Fiona McGill, Michael J Griffiths, Laura J Bonnett, Anna Maria Geretti, Benedict D Michael, Nicholas J Beeching, David McKee, Paula Scarlett, Ian J Hart, Kenneth J Mutton, Agam Jung, Guleed Adan, Alison Gummery, Wan Aliaa Wan Sulaiman, Katherine Ennis, Antony P Martin, Alan Haycox, Alastair Miller, Tom Solomon, UK Meningitis Study Investigators

Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services.

M. Klein, C. Höhne, B. Angele, T. Högen, H.W. Pfister, H. Tüfekci, U. 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.

Stott, K. E., Beardsley, J., Whalley, S., Kibengo, F. M., Mai, N. T. H., Kolamunnage-Dona, R., Hope, W., Day, J.

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis (CM). A PK study was conducted in n=42 patients receiving DAmB 1 mg/kg q24h. A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of CM patients treated with DAmB monotherapy and a meta-analysis was performed.The PK parameter means (standard deviation) were: clearance, 0.03 (0.01) x weight + 0.95 (0.02) litres/hour; volume, 0.89 (0.90) x weight + 1.54 (1.13) litres; first-order rate constant from central to peripheral compartment, 7.12 (6.50) hours-1; from peripheral to central compartment, 12.13 (12.50) hours-1. The meta-analysis suggested that DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility, but not in mortality outcomes. Simulations of area under concentration-time curve (AUC144-168) resulted in median (interquartile range) values 5.83 mg.h/litre (4.66-8.55), 10.16 (8.07-14.55) and 14.51 (11.48-20.42), with dosages of 0.4, 0.7 and 1.0 mg/kg q24h respectively.DAmB PK is described adequately by a linear model that incorporates weight on clearance and volume. Inter-patient PK variability is modest and unlikely to be responsible for variability in clinical outcome. There is a discord between the impact that drug exposure has on CSF sterility and on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

Yoon H, Nakouzi A, Chang C, et al.

AbstractBackgroundInitiation of antiretroviral therapy (ART) in HIV-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated.MethodsWe compared plasma levels of immunoglobulins, Cryptococcus neoformans (CN) glucuronoxylomannan (GXM) capsule-specific and (Lam)inarin-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not and evaluated associations of these parameters with risk of C-IRIS.ResultsPrior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P=0.0003), Lam-IgM (P=0.0005), Lam-IgG (P=0.002), and GXM-IgM (P=0.002) independent of age, sex, HIV viral load, CD4+ T cell count and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells.DiscussionAntibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM, may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.

Yuvaraj Jayaraman, Balaji Veeraraghavan, Girish Kumar Chethrapilly Purushothaman, Bharathy Sukumar, Boopathi Kangusamy, Ambujam Nair Kapoor, Nivedita Gupta, Sanjay Madhav Mehendale, Hospital Based Sentinel Surveillance of Bacterial Meningitis (HBSSBM) Network Team

by Yuvaraj Jayaraman, Balaji Veeraraghavan, Girish Kumar Chethrapilly Purushothaman, Bharathy Sukumar, Boopathi Kangusamy, Ambujam Nair Kapoor, Nivedita Gupta, Sanjay Madhav Mehendale, Hospital Based Sentinel Surveillance of Bacterial Meningitis (HBSSBM) Network Team Background Worldwide, acute bacterial meningitis is a major cause of high morbidity and mortality among under five children, particularly in settings where vaccination for H. influenzae type b, S. pneumoniae and N. meningitidis is yet to be introduced in the national immunization programs. Estimation of disease burden of bacterial meningitis associated with these pathogens can guide the policy makers to consider inclusion of these newer vaccines in the immunization programs. A network of hospital based sentinel surveillance was established to generate baseline data on the burden of bacterial meningitis among children aged less than 5 years in India and to provide a platform for impact assessment following introduction of the Pentavalent and Pneumococcal Conjugate Vaccines (PCV). Methods During surveillance carried out in select hospitals across India in 2012–2013, information regarding demographics, immunization history, clinical history, treatment details and laboratory investigations viz. CSF biochemistry, culture, latex agglutination and PCR was collected from children aged 1 to 59 months admitted with suspected bacterial meningitis. Results A total of 3104 suspected meningitis cases were enrolled from 19,670 children admitted with fever at the surveillance hospitals. Of these, 257 cases were confirmed as cases of meningitis. They were due to S. pneumoniae (82.9%), H. influenzae type b (14.4%) and N. meningitidis (2.7%). Highest prevalence (55.3%) was observed among children 1 to 11 months. Antimicrobial susceptibility testing revealed considerable resistance among S. pneumoniae isolates against commonly used antibiotics such as cotrimoxazole, erythromycin, penicillin, and cefotaxime. More commonly prevalent serotypes of S. pneumoniae in circulation included 6B, 14, 6A and 19F. More than 90% of serotypes identified were covered by Pneumococcal Conjugate Vaccine 13. Conclusions We observed that S. pneumoniae was the commonest cause of bacterial meningitis in hospitalized children under five years of age in India. Continued surveillance is expected to provide valuable information and trends in future, to take an informed decision on introduction of pneumococcal vaccination in Universal Immunization Programme in India and will also eventually help in post-vaccination impact evaluation.

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.

Chi Li, Wen-ya Feng, Ai-wei Lin, Guo Zheng, Yan-chun Wang, Yan-jun Han, Jian-min Zhong, Jing Bi, Qiong Luo, Fang-chao Zhao, Ping Jin, Ling-yun Guo, Na Li, Jie Yu, Xiao-tao Yang, Jun Liang, Ji-kui Deng, Yong-jun Li, Yu-jiao Wang, Xiong-ying Yu, Dong-meng Wang, Liang Ru, Juan Chen, Yong-hong Yang, Qiao-zhi Yang, Gang Liu

To explore the clinical characteristics and etiology of bacterial meningitis (BM) in Chinese children.

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.

J.M. Balada-Llasat, Ning Rosenthal, Rodrigo Hasbun, Louise Zimmer, Christine C. Ginocchio, Steven Duff, Jessica Chung, Samuel Bozzette

To determine the associated cost related to diagnosis and treatment of meningoencephalitis (ME) in adult patients in the United States.

L. Allan-Blitz et al.

Lindi-Marie Coetzee, Naseem Cassim, Charlotte Sriruttan, Mabatho Mhlanga, Nelesh P. Govender, Deborah Kim Glencross

by Lindi-Marie Coetzee, Naseem Cassim, Charlotte Sriruttan, Mabatho Mhlanga, Nelesh P. Govender, Deborah Kim Glencross Introduction Cryptococcal meningitis (CM) is an opportunistic fungal disease with a high mortality among HIV-positive patients with severe immunosuppression (CD4 count…

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.

Gallegos, Cinthia; Tobowlosky, Farrell; Nigo, Masayuki; Hasbun, Rodrigo

Objectives: To report the prevalence of delayed cerebral injury in adults with bacterial meningitis and explore its association with adjunctive steroids. Design: Retrospective analysis of adults with bacterial meningitis between 2005 and 2016. Setting: Ten hospitals in the Greater Houston area. Patients: Consecutive subjects with culture proven community-acquired bacterial meningitis. Intervention: Subjects were categorized as receiving or not adjunctive steroids within 4 hours. Measurements and Main Results: A total of 120 patients were identified who were admitted with community-acquired bacterial meningitis. Delayed cerebral injury was seen in five of 120 patients (4.1%); all five patients had fever and abnormal neurologic examinations. Adjunctive steroids within 4 hours were more likely given to those with delayed cerebral injury (5/5,100% vs 43/115, 37.5%; p = 0.01). Of the patients who developed delayed cerebral injury, three had Streptococcus pneumoniae, one had methicillin-resistant Staphylococcus aureus, and one had Listeria monocytogenes isolated. We observed an adverse clinical outcome as defined by the Glasgow Outcome Scale in four of the five patients (80%). Conclusions: Delayed cerebral injury occurred in 4.1% of adults with bacterial meningitis, and it was associated with the use of adjunctive steroids. Future studies should explore the etiology and prevention of this devastating complication. Drs. Gallegos, Nigo, and Tobowlosky screened the patients and did the data collection. Dr. Gallegos created the first draft of the article. Dr. Hasbun designed the study. Dr. Hasbun participated in the data interpretation and edited the article. Dr. Hasbun wrote the final draft of the article and made all the changes suggested by the coauthors. Supported, in part, by Grant A Starr Foundation. Dr. Hasbun is a consultant for bioMérieux and a speaker for Pfizer, Merck, Medicines Company, and BioFire. Dr. Hasbun received funding from BioFire Diagnostics, Biomeriaux, and Merck. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Rodrigo.Hasbun@uth.tmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Tropical Medicine & International Health, EarlyView.

T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov

by T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov Streptococcus agalactiae, or group B streptococcus (GBS), is an important pathogen as it is the leading cause of neonatal deaths due to sepsis, meningitis or bacterial pneumonia. Although the development of an effective and safe GBS vaccine is on the agenda of many research labs, there is no GBS vaccine on the market yet. In the present study we attempted to engineer a live vaccine strain based on Bac, a surface protein of GBS, incorporated into a surface fimbrial protein of probiotic Enterococcus. The resulting strain induced specific systemic and local immune responses in mice and provided protection against GBS when administered via the intranasal, oral or intravaginal immunization routes.

Jimenez de Oya, N., Blazquez, A.-B., Casas, J., Saiz, J.-C., Martin Acebes, M. A.

Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of Adenosine Monophosphate-activated Protein Kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses: West Nile virus (WNV), Zika virus (ZIKV) and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease that can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced both WNV, ZIKV, and DENV infection. This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery.

Hickerson B, Westover J, Jung K, et al.

AbstractLymphocytic choriomeningitis virus (LCMV) poses a substantial risk to immunocompromised individuals. The case fatality rate in recent clusters of LCMV infection in immunosuppressed organ transplantation recipients has exceeded 70%. In the present study, we demonstrate potent antiviral activity of favipiravir against acute, disseminated LCMV infection in NZB mice. Treatment resulted in complete protection against mortality and dramatic reductions in viral loads. In contrast, ribavirin, the current antiviral of choice, was mostly ineffective. Our findings, and the high lethality associated with LCMV infection in transplant recipients, support the consideration of favipiravir as a first-line therapeutic option.

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.

Abstract Background As an opportunistic pathogen, E. gallinarum mainly leads to nosocomial infections, and it’s multi-drug resistance has gained more and more attention. Central nervous system infections caused by E. gallinarum are rare, but have been reported more often in recent years. The previous cases were generally secondary to neurosurgery, especially ventriculoperitoneal shunts. In recent years, the cases largely occurred in patients with impaired immune function. The patient in our report may have had dual risk factors (immune impairment and an invasive surgical procedure). Case presentation The patient, a 35-year-old female, was admitted to our hospital for headaches of 3 days duration accompanied by nausea and vomiting for 2 days. The patient had fevers and chills for 3 days before admission; the peak body temperature was 38.5 °C. The patient had a splenectomy in our hospital 2 years earlier for thrombocytopenia and was thought to be immunocompromised. The abnormal findings on physical examination and laboratory testing were as follows: neck stiffness, present; lumbar puncture: pressure, 300 mmH2O; Pandy’s test, positive; white blood cell (WBC) count, 1536 × 106/L; monocyte count, 602 × 106/L; monocyte percentage, 39.2%; multinucleate cell count, 934 × 106/L; multinucleate cell percentage, 60.8%; protein, 1.08 g/L; WBC count, 21.1 × 109/ L; neutrophil percentage, 85.3%; neutrophil count, 20.55 × 109/L; C reactive protein (CRP): 136.4 mg/L; procalcitonin, 6.70 ng/mL. The patient was given meropenem (2.0 g, intravenous infusion, every 8 h) for anti-infection supplemented with other symptomatic support treatments. The patient’s fever and headache had no significant relief. Conclusions Central nervous system infections caused by E. gallinarum are rare, but should be suspected, particularly inpatients with impaired immune function or ineffective treatment. Avoiding long-term invasive treatment and improving immunity are helpful to reduce the occurrence of E. gallinarum infections. Early detection and diagnosis, as well as rational antibiotic use, are the keys to achieve satisfactory efficacy.

Tatiana Metcalf, Jaime Soria, Silvia M. Montano, Eduardo Ticona, Carlton A. Evans, Luz Huaroto, Matthew Kasper, Eric S. Ramos, Nicanor Mori, Podjanee Jittamala, Kesinee Chotivanich, Irwin F. Chavez, Pratap Singhasivanon, Sasithon Pukrittayakamee, Joseph R. Zunt

by Tatiana Metcalf, Jaime Soria, Silvia M. Montano, Eduardo Ticona, Carlton A. Evans, Luz Huaroto, Matthew Kasper, Eric S. Ramos, Nicanor Mori, Podjanee Jittamala, Kesinee Chotivanich, Irwin F. Chavez, Pratap Singhasivanon, Sasithon Pukrittayakamee, Joseph R. Zunt Background Meningitis caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. We evaluated the performance of cerebrospinal fluid (CSF) testing with the GeneXpert MTB/RIF assay versus traditional approaches for diagnosing tuberculosis meningitis (TBM). Methods Patients were adults (n = 37) presenting with suspected TBM to the Hospital Nacional Dos de Mayo, Lima, Peru, during 12 months until 1st January 2015. Each participant had a single CSF specimen that was divided into aliquots that were concurrently tested for M. tuberculosis using GeneXpert, Ziehl-Neelsen smear and culture on solid and liquid media. Drug susceptibility testing used Mycobacteria Growth Indicator Tube (MGIT 960) and the proportions method. Results 81% (30/37) of patients received a final clinical diagnosis of TBM, of whom 63% (19/30, 95% confidence intervals, CI: 44–80%) were HIV-positive. 22% (8/37, 95%CI: 9.8–38%), of patients had definite TBM. Because definite TBM was defined by positivity in any laboratory test, all laboratory tests had 100% specificity. Considering the 30 patients who had a clinical diagnosis of TBM: diagnostic sensitivity was 23% (7/30, 95%CI: 9.9–42%) for GeneXpert and was the same for all culture results combined; considerably greater than 7% (2/30, 95%CI: 0.82–22%) for microscopy; whereas all laboratory tests had poor negative predictive values (20–23%). Considering only the 8 patients with definite TBM: diagnostic sensitivity was 88% (7/8, 95%CI: 47–100%) for GeneXpert; 75% (6/8, 95%CI: 35–97%) for MGIT culture or LJ culture; 50% (4/8, 95%CI 16–84) for Ogawa culture and 25% (2/8, 95%CI: 3.2–65%) for microscopy. GeneXpert and microscopy provided same-day results, whereas culture took 20–56 days. GeneXpert provided same-day rifampicin-susceptibility results, whereas culture-based testing took 32–71 days. 38% (3/8, 95%CI: 8.5–76%) of patients with definite TBM with data had evidence of drug-resistant TB, but 73% (22/30) of all clinically diagnosed TBM (definite, probable, and possible TBM) had no drug-susceptibility results available. Conclusions Compared with traditional culture-based methods of CSF testing, GeneXpert had similar yield and faster results for both the detection of M. tuberculosis and drug-susceptibility testing. Including use of the GeneXpert has the capacity to improve the diagnosis of TBM cases.

Abstract Background With a prevalence of 4.7–13% in Danish Ixodes ricinus ticks, Rickettsia helvetica is one of the most frequently detected tick-borne organisms in Denmark. Most reports of human exposure have described asymptomatic seroconversion or a mild, self-limiting flu-like illness but it has also been implicated as a cause of subacute lymphocytic meningitis. Because Borrelia burgdorferi sensu lato (Bbsl) and R. helvetica are both found in the same tick species, potential co-transmission is a possibility. We examined 1) the seroprevalence of anti-rickettsia antibodies in patients investigated for Lyme neuroborreliosis (LNB), and 2) the cerebrospinal fluid (CSF) and sera of same patients for the presence of Rickettsia DNA. Methods Ninety-nine sera and 87 CSF samples from patients with intrathecal synthesis of anti-Borrelia antibodies and 101 sera and 103 CSF samples from patients with no detectable intrathecal synthesis were retrospectively examined for this study. Sera were analyzed for antibodies against spotted fever group (SFG) rickettsiae and both the CSF and sera were tested for Rickettsia DNA using a genus-specific real-time PCR. Results Of the patients tested for LNB, 32% (64/200) had IgG antibodies against SFG rickettsiae. Among patients with confirmed intrathecal synthesis of Borrelia-specific antibodies, 38% (38/99) exhibited IgG antibodies. None of these values were statistically significant when compared with sera from healthy blood donors (p = 0.7 and 0.19). Rickettsia DNA was found in the CSF of 4% (8/190) of patients. Conclusion No statistically significant difference was found in the seroprevalence of anti-rickettsia antibodies in patients tested for LNB and healthy blood donors, indicative of a low rate of exposure in this group of patients. Eight patients showed evidence of Rickettsia DNA in the CSF, five of whom had LNB. However, cycle threshold (Ct) values were high, indicating low concentrations of DNA, and no apparent alteration in the clinical manifestations of LNB were noted in the medical records of these patients.

Anouk M. Oordt-Speets, Renee Bolijn, Rosa C. van Hoorn, Amit Bhavsar, Moe H. Kyaw

by Anouk M. Oordt-Speets, Renee Bolijn, Rosa C. van Hoorn, Amit Bhavsar, Moe H. Kyaw Bacterial meningitis is a global public health concern, with several responsible etiologic agents that vary by age group and geographical area. The aim of this systematic review and meta-analysis was to assess the etiology of bacterial meningitis in different age groups across global regions. PubMed and EMBASE were systematically searched for English language studies on bacterial meningitis, limited to articles published in the last five years. The methodological quality of the studies was assessed using a customized scoring system. Meta-analyses were conducted to determine the frequency (percentages) of seven bacterial types known to cause meningitis: Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus agalactiae, Staphylococcus aureus, and Listeria monocytogenes, with results being stratified by six geographical regions as determined by the World Health Organization, and seven age groups. Of the 3227 studies retrieved, 56 were eligible for the final analysis. In all age groups, S. pneumoniae and N. meningitidis were the predominant pathogens in all regions, accounting for 25.1–41.2% and 9.1–36.2% of bacterial meningitis cases, respectively. S. pneumoniae infection was the most common cause of bacterial meningitis in the ‘all children’ group, ranging from 22.5% (Europe) to 41.1% (Africa), and in all adults ranging from 9.6% (Western Pacific) to 75.2% (Africa). E. coli and S. pneumoniae were the most common pathogens that caused bacterial meningitis in neonates in Africa (17.7% and 20.4%, respectively). N. meningitidis was the most common in children aged ±1–5 years in Europe (47.0%). Due to paucity of data, meta-analyses could not be performed in all age groups for all regions. A clear difference in the weighted frequency of bacterial meningitis cases caused by the different etiological agents was observed between age groups and between geographic regions. These findings may facilitate bacterial meningitis prevention and treatment strategies.

Depledge D, Cudini J, Kundu S, et al.

AbstractBackgroundVaricella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples.MethodsEnrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS.ResultsViral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades.ConclusionsLow viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.

Ali Pormohammad , Mohammad Javad Nasiri , Seyed Mohammad Riahi , Fatemeh Fallah

Abstract Introduction Human immunodeficiency virus (HIV)‐infected individuals are at increased risk for all forms of extrapulmonary tuberculosis (TB), including tuberculous meningitis (TBM). This study aimed to investigate the frequency of HIV in patients with TBM. Methods PubMed, Embase, Web of Science and Cochrane Library were searched for articles including relevant data. Stata version 14.0 (StataCorp, College Station, Texas, USA) was used to analyse the data. Results Twenty studies were identified. The pooled frequency of HIV among adult patients with TBM was 38.0% (95% CI: 21.0–57.0; I2 = 97%). In children (under the age of 15 years), 6.0% (95% CI: 1.0–13.0; I2 = 0.0%) had HIV infection. In patients with bacterial meningitis other than TBM, 36.0% (95% CI: 19.0–53.0; I2 = 100%) were HIV‐infected. Conclusions A relatively high frequency of HIV in patients with TBM was indicated by our study. Establishment of diagnostic criteria and effective treatment strategies for TBM/HIV co‐infection are recommended for better management of patients with TBM+HIV.

Shaw, K. J., Schell, W. A., Covel, J., Duboc, G., Giamberardino, C., Kapoor, M., Moloney, M., Soltow, Q. A., Tenor, J. L., Toffaletti, D. L., Trzoss, M., Webb, P., Perfect, J. R.

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds including APX001A and its prodrug APX001, currently in clinical development for invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidyl inositol (GPI)-anchored cell wall mannoproteins in fungi.The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/mL to 0.5 μg/mL against both C. neoformans and C. gattii. APX001A and APX2020 demonstrated in vitro synergy with fluconazole (FICI 0.37). In a CM model, APX001 and fluconazole each, alone, reduced log10 colony forming units (CFU)/g brain (0.78 and 1.04, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain.Efficacy as measured by a reduction in brain and lung fungal burden was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose dependent reductions in fungal burden ranged between 5.91 and 1.79 log10 CFU/g lung and between 7.00 and 0.92 log10 CFU/g brain, representing near or complete sterilization of lung and brain tissue at the higher doses. These data support further clinical evaluation of this new class of antifungal agents for CM.

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.

Abstract Background Although paradoxical reactions (PRs) to anti-tuberculosis (anti-TB) therapy during treatment are well-established occurrences, PRs presenting as a new lesion after the completion of treatment are extremely rare, and little is known about the management of such cases, particularly of central nervous system (CNS) tuberculosis. Case presentation A 27-year-old female, with a past medical history of tuberculous meningitis 10 years ago and who completed the anti-TB treatment with asymptomatic remnant tuberculomas in the basal cistern, was admitted to our hospital because of a headache and the worsening of pre-existing visual disturbance. Contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI) revealed new tuberculomas in the left sylvian fissure with a diffuse low signal around it. Because repeated polymerase chain reaction and Mycobacterium tuberculosis culture presented negative results and the patient had no laboratory data suggestive of a relapse of tuberculous meningitis, she was diagnosed with late-onset post-treatment PRs and treated with oral corticosteroids, tapered off over 1 year. Eventually, the symptoms were relieved, and the tuberculomas disappeared. Conclusions Clinicians should consider the possibility of PRs long after the completion of tuberculous meningitis treatment. Hence, a precise MRI-based examination is imperative for the follow-up of CNS tuberculosis, and the unnecessary administration of anti-TB drugs should be avoided. The use of corticosteroids as a treatment option for post-treatment PRs is seemingly safe when the isolated M. tuberculosis is sensitive to the first-line anti-TB therapy.

Nahoko Katayama Ueda, Kiwamu Nakamura, Hayato Go, Hiroki Takehara, Nozomi Kashiwabara, Kazuaki Arai, Hiromu Takemura, Yoshiyuki Namai, Keiji Kanemitsu

Abstract Background Fungal infections of the central nervous system (FIs-CNS) have become significantly more common over the past 2 decades. Invasion of the CNS largely depends on the immune status of the host and the virulence of the fungal strain. Infections with fungi cause a significant morbidity in immunocompromised hosts, and the involvement of the CNS may lead to fatal consequences. Methods One hundred and thirty-five articles on fungal neuroinfection in PubMed, Google Scholar, and Cochrane databases were selected for review using the following search words: “fungi and CNS mycoses”, CNS fungal infections”, “fungal brain infections”, " fungal cerebritis”, fungal meningitis”, “diagnostics of fungal infections”, and “treatment of CNS fungal infections”. All were published in English with the majority in the period 2000–2018. This review focuses on the current knowledge of the epidemiology, clinical presentations, diagnosis, and treatment of selected FIs-CNS. Results The FIs-CNS can have various clinical presentations, mainly meningitis, encephalitis, hydrocephalus, cerebral abscesses, and stroke syndromes. The etiologic factors of neuroinfections are yeasts (Cryptococcus neoformans, Candida spp., Trichosporon spp.), moniliaceous moulds (Aspergillus spp., Fusarium spp.), Mucoromycetes (Mucor spp., Rhizopus spp.), dimorphic fungi (Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum), and dematiaceous fungi (Cladophialophora bantiana, Exophiala dermatitidis). Their common route of transmission is inhalation or inoculation from trauma or surgery, with subsequent hematogenous or contiguous spread. As the manifestations of FIs-CNS are often non-specific, their diagnosis is very difficult. A fast identification of the etiological factor of neuroinfection and the application of appropriate therapy are crucial in preventing an often fatal outcome. The choice of effective drug depends on its extent of CNS penetration and spectrum of activity. Pharmaceutical formulations of amphotericin B (AmB) (among others, deoxycholate-AmBd and liposomal L-AmB) have relatively limited distribution in the cerebrospinal fluid (CSF); however, their detectable therapeutic concentrations in the CNS makes them recommended drugs for the treatment of cryptococcal meningoencephalitis (AmBd with flucytosine) and CNS candidiasis (L-AmB) and mucormycosis (L-AmB). Voriconazole, a moderately lipophilic molecule with good CNS penetration, is recommended in the first-line therapy of CNS aspergillosis. Other triazoles, such as posaconazole and itraconazole, with negligible concentrations in the CSF are not considered effective drugs for therapy of CNS fungal neuroinfections. In contrast, clinical data have shown that a novel triazole, isavuconazole, achieved considerable efficacy for the treatment of some fungal neuroinfections. Echinocandins with relatively low or undetectable concentrations in the CSF do not play meaningful role in the treatment of FIs-CNS. Conclusion Although the number of fungal species causing CNS mycosis is increasing, only some possess well-defined treatment standards (e.g., cryptococcal meningitis and CNS aspergillosis). The early diagnosis of fungal infection, accompanied by identification of the etiological factor, is needed to allow the selection of effective therapy in patients with FIs-CNS and limit their high mortality.

Lauren O. Bakaletz, Laura A. Novotny

In this infographic the diseases caused by nontypeable Haemophilus influenzae (NTHi), including otitis media, are discussed.Encapsulated type b Haemophilus influenzae (Hib) was responsible for most of the invasive disease (meningitis) prior to the use of Hib vaccines. As Hib vaccines have no effect on infections due to nontypeable H. influenzae (NTHi), in areas where Hib vaccines are used, nontypeable strains are now the most common cause of invasive disease. Moreover, NTHi contributes to the ∼21000 otitis media (OM)-associated deaths per year.

Smilnak G, Charalambous L, Cutshaw D, et al.

AbstractCryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared to uniform mortality without treatment, this drug paradigm has not led to a consistent cure. NeurapheresisTM therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a five-log reduction in concentration of the yeast and a one-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly-removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.

Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein

by Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein Background The mortality and neurologic sequelae associated with acute bacterial meningitis (ABM) remain high despite advances in medical care. The main aim of this study was to evaluate short-term outcome in patients treated as bacterial meningitis at a teaching hospital in Ethiopia to identify factors that could be focused on to improve outcome in this setting. Methods A hospital based longitudinal study was conducted at Jimma University Hospital in southwest Ethiopia from March 1, 2013 to December 31, 2015. Participants of this study were patients of age 18 years and older who were treated as confirmed or possible cases of ABM. Patients were followed throughout their hospital stay for change in their clinical course and predefined end points. A multivariable analysis was done to identify factors associated with unfavorable outcomes. Result 90 patients admitted with diagnosis of acute bacterial meningitis were included in the study; cerebrospinal fluid was analysed for 85 (94.4%) of them. Causative bacteria were isolated in 26 (28.9%) patients only; most of these isolates (84.6%) were either Streptococcus pneumoniae or Neisseria meningitidis. Patients managed as cases of ABM at the hospital suffered from a high rate of unfavorable outcome (36.7%) and an overall mortality rate of 22.2%. Impaired level of consciousness (AOR = 0.766, 95% CI = 0.589–0.995), dexamethasone therapy (AOR = 4.676, 95% CI = 1.12–19.50) and fever persisting after two days of admission (AOR = 24.226, 95% CI = 5.24–111.96) were found to be independently associated with unfavorable outcome. Conclusion Outcome in patients treated for ABM at the hospital was found to be poor. Impaired mentation, treatment with adjunctive dexamethasone and persistent fever were found to be associated with poor outcome. Thus, development of clinical guidelines for treatment of ABM that suit the local context is essential to improve patient management and outcome.

Wondemagegn Mulu, Endalew Yizengaw, Megbaru Alemu, Daniel Mekonnen, Derese Hailu, Kassaw Ketemaw, Bayeh Abera, Mulugeta Kibret

by Wondemagegn Mulu, Endalew Yizengaw, Megbaru Alemu, Daniel Mekonnen, Derese Hailu, Kassaw Ketemaw, Bayeh Abera, Mulugeta Kibret Background Asymptomatic pharyngeal colonization by potential bacteria is the primary reservoir for bacterial species within a population and is considered a prerequisite for development of major childhood diseases such as sinusitis, otitis media, pneumonia, bacteremia, and meningitis. However, there is dearth of data on the colonization and drug resistance pattern of the main bacterial pathogens in the pharynx of HIV infected children in Ethiopia. Therefore, this study determined the pharyngeal colonization and drug resistance profile of bacterial pathogens in HIV infected children attending ART clinic of Felegehiwot Referral Hospital (FHRH), Amhara Region, Ethiopia. Methods A hospital based cross-sectional study was conducted from May 2016 to June 2017 at the ART clinic of FHRH. A total of 300 HIV infected children were enrolled in the study. Data on socio-demographic characteristics of the study participants were collected with face-to-face interview and patient—card review using structured questionnaire. Bacterial species were identified using standard bacteriological techniques. Drug susceptibility testing was performed using disk diffusion technique. Chi-square test was done to determine associations among variables. Results The median age of the participants was 11 years. Overall, 153 (51%) of children were colonized by respiratory bacteria in their pharynx. Colonization rate was higher in children from mothers who had attained college and above levels of education than others (P = 0.04). It was also higher in children without the sign of malnutrition than others (P = 0.004). The colonization rate of S.aureus, M.catarrhalis, S.pneumoniae and H.influenzae were 88 (29%), 37 (12.3%), 31 (10.3%) and 6 (2%), respectively. S.aureus—M.catarrhalis concurrent colonization was found in 14 (4.7%) of children. Age (P = 0.03), schooling (P = 0.045) and history of running nose (P = 0.043) were significantly associated with S.aureus colonization. Living in urban setting (P = 0.042) and children from mothers with college and above levels of education (P = 0.002) were significantly associated with M.catarrhalis colonization. Majority of the isolates were resistant to penicillin (68.5%) and cotrimoxazole (52.5%).S.aureus isolates were resistant to penicillin (84.1%) and cotrimoxazole (51.1%).M.catarrhalis isolates were resistant to penicillin (94.6%), erythromycin (86.5%)and cotrimoxazole (78.4%). Overall, 99 (59.3%) of the isolates were multi-drug (MDR) resistant. The overall MDR rates among S.aureus, M.catarrhalis and S.pneumoniae isolates were 65.9%, 78.4% and 22.6%, respectively. Conclusions Pharyngeal colonization of respiratory bacteria in HIV infected children is a major public health problem. Single and multiple antibiotic resistant is alarmingly high among respiratory colonizers. Therefore, regular screening of HIV infected children for culture and antimicrobial susceptibility testing is recommended to prevent the development of severe opportunistic infections.

G. Regev-Yochay et al.

Wake, Rachel M; Jarvis, Joseph N; Harrison, Thomas S; Govender, Nelesh P

Background Cryptococcal antigen (CrAg) screening at point of care could improve cryptococcal meningitis prevention where laboratory resources are limited. We evaluated the accuracy of Immuno-Mycologics (IMMY, Norman, OK) CrAg lateral flow assay (LFA) using different techniques at point of care. Setting Two tertiary-level hospitals in Johannesburg and a community health clinic in Soweto, South Africa. Methods A case-control diagnostic validation study, and a prospective clinic-based implementation study using the IMMY CrAg LFA on finger-prick blood. Accuracy, using direct application of LFA to sample, or pipette to transfer sample to diluent, and reading after 10 and 20 minutes, was compared to laboratory-based plasma testing. Results The validation study tested 64 CrAg-positive and 152 CrAg-negative patients with no symptoms or signs of meningitis, identified by routine laboratory screening, recruited by convenience sampling. Consecutively-diagnosed HIV-infected adults (n=654) were included in the implementation study. Sensitivity was 82% and 20% when the LFA was read 10 minutes after direct application to finger-prick blood in the validation and implementation studies respectively. Using a pipette to transfer blood and reading after 20 minutes improved sensitivity to 100%, while retaining 100% specificity, in both studies. Conclusions Although the IMMY CrAg LFA performs well when applied directly to finger-prick blood for diagnosing cryptococcal meningitis, this technique may not provide adequate volume to detect low concentrations of CrAg when screening asymptomatic patients. Using a pipette to transfer larger volumes of blood to diluent prior to CrAg LFA testing and reading results after 20 minutes is a more reliable point-of-care method. Conflicts of Interest and Source of Funding: Grants for funding this research were awarded to RW by the Sir Halley Stewart Trust, St George’s Hospital Research Charity and the Sir Ratanji Dalal Research Trust. TH is on the Scientific Board of Viamet, has received honoraria from Pfizer, an Investigator award from Gilead Sciences and tests for research purposes from Immuno-Mycologics. NPG is partially supported by a US National Institutes of Health R01 grant (5R01AI118511-03) and has also received tests for research purposes from Immuno-Mycologics. For the remaining authors none were declared. Part of the data was presented at the International AIDS Conference, Durban, 2016. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Stott, K. E., Beardsley, J., Kolamunnage-Dona, R., Santoyo Castelazo, A., Kibengo, F. M., Mai, N. T. H., Day, J., Hope, W.

Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the CNS is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg q24h) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A 4-compartment PK model was developed and Monte Carlo simulations performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were: clearance, 0.72 (0.24) litres/hour; volume of the central compartment, 18.07 (6.31) litres; volume of central nervous system (CNS) compartment, 32.07 (17.60) litres; first-order rate constant from central to peripheral compartment, 12.20 (11.17) hours-1; from peripheral to central compartment, 18.10 (8.25) hours-1; from central to CNS compartment 35.43 (13.74) hours-1; from CNS to central compartment 28.63 (10.03) hours-1. Simulations of area under concentration-time curve resulted in median (interquartile range) values 1143.2 mg.h/litre (988.4 – 1378.0) in plasma and 982.9 (781.0 – 1185.9) in CSF after a dosage of 1200mg q24h. The mean simulated ratio of AUCCSF:AUCplasma was 0.89 (SD 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the PD target in respect to the wild-type MIC distribution of C. neoformans. The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognised fact that fluconazole monotherapy is an inadequate induction regimen for CM.

Abstract Background Defined by an infection of the ventricular system of the brain, ventriculitis is usually known as a health-care associated infection. In contrast, primary pyogenic ventriculitis complicating community-acquired meningitis is uncommon, and mainly described in infants. Only seven cases that have occured in adults have been found in the international literature. Case presentation We report here a new case due to Neisseria meningitidis occurring in an 85 year-old-man. The comparison with previous reports allows to drawn several conclusions: (i) cases occurred in relatively old adults (median age: 65 years); (ii) Streptococcus pneumoniae, N. meningitiditis and Staphylococcus aureus are the leading responsible pathogens; (iii) atypical clinical presentation seems the rule in which meningism often lacks; (iv) in absence of clinical or biological specific parameters, modern brain imaging such as magnetic resonance imaging with gadolinium enhancement is of utmost importance for the diagnosis, leading to anticipate an increase of the diagnosis in the near future, thanks to easier access to such exploration; (v) death or serious sequelae commonly occurred; (vi) prolonged antibiotic courses (6 weeks to 3 months) have been used, without strong rational. In the given case, the patient presented with a lack of meningeal irritation signs. The diagnosis was made by MRI considering a lasting confused state. A four-week antibiotic regimen was successful, combining two weeks of intravenous cefotaxime followed by two weeks of oral levofloxacin much easier to administrate and allowing early rehabilitation. Conclusion Primary bacterial ventriculitis is a real diagnosis challenge. Larger indications of MRI for bacterial meningitis, particularly in cases with an atypical presentation or poor evolution would certainly increase the number of diagnosis.

Iovino F, Thorsdottir S, Henriques-Normark B.

AbstractBackgroundPneumococci are the major cause of bacterial meningitis globally. To cause meningitis pneumococci interact with the 2 endothelial receptors, polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1), to penetrate the blood-brain barrier (BBB) and invade the brain.MethodsC57BL/6 mice were infected intravenously with bioluminescent pneumococci, and treated with ceftriaxone (1 hour postinfection) and anti-pIgR and PECAM-1 antibodies (1 or 5 hours postinfection), then monitored for 5 and 10 days. Bacterial brain invasion was analyzed using IVIS imaging and bacterial counts.ResultsCeftriaxone, given early after pneumococcal challenge, cleared pneumococci from the blood but not from the brain. After combining ceftriaxone with receptor blockade, using anti-pIgR and PECAM-1 antibodies, we found 100% survival after 5 and 10 days of infection, in contrast to 60% for ceftriaxone alone. Combined antibiotic and antibody treatment resulted in no or few viable bacteria in the brain and no microglia activation. Antibodies remained bound to the receptors during the study period. Receptor blockade did not interfere with antibiotic permeability through the BBB.ConclusionsWe suggest that adjunct treatment with pIgR and PECAM-1 antibodies to antibiotics may prevent pneumococcal meningitis development and associated brain damages. However, further evaluations are required.

Abstract Background Escherichia coli (E. coli) is known to cause urinary tract infection (UTI) and meningitis in neonates, as well as existing as a commensal flora of the human gut. Extended-spectrum β-lactamase (ESBL)-producing E. coli has increased in the community with the spread of CTX-M type ESBL-producing sequence type 131 (ST131)-O25-H30Rx E. coli clone. The role of ESBL-producing E. coli in female genital tract infection has not been elucidated. The clinical and molecular features of E. coli isolated from community-onset female genital tract infections were evaluated to elucidate the current burden in the community, focusing on the highly virulent and multidrug-resistant ST131 clone. Methods We collected and sequenced 91 non-duplicated E. coli isolates from the female genital tract of 514 patients with community-onset vaginitis. ESBL genotypes were identified by PCR and confirmed to be ESBL-producers by sequencing methods. ST131 clones were screened by PCR for O16-ST131 and O25b-ST131. Pulsed-field gel electrophoresis (PFGE) and PCR-based replicon typing (PBRT) were conducted in ESBL producers. Independent clinical risk factors associated with acquiring ESBL-producing E. coli and ST131 clone were analyzed using multivariate logistic regression analysis. Results Of the 514 consecutive specimens obtained from the infected female genital tract, 17.7% (91/514) had E. coli infection, of which 19.8% (18/91) were ESBL producers. CTX-M-15 was the most common type (n = 15). O25b-ST131 and O16-ST131 clones accounted for 15.4% (14/91) and 6.6% (6/91), respectively. In plasmid analysis, ten isolates succeeded in conjugation and plasmid types were IncFII (n = 4), IncFI (n = 3), IncI1-Iγ (n = 3) with one non-typable case. Compared to ESBL-nonproducing E. coli, ESBL-producing E. coli acquisition was strongly associated with recurrent vaginitis (OR 40.130; 95% CI 9.980–161.366), UTI (OR 18.915; 95% CI 5.469–65.411), and antibiotics treatment (OR 68.390; 95% CI 14.870–314.531). Conclusion A dominant clone of CTX-M type ESBL-producing E. coli in conjugative plasmids seems to be circulating in the community and considerable number of ST131 E. coli in the genital tract of Korean women was noted. Sustained monitoring of molecular epidemiology and control of the high-risk group is needed to prevent ESBL-producing E. coli from spreading throughout the community.

Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk

by Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk Streptococcus suis serotype 2 is an important porcine bacterial pathogen and zoonotic agent responsible for sudden death, septic shock, and meningitis. However, serotype 2 strains are heterogeneous, composed of a multitude of sequence types (STs) whose distribution greatly varies worldwide. Of the virulence factors presently described for S. suis, the capsular polysaccharide (CPS) is a critical factor implicated in a multitude of functions, including in impairment of phagocytosis and innate immune cell activation by masking underlying bacterial components. However, these roles have been described using Eurasian ST1 and ST7 strains, which greatly differ from North American ST25 strains. Consequently, the capacity of the CPS to mask surface antigens and putative virulence factors in non-Eurasian strains remains unknown. Herein, the role of the S. suis serotype 2 CPS of a prototype intermediate virulent North American ST25 strain, in comparison with that of a virulent European ST1 strain, with regards to interactions with dendritic cells, as well as virulence during the systemic phase of infection, was evaluated. Results demonstrated that the CPS remains critical for virulence and development of clinical disease regardless of strain background, due to its requirement for survival in blood. However, its role in the interactions with dendritic cells is strain-dependent. Consequently, certain key characteristics associated with the CPS are not necessarily applicable to all S. suis serotype 2 strains. This indicates that though certain factors may be important for S. suis serotype 2 virulence, strain background could be as determining, reiterating the need in using strains from varying backgrounds in order to better characterize the S. suis pathogenesis.

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

Timothy Barkham, Anna Sheppard, Nicola Jones, Swaine Chen

Fazle Rabbi Chowdhury, Quazi Shihab Uddin Ibrahim, Md. Shafiqul Bari, M. M. Jahangir Alam, Susanna J. Dunachie, Alfonso J. Rodriguez-Morales, Md. Ismail Patwary

by Fazle Rabbi Chowdhury, Quazi Shihab Uddin Ibrahim, Md. Shafiqul Bari, M. M. Jahangir Alam, Susanna J. Dunachie, Alfonso J. Rodriguez-Morales, Md. Ismail Patwary Bangladesh is one of the world’s most vulnerable countries for climate change. This observational study examined the association of temperature, humidity and rainfall with six common climate-sensitive infectious diseases in adults (malaria, diarrheal disease, enteric fever, encephalitis, pneumonia and bacterial meningitis) in northeastern Bangladesh. Subjects admitted to the adult medicine ward of a tertiary referral hospital in Sylhet, Bangladesh from 2008 to 2012 with a diagnosis of one of the six chosen climate-sensitive infectious diseases were enrolled in the study. Climate-related data were collected from the Bangladesh Meteorological Institute. Disease incidence was then analyzed against mean temperature, humidity and average rainfall for the Sylhet region. Statistical significance was determined using Mann-Whitney test, Chi-square test and ANOVA testing. 5033 patients were enrolled (58% male, 42% female, ratio 1.3:1). All six diseases showed highly significant (p = 0.01) rises in incidence between the study years 2008 (540 cases) and 2012 (1330 cases), compared with no significant rise in overall all-cause hospital admissions in the same period (p = 0.19). The highest number of malaria (135), diarrhea (266) and pneumonia (371) cases occurred during the rainy season. On the other hand, the maximum number of enteric fever (408), encephalitis (183) and meningitis (151) cases occurred during autumn, which follows the rainy season. A positive (P = 0.01) correlation was observed between increased temperature and the incidence of malaria, enteric fever and diarrhea, and a negative correlation with encephalitis, meningitis and pneumonia. Higher humidity correlated (P = 0.01) with a higher number of cases of malaria and diarrhea, but inversely correlated with meningitis and encephalitis. Higher incidences of encephalitis and meningitis occurred while there was low rainfall. Incidences of diarrhea, malaria and enteric fever, increased with rainfall, and then gradually decreased. The findings support a relationship between weather patterns and disease incidence, and provide essential baseline data for future large prospective studies.

Wiederhold, N. P., Najvar, L. K., Garvey, E. P., Brand, S. R., Xu, X., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., Patterson, T. F.

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with C. neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28 after which mice were monitored off-therapy until day 30 or day 60, respectively, to assess survival. Fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg once daily. VT-1129 at doses of ≥ 0.3 mg/kg/day and each dose of fluconazole significantly reduced brain tissue fungal burden compared to control after both 7 and 14 days of dosing. Fungal burden was also undetectable in most mice treated with dose of ≥ 3 mg/kg/day, even ≥ 20 days after dosing had stopped in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

Abstract Background Many of the currently used models of bacterial meningitis have limitations due to direct inoculation of pathogens into the cerebrospinal fluid or brain and a relatively insensitive assessment of long-term sequelae. The present study evaluates the utility of a Streptococcus (S.) suis intranasal infection model for the investigation of experimental therapies in meningitis. Methods We examined the brains of 10 piglets with S. suis meningitis as well as 14 control piglets by histology, immunohistochemistry and in-situ tailing for morphological alterations in the hippocampal dentate gyrus and microglial activation in the neocortex. Results In piglets with meningitis, the density of apoptotic neurons was significantly higher than in control piglets. Moreover, scoring of microglial morphology revealed a significant activation of these cells during meningitis. The slight increase in the density of dividing cells, young neurons and microglia observed in piglets suffering from meningitis was not statistically significant, probably because of the short time frame between onset of clinical signs and organ sampling. Conclusions The morphological changes found during S. suis meningitis are in accordance with abnormalities in other animal models and human autopsy cases. Therefore, the pig should be considered as a model for evaluating effects of experimental therapeutic approaches on neurological function in bacterial meningitis.

Assad Hassan, G. U. Mustapha, Bola B. Lawal, Aliyu M. Na’uzo, Raji Ismail, Eteng Womi-Eteng Oboma, Oyeronke Oyebanji, Jeremiah Agenyi, Chima Thomas, Muhammad Shakir Balogun, Mahmood M. Dalhat, Patrick Nguku, Chikwe Ihekweazu

by Assad Hassan, G. U. Mustapha, Bola B. Lawal, Aliyu M. Na’uzo, Raji Ismail, Eteng Womi-Eteng Oboma, Oyeronke Oyebanji, Jeremiah Agenyi, Chima Thomas, Muhammad Shakir Balogun, Mahmood M. Dalhat, Patrick Nguku, Chikwe Ihekweazu Background Nigeria reports high rates of mortality linked with recurring meningococcal meningitis outbreaks within the African meningitis belt. Few studies have thoroughly described the response to these outbreaks to provide strong and actionable public health messages. We describe how time delays affected the response to the 2016/2017 meningococcal meningitis outbreak in Nigeria. Methods Using data from Nigeria Centre for Disease Control (NCDC), National Primary Health Care Development Agency (NPHCDA), World Health Organisation (WHO), and situation reports of rapid response teams, we calculated attack and death rates of reported suspected meningococcal meningitis cases per week in Zamfara, Sokoto and Yobe states respectively, between epidemiological week 49 in 2016 and epidemiological week 25 in 2017. We identified when alert and epidemic thresholds were crossed and determined when the outbreak was detected and notified in each state. We examined response activities to the outbreak. Results There were 12,535 suspected meningococcal meningitis cases and 877 deaths (CFR: 7.0%) in the three states. It took an average time of three weeks before the outbreaks were detected and notified to NCDC. Four weeks after receiving notification, an integrated response coordinating centre was set up by NCDC and requests for vaccines were sent to International Coordinating Group (ICG) on vaccine provision. While it took ICG one week to approve the requests, it took an average of two weeks for approximately 41% of requested vaccines to arrive. On the average, it took nine weeks from the date the epidemic threshold was crossed to commencement of reactive vaccination in the three states. Conclusion There were delays in detection and notification of the outbreak, in coordinating response activities, in requesting for vaccines and their arrival from ICG, and in initiating reactive vaccination. Reducing these delays in future outbreaks could help decrease the morbidity and mortality linked with meningococcal meningitis outbreaks.

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.

Henao-Martínez, Andrés F.; Chastain, Daniel B.; Franco-Paredes, Carlos

Purpose of review Cryptococcosis has become a common opportunistic infection among non-HIV immunocompromised hosts. Recent reports have shown the incidence of Cryptococcosis among HIV-negative immunocompromised patients reaches close to half of the overall cases reported in the USA. Management of this infection in this population carries unique challenges. We aim to review relevant and recent research findings to develop treatment recommendations for this type of population. Recent findings Most of the recommendations for the management of non-HIV immunocompromised host are extrapolated from HIV studies. Cryptococcosis among non-HIV patients is common but often overlooked. Some clinical factors, when present, may increase the risk of Cryptococcosis among HIV-negative patients and appropriate screening and assessment for the disease is necessary. Treating clinicians should consider a longer duration of induction with Amphotericin B depending on the type of host, immunocompromised state, antifungal response and presence of neurological complications. Baseline fluconazole resistance can reach up to 12%, which is an important consideration for cryptococcal meningitis relapses or suboptimal responses to therapy. Summary Cryptococcus spp. conveys a high disease burden among immunocompromised hosts. Clinicians must consider numerous variables and factors in a dynamic way to offer the best possible treatment and to monitor their response to therapy. Due to the high cost and associated toxicities, we still need new affordable therapies and studies among non-HIV immunocompromised patients. Correspondence to Andrés F. Henao-Martínez, MD, University of Colorado Denver 12700 E. 19th Avenue, Mail Stop B168, Aurora, CO 80045,. USA. Tel: +1 (720) 848 0820; fax: +1 (720) 848 0191; e-mail: andres.henaomartinez@ucdenver.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Jarvis J, Harrison T.