The effort regarding the prevention of bacterial meningitis (BM) with the use of vaccines began many years ago. The first available vaccines were from bacterial capsular polysaccharides and were the serogroup-specific 2-valent (A and C groups) and 4-valent (A, C, Y and W-135) meningococcal vaccines (1981), and the 23-valent pneumococcal vaccine (1983) and Haemophilus influenza type b (Hib) vaccine.

Immunization of children <2 years of age with polysaccharide vaccines is not effective because the immune response is poor. These vaccines are recommended for children >2 years of age and older in high-risk groups, including those with functional or anatomic asplenia and chronic diseases. A meningococcal vaccine is also recommended for college student travelers to hyperendemic countries and for patients with terminal complement component deficiency.

The revolutionary technique of a protein carrier conjugated with polysaccharides produced vaccines with enhanced immunogenicity in infants.

The first conjugate vaccine Hib was introduced in Greece in 1994 with a recommended schedule of four doses (at 2 months, 4 months, 6 months and a booster at 15–18 months), with remarkable success. Invasive Hib infections vanished. The short period of time in which the control of infection was evident suggests that children’s immunization also had an indirect positive effect on unimmunized people.

Fifteen years after implementation of the Hib vaccination, no increase in infection at older ages has been noticed.

The next available conjugate vaccine in Greece was for meningococcal serogroup C infection (2001). The vaccine coverage was soon high because of the recent experience of a meningococcal C outbreak (1996-97) with a high mortality rate.

The available meningococcal C vaccines are conjugated with different protein carriers [Meningitec (C. diphtheriae), Menjugate (C. diphtheriae) and Neisvac C (tetanus toxoid)]. According to current recommendations in the national vaccination schedule, the conjugate meningococcal C vaccine is given in three doses (2+1) to infants.

The impact of a high acceptance of the vaccine has resulted in the disappearance of meningococcal serogroup C infection in Greece for the last 10 years. Because there is a lot of evidence that immunity wanes, concerns have been raised about the possible need of a booster dose. Recently available in Greece is the 4-valent meningococcal conjugate vaccine (A, C, Y and W135) (MCV4) (Menveo, Novartis). This vaccine is included in the national vaccination schedule for adolescents and adults. In Europe Menveo is currently licensed for the immunization of people >11 years old. However, it is expected that a new guideline will be released for vaccination from age >2 years, as is already used in America.

In America the vaccine is called Menactra (Sanofi-Pasteur). Another 4-valent vaccine from Glaxo-Smith Klein is expected. This vaccine awaits approval from EMEA (i.e. European Medicines Agency) and has been assessed in children >1 year old.

The vaccine has proven to be immunogenic, effective and safe. A booster dose of the 4-valent meningococcal vaccine MCV4 is recommended in high-risk groups 3 years after the first dose.

It is worth noting that people who take booster vaccines with polysaccharide vaccines or polysaccharide conjugate vaccines have been found to show hypo-responsiveness. So the recommended strategy is to give the conjugate vaccine first and then follow with the polysaccharide vaccine.

It is well known that meningococcal serogroup B is the most common in Greece.

Although efforts have lagged behind in the development of a meningococcal b vaccine, a recent revolutionary technique has  enabled vaccine production, which will be available at the end of 2012 (Bexsero, Novartis). The new approach provides full access to all the proteins that a micro-organism can encode and, by computer analysis, it is possible to identify potential surface-exposed proteins in a reverse manner, starting from the genome rather than the micro-organism. The vaccine contains four proteins that are stable for all strains of meningococcus serogroup B in different geographical areas.

A study is in progress from the National Meningitis Center concerning the constructive differences of Greek meningococcal group B stains.

The first pneumococcal conjugate vaccine was 7-valent. The carrier protein is diphtheria toxin CRM 197 and the serotypes included are 4, 6B, 9V, 18C, 19F and 23F.

This vaccine implementation resulted in a sharp decrease in the incidence of invasive pneumococcal disease (meningitis and septicemia) as well as a decrease in pneumonia and otitis. It is important that the percentage of penicillin-resistant strains of pneumococcus was also decreased. An unexpected positive effect of the children’s vaccination was a decrease in infections at older ages because of the diminished spread of the pathogen. The vaccine schedule is a (3+1) dose for infants. Children >1–2 years, unvaccinated in infancy, receive two doses, and those over the age of 2 years one dose.

The vaccine intervention provoked the ‘replacement phenomenon’, with the emergence of other serotypes not included in the 7-valent vaccine. So there was a need for second-generation vaccines. The next vaccine was the 10-valent conjugate vaccine, with the D protein of non-typable H. influenzae as the carrier protein. The task of the vaccine was dual: to increase protection against pneumococcal infection with three more serotypes (1, 3 and 7F) and to offer protection against causative infections of the upper respiratory system (otitis and sinusitis) and exacerbation of chronic lung disease.

Recently a 13-valent vaccine has become available that includes the additional serotypes 1, 3, 5, 6A, 7F and 19A.  Of major importance is the increase in serotype 19A, which is responsible for invasive disease and resistance to penicillin. According to Greek epidemiological data, 19A is increasing and the 13-valent vaccine seems to offer protection for almost 89.7% of the pneumococcal serotypes. In practice the 7-valent vaccine has been completely replaced by the 13-valent pneumococcal vaccine. Recently the 13-valent vaccine has been recommended for adults of high-risk groups.

The fight against anti-bacterial meningitis with the production of vaccines appears likely to be fulfilled in the near future. However, the big challenge of the 21st century will be preventing the disease with the new vaccines, which must not be a privilege for only financially strong countries.

Papagrigoriou-Theodoridou Maria, Professor of Pediatrics, National & Kapodistrian University of Athens

Abstract

Bacterial meningitis continues to be a significant cause of mortality and morbidity world-wide. Empirical antimicrobial therapy must be started promptly in patients with bacterial meningitis. Penetration of the antibiotic across the blood–brain barrier and into the CSF (i.e. Cerebrospinal fluid) is the most important factor. The empirical antimicrobial therapy administered depends on the age of the patient, his/her vaccination coverage, risk factors and the prevalence of resistant bacteria in the area.  In this review, empirical antimicrobial regimens and the use of adjunctive therapy with dexamethasone are discussed.

Introduction

Eradication of the infecting organism from the CSF depends on antibiotics. Bactericidal antibiotics should be administered intravenously at the highest clinically validated doses to patients with suspected bacterial meningitis [1]. Several retrospective and prospective studies have shown that delay in antibiotic treatment is associated with adverse outcomes [2]. In patients with suspected bacterial meningitis for which immediate lumbar puncture is delayed pending brain imaging or the presence of disseminated intravascular coagulation, blood cultures must be obtained and antimicrobial treatment should be initiated immediately.

Empirical antimicrobial therapy

The selection of empirical antimicrobial regimens is designed to cover the probable pathogens, based on the age of the patient and specific risk factors (Table 1), with modifications if the CSF Gram stain is diagnostic. The ability of an antimicrobial agent to penetrate the blood–brain barrier (BBB) is the most important factor that determines whether efficient bacterial killing happens in the CSF [3, 4]. The environment of the CSF is unique, and antimicrobial agents are generally not metabolized significantly in the CSF. Therefore their concentration largely depends on their penetration and elimination through the BBB. In inflamed meninges, inflammatory cytokines act to damage and separate the tight junctions and increase the number of pinocytotic vesicles in the endothelial cells of the BBB, which enhances drug entry into the CSF [4]. BBB penetration is affected by the lipophilic properties, molecular weight, ionization (the CSF has a low pH with bacterial meningitis) and protein-binding ability of the drugs, inflammation of the meninges, and efflux transporters [3]. Lipophilic agents (i.e. fluoroquinolones and rifampicin) penetrate relatively well into the CSF even if the meninges are not inflamed, whereas hydrophilic agents (i.e. β-lactams and vancomycin) have a decreased penetration into the CSF in the absence of meningeal inflammation.

Antibacterial killing activity in the CSF also depends on the bacterial burden at the start of treatment. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration are established in laboratories using a bacterial inoculum size of 10⁴–10⁵ organisms/mL. However, some patients with bacterial meningitis (e.g. caused by group B streptococcus and Streptococcus pneumoniae), who have many Gram stain-positive organisms in the CSF, are likely to yield 10⁷–10⁸ organisms/mL, and MIC values can be 100–1000 times higher than would normally be expected. Therefore, careful monitoring of the response to antimicrobial treatment is necessary in patients with bacterial meningitis who have a high bacterial burden on the basis of the initial CSF Gram stain.

An important factor in the choice of empirical antimicrobial agents is the emergence of antimicrobial-resistant organisms, including S. pneumoniae that is resistant to penicillin and third-generation cephalosporins, and Gram-negative bacilli that are resistant to many β-lactam drugs. For example, the prevalence of S. pneumoniae strains that are relatively resistant to penicillin (MIC 0.1–1.0 μg/mL) or highly resistant to penicillin (MIC greater than 1.0 μg/mL) is increasing, and many of the penicillin-resistant pneumococci have reduced susceptibility to third-generation cephalosporins (i.e. cefotaxime and ceftriaxone) [3]. Treatment failures in bacterial meningitis as a result of multiresistant organisms have been reported [3]. Therefore, empirical treatment for patients with bacterial meningitis in areas where resistant S. pneumoniae strains are prevalent must include the addition of vancomycin (Table 1). However, penetration of vancomycin into the CSF can be reduced in the absence of meningeal inflammation and also in patients who receive adjunctive dexamethasone treatment [5].

Treatment of patients at risk of infection with Listeria monocytogenes must include a synergistic regimen containing ampicillin and an aminoglycoside (e.g. gentamicin), whereas a regimen for Gram-negative bacilli with a high likelihood of resistance (e.g. nosocomial meningitis) should also include an aminoglycoside (e.g. amikacin). However, the penetration of intravenously given aminoglycosides into the CSF remains variable or poor even in the presence of meningeal inflammation, and thus cannot be used as monotherapy for bacterial meningitis.

Antimicrobial susceptibility patterns must be established for all organisms isolated from the CSF. For example, although penicillins are the treatment of choice for meningococcal meningitis there have been recent reports of an increased incidence of resistant strains in Spain [3]. Therefore, third-generation chephalosporins should be used initially and treatment changed to penicillin once penicillin susceptibility is confirmed.

The use of newer antimicrobials has been reported from animal studies as well as from case reports and case series of patients infected with resistant organisms. Meropenem is less neurotoxic and has a lower risk of inducing seizures compared with imipenem. Recent clinical trials in both children and adults have indicated that meropenem is clinically and microbiologically comparable with cefotaxime and ceftriaxone [6]. Teicoplanin has been used alone in the experimental treatment of pneumococcal meningitis and meningitis caused by methicillin-resistant Staphylococcus aureus (MRSA). Fluoroquinolones have excellent in vitro activity against many of the meningeal pathogens, and good penetration in CSF. Recent studies have demonstrated that moxifloxacin and levofloxacin are efficacious when used to treat patients with meningitis caused by resistant organisms [4]. Daptomycin is a lipopeptide with potent bactericidal activity against multidrug-resistant Gram-positive organisms, but there is limited experience of its use in bacterial meningitis [4]. Finally, linezolid has been used successfully in patients with resistant pneumococcus, vancomycin-resistant enterococcus and MRSA [7]. However, the use of these new drugs should be limited to patients with multidrug-resistant organisms and only based on CSF culture results.

Adjunctive treatment

Neurological sequelae are common in survivors of meningitis, and include hearing loss, cognitive impairment and developmental delay. Hearing loss happens in 22–30% of survivors of pneumococcal meningitis, compared with 1–8% after meningococcal meningitis [3]. The beneficial effect of adjunctive dexamethasone treatment is evident in children and adults with bacterial meningitis, mainly pneumococcal. Dexamethasone should be given shortly before or when antibiotics are first given.  Rifampin should be added for patients treated with vancomycin.

In a 2007 Cochrane review, adjunctive treatment with dexamethasone was associated with lower mortality rates, and lower rates of severe hearing loss and long-term neurological sequelae [8]. However, recently the benefit of adjunctive dexamethasone has been questioned, as new meta-analyzes have indicated that although its use reduces hearing loss there is no observed reduction in death or severe neurological sequelae [9, 10]. Currently, corticosteroids are used as an adjunctive treatment in bacterial meningitis.

Table 1: Empirical antimicrobial regimens for the treatment of bacterial meningitis by age

References

1. Chaudhuri A, Martinez-Martin P, Kennedy PG, et al. EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS task force on acute bacterial meningitis in older children and adults. Eur J Neurol 2008;15:649–59.
2. Aronin SI, Pedruzzi P, Quagliarello VJ. Community-acquired meningitis: risk stratification for adverse outcome and effect of antibiotic timing. Ann Intern Med 1998;129:862–69.
3. Kim KS. Acute bacterial meningitis in infants and children. Review. Lancet Infect Dis 2010;10:32–42.
4. Miranda J, Tunkel AR. Strategies and new developments in the management of bacterial meningitis. Infect Dis Clin N Am 2009:23;925–943.
5. HCDCP. Treatment of bacterial meningitis: Guidelines on diagnosis and empirical treatment of infections (Chapter 9). Athens 2007.
6. Klugman KP, Dagan R. Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Antimicrob Agents Chemother 1995;39:1140–1146.
7. Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother 2007;41:296–308.
8. van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2007;1:CD004405.
9. van de Beek D, Farrar JJ, de Gans J, et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol 2010;9:254–263.
10. Spapen H, van Berlaer G, Moens M, Hubloue I. 1. Adjunctive steroid treatment in acute bacterial meningitis. “To do or not to do: that is the question”. Acta Clin Belg 2011;66:42–45.

The polysaccharide–encapsulated bacteria Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) are leading causes of serious bacterial infections, accounting for 80-90% of bacterial meningitis world-wide.

The rapid progression of symptoms and the need for immediate treatment have led to the necessity of applying molecular techniques for rapid and accurate diagnosis, providing important information for the management and control of the disease. These techniques have advantages in terms of speed, accuracy and high sensitivity.

By using the polymerase chain reaction (PCR), the detection, identification and standardization of a virion can be achieved in less than 2 hours, and this technique is less affected than conventional techniques by the administration of antimicrobial therapy before entering the hospital.

At the National Meningitis Reference Laboratory, multiplex PCR assays (mPCR) have been developed for the simultaneous detection of  the main causes of invasive disease, with high sensitivity and specificity [1–3], thus enabling rapid and cost-effective confirmation of bacterial meningitis cases, especially those in which early antibiotic treatment disqualifies detection by culture. From the data obtained, it has been shown that confirmed cases have increased dramatically from 44.4% (1998) to 91.4% (2011). Furthermore, 70.2% of the clinical specimens were confirmed only by PCR, in contrast to the 13.2% culture-confirmed cases.

Neisseria meningitidis

During the period 1999-2011, serogroup B was most predominant, in contrast to the two previous years (1997-1998) in which serogroup C predominated, with a high mortality rate. Serogroups A, W-135 and Y have been found in low percentages (Figure 1), although there has been an increase in serogroup Y cases in northern European countries in the last 3 years (2009-2011).

Correct identification can be achieved using rapid and sensitive DNA-based methods such as the following.

1. Multilocus sequence typing (MLST)

MLST is based on DNA sequencing of segments of seven housekeeping loci and is recognized as the gold standard for accurate strain characterization and epidemiological surveillance of meningococcus. As MLST is PCR based, characterization of N. meningitidis from clinical samples can be carried out successfully. Applying the MLST technique on N. meningitides-positive samples revealed that the most prevalent sequence types are ST-269 (20%), ST-162 (15%), ST-41/44 (14%) and ST-32 (13%). In addition, a considerable percentage (26%) did not belong to any clonal complex.

2. PorA

Determination of the nucleotide sequence of the PorA gene coding for the meningococcal class 1 outer membrane protein encoding the variable regions (VR) VR1 and VR2 resolves immunological typing issues, enabling the peptide sequence of all variants to be deduced. This is particularly important for the development of meningococcal vaccines that include PorA.  Analysis of the positive samples revealed that there is considerable diversity among the Greek clinical samples. The most prevalent PorA combination is P1.19-1, 15-11 for VR1 and VR2, respectively, followed by a combination of P1.22, 14.

3. Variable number tandem repeat analysis (VNTR)

In VNTR, the variability in the numbers of short tandem repeated sequences are indexed to create DNA fingerprints for epidemiological studies, and it has been shown to outperform MLST in discriminatory power. This has application in discriminating very closely related meningococcal strains as well as DNA samples isolated from clinical specimens. VNTR was a powerful tool for the investigation of four outbreaks in Athens, with which the clone responsible for the outbreaks was identified successfully, because the phenotypic and genotypic characteristics of the particular  clone were identical to those isolated from sporadic cases [4, 5].

4. Factor H-binding protein (fHbp)

The fHbp is a surface-exposed lipoprotein present in all N. meningitidis isolates. Its important activity is to bind the human complement factor H, which is thought to decrease the activation of the alternative pathway, thereby contributing to the ability of the organism to avoid complement-mediated killing by non-immune human serum or blood.

Analysis of our positive samples by this method showed that fHbp variant 21 is correlated with ST-162 cc, while variant 15 is found among strain ST-269. Further studies are ongoing because the presence of this gene is very important for the successful implementation of the new serogroup B vaccine in Greece.

5. Streptococcus pneumoniae

Streptococcus pneumoniae is the most common organism responsible for invasive bacterial infection in young children and is the second leading cause of bacterial meningitis in young children. Mortality in children with pneumococcal meningitis is at least twice as high as meningococcal meningitis.  Surveillance has been suboptimal because of either an absence of national networks or the use of Sentinel sites that may not reflect accurately the national burden, and it remains difficult to obtain the actual rates for some countries.

The increase in the number of cases in the last 10 years in Greece has led to the molecular identification and typing of S. pneumoniae directly from clinical samples with the use of mPCR assays. A high percentage (54%) of the samples was confirmed only by PCR, in contrast with culture-confirmed cases (33.9%). From the results obtained, the number of cases for the period 2006-2008 has been decreased by 50% compared with the previous years (2000-2005). A further decrease has been noted for the last 3 years (2009-2011) (Figure 2). In addition, molecular typing of the nine most frequent pneumococcal serotypes has  revealed that there was an increase in the  serotypes 19A, 3 and 1 after the introduction of the 7-valent vaccine in Greece (2005) (Figure 3).

Haemophilus influenzae

Haemophilus influenza has been an important cause of serious invasive diseases such as meningitis and septicemia in children under the age of 5 years. This led to the introduction of vaccination with H. influenzae type b (Hib) polysaccharide conjugate vaccines, leading to dramatic reductions in Hib disease in many countries across the globe.  The application of molecular techniques for the identification H. influenzae revealed that, although there has been a dramatic reduction in Hib cases, there is an increase in non-b H. influenzae cases (Figure 4). Further serotyping with the application of mPCR has revealed that all cases are non-typable. Considering the age of the patients, most of the cases were from patients >20 years of age, and in particular age groups 40-60 years old and >60 years old.

References

1. Tzanakaki G, Tsopanomichalou M, Kesanopoulos K, et al. Simultaneous single-tube PCR assay for the detection of N. meningitidis, H. influenzae type b and streptococcus pneumoniae. Clin Microb Infect 2005;11:386-390.
2. Xirogianni A, Tzanakaki G, Karagianni E, et al. Development of a single-tube polymerase chain reaction assay for the simultaneous detection of Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus spp. directly in clinical samples. Diagn Microbiol Infect Dis 2009;63:121-126.
3. Drakopoulou Z, Kesanopoulos K, Sioumala M, et al. Simultaneous single tube assay for the identification of 5 most common meningococcal serogroups directly in clinical samples. FEMS Immunol Med Microbiol 2008;53:178-182.
4. Tzanakaki G, Kesanopoulos K, Yazdankhah S, et al. Conventional and molecular investigation of meningococcal isolates in relation to two outbreaks in the area of Athens, Greece. Clin Microbiol Infect 2006;12:1024-1026
5. Kesanopoulos K, Tzanakaki G, Sioumala M, Kourea-Kremastinou J. Direct application of variable number tandem repeats polymerase chain reaction in clinical samples obtained from patients with meningococcal disease. Diagn Microbiol Infect Dis 2010;66:124-127.

Introduction

Bacterial meningitis is considered to be a disease of high interest and one of the issues that public health is often concerned with. Bacterial meningitis is defined as an acute infection of the central nervous system and meninges. The infection is usually caused by Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib) and, less often, beta-hemolytic Streptococcus group A, Gram (–) bacteria and Listeria monocytogenes [1,2].

Neisseria meningitidis, S. pneumoniae and Hib cause more than 75% of all cases of bacterial meningitis and 90% of bacterial meningitis in children [1]. Recently, because of the systematic application of mandatory vaccination, a significant reduction in Hib meningitis cases has been recorded, and a similar reduction in pneumococcal meningitis is expected. Streptococcus pneumoniae is the main cause in adults, followed by N. meningitidis and then L. monocytogenes, which shows an increase in the >50 year age group (and also in neonates) [2]. The less common bacterial causes of meningitis, such as Staphylococcus aureus, Enterobacteriaceae, Streptococcus group b and L. monocytogenes, occur in people with specific susceptibilities, often those who are immunocompromised [1,2].

Infectious agents can be transmitted by direct, person-to-person, contact, including respiratory droplets. Asymptomatic carriers of N. meningitidis, which account for 10% of the general population and up to 25% of juvenile and young adults, are usually the source of transmission [3].

Epidemiological surveillance

In Greece, all meningitis cases come under epidemiological surveillance, including meningococcal disease cases (which are the main target of the surveillance) and other bacterial and aseptic meningitis cases.

The Department of Epidemiological Surveillance and Intervention of the Hellenic Center for Disease Control and Prevention (HCDCP) collects data from all meningitis cases from all over the country through the mandatory notification system, by the directorates of public health and the National Reference Center for Meningitis in the National School of Public Health. Additional information regarding the clinical signs and laboratory findings of each case is obtained by communicating with the hospital where each case is hospitalized. In order to take all the necessary preventive measures (chemoprophylaxis when needed and/or immunization) to avoid disease transmission to all individuals who have been in close contact with a patient, it is essential to assign each case to its cause.
Data are recorded and analyzed by week, month, year, prefecture, causative agent, classification, age and gender, in order to detect outbreaks.

Epidemiological data for meningitis (meningococcal disease and bacterial meningitis) in Greece 1998-2011

Meningococcal disease

Time trend

For the period 1998-2011, 1,952 cases of meningococcal disease were reported to HCDCP; the number of cases ranged between 50 and 263 per year and the mean annual notification rate was 1.29 cases per 100,000 population (Figure 1). During this period, the notification rate consistently decreased.

Age distribution

For the period 1998-2011, the number of cases of meningococcal disease, with known date of birth of the patient, was 1,843 (109 cases with unknown date of birth). The disease appeared to be more frequent among children in the 0-4 year age group, with a mean annual notification rate of 9.1 cases per 100,000 population. The mean annual notification rate decreased progressively in the 5-14 and 15-24 year age groups (3.8 cases and 1.3 cases per 100,000 population, respectively). In other age groups (over 25 years), the mean annual notification rate did not exceed 0.3 cases per 100,000 population (Figure 2).

Laboratory data

During 1998-2011, 78% of the meningococcal disease cases were laboratory confirmed. In the same period, 63.7% (1,244) of meningococcal disease cases were serotyped and 1,062 of them (54.4%) were identified as belonging to one of five serotypes (A, B, C, W135 and Y), which are responsible for the majority of invasive meningococcal infections world-wide. In Greece, 61% of meningococcal disease cases are caused by serotype B, followed by serotype C (Figure 3).

Fatality–mortality

During 1998-2011, 117 deaths due to meningococcal disease were recorded, indicating a case fatality rate of 6%. The highest fatality rate was observed in the year 1998 (12.3%) and the lowest fatality rate in the year 2011 (2%). The mean annual mortality rate for the period 1998-2011 was 1.3 deaths per 100,000 population.

Other bacterial non-meningococcal meningitis

Time trend

For the period 1998-2011, 2,407 cases of bacterial non-meningococcal meningitis were reported to HCDCP; the number of cases ranged between 60 and 250 per year (annual average of total number of cases, 172; total number of cases, 2,407). The mean annual notification rate of other bacterial meningitis for the period 1998-2011 in Greece was 1.6 per 100,000 population (Figure 1). The annual notification rate of bacterial non-meningococcal meningitis, for the period 1998-2008, had increased but for the next 3 years (2009-2011) it decreased (Figure 2).

Age distribution

During 1998-2011, the number of cases of bacterial non- meningococcal meningitis, with known date of birth, totaled 2,164 (243 cases with unknown date of birth). The disease was more frequent among children in the 0-4 year age group and the mean annual notification rate was 7.9 cases per 100,000 population. The mean annual notification rate was progressively reduced in the 5-14 and 15-24 year age groups (2.4 cases and 0.8 cases per 100,000 population, respectively), while in the age group >25 years old the mean annual notification rate showed a progressive increase, with a highest value of 1.5 cases per 100,000 population in the age group >65 years old (Figure 3).

Laboratory data

During 1998-2011, 41% of the bacterial non-meningococcal meningitis cases were laboratory confirmed. In the same period,  47.3% (1,139 cases) of the total number of cases with clinical and laboratory findings compatible with bacterial non-meningococcal meningitis were laboratory tested and presented some sort of micro-organism.  The main micro-organisms identified are summarized in Table 1; Streptococcus pneumoniae obviously occurred most often.

Table 1: Distribution of bacterial non-meningococcal meningitis by causative agent, Greece, 1998-2011

Fatality–mortality

For the period 1998-2011, 114 deaths due to bacterial non-meningococcal meningitis were recorded, indicating a case fatality rate of 4.7%. The highest fatality rate was observed in the year 2000 (7%) and the lowest fatality rate in the year 1998 (1.6%). The mean annual mortality rate for the period 1998-2011 was 0.07 deaths per 100,000 population.

Preventive measures

A. Meningococcal disease

In the case of meningococcal disease, the following actions should take place.

• The case must be reported to HCDCP.
• The patient should be isolated for 24 hours after the beginning of the necessary antibiotic therapy [1].
• The disinfection of schools or any other public places is of no use to prevent disease transmission.
• Quarantine is not applicable [1].
• Close contact prophylaxis: all individuals who were in close, high-risk contact with the invasive meningococcal disease patient for up to 7 days before the onset of symptoms, have to receive chemoprophylaxis as soon as possible, so long as there are no contraindications [1,4]. The incidence of secondary transmission to close contacts seems to be higher during the first days of initial infection and chemoprophylaxis has to be received 24 hours after the identification of the first case [5,6]. It is useless to receive chemoprophylaxis after 10 days of high-risk contact.
• Rifampicin is the drug of choice [1,2,4,7], given twice daily for 2 days: infants <1 year of age receive 5 mg/kg, infants >1 year of age receive 10 mg/kg and adults receive 600 mg. Pregnant women sound not receive rifampicin. A single intramuscular dose of ceftriaxone, 250 mg for adults and 125 mg for children <15 years, can also be administered, or a single oral dose of ciprofloxacin 500 mg given to adults. These antibiotics can reduce (90–95%) [8–10] and effectively eradicate nasopharyngeal carriage of N. meningitidis.
• A high-risk contact is defined as a close and prolonged ( >8 hours) contact with the initial patient or direct contact with the patient’s saliva or nasopharyngeal secretions, for a period of 7 days preceding the onset of symptoms until 24 hours after the beginning of the antibiotic therapy [11]. High-risk contacts include:
  • household contacts
  • people living under crowded conditions and those who share the same dormitory
  • individuals who were in close contact with the initial patient or the patient’s respiratory secretions (such as close friends and sexual partners, or health care worker contacts who were directly exposed to the patient or the patient’s  respiratory secretions, e.g. when carrying out  intubation or mouth-to-mouth resuscitation)
  • travel contacts seated immediately adjacent to a patient on a flight of more than 8 hours duration\
  • children and adults who had contact with the patient within the patient’s educational institution (kindergarten, primary/high school, university).

If a meningococcal disease case occurs in kindergarten, all children and personnel attending the same classroom must receive chemoprophylaxis. If the initial patient presents from a primary or high school, chemoprophylaxis must be given only to close contacts (close friends, adjacent pupils, etc.) of the patient and not to all classmates. Individuals who were involved in the patient’s extracurricular activities (tutorial classes, gyms, etc.) and had close contact should also receive chemoprophylaxis.

Continuous monitoring of the patient’s environment (household, professional, kindergarten, school, etc.) for other suspicious cases is critical. Monitoring for other meningococcal disease cases must be carried out for the period of 7 days preceding the onset of the first patient’s symptoms up to 24 hours after the beginning of contact antibiotic therapy. Onset of fever in a household or other group contact, within 10 days of exposure, is considered a critical point for immediate medical assessment and application of appropriate diagnostic and therapeutic measures.

The available vaccine prevents meningitis caused by the following N. meningitidis serotypes: A, C, Y and W135. A vaccine for the prevention of meningitis caused by N. meningitidis serotype B is not available internationally but it is expected to be within the next few years.

B. Streptococcus pneumoniae

Chemoprophylaxis to close, high-risk contacts of pneumococcal meningitis case is not recommended. Vaccination against S. pneumoniae has proven to be an effective measure for preventing invasive pneumococcal disease.

C. Haemophilus influenzae type b meningitis

If Hib meningitis occurs, children <4 years old who are not fully vaccinated and household adult close contacts should receive chemoprophylaxis. If only one case occurs in the kindergarten, a recommendation of chemoprophylaxis is debatable. If two cases of Hib meningitis occur in a kindergarten in a 60-day period, where children are unvaccinated or not fully vaccinated, then all children and personnel should receive chemoprophylaxis. Rifampicin is the drug of choice, to be given daily at a dose of 20 mg/kg (maximum 600 mg/kg) for 4 days. Vaccination is an effective measure for disease prevention.

References

1.    Heymann DL, ed. Control of communicable diseases manual, 19th edn. American Public Health Association: 2008, pp. 414-426.

2.    Tunkel A, Scheld M. Acute meningitis In: Mandell G, Bennett J, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, 6th edn. Philadelphia, PA: Elsevier/Churchill Livingston, 2005; pp. 1083-1126.

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