation of a meningococcus (or detection of meningococcal DNA by polymerase chain reaction – PCR) from a deep, normally sterile site such as peripheral blood or cerebrospinal fluid (CSF). Emergency examination of CSF in suspected meningitis usually reveals an excess of polymorphonuclear leucocytes, a low glucose, and a high protein; Gram-negative diplococci are usually seen but if scanty may require very careful examination of films of centrifuged CSF deposit. Blood cultures are negative in about 50% of patients even when antibiotics have not been administered. In about 5% of patients with meningococcal meningitis, initial examination of CSF will reveal no abnormality at all in microscopy or chemistry, yet a meningococcus will subsequently grow on culture plates. Therefore if meningococcal meningitis or septicemia are suspected, parenteral antibiotic treatment must be initiated immediately regardless of the CSF findings. Antibiotic treatment must not be delayed in order to carry out microbiologic investigations.

Throat cultures are sometimes the only source of a meningococcus for antimicrobial sensitivity testing, but in diagnostic terms, it must be remembered that meningococci are common nasopharyngeal commensals, particularly in young adults. Meningococci have been visualized in (and sometimes grown from) skin biopsies and aspirates of areas of ecchymosis.

PATHOGENESIS

Natural Immunity

The pathogenesis and pathophysiology of invasive meningococcal disease have been the subject of an excellent review by van Deuren et al (70). Natural protection against invasive meningococcal infection is associated with acquisition of protective bactericidal antibodies. Most infants aged up to around four months are protected transiently by passively transferred maternal antibodies. As maternal protection wanes, susceptibility to infection rises rapidly. Bactericidal antibodies are acquired progressively by exposure to various bacteria that express non-capsular antigens in common with meningococci. The strictly commensal Neisseria lactamica probably plays a major role in evoking protective antimeningococcal antibodies in the first few years of life. Later in life, immunity is sustained by exposure to many immunizing organisms including nonpathogenic meningococci.

Invasive Disease

Meningococci breaching the nasopharyngeal mucosa may reach the bloodstream, where they may shed large amounts of endotoxin, the main effector of tissue damage and main activator of the host inflammatory cytokine cascade. Although the blood-brain barrier is normally highly effective in excluding bacteria, the majority of patients with invasive meningococcal disease have meningitis. Liberation of endotoxin into the subarachnoid space provokes a marked cytokine-mediated inflammatory response that causes the blood-brain barrier to become leaky, facilitating the penetration of antibiotics. As meningeal inflammation subsides, the penetration of antibiotics into the subarachnoid space declines progressively (37, 45). Therefore, when treating bacterial meningitis of any etiology, antibiotic doses should be kept high throughout the period of parenteral treatment.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Although globally there has been a very slow decrease in the sensitivity of meningococci to penicillin G over the past two decades, this has yet to become clinically significant. The vast majority ofmeningococci continue to demonstrate exquisite sensitivity in vitro to the antibiotics commonly used in the empirical treatment of bacterial meningitis or for the elimination of nasopharyngeal carriage. Typical inhibitory concentrations for relevant antibiotics are given in Table 1. Many newer ß-lactam antibiotics also exhibit high activity against meningococci, but either offer no particular advantages over currently used agents, or have yet to be evaluated adequately in clinical trials.

ANTIMICROBIAL THERAPY

General

In addition to being safe in use and showing a high level of activity against meningococci in vitro, antibiotics for the treatment of meningitis must be able to penetrate the inflamed meninges and reach the subarachnoid space (5). Some of the factors determining such penetration are listed in Table 2 (58). All antibiotics given for the treatment of bacterial meningitis must be administered, at least initially, by the parenteral route, normally intravenously. In uncomplicated bacterial meningitis intrathecal treatment is rarely if ever needed. Misinterpretation of intrathecal penicillin G doses by junior medical staff continues to result in occasional avoidable deaths due to penicillin encephalopathy.

Penicillin G (Benzylpenicillin)

With its high intrinsic activity and outstanding safety record, penicillin G remains the drug of choice for treatment of all types of invasive meningococcal disease. In the U.K., a small (< 5%) but increasing proportion of clinical isolates of meningococci have shown reduced sensitivity to penicillin G (minimum inhibitory concentrations (MICs) between 0.16 and 1.28 mg/L) (32). Reports of similar prevalence followed from the North and South American continents, the Netherlands and Australia, but Spanish workers reported a far higher prevalence of 20-40% (69) and in the U.K., the proportion of clinical isolates showing reduced sensitivity has continued to increase, albeit slowly.

Spratt et al. showed that the reduced sensitivity was due to a decreased affinity of meningococcal penicillin-binding protein 2 for penicillin G, caused by transformation of the meningococcal penA gene by nucleotide sequences most probably originating in the commensal Neisseria spp. N. flavescens (60) and N. cinerea. Clinical concerns eased when it became clear that such strains continued to respond to standard treatment (28, 69), though treatment failure has been documented in a patient with meningitis due to a meningococcus of reduced sensitivity to penicillin who received a relatively low dose of penicillin G (68) and may have led to delayed recovery in a case of meningococcal pneumonia and empyema (22).

There have been very occasional anecdotal reports of the isolation of ß-lactamase-producing strains of meningococci from clinical sources (7, 16, 21) and a plasmid-borne gonococcal ß‑lactamase has been transferred to a meningococcus in the laboratory (9) but as yet, no adverse clinical outcomes have been caused by such strains.

Prehospital Treatment

Effect of Oral Antibiotic Therapy

In its early clinical stages, meningococcal meningitis is very hard to differentiate from more trivial respiratory infections. Thus, up to 50% of patients with what is later confirmed to be meningococcal disease, receive oral antibiotic treatment prior to admission to hospital, often with agents to which the invading meningococcus is sensitive in vitro (23). There is no way of knowing how many cases of invasive meningococcal disease are aborted by such treatment. Oral antibiotic treatment may fail to prevent the further progression of meningococcal disease because of intrinsic lack of activity of the antibiotic against the invading strain, failure of absorption from the bowel, or failure of distribution.

Prehospital Parenteral Antibiotic Treatment

Most (6, 13, 43) but not all (47) authorities are persuaded that early parenteral antibiotic treatment improves outcome substantially in meningococcal disease. Some uncertainty remains because no prospective randomized placebo-controlled studies stratified by disease severity have been undertaken. The authors of a systematic review of such treatment concluded that robust evidence of benefit is unlikely ever to be obtained, but that the data reviewed was consistent with benefit when large numbers of patients were treated (25). Preadmission parenteral antibiotic therapy is recommended in many European countries where patients with early meningococcal disease are often seen first outside the hospital environment. Primary care doctors in the U.K. are advised to carry penicillin G (which has a half-life of about 3 years in the doctor's bag) at all times and to use it as soon as the possibility of meningococcal disease is recognized. The same advice applies if the patient is admitted to hospital via the Accident & Emergency Department (Emergency Room). Penicillin G should be given swiftly, ideally by the intravenous route. The doses are probably not critical, but those recommended in the U.K. are:

Adults and children aged 10 years and over: 1200 mg
Children aged 1 to 9 years: 600 mg
Children under 1 year of age: 300 mg

Penicillin Anaphylaxis and Allergy

The only contraindication is a history of penicillin anaphylaxis, which is very rare, with an estimated incidence of around 0.01% (27), and not penicillin allergy, which is commoner, though greatly over-diagnosed (54, 63). Intravenous chloramphenicol, if available, can be used in patients with a true history of penicillin anaphylaxis. The dose is 1.2 g for adults and 25mg/kg in children under 12 years of age. A parenteral cephalosporin is another alternative; the true rate of cross-sensitivity with penicillin G is not known accurately, but is probably low (35).

Routes of Antibiotic Administration

Gaining access to a vein may be difficult in profoundly shocked patients, infants and small children or in patients being treated in poorly lit surroundings. In such circumstances, the intramuscular route can be used, but may not be so effective, particularly in shocked patients. The intraosseous route is another possibility in shocked small infants. Regardless of whether a dose of parenteral antibiotic has been given, the patient should be transferred to a hospital as quickly as possible. Intravenous fluid resuscitation is an equally important facet of emergency management.

Inpatient Treatment

Diagnostic Considerations

The question facing the admitting hospital doctor is often not "How do I treat this case of invasive meningococcal disease?" but, "How do I treat this case of possible meningitis or septicaemia, that may be meningococcal?" If the patient is sick, has fever and a hemorrhagic rash, meningococcal disease is the most likely diagnosis. Other causes of fever with purpura may need to be excluded. Unless meningococcal disease has been confirmed by visualization of Gram-negative diplococci in a sample of cerebrospinal fluid (CSF), or better, by culture from a deep site such as blood or CSF, it is wise to commence a broad-spectrum antibiotic regime.

Empirical Antibiotic Treatment of Bacterial Meningitis

Many antibiotics and combinations have been advocated for the empirical treatment of suspected bacterial meningitis. Selection of particular combinations will be influenced by the age, clinical history and overall condition of the patient; by pharmacokinetic factors; and by a range of local factors including the incidence of invasive Haemophilus influenzae type b (Hib) disease (dependent on whether Hib vaccines have been introduced), the prevalence of penicillin-resistant pneumococci and of other types of bacterial meningitis and septicaemia in the community.

Penicillin G or ampicillin, or monotherapy with cefotaxime or ceftriaxone are all suitable empirical treatments for bacterial meningitis in children (excluding neonates) (19, 46), although cefuroxime (56) appears to be an inferior single agent. In practice, the simplicity of single daily dosing with ceftriaxone has undoubtedly contributed to its increasing use both in empirical treatment of bacterial meningitis and in confirmed meningococcal disease. The relative expense of both cefotaxime and ceftriaxone continue to restrain their use in developing countries where chloramphenicol still has a role. Dosages for all these agents are given in Table 3.

Empirical antibiotic treatment of community-acquired pyogenic meningitis in immunocompetent adults and children should take into account the possibility of a wider range of potential pathogens including Streptococcus pneumoniae and Listeria monocytogenes.

Effect of Prehospital Parenteral Antibiotic Treatment on Inpatient Laboratory Investigation

Administration of penicillin G prior to hospital admission reduces considerably the chances of isolating a meningococcus from a deep site (usually blood or CSF), though isolation of meningococci from nasopharyngeal swabs is unaffected and offers good chances of obtaining a meningococcus for sensitivity testing and for epidemiologic purposes (72). Establishing as swiftly as possible whether a meningococcal infection is presenting primarily as septicaemia or meningitis will help to guide inpatient management. Improved nonculture methods of diagnosis, including polymerase chain reaction (PCR) of CSF and peripheral blood (24) and better serologic tests, means that antibiotic treatment should never be withheld while diagnostic specimens are collected. Optimizing treatment must always have priority over diagnostic niceties.

Inpatient Management of Suspected Meningococcal Disease

Guidance on the management of bacterial meningitis and meningococcal disease has been published in many countries (50, 67, 70).

Once meningococcal disease has been confirmed in either a child or an adult, penicillin G monotherapy is effective, cheap, and exerts minimum selective pressure on the patient's (and the hospital's) indigenous bacterial flora. It remains the drug of choice.

Alternative Antibiotic Therapy

A number of different antibiotics and regimens are suitable alternatives for the treatment of invasive meningococcal disease, and choice will depend on local circumstances. The likelihood of encountering truly penicillin resistant (ß-lactamase-producing) meningococci is so low throughout the world that penicillin G (given in adequate dosage, see above) can be recommended strongly for the antibiotic monotherapy of confirmed meningococcal meningitis or septicaemia. Alternative single agents in allergic patients are ceftriaxone, cefotaxime, or (if the patient is allergic to all ß‑lactams) chloramphenicol. Doses are the same as those used for the empirical treatment of bacterial meningitis of unknown etiology (Table 3).

Duration of Parenteral Antibiotic Treatment

There are few hard data on which to base a recommendation for the duration of antibiotic treatment. If the CSF is re-sampled during treatment of meningococcal meningitis, it is almost always sterile within 24 to 36 hours. Despite this, 7 days of treatment are still normally recommended for meningococcal meningitis (19, 41, 44) though shorter courses of 4 days may be sufficient in uncomplicated cases (40) and single dose treatment with long acting penicillin or chloramphenicol has been used in Nigeria with success. Antibiotic treatment of meningococcal septicaemia is often prolonged because patients are sicker even though the bloodstream is likely to be sterilized more rapidly than the CSF.

Elimination of Meningococcal Nasopharyngeal Carriage

Chloramphenicol and most ß-lactam antibiotics are not completely effective in eliminating meningococci from the nasopharynx (1, 4). In the U.K., patients recuperating from meningococcal disease are given a course of a chemoprophylactic antibiotic (see below) just prior to discharge from hospital. Others do not consider the small risk of persistent carriage to be worth specific treatment (4, 72).

ADJUNCTIVE THERAPY

Supportive therapy for shock caused by meningococcal lipo-oligosaccharide (LOS) and mediated by tumor necrosis factor-α (TNF-α) and by other inflammatory cytokines is often necessary and will require intensive care with correction of metabolic acidosis and electrolyte abnormalities such as hyponatremia, as well as consideration of the need for cardiac, respiratory, renal and hepatic support and management of disseminated intravascular coagulation (50). Gangrene, severe skin scarring and damage to long bone growth plates mandates early involvement of plastic and orthopaedic surgical expertise.

Corticosteroids

Experimental immunomodulators continue to undergo clinical evaluation but they have failed to fulfill their anticipated promise. Dexamethasone given prior to, or concurrently with, the first dose of parenteral antibiotic is associated with improved outcome in bacterial meningitis caused by Hib (36) and by some other organisms (57, 66); its use is also supported by animal models of bacterial meningitis. It is postulated to act by blocking the host inflammatory cytokine cascade normally initiated by release of endotoxin from dead and dying meningococci (29). Dexamethasone can be given in meningococcal meningitis if treatment starts at the same time as, or very soon after the first parenteral dose of antibiotic, but is not advised in meningococcal septicaemia (43). Its lack of efficacy in septicaemia combined with its potential toxicity, mandate clearly against its widespread use as part of pre-hospital treatment given at a time when the diagnosis is uncertain. When used in the inpatient setting, a 2 day course (0.15 mg/kg i.v. q 6 hours) is probably sufficient (64).

ENDPOINTS FOR MONITORING THERAPY

Monitoring of peripheral blood to check for sterility and to ensure that antibiotic levels are satisfactory is not normally undertaken in meningococcal disease. The margin between therapeutic and toxic concentrations of the antibiotics most frequently used in treatment is very wide. There is a greater risk that antibiotic concentrations in the subarachnoid space may not be adequate and therefore at least a theoretical case for resampling CSF during the course of treatment in order to check for sterility (55). However, lumbar puncture is not without risk (30, 59) and resampling CSF is not part of routine management in the U.K., unless the patient's clinical condition is a cause for concern.

VACCINES

Nonconjugated polysaccharide vaccines

Two purified polysaccharide vaccines for the prevention of meningococcal disease are currently commercially available – a bivalent product covering serogroups A and C, and a quadrivalent preparation covering serogroups A, C, W and Y are available commercially. Both are safe and effective and have been used widely in the past. However, purified polysaccharide vaccines have two principal drawbacks: they do not stimulate memory lymphocytes and therefore give only short-term protection, and they are not immunogenic in infants, the age group with the highest disease attack rate. For these two reasons they are not suitable for programmes of universal childhood immunization.

Despite these deficiencies, bivalent A+C or quadrivalent ACWY nonconjugated vaccines have a number of potential indications including:

Protection of close contacts of sporadic cases of meningococcal disease caused by the homologous serogroup; close contacts are normally defined as: household contacts, mouth kissing contacts, and healthcare staff carrying out mouth to mouth resuscitation or who are exposed to heavy contamination of eyes, mouth or mucous membranes by secretions from an infected patient.
Mass vaccination of members of closed or semi-closed communities (schools, universities, military recruit training establishments etc.) following clusters of cases caused by the homologous serogroup.
Mass vaccination of members of wider communities during prolonged clusters or outbreaks of disease caused by strains of a vaccine serogroup.
Protection of travelers to endemic or epidemic meningococcal disease areas (principally but not limited to sub-Saharan Africa) or to countries requiring evidence of vaccination as a condition of entry - Saudi Arabia requires vaccination of all incoming travelers during the Haj religious festival and Umrah pilgrimages. This requirement was introduced after outbreaks of men W disease in Haj pilgrims.

Vaccination should be considered particularly for those living or working with local people or visiting an area of risk during an outbreak. Younger persons (who are less likely to have acquired natural protection), those making prolonged visits, those travelling rough or to areas of deprivation, and those who are functionally or surgically asplenic are at higher than average risk and should be targeted specifically. Other groups for whom vaccination may be indicated include medical and paramedical staff providing clinical care to patients during an epidemic caused by serogroup A or C. meningococci.

Quadrivalent ACWY vaccine can be used for any of the indications listed above for the bivalent vaccine, but is specifically indicated for protection of close contacts of patients with disease due to strains of serogroup W or Y. These were both rare causes of invasive meningococcal disease in the U.S.A. until the 1990s, when their relative frequency increased, the latter being seen in particular in association with Haj pilgrims and their families on return from Saudi Arabia. Strains of serogroup Y continue to circulate and to cause invasive infections up to the present day, but men W strains have now declined again in frequency.

When invasive meningococcal disease is caused by strains of serogroups other than A, B or C (or serogroup Y in the U.S.A.), patients (and their first degree relatives) should undergo careful investigation to exclude immunologic abnormality, most frequently a deficiency of a terminal complement component (C5 through C9) (20).

Patients with complement deficiency or the extremely rare condition of properdin deficiency (with a consequent very high lifetime risk of fatal meningococcal disease) can (in theory) be protected from meningococcal disease caused by vaccine serogroups and should be offered quadrivalent ACWY conjugated vaccine (see below).

Doses and Schedules

The dose of each of these purified polysaccharide (nonconjugated) vaccines is 0.5 mL; administration is by the intramuscular route and a single dose only is needed. Protection wanes after about three years. Revaccination, if necessary, is acceptable, but there is little published experience of repeated revaccination. Because of their lack of efficacy in infants and younger children, vaccination with any of the nonconjugated meningococcal polysaccharide vaccines is not recommended for children under the age of 18 months.

Adverse Effects

Both the bivalent and quadrivalent nonconjugated polysaccharide vaccines are extremely safe. They cause slight redness and swelling at the site of injection in about 1% of recipients. In a study of 1.2 million children vaccinated in Canada with a nonconjugated A+C vaccine, the incidence of allergic reactions was 9.2 per 100,000 doses, and for anaphylaxis, 0.1 per 100,000 doses (73).

Conjugated protein-polysaccharide vaccines

Conjugated protein-polysaccharide vaccines for serogroups A, C, W and Y have been developed and subjected to extensive clinical evaluation. Conjugated meningococcal vaccines offer a number of important advantages over purified polysaccharide vaccines. Most importantly they stimulate memory T lymphocytes (meaning that they offer long-term protection and that the immune response can be boosted by repeat exposure), and they are highly immunogenic in infants (although the memory immune response is muted in this age group).

Conjugated serogroup C meningococcal vaccines were first introduced into the U.K infant immunization schedule in November 1999, with a catch-up program in which the vaccine was offered to all children up to age 17 years. The roll out of the vaccine was driven by an ongoing high incidence of men C disease. Within a few years there was a reduction of more than 90% in the incidence of men C disease and a commensurate reduction in deaths in the age groups offered vaccine. There was also a marked reduction in the incidence of men C disease in unimmunized individuals due to a reduction in nasopharyngeal carriage of serogroup C meningococci in the immunized population - the herd immunity effect (39).

Unlike the changing epidemiology of invasive pneumococcal disease that followed the introduction of conjugated pneumococcal vaccines in the U.S.A. there has thus far been no evidence of serogroup shift, i.e. replacement of serogroup C. meningococci by strains of the same clone, but expressing other capsular polysaccharides e.g. serogroup B. Conjugated protein-polysaccharide meningococcal vaccines are immunogenic in all age groups, and confer long-term immunity. Many other countries are now deploying these vaccines. A sharp upsurge of meningococcal disease in the U.K. in 2015 caused by a virulent clone ('cc11') expressing the W polysaccharide has led to a recommendation to offer conjugated men ACWY vaccine to all adolescents aged 14 – 18 years.

Laboratory staff exposed regularly to live cultures of meningococci should be offered conjugated men ACWY vaccine.

Serogroup A conjugates have now been used in several countries in the meningitis belt of Africa. If high uptake rates can be achieved, there are good prospects of halting the major epidemics of meningococcal disease that have afflicted the sub-Saharan countries in the past.

In the U.S.A. quadrivalent ACWY conjugated vaccine is recommended for infants aged two to 23 months who are deemed at increased risk of meningococcal disease (38). These are:

infants with persistent complement component deficiencies including C3, C5-9, properdin, factor D and factor H;
those with functional or anatomic asplenia;
healthy infants in communities with a meningococcal disease outbreak caused by a serogroup contained within the vaccine;
those travelling to, or resident in areas where meningococcal disease is hyperendemic or endemic.

Doses and Schedules

The dose of the conjugated A+C and ACWY vaccines is 0.5 mL; administration is by the intramuscular route or deep subcutaneous route (see the manufacturer's literature) and a single dose only is needed. Revaccination, if necessary, is acceptable.

Adverse Effects

Both the bivalent and quadrivalent conjugated polysaccharide vaccines are extremely safe.

Serogroup B meningococcal vaccines

The protective immune response to serogroup B ('men B') meningococcal infection is not directed towards the capsular polysaccharide which exhibits homology with a human antigen expressed on neural cells and in repairing tissues ('NCAM-1'). Vaccines using this antigen are thus ineffective and could be potentially dangerous. A number of alternative candidate vaccines for prevention of men B disease based on alternative surface-expressed meningococcal proteins have been developed (49) some of which have now undergone extensive clinical evaluation.

Two vaccines offering protection against men B disease have recently been licensed. 'Trumenba'® is licensed in the U.S.A. as a three-dose schedule for use in those aged from 10 to 25 years. It comprises two recombinant factor H binding protein (fHBP) variants derived from a clinical men B strain. 'Bexsero'® is licensed in Europe and in the U.S.A. as a two dose schedule (three doses in infants) for all ages from 2 months. It contains three surface-exposed meningococcal proteins - NHBA (Neisseria Heparin Binding Antigen), NadA (Neisserial adhesin A) and fHbp (factor H binding protein), together with men B outer membrane vesicles. It is estimated that 'Bexsero' should provide protection against around 80% of prevalent European men B strains. The duration of protection provided by each of these newly licensed vaccines remains to be determined.

Doses and Schedules

The dose of both the licensed men B vaccines is 0.5 mL; administration is by the intramuscular route.

Adverse Effects

Local injection site reactions to both these new men B vaccines are common, as is fever. Serious adverse reactions are uncommon or rare.

PREVENTION

Prophylaxis of Close Contacts

Close contacts of patients with meningococcal disease are at increased risk of developing infection themselves. Though the relative risk for household contacts is very high (500-1000x), albeit transiently, the absolute risk is very low - only 1-2% of all cases of meningococcal disease are secondary (15). Part of the management of an acute case is the identification and antibiotic treatment of the close contact group, normally the immediate family, together with any additional mouth-kissing contacts such as boyfriends and girlfriends.

Close contacts should be identified as swiftly as possible, given accurate information on the symptoms and signs of meningococcal disease, and offered chemoprophylaxis. The antibiotics employed to eliminate meningococci from the nasopharynx, and the recommended dosage regimens are listed in Table 4. For the UK, detailed advice on the practicalities of using the different chemoprophylactic antibiotics has been set out (48). If the index case strain is of serogroup A, B, C, W or Y vaccine should be offered in addition to chemoprophylaxis. When prevention of secondary cases rests solely on antibiotic chemoprophylaxis, contacts must be reminded that prophylaxis can fail; secondary cases may then occur weeks or months after the index case (61). Familiarity with the symptoms and signs of meningococcal disease may then be lifesaving.

Guidance on management of clusters of cases is available in both the U.S.A. and the U.K. (14, 62). Expert advice should be sought when clusters of cases occur within families, day-care centers, schools and universities, military training establishments or wider communities. The key principle of management underpinning intervention is the definition of logical at-risk groups, together with the calculation of disease attack rates relative to the surrounding community.

CONTROVERSIES, CAVEATS OR COMMENTS

Frapper Fort ou Frapper Doucement?

Concerns have been expressed for years that release of endotoxin from Gram-negative bacteria following first administration of antibiotics may cause clinical deterioration (10, 53). Endotoxin release from meningococci may be slower when the bacteria are exposed to lethal doses of chloramphenicol, a bacteriostatic antibiotic, than to penicillin G, a bactericidal agent (42, 51), but this laboratory observation is of uncertain clinical relevance. Brandtzaeg et al. treated a small series of Norwegian patients with meningococcal disease with an initial combination of penicillin G and chloramphenicol; in all, plasma levels of endotoxin fell, despite presumed rapid death of circulating meningococci (8).

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Tables

Table 1. Meningococcal Inhibitory Concentrations of Antibiotics Commonly Used in the Treatment of Bacterial Meningitis

Antibiotic	MIC₅₀ (mg/L)	MIC₉₀ (mg/L)	Range (mg/L)	% Strains Resistant
Penicillin G^a	0.032	0.05	0.016-1.28	<<1
Ampicillin/Amoxycillin^a	0.075	0.2	0.016-2.0	0
Cefotaxime	<0.008	<0.008	<0.008	0
Ceftriaxone	<0.002	<0.002	<0.008	0
Chloramphenicol	0.75	1.0	0.5-16	0
Meropenem	0.007	0.015	≤0.0015-0.06	0
Tetracycline	0.5	1.0	0.12-16	0
Minocycline	0.12	0.25	≤0.06-0.5	0
Doxycycline	0.5	1.0	0.12-2.0	0
Sulfisoxazole	8	>64	≤0.25->64	~50
Trimethoprim-sulfamethoxazole	0.5	2	≤0.03-8	~50
Trimethoprim	>8	>8	4->8	Most
Rifampin	0.03	0.12	≤0.007->256	1-2
Ciprofloxacin	0.003	0.003	≤0.0015-0.25	<<1
Nalidixic acid	1	1	0.5->64	<<1
Levofloxacin	0.007	0.007	0.007-0.25	<<1
Azithromycin	0.06	0.12	≤0.03-0.25	0

Data adapted from Emmerson 1985 (17), Enting 1996 (18) and Jorgensen 2005 (34)

^aThree β-lactamase producing clinical isolates have been described (see text).

Table 2. Factors Increasing the Penetration of Antibiotics into the Subarachnoid Space

Antibiotic Related	Host Related
Low protein binding	Meningeal inflammation
Hydrophobicity	Blockage of CSF efflux pump (e.g. by probenecid)
Low molecular weight
Neutral surface isoelectric charge

Table 3. Dosages of Antibiotics Commonly Used in the Treatment of Bacterial Meningitis

Antibiotic	Total Daily Dose	Number of Daily Doses
Penicillin G	Adults & children > 12 Years: 9.6 -14.4 g	4 - 6
Penicillin G	Children 1 month - 12 years: 180-300 mg/kg	4 - 6
Ampicillin	250 mg/kg	4
Cefotaxime	200 mg/kg	4 - 6
Ceftriaxone	80-100 mg/kg	1 - 2
Chloramphenicol	75-100 mg/kg	4

Table 4. Dosage Regimens of Antibiotics Commonly Used for Meningococcal Chemoprophylaxis

Antibiotic	Treatment Group	Dose	Route and Frequency	% Strains Resistant
Rifampicin	Adults and children over 12 years	600 mg	Oral, twice daily for 2 days	<1
	Children 6-12 years	300 mg
	Children 1-5 years	150 mg
	Infants 3-11 months	40 mg
	Infants 0-2 months	20 mg
Ciprofloxacin	Adults (not licensed in children)	500 mg	Oral, single dose	<1
Ceftriaxone	Adults	250 mg	Intramuscular, single dose	<1
Ceftriaxone	Children under 12 years	125 mg	Intramuscular, single dose	<1