Matthias Klein, Christopher Höhne, Barbara Angele, Tobias Högen, Hans-Walter Pfister, Hatice Tüfekci, Uwe Koedel

Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis.

Deng, L., Mu, R., Weston, T. A., Spencer, B. L., Liles, R., Doran, K. S.

Streptococcus agalactiae (Group B Streptococcus, GBS) is often a commensal bacterium that colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, in immune-compromised individuals, particularly the newborn, GBS may transition to an invasive pathogen and cause serious disease. Despite currently recommended intrapartum antibiotic prophylaxis for GBS-positive mothers, GBS remains a leading cause of neonatal septicemia and meningitis. To adapt to the various host environments encountered during its disease cycle, GBS possesses multiple two-component regulatory systems (TCS). Here we investigate the contribution of a transcriptional regulator containing a LytTR domain, LtdR, to GBS pathogenesis. Disruption of the ltdR gene in the GBS chromosome resulted in a significant increase in bacterial invasion into human cerebral microvascular endothelial cells (hCMEC) in vitro as well as greater penetration of the Blood-Brain Barrier (BBB) and the development of meningitis in vivo. Correspondingly, infection of hCMEC with the ltdR mutant resulted in increased secretion of pro-inflammatory cytokines IL-8, CXCL-1, and IL-6. Further, using a mouse model of GBS vaginal colonization, we observed that the ltdR mutant was cleared more readily from the vaginal tract and also resulted in increased cytokine production from human vaginal epithelial cells. RNA-sequencing revealed global transcriptional differences between the ltdR mutant and the parental WT GBS strain. These results suggest that LtdR regulates many bacterial processes that can influence GBS-host interactions to promote both bacterial persistence and disease progression.

Yu, J., Li, B., Chen, X., Lu, J., Wang, D., Gu, T., Kong, W., Wu, Y.

Streptococcus pneumoniae is a major cause of invasive pneumococcal disease, septicemia and meningitis that can result in high morbidity rates in children under five years old. The current polysaccharide-based vaccines can provide type-specific immunity, but a broad spectrum vaccine would provide greater coverage. Therefore, developing pneumococcal protein-based vaccines that can extend to more sera types is highly important.In this study, we vaccinated mice with a systemic vaccine via the subcutaneous (s.c.) route, which is a mixture of fusion protein PsaA-PspA23 and a single protein PspA4, with aluminum hydroxide as an adjuvant. As a comparison, mice were immunized intranasally with a mucosal vaccine, which is a mixture of PspA2-PA-BLP and PspA4-PA-BLP, via the intranasal (i.n.) route. Both immunization processes were followed by challenging with Streptococcus pneumonia bacterial from two different PspA families. Specific IgG titers in the serum and specific IgA titers in the mucosa were determined following immunizations. Bacteria loads and survival rates after challenge were compared.Both the systemic vaccine and the mucosal vaccine induced a significant increase of IgG against PspAs. Only the mucosal vaccine also induced specific IgA in the mucosa. The two vaccines provided protection, but each vaccine showed an advantage. The systemic vaccine induced higher serum antibodies, whereas the mucosal vaccine limited the bacterial load in the lung and blood. Therefore, co-immunizations with both types of vaccines may be implemented in the future.

K.L. Chew, C.K. Lee, G.B. Cross, L.H.W. Lum, B. Yan, R. Jureen

Cryptococcosis is a fungal infection caused by Cryptococcus neoformans and Cryptococcus gattii. Although it typically affects immunocompromised patients, it can cause disease in immunocompetent patients. The range of clinical infections includes chronic skin infections, lung infections and meningitis. Diagnostic modalities include cryptococcal antigen (CrAg) detection tests and culture from infected sites. More recently, the Biofire meningitis/encephalitis (ME) panel (bioMérieux, Marcy l’Etoile, France) was added to the range of available tests for cryptococcal meningitis.

Tropical Medicine & International Health, EarlyView.

Abstract Background Limited data are available on the effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in resource-poor settings and PCV naïve populations. The Dominican Republic introduced PCV13 in September 2013 using a 2 + 1 schedule (2, 4, and 12 months) without a catch-up campaign. We evaluated PCV13 effectiveness against vaccine-type (VT) invasive pneumococcal disease (IPD) among children in the Dominican Republic. Methods We conducted a matched case-control study. A case-patient was defined as VT-IPD identified by culture or polymerase chain reaction (PCR) from a normally sterile-site in a hospitalized child who was age-eligible to have received ≥1 PCV13 dose. Four age- and neighborhood-matched controls were enrolled for each case-patient. We collected demographic, vaccination history, and risk factor data. Conditional logistic regression was performed. Vaccine effectiveness was calculated as (1- adjusted matched odds ratio for vaccination) X 100%. Results We enrolled 39 case-patients and 149 matched-controls. Most case-patients had pneumonia with pleural effusion (64%), followed by meningitis (28%) and septicemia (13%). The most common pneumococcal serotypes identified included 14 (18%), 3 (13%), 19A (10%), and 1 (8%). Fewer case-patients had ≥1 PCV13 dose as compared to controls (61.5% vs. 80.0%; p = 0.006). Adjusting for malnutrition and socioeconomic status, VE of ≥1 PCV13 dose compared to no doses was 67.2% (95% CI: 2.3% to 90.0%). Only 44% of controls were up-to-date for PCV13, suggesting low vaccine coverage in the population. Conclusions We found that PCV13 provided individual protection against VT-IPD in this resource-poor setting with a PCV-naïve population, despite low PCV13 coverage. Expanding vaccination coverage might increase PCV13 impact.

J. Bodilsen, Merete Storgaard, L. Larsen, L. Wiese, J. Helweg-Larsen, A.-M. Lebech, C. Brandt, C. Østergaard, H. Nielsen, the DASGIB study group

To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark.

Abstract Background Invasive Meningococcal Disease (IMD) is a rare and critical disease in Japan. Most of these cases are caused by capsulated Neisseria meningitidis strains. Non-capsulated (non-typable) strains are considered relatively low-pathogenic and can colonize in the nasopharynx of healthy children and young adults. As far as could be ascertained, only twelve IMD cases due to non-capsulated strains have been reported in the literature. No clear risk factors could be identified in a literature review (unknown or immunocompetent, seven cases; C6 deficiency, three cases). Case presentation We report a Japanese male taxi driver with bacteremia and meningitis due to non-capsulated N. meningitidis. He had a fever and shaking chills. Ceftriaxone was administered, and the patient finally recovered. During the clinical course, relative adrenal insufficiency occurred and was treated with hydrocortisone. A hidden co-morbidity, immunoglobulin G4 (IgG4)-related disease, was revealed in the past surgical history (a resection of bilateral orbital tumors), which included symptoms (swelling lachrymal glands and lymph nodes), elevated IgG4, immunoglobulin E, and hypocomplementemia. He recovered finally and no recurrence was observed. Conclusions Our IMD case is the first reported in Japan, where IMD is not considered pandemic. The patient had a history of IgG4-related disease, although we could not establish a clear relationship between the patient’s IMD and co-morbidity. A collection of further clinical cases might establish the risk factors and characteristics of IMD that could be caused by this neglected pathogen, non-capsulated N. meningitidis.

Martin Wardle, Andre Mu, Steven Y.C. Tong

Timothy Barkham, Anna Sheppard, Nicola Jones, Swaine Chen

Ben-Shmuel, A., Glinert, I., Sittner, A., Bar-David, E., Schlomovitz, J., Brosh, T., Kobiler, D., Weiss, S., Levy, H.

Treatment of Anthrax is challenging, especially during the advanced stages of the disease. Recently the CDC updated its recommendations for post-exposure prophylaxis and treatment of exposed populations (pre and post symptoms onset). These recommendations distinguished, for the first time, between the systemic disease with and without meningitis, a common and serious complication of anthrax. The CDC considers all systemic patients as meningeal unless positively proven otherwise. The treatment of patients suffering from systemic Anthrax with suspected or confirmed meningitis includes the combination of three antibiotics -- a fluoroquinolone (Levofloxacin or Ciprofloxacin), a β-lactam (Meropenem or Imipenem) and a protein-synthesis inhibitor (Linezolid or Clindamycin). In addition, treatment with an antitoxin (αPA antibodies) and Dexamethasone should also be applied. Since the efficacy of most of these treatments was not demonstrated, especially in meningeal animal models, we developed an Anthrax-meningitis model in rabbits and tested several of these recommendations. We demonstrate that in this model, Ciprofloxacin, Linezolid and Meropenem are ineffective as single treatments while Clindamycin is highly effective. Furthermore, combined treatments of Ciprofloxacin and Linezolid, or Ciprofloxacin and Dexamethasone failed in treating meningeal rabbits. We demonstrate that Dexamethasone actually hinders the blood brain barrier penetration of antibiotics, reducing the effectiveness of antibiotic treatment of Anthrax-meningitis in the rabbit model.