Community-acquired bacterial meningitis in adults: in-hospital prognosis, long-term disability and determinants of outcome in a multicentre prospective cohort.

OBJECTIVES: To identify factors associated with unfavourable in-hospital outcome (death or disability) in adults with community-acquired bacterial meningitis (CABM). METHODS: In a prospective multicentre cohort study (COMBAT; February 2013 to July 2015), all consecutive cases of CABM in the 69 participating centres in France were enrolled and followed up for 12 months. Factors associated with unfavourable outcome were identified by logistic regression and long-term disability was analysed. RESULTS: Among the 533 individuals enrolled, (Streptococcus pneumoniae 53.8% (280/520 isolates identified), Neisseria meningitidis 21.3% (111/520), others 24.9% (129/520)), case fatality rate was 16.9% (90/533) and unfavourable outcome occurred in 45.0% (225/500). Factors independently associated with unfavourable outcome were: age >70 years (adjusted odds ratio (aOR) 4.64; 95% CI 1.93-11.15), male gender (aOR 2.11; 95% CI 1.25-3.57), chronic renal failure (aOR 6.65; 95% CI 1.57-28.12), purpura fulminans (aOR 4.37; 95% CI 1.38-13.81), localized neurological signs (aOR 3.72; 95% CI 2.29-6.05), disseminated intravascular coagulation (aOR 3.19; 95% CI 1.16-8.79), cerebrospinal fluid (CSF) white-cell count <1500 cells/µL (aOR 2.40; 95% CI 1.42-4.03), CSF glucose concentration (0.1-2.5 g/L: aOR 1.92; 95% CI 1.01-3.67; <0.1 g/L: aOR 2.24; 95% CI 1.01-4.97), elevated CSF protein concentration (aOR 1.09; 95% CI 1.03-1.17), time interval between hospitalization and lumbar puncture >1 day (aOR 2.94; 95% CI 1.32-6.54), and S. pneumoniae meningitis (aOR 4.99; 95% CI 1.98-12.56), or meningitis other than N. meningitidis (aOR 4.54; 95% CI 1.68-12.27). At 12 months, 26.7% (74/277) had hearing loss, 32.8% (87/265) depressive symptoms, 31.0% (86/277) persistent headache, and 53.4% had a physical health-related quality of life (142/266) <25th centile of the distribution of the score in the general French population (p < 0.0001). CONCLUSIONS: The burden of CABM (death, disability, depression, impaired quality of life and hearing loss) is high. Identification of cases from the first symptoms may improve prognosis. CLINICALTRIAL: Gov identification number: NCT01730690.

Identification of Neisseria meningitidis by MALDI-TOF MS may not be reliable.

OBJECTIVES: The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique is increasingly used in hospital laboratories for routine identification of microorganisms. However, its performance is variable, particularly for highly variable species such as Neisseria meningitidis. Reliable identification of N. meningitidis is crucial for the management of invasive meningococcal disease by rapid implementation of treatment and preventive measures among close contacts. We assessed and improved N. meningitidis identification by MALDI-TOF MS by enriching the databases with reference strains identified using whole genome sequencing (WGS) as a reference standard. METHODS: We first built a collection of 24 strains from several species of the Neisseria genus that we characterized by WGS. This collection was added to the available database to test by MALDI-TOF MS another collection of 32 clinical isolates received between 2015 and 2017 at the French National Reference Laboratory for Meningococci. RESULTS: Using the commercially available library of mass spectrometry profiles, only 67% (95% confidence interval (CI), 47-82) concordance was observed at the species level between MALDI-TOF MS and WGS characterization. However, when the new enriched reference collection was used on the second subset of isolates, the identification of N. meningitidis was significantly improved (p 0.0016), showing 92% (95% CI, 75-98) specificity while that of the manufacturer's database alone was 52% (95% CI, 34-70). CONCLUSIONS: Our data highlight the need to update the available MALDI-TOF MS database with high-quality references to enhance the identification of N. meningitidis and avoid unwarranted preventive measures or missing identification.

Characterization of invasive Neisseria meningitidis strains isolated at the Children's Hospital of Tunis, Tunisia.

Neisseria meningitidis, a leading cause of bacterial meningitis and other serious infections, is responsible for approximately one-third of cases of bacterial meningitis in the Children's Hospital of Tunis. The serogroup distribution, antibiotic susceptibility and antigenic and molecular characteristics of N. meningitidis isolates were determined in patients aged 3 days-13 years between February 1998 and June 2013. In all 107 invasive strains of N. meningitidis were isolated. Reduced susceptibility to penicillin G was seen in 55.7% of isolates, with a low level of resistance in all cases; 28.4% showed a low level of resistance to amoxicillin. Serogroup B isolates were the most frequent (80.4%), followed by serogroups C (12.2%) and A (5.6%). Isolates of serogroup A had the same antigenic formula (A:4:P1.9), the same variable regions VR1, VR2 and VR3, and belonged to the same clonal complex (CC5). Isolates of serogroups B and C were more heterogeneous with several antigenic formulae. The most frequent clonal complex in these isolates was CC35. Serogroup B accounted for a large percentage of our isolates with marked diversity.

Characterization of invasive Neisseria meningitidis strains isolated at the Children's Hospital of Tunis, Tunisia

Neisseria meningitidis, a leading cause of bacterial meningitis and other serious infections, is responsible for approximately one-third of cases of bacterial meningitis in the Children's Hospital of Tunis. The serogroup distribution, antibiotic susceptibility and antigenic and molecular characteristics of N. meningitidis isolates were determined in patients aged 3 days-13 years between February 1998 and June 2013. In all 107 invasive strains of N. meningitidis were isolated. Reduced susceptibility to penicillin G was seen in 55.7% of isolates, with a low level of resistance in all cases; 28.4% showed a low level of resistance to amoxicillin. Serogroup B isolates were the most frequent [80.4%], followed by serogroups C [12.2%] and A [5.6%]. Isolates of serogroup A had the same antigenic formula [A:4:P1.9], the same variable regions VR1, VR2 and VR3, and belonged to the same clonal complex [CC5]. Isolates of serogroups B and C were more heterogeneous with several antigenic formulae. The most frequent clonal complex in these isolates was CC35. Serogroup B accounted for a large percentage of our isolates with marked diversity

La bactérie Neisseria meningitidis, l'une des causes principales de méningite bactérienne et d'autres infections graves, est responsable d'environ un tiers des cas de méningite bactérienne à l'Hôpital d'enfants de Tunis. La distribution par sérogroupe, la sensibilité aux antibiotiques et les propriétés antigéniques et moléculaires des isolats de N. meningitidis ont été déterminées chez des patients âgés de 3 jours à 13 ans entre février 1998 et juin 2013. En tout, 107 souches invasives de N. meningitidis ont été isolées. Une sensibilité réduite à la pénicilline G a été observée dans 55,7% des isolats, avec un bas niveau de résistance pour tous les cas ; et 28,4% ont montré un bas niveau de résistance à l'amoxicilline. Les isolats du sérogroupe B étaient les plus fréquents [80,4%], suivis par les sérogroupes C [12,2%] et A [5,6%]. Les isolats du sérogroupe A avaient la même formule antigénique [A:4:P1.9], les mêmes régions variables VR1, VR2 et VR3, et appartenaient au même complexe clonal [CC5]. Les isolats des sérogroupes B et C étaient davantage hétérogènes, avec plusieurs formules antigéniques. Le complexe clonal le plus fréquent de ces isolats était CC35. Le sérogroupe B comptait pour un pourcentage élevé des isolats avec une diversité marquee

[Complement terminal fraction deficiency revealed at first invasive meningococcal infection]. / Déficit en fraction terminale du complément révélé dès le premier épisode d'infection invasive à méningocoque.

Prevalence of complement protein deficiency in the general population is rare and its association with an increased risk of meningococcal infection is well established. However, management of these patients with potentially serious infections and indications warranting a search for such a deficiency have not met with consensus. We report the case of a 3-year-old child with no significant medical history who consulted in an emergency department for a fever after a stay in Senegal. Medical explorations concluded in septicemia and meningococcal W meningitis with a favorable outcome. Secondarily, we highlighted a complete deficiency of complement component C6. We diagnosed the same deficit in his twin sister who presented no infection. A long-term prophylactic antibiotic therapy and a meningococcal conjugate vaccine A,C,Y,W were set up for the twins. Recurrent invasive meningococcal infections and highlighting certain meningococcal serogroups are currently indications for complement protein exploration. We suggest expanding the search criteria for a complement protein deficiency after a single event of invasive meningococcal infection. This is an easy, rapid, and cost-effective screening system by dosage of CH50, C3, C4, and AP50. The arrival of the new meningococcal B vaccine will contribute to improving these patients' care. Family screening is necessary for prophylactic therapy.

[Changes in bacterial meningitis in French children resulting from vaccination]. / Évolution des méningites bactériennes de l'enfant en France sous l'effet des vaccinations.

BACKGROUND: For the past 20 years, three vaccines against the three main bacterial species implicated in meningitis in children have been included in the French vaccine calendar: Haemophilus influenzae b in 1993, 7-valent pneumococcal conjugate vaccine (PCV7) in 2003 (replaced by 13-valent in 2010) and Neisseria meningitidis C in 2009. The French active surveillance network from the GPIP/ACTIV monitors the change in the epidemiological, clinical, and biological features of bacterial meningitis due to vaccine use. METHODS: Over a 12-year period, 233 pediatric wards working with 168 microbiology departments throughout France were asked to report all cases of bacterial meningitis. RESULTS: From January 2001 to December 2012, 4808 bacterial meningitis cases were reported. Between 2001 and 2012, the number of pneumococcal meningitis (PM) cases decreased by 23.4%, and by 32.2% for children less than 2 years old. During this period, the proportion of cases attributable to PCV7 and six additional PCV13 types decreased from 63.3% to 8.1% and 83.7% to 32.4%, respectively. In 2012, the main vaccine types (accounting for 25.8% of cases) were 7F (12.2%), 19A (6.8%), and 19F (6.8%), and the most frequent non-vaccine types were 12F (14.9%), 24F (14.9%), 15B/C (6.8%), 22F (6.8%), and 10A (5.4%). In 2012, the rate of strains with decreased susceptibility to cefotaxime/ceftriaxone (MIC>0.5 µg/mL) represented less than 3% of cases, with no identified resistant strain since 2010 (MIC>2 µg/mL). Between 2001 (n=67) and 2012 (n=9), the number of NmC meningitis cases decreased by 87%. CONCLUSION: With more than 4800 bacterial meningitis cases reported in 12 years, this nationwide survey provides essential information on the microbiological and clinical characteristics of bacterial meningitis (epidemiology or resistance data). These results could lead to changing antibiotic treatment of pneumococcal meningitis before the results of antibiotic susceptibility tests.

[Impact of corticosteroids in the immediate management of invasive meningococcal disease associated with hyperinvasive strains of the ST-11 clonal complex in children]. / Impact des corticoïdes dans la prise en charge immédiate des infections invasives à méningocoque liées aux souches hyper-invasives du complexe clonal ST-11 chez l'enfant.

OBJECTIVES: We used data from the Groupe de pathologie infectieuse pédiatrique and Association clinique et thérapeutique infantile du Val-de-Marne (GPIP/ACTIV) National Survey of Bacterial Meningitis in children and the National Reference Center for Meningococci (CNRM) microbiological data to assess the potential impact of corticosteroids on the immediate management of invasive meningococcal disease (IMD) associated with different genotypes, including highly pro-inflammatory strains of the ST-11 clonal complex (genotype ST-11). METHODS: From 2001 to 2009, 259 pediatric wards and 168 microbiology laboratories distributed throughout France prospectively included all under-18-year-old patients with IMD (meningitis or purpura fulminans). The strains were sent to the CNRM for genotyping. We linked the ACTIV clinical data of IMD cases, where information on corticosteroid therapy was available, to strains isolated by the CRNM. RESULTS: A total of 1981 IMD cases were identified during the 8-year study, 805 cases (712 [88.5%] bacterial meningitis and 93 [11.5%] purpura fulminans) had steroid treatment data (33.8% received corticosteroids). The genotype of the strains was available for 410 patients (24.4% related to genotype ST-11; 100 patients). For all cases and regardless of the corticosteroids, mortality was significantly associated with the genotype ST-11 (OR=2.39, 95% CI [1.29; 4.42], P=0.004). For all cases and regardless of the genotypes of the isolates, mortality was also significantly higher for children with than without corticosteroid therapy (12.7% versus 4.5%, P<0.001). However, this treatment had been prescribed more frequently in severe cases, including shock, PF, coma and/or mechanical ventilation. For children who did not receive corticosteroids, the mortality rate was significantly higher with genotype ST-11 compared to other genotypes (OR=4.68 [1.91, 11.46], P=0.001). This difference disappeared in children who received corticosteroids. CONCLUSION: This study indicates that in the absence of corticosteroids, higher mortality in invasive meningococcal disease is associated with the ST-11 clonal complex strains. This suggests a possible positive effect of corticosteroid therapy depending on the genotype of the strain involved.

Meningococcal carriage during a clonal meningococcal B outbreak in France.

The aim of this study performed in Normandy, France, was to analyze the pharyngeal meningococcal carriage at the peak of a clonal meningococcal B outbreak, which was subsequently controlled using an outer membrane vesicle vaccination. This cross-sectional study included randomly selected subjects aged 1-25 years. Carriers and non carriers were compared using unconditional logistic regression. Among the 3,522 volunteers, there were 196 (standardized rate: 6.46 %) Neisseria meningitidis carriers, of which there were only five with the outbreak strain (B:14:P1.7,16/ST-32; standardized rate: 0.18 %). From the multivariate analysis, older age, smoking, higher degree of socialization, and social deprivation appear to favor the carriage of all the strains included. Prior antibiotic treatment up to 12 months before swabbing, even with ß-lactam, was protective against carriage. Our data indicate a low overall meningococcal carriage rate with a surprising protective effect of prior antibiotic exposure. The observed low carriage rate of the epidemic strain (B:14:P1.7,16/ST-32) contrasts with the high incidence of invasive meningococcal diseases (IMD) due to this strain. Hence, our data underline the high virulence of the strain and suggest a low level of natural immunity of the population against this strain. Although highly resource-consuming, carriage studies are helpful in guiding the implementation of control measures of IMD, such as mass vaccination or chemoprophylaxis.

Management of a rifampicin-resistant meningococcal infection in a teenager.

We report a secondary case of rifampicin-resistant meningococcal disease and our experience in managing contact cases. Rifampicin resistance resulting from rpoB gene mutations is still uncommon enough that changing the current recommendations for chemoprophylaxis is unwarranted. However, ensuring limited but appropriate chemoprophylaxis may prevent the development of antimicrobial resistance. Thus, the definition of contact cases should be strictly respected. In the case of culture-positive Neisseria meningitidis, in vitro susceptibility testing to rifampicin must be systematically performed in order to detect rifampicin-resistant strains and, thus, institute appropriate prophylaxis in order to prevent secondary transmission.

A cluster of meningococcal disease caused by rifampicin-resistant C meningococci in France, April 2012.

In April 2012, a cluster of two cases of meningococcal disease caused by rifampicin-resistant C meningococci was reported in the Champagne-Ardenne region, France. The two cases occurred in a student population living in the same town but studying at different schools. Bacteriological and epidemiological investigations of cases have shown that the isolates of both cases were non-differentiable.

[Paediatric meningococcal meningitis in France: ACTIV/GPIP network results]. / Méningites à méningocoques de l'enfant en France: résultats de l'observatoire ACTIV/GPIP.

BACKGROUND: The GPIP/ACTIV (Groupe de Pathologie Infectieuse Pédiatrique and Association Clinique et Thérapeutique Infantile du Val de Marne) set up an active surveillance network to analyze the epidemiological, clinical and biological features of meningococcal meningitis. METHODS: French pediatric wards working with 166 microbiology laboratories enrolled all children (0-18 years old) with bacterial meningitis. Risk factors, signs and symptoms, vaccination status, cerebrospinal fluid analysis, treatments and case fatality rate were recorded. RESULTS: Since 2001, 1661 meningococcal meningitis were reported among 3769 (44.1%) bacterial meningitis. Mean age was 4.4- year- old (± 4.8, median 2.5) and 2/3 cases occurred in children under 5- year- old (68.8%). Serogroup B (61.3%) is preponderant following by serogroup C (27.0%). 27.5% of children had received an antibiotic treatment 24 hours before lumbar puncture. A shock is reported in 31.0% of cases. No cases of meningococcal meningitis C has been reported in children vaccinated with a conjugate vaccine. Two children vaccinated with MenBvac(®) vaccine had a meningitis B14:P1.7,16. Global case fatality rate was 6.5% but was higher (9.2%) for serogroup C than for serogroup B (5.9%) (p=0.02). CONCLUSION: This is among the largest series of microbiologically documented meningococcal meningitis to date (1661 cases). In France, meningococcal is responsible for approximately 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could control the burden of meningococcal meningitis.

Molecular characterization of resistance to rifampicin in clinical isolates of Neisseria meningitidis.

Among 3904 meningococcal isolates collected between October 2002 and June 2007 by the French Meningococcal Reference Centre, eight (0.20%) were resistant to rifampicin (Rif-R; MIC >1 mg/L) and 27 (0.69%) were intermediate-resistant to rifampicin (Rif-I; MICs between 0.38 mg/L and 1 mg/L) according to the E-test method. The MICs determined by agar dilution were lower, eliminating the E-test intermediate category. All Rif-R isolates had mutations in the rpoB gene, resulting in substitutions at or near amino acid position 552, which were absent in non-resistant isolates. These data suggest that a rifampicin clinical breakpoint of 1.0 mg/L should be adopted for Neisseria meningitidis.

Hyperinvasive genotypes of Neisseria meningitidis in France.

Clinical isolates of Neisseria meningitidis from cases of meningococcal disease, collected between January 2000 and December 2004, were identified and typed at the French National Reference Centre. A representative subset of 546 isolates from among 2882 isolates was further genotyped by multilocus sequence typing to determine their genetic lineages (clonal complexes) and the degree of diversification among different clonal complexes. Representative isolates of the main clonal complexes were tested for their virulence in mice and for proapoptotic effects on human epithelial cells. High genetic diversity in some genetic lineages (ST-32 and ST-41/44) was correlated with heterogeneity in virulence in mice and proapoptotic effects on human epithelial cells. In contrast, the homogeneous genetic structure of isolates of the ST-11 clonal complex, regardless of their serogroup, correlated positively with a fatal outcome of the infection, increased virulence in mice and increased proapoptotic effects on human epithelial cells.

Neisseria meningitidis serogroup W135 in Portugal: presence of the ST-11/ET-37 clonal complex.

Invasive serogroup W135 Neisseria meningitidis strains were isolated in Portugal between 1995 and 2002. Nine of 12 isolates showed "Hajj-2000"-associated phenotypes and belonged to the ST-11/ET-37 clonal complex. Pulsed-field gel electrophoresis clustered the ST-11/ET-37 isolates together with the "Hajj-2000" strain although the profiles were distinguishable.

[Characteristics of meningococcal meningitis in children in France]. / Caractéristiques des méningites à méningocoque de l'enfant en France.

BACKGROUND: In France, meningococcal meningitis account for 50% of bacterial meningitis in children. The GPIP/ACTIV (Groupe de Pathologie Infectieuse Pédiatrique and Association Clinique et Thérapeutique Infantile du Val de Marne) set up an active surveillance network to analyze the epidemiological, clinical and biological features of meningococcal meningitis. METHODS: From 2001 to 2007, 252 French paediatric wards working with 166 microbiology laboratories enrolled all children (0-18 years old) with bacterial meningitis. Risk factors, signs and symptoms, vaccination status, cerebrospinal fluid analysis, treatments and case fatality rate were recorded. RESULTS: During the period of the study, 1344 meningococcal meningitis were reported among 2951 (45.5%) bacterial meningitis. Mean age was 4.4 years (+/-4.7, median 2.5) and 2/3 cases occurred in children under 5 years (68.5%). Serogroup B (59.1%) was preponderant following by serogroup C (28.9%). 25% of children had received an antibiotic treatment 24hours before lumbar puncture. A shock was reported in 31.3% of cases. Cerebrospinal fluid culture was positive in 73% of cases. All N. meningitidis isolates were susceptible to cefotaxime and ceftriaxone while 41.6% and 25.7% showed reduced susceptibility to penicillin and amoxicillin respectively. Two cases of meningitis due to isolates of serogroups C and B were reported in two children that were respectively vaccinated using A+C plain saccharide vaccine or two doses of MenBvac vaccine. All patients had received beta-lactamin. Global case fatality rate was 6.6% but was higher (9.9%) for serogroup C than for serogroup B (5.5%) (p=0,007). CONCLUSION: This study is among the largest series of microbiologically documented meningococcal meningitis to date (more than 1300 cases). In France, meningococal is responsible for 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could lessen considerably the burden of meningococal meningitis.

[3rd Workshop on Epidemiology, Prevention and Treatment of Invasive Meningococcal Disease in Würzburg 2006]. / 3. Würzburger Workshop zur Epidemiologie, Prävention und Therapie der invasiven Meningokokkenerkrankung 2006.

On October 5th, 2006, the German Reference Centre for Meningococci (NRZM) held the 3rd Workshop on Epidemiology, Prevention and Treatment of Invasive Meningococcal Disease, in collaboration with the German Society for Hygiene and Microbiology (DGHM). Given the recent recommendation of the German Standing Committee on Vaccination (STIKO) for conjugate meningococcal C vaccination of all children in the second year of life, observations from meningococcal C conjugate vaccination campaigns in other European countries were presented and compared to the German situation. Moreover, the newly implemented cluster detection routines employed at the NRZM and their integration into the interactive geographical information system EpiScanGIS were shown. Based on recent experiences from regional outbreaks in Oberallgäu, Sangerhausen, and Greater Aachen, examples for public health intervention were given at the conference. In addition, current developments in the area of meningococcal research, as well as trends in antimicrobial susceptibility were covered. Finally, the latest evidence concerning the clinical management and chemoprophylaxis of this invasive bacterial disease was discussed.

[Respiratory virosis and invasive bacterial superinfections. The case for influenza and meningococcal diseases]. / Viroses respiratoires et surinfections bactériennes invasives. Le cas de la grippe et des méningococcies.

The pathophysiology of bacterial superinfections of influenza, including meningococcal diseases, remains obscure. Mice, normally resistant to the meningococcus, become susceptible after previous influenza A virus infection. This immunosuppressive effect is transitory and is associated with the peak of the inflammatory anti-virus reaction. These results underline the importance of preventing bacterial superinfections of influenza by the surveillance of any relapse of fever after improvement of the influenza syndrome. At the community level, influenza vaccine, beside its specific effects, might also prevent many cases of invasive superinfections, including meningococcal diseases.