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Background: It is uncertain whether all adults with bacterial meningitis benefit from treatment with adjunctive dexamethasone.Methods: We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone in 435 patients over the age of 14 years who had suspected bacterial meningitis. The goal was to determine whether dexamethasone reduced the risk of death at 1 month and the risk of death or disability at 6 months.Results: A total of 217 patients were assigned to the dexamethasone group, and 218 to the placebo group. Bacterial meningitis was confirmed in 300 patients (69.0%), probable meningitis was diagnosed in 123 patients (28.3%), and an alternative diagnosis was made in 12 patients (2.8%). An intention-to-treat analysis of all the patients showed that dexamethasone was not associated with a significant reduction in the risk of death at 1 month (relative risk, 0.79; 95% confidence interval [CI], 0.45 to 1.39) or the risk of death or disability at 6 months (odds ratio, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (relative risk, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (odds ratio, 0.56; 95% CI, 0.32 to 0.98). These effects were not found in patients with probable bacterial meningitis. Results of multivariate analysis indicated that dexamethasone treatment for patients with probable bacterial meningitis was significantly associated with an increased risk of death at 1 month, an observation that may be explained by cases of tuberculous meningitis in the treatment group.Conclusions: Dexamethasone does not improve the outcome in all adolescents and adults with suspected bacterial meningitis; a beneficial effect appears to be confined to patients with microbiologically proven disease, including those who have received prior treatment with antibiotics. (Current Controlled Trials number, ISRCTN42986828 [controlled-trials.com] .). [ABSTRACT FROM AUTHOR]

Background: Tuberculous meningitis kills or disables more than half of those affected with the disease. Previous studies have been too small to determine whether adjunctive treatment with corticosteroids can reduce the risk of disability or death among adults with tuberculous meningitis, and the effect of coinfection with the human immunodeficiency virus (HIV) is unclear.Methods: We performed a randomized, double-blind, placebo-controlled trial in Vietnam in patients over 14 years of age who had tuberculous meningitis, with or without HIV infection, to determine whether adjunctive treatment with dexamethasone reduced the risk of death or severe disability after nine months of follow-up. We conducted prespecified subgroup analyses and intention-to-treat analyses.Results: A total of 545 patients were randomly assigned to groups that received either dexamethasone (274 patients) or placebo (271 patients). Only 10 patients (1.8 percent) had been lost to follow-up at nine months of treatment. Treatment with dexamethasone was associated with a reduced risk of death (relative risk, 0.69; 95 percent confidence interval, 0.52 to 0.92; P=0.01). It was not associated with a significant reduction in the proportion of severely disabled patients (34 of 187 patients [18.2 percent] among survivors in the dexamethasone group vs. 22 of 159 patients [13.8 percent] in the placebo group, P=0.27) or in the proportion of patients who had either died or were severely disabled after nine months (odds ratio, 0.81; 95 percent confidence interval, 0.58 to 1.13; P=0.22). The treatment effect was consistent across subgroups that were defined by disease-severity grade (stratified relative risk of death, 0.68; 95 percent confidence interval, 0.52 to 0.91; P=0.007) and by HIV status (stratified relative risk of death, 0.78; 95 percent confidence interval, 0.59 to 1.04; P=0.08). Significantly fewer serious adverse events occurred in the dexamethasone group than in the placebo group (26 of 274 patients vs. 45 of 271 patients, P=0.02).Conclusions: Adjunctive treatment with dexamethasone improves survival in patients over 14 years of age with tuberculous meningitis but probably does not prevent severe disability. [ABSTRACT FROM AUTHOR]

Mortality from tuberculous meningitis (TBM) remains around 30%, with most deaths occurring within 2 months of starting treatment. Mortality from drug-resistant strains is higher still, making early detection of drug resistance (DR) essential. Targeted next-generation sequencing (tNGS) produces high read depths, allowing the detection of DR-associated alleles with low frequencies. We applied Deeplex Myc-TB-a tNGS assay-to cerebrospinal fluid (CSF) samples from 72 adults with microbiologically confirmed TBM and compared its genomic drug susceptibility predictions to a composite reference standard of phenotypic susceptibility testing (pDST) and whole genome sequencing, as well as to clinical outcomes. Deeplex detected Mycobacterium tuberculosis complex DNA in 24/72 (33.3%) CSF samples and generated full DR reports for 22/24 (91.7%). The read depth generated by Deeplex correlated with semi-quantitative results from MTB/RIF Xpert. Alleles with <20% frequency were seen at canonical loci associated with first-line DR. Disregarding these low-frequency alleles, Deeplex had 100% concordance with the composite reference standard for all drugs except pyrazinamide and streptomycin. Three patients had positive CSF cultures after 30 days of treatment; reference tests and Deeplex identified isoniazid resistance in two, and Deeplex alone identified low-frequency rifampin resistance alleles in one. Five patients died, of whom one had pDST-identified pyrazinamide resistance. tNGS on CSF can rapidly and accurately detect drug-resistant TBM, but its application is limited to those with higher bacterial loads. In those with lower bacterial burdens, alternative approaches need to be developed for both diagnosis and resistance detection., Competing Interests: The authors declare no conflict of interest.

Salmonella enterica serotype 1,4,[5],12:i:- (Typhimurium monophasic variant) of sequence type (ST) 34 has emerged as the predominant pandemic genotype in recent decades. Despite increasing reports of resistance to antimicrobials in Southeast Asia, Salmonella ST34 population structure and evolution remained understudied in the region. Here we performed detailed genomic investigations on 454 ST34 genomes collected from Vietnam and diverse geographical sources to elucidate the pathogen's epidemiology, evolution and antimicrobial resistance. We showed that ST34 has been introduced into Vietnam in at least nine occasions since 2000, forming five co-circulating major clones responsible for paediatric diarrhoea and bloodstream infection. Most expansion events were associated with acquisitions of large multidrug resistance plasmids of IncHI2 or IncA/C2. Particularly, the self-conjugative IncA/C2 pST34VN2 (co-transferring bla CTX-M-55 , mcr-3.1, and qnrS1) underlies local expansion and intercontinental spread in two separate ST34 clones. At the global scale, Southeast Asia was identified as a potential hub for the emergence and dissemination of multidrug resistant Salmonella ST34, and mutation analysis suggests of selection in antimicrobial responses and key virulence factors., (© 2023. Springer Nature Limited.)

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism., Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins., Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis., Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy., Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z)., Competing Interests: EA, JA, LN, SD, DV, HH, KB, BA, RE, TT, JD, DH, TC, NB, AG, RR, VK, RH, DI, KM, VK, CC, Rv, GT, Av, NT No competing interests declared, MN has received consulting fees from Scientific Board TTxD and is a scientific founder of TTxD, Lemba and BioTRIP. The author has no other competing interests to declare, (© 2023, Ardiansyah et al.)

Purpose: The purpose is to study the 5-year results of aflibercept monotherapy using an individualized regimen in naïve patients with neovascular AMD (nAMD)., Materials and Methods: This is a prospective observational study including naïve nAMD patients who underwent aflibercept injections with at least 5 years of follow-up. All of them received 3 monthly injections at the loading phase, followed by an observation period, then treated with an individualized treat-and-extend regimen. Visual acuity (VA) measurement and optical coherence tomography were performed at each visit., Results: Forty-eight eyes were included. Of these, 30 were followed up for 5 years. The mean follow-up was 61.7 ± 2.3 months. The mean age was 81 ± 8 years. The visual gain was 7.3 ± 12.7 letters at 1 year, 6.5 ± 12.5 letters at 2 years, 5.2 ± 17 letters at 3 years, 6.2 ± 18.6 letters at 4 years, and 5.6 ± 20 letters at 5 years. At the last observation, 53% of eyes had VA > 70 letters. A complete fluid resolution was obtained in 53% of the eyes. At the 5-year endpoint, the total number of injections was 21.6 ± 13.4. Macular atrophy was observed in 18 eyes (60%) and subretinal fibrosis in 14 eyes (46%)., Conclusion: Patients with exudative AMD can maintain their visual function at 5 years with aflibercept using an individualized treatment. The loss of visual gain beyond 2 years could be related to the natural progression of the disease than the direct effect of anti-vascular endothelial growth injections., Competing Interests: The authors declare that there are no conflicts of interests of this paper., (Copyright: © 2023 Taiwan J Ophthalmol.)

Non-typhoidal Salmonella (NTS) is a major cause of bacterial enterocolitis globally but also causes invasive bloodstream infections. Antimicrobial resistance (AMR) hampers the treatment of these infections and understanding how AMR spreads between NTS may help in developing effective strategies. We investigated NTS isolates associated with invasive disease, diarrhoeal disease and asymptomatic carriage in animals and humans from Vietnam. Isolates included multiple serovars and both common and rare phenotypic AMR profiles; long- and short-read sequencing was used to investigate the genetic mechanisms and genomic backgrounds associated with phenotypic AMR profiles. We demonstrate concordance between most AMR genotypes and phenotypes but identified large genotypic diversity in clinically relevant phenotypes and the high mobility potential of AMR genes (ARGs) in this setting. We found that 84 % of ARGs identified were located on plasmids, most commonly those containing IncHI1A&#95;1 and IncHI1B(R27)&#95;1&#95;R27 replicons (33%), and those containing IncHI2&#95;1 and IncHI2A&#95;1 replicons (31%). The vast majority (95%) of ARGS were found within 10 kbp of IS6/IS26 elements, which provide plasmids with a mechanism to exchange ARGs between plasmids and other parts of the genome. Whole genome sequencing with targeted long-read sequencing applied in a One Health context identified a comparatively limited number of insertion sequences and plasmid replicons associated with AMR. Therefore, in the context of NTS from Vietnam and likely for other settings as well, the mechanisms by which ARGs move contribute to a more successful AMR profile than the specific ARGs, facilitating the adaptation of bacteria to different environments or selection pressures.

The major human genes regulating Mycobacterium tuberculosis -induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2 + CD4 + T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background and Aim: Salmonella is one of the leading causes of zoonotic and foodborne infectious outbreaks in humans and poultry and its associated environment is a potential reservoir of Salmonella . In recent years, the antibiotic resistance of bacteria, including Salmonella , has been increasing. This study aimed to investigate the prevalence and antibiotic resistance of Salmonella isolated from poultry, its environment, and the pest animals found at poultry farms and households of the Mekong Delta, Vietnam., Materials and Methods: A total of 3,055 samples were collected from the broiler farms and households of the Mekong Delta from 2017 to 2020. Salmonella was isolated using conventional methods (culturing on selective agar - BPLS and biochemical test) and the isolates were examined for antibiotic resistance against 14 antibiotics using the disk diffusion method., Results: Salmonella was isolated from 181 samples (5.92%), which included chicken feces (7.67%), pest animals (5.98%), and environmental samples (4.33%). The environmental samples comprised bedding (5.88%), feed (5.48%), and drinking water (0.70%). The prevalence of Salmonella was the highest in rats (15.63%) and geckos (12.25%) followed by ants (2.83%) and cockroaches (2.44%); however, Salmonella was not isolated from any fly species. Most of the isolates exhibited resistance to 1-9 antibiotics. The isolates were relatively resistant to chloramphenicol (62.98%), tetracycline (55.80%), ampicillin (54.14%), and sulfamethoxazole/trimethoprim (53.04%). Sixty-two multiple resistance patterns were found in the isolates, with ampicillin-cefuroxime-chloramphenicol-tetracycline- sulfamethoxazole/trimethoprim being the most frequent (7.18%)., Conclusion: The chickens, husbandry environment, and pest animals at poultry farms and households were found to be important Salmonella sources in the Mekong Delta. Salmonella isolates from these sources also exhibited a wide-ranging resistance to antibiotics as well as several resistance patterns. Hence, biosecurity should be addressed in poultry farms and households to prevent cross-contamination and reduce the spread of Salmonella infections., (Copyright: © Nguyen, et al.)

We investigated the value of susceptibility testing in predicting response in AIDS-associated cryptococcal meningitis using clinical isolates from a randomized controlled trial of antifungal treatment (amphotericin monotherapy, amphotericin with flucytosine, or amphotericin with fluconazole). We found no correlation between antifungal susceptibility and either early or late survival, or fungal clearance., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Approximately 6% of children hospitalized with severe falciparum malaria in Africa are also bacteremic. It is therefore recommended that all children with severe malaria should receive broad-spectrum antibiotics in addition to parenteral artesunate. Empirical antibiotics are not recommended currently for adults with severe malaria., Methods: Blood cultures were performed on sequential prospectively studied adult patients with strictly defined severe falciparum malaria admitted to a single referral center in Vietnam between 1991 and 2003., Results: In 845 Vietnamese adults with severe falciparum malaria admission blood cultures were positive in 9 (1.07%: 95% confidence interval [CI], .37-1.76%); Staphylococcus aureus in 2, Streptococcus pyogenes in 1, Salmonella Typhi in 3, Non-typhoid Salmonella in 1, Klebsiella pneumoniae in 1, and Haemophilus influenzae type b in 1. Bacteremic patients presented usually with a combination of jaundice, acute renal failure, and high malaria parasitemia. Four bacteremic patients died compared with 108 (12.9%) of 836 nonbacteremic severe malaria patients (risk ratio, 3.44; 95% CI, 1.62-7.29). In patients with >20% parasitemia the prevalence of concomitant bacteremia was 5.2% (4/76; 95% CI, .2-10.3%) compared with 0.65% (5/769; 0.08-1.2%) in patients with <20% parasitemia, a risk ratio of 8.1 (2.2-29.5)., Conclusions: In contrast to children, the prevalence of concomitant bacteremia in adults with severe malaria is low. Administration of empirical antibiotics, in addition to artesunate, is warranted in the small subgroup of patients with very high parasitemias, emphasizing the importance of quantitative blood smear microscopy assessment, but it is not indicated in most adults with severe falciparum malaria., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Nontyphoidal Salmonella (NTS) are among the most common etiological agents of diarrheal diseases worldwide and have become the most commonly detected bacterial pathogen in children hospitalized with diarrhea in Vietnam. Aiming to better understand the epidemiology, serovar distribution, antimicrobial resistance (AMR), and clinical manifestation of NTS gastroenteritis in Vietnam, we conducted a clinical genomics investigation of NTS isolated from diarrheal children admitted to one of three tertiary hospitals in Ho Chi Minh City. Between May 2014 and April 2016, 3,166 children hospitalized with dysentery were recruited into the study; 478 (∼15%) children were found to be infected with NTS by stool culture. Molecular serotyping of the 450 generated genomes identified a diverse collection of serogroups (B, C1, C2 to C3, D1, E1, G, I, K, N, O, and Q); however, Salmonella enterica serovar Typhimurium was the most predominant serovar, accounting for 41.8% (188/450) of NTS isolates. We observed a high prevalence of AMR to first-line treatments recommended by WHO, and more than half (53.8%; 242/450) of NTS isolates were multidrug resistant (MDR; resistant to ≥3 antimicrobial classes). AMR gene detection positively correlated with phenotypic AMR testing, and resistance to empirical antimicrobials was associated with a significantly longer hospitalization (0.91 days; P =  0.04). Our work shows that genome sequencing is a powerful epidemiological tool to characterize the serovar diversity and AMR profiles in NTS. We propose a revaluation of empirical antimicrobials for dysenteric diarrhea and endorse the use of whole-genome sequencing for sustained surveillance of NTS internationally., (Copyright © 2020 Duong et al.)

Background: Diarrhoeagenic Escherichia coli (DEC) infections are common in children in low-middle income countries (LMICs). However, detecting the various DEC pathotypes is complex as they cannot be differentiated by classical microbiology. We developed four multiplex real-time PCR assays were to detect virulence markers of six DEC pathotypes; specificity was tested using DEC controls and other enteric pathogens. PCR amplicons from the six E. coli pathotypes were purified and amplified to be used to optimize PCR reactions and to calculate reproducibility. After validation, these assays were applied to clinical samples from healthy and diarrhoeal Vietnamese children and associated with clinical data., Results: The multiplex real-time PCRs were found to be reproducible, and specific. At least one DEC variant was detected in 34.7% (978/2815) of the faecal samples from diarrhoeal children; EAEC, EIEC and atypical EPEC were most frequent Notably, 41.2% (205/498) of samples from non-diarrhoeal children was positive with a DEC pathotype. In this population, only EIEC, which was detected in 34.3% (99/289) of diarrhoeal samples vs. 0.8% (4/498) non-diarrhoeal samples (p < 0.001), was significantly associated with diarrhoea. Multiplex real-time PCR when applied to clinical samples is an efficient and high-throughput approach to DEC pathotypes., Conclusions: This approach revealed high carriage rates of DEC pathotypes among Vietnamese children. We describe a novel diagnostic approach for DEC, which provides baseline data for future surveillance studies assessing DEC burden in LMICs.

Background: Nontyphoidal Salmonella (NTS) organisms are a major cause of gastroenteritis and bacteremia, but little is known about maternally acquired immunity and natural exposure in infant populations residing in areas where NTS disease is highly endemic., Methods: We recruited 503 pregnant mothers and their infants (following delivery) from urban areas in Vietnam and followed infants until they were 1 year old. Exposure to the dominant NTS serovars, Salmonella enterica serovars Typhimurium and Enteritidis, were assessed using lipopolysaccharide (LPS) O antigen-specific antibodies. Antibody dynamics, the role of maternally acquired antibodies, and NTS seroincidence rates were modeled using multivariate linear risk factor models and generalized additive mixed-effect models., Results: Transplacental transfer of NTS LPS-specific maternal antibodies to infants was highly efficient. Waning of transplacentally acquired NTS LPS-specific antibodies at 4 months of age left infants susceptible to Salmonella organisms, after which they began to seroconvert. High seroincidences of S. Typhimurium and S. Enteritidis LPS were observed, and infants born with higher anti-LPS titers had greater plasma bactericidal activity and longer protection from seroconversion., Conclusions: Although Vietnamese infants have extensive exposure to NTS, maternally acquired antibodies appear to play a protective role against NTS infections during early infancy. These findings suggest that prenatal immunization may be an appropriate strategy to protect vulnerable infants from NTS disease.

Background: Enteroviruses are the most common causative agents of human illness. Enteroviruses have been associated with regional and global epidemics, recently, including with severe disease (Enterovirus A71 and D68), and are of interest as emerging viruses. Here, we typed Enterovirus A-D (EV) from central nervous system (CNS) and respiratory infections in Viet Nam., Methods: Data and specimens from prospective observational clinical studies conducted between 1997 and 2010 were used. Species and serotypes were determined using type-specific RT-PCR and viral protein 1 or 4 (VP1, VP4) sequencing., Results: Samples from patients with CNS infection (51 children - 10 CSF and 41 respiratory/rectal swabs) and 28 adults (28 CSF) and respiratory infection (124 children - 124 respiratory swabs) were analysed. Twenty-six different serotypes of the four Enterovirus species (A-D) were identified, including EV-A71 and EV-D68. Enterovirus B was associated with viral meningitis in children and adults. Hand, foot and mouth disease associated Enteroviruses A (EV-A71 and Coxsackievirus [CV] A10) were detected in children with encephalitis. Diverse serotypes of all four Enterovirus species were found in respiratory samples, including 2 polio-vaccine viruses, but also 8 CV-A24 and 8 EV-D68. With the exception of EV-D68, the relevance of these viruses in respiratory infection remains unknown., Conclusion: We describe the diverse spectrum of enteroviruses from patients with CNS and respiratory infections in Viet Nam between 1997 and 2010. These data confirm the global circulation of Enterovirus genera and their associations and are important for clinical diagnostics, patient management, and outbreak response.

Background: Pediatric diarrheal disease presents a major public health burden in low- to middle-income countries. The clinical benefits of empirical antimicrobial treatment for diarrhea are unclear in settings that lack reliable diagnostics and have high antimicrobial resistance (AMR)., Methods: We conducted a prospective multicenter cross-sectional study of pediatric patients hospitalized with diarrhea containing blood and/or mucus in Ho Chi Minh City, Vietnam. Clinical parameters, including disease outcome and treatment, were measured. Shigella, nontyphoidal Salmonella (NTS), and Campylobacter were isolated from fecal samples, and their antimicrobial susceptibility profiles were determined. Statistical analyses, comprising log-rank tests and accelerated failure time models, were performed to assess the effect of antimicrobials on disease outcome., Results: Among 3166 recruited participants (median age 10 months; interquartile range, 6.5-16.7 months), one-third (1096 of 3166) had bloody diarrhea, and 25% (793 of 3166) were culture positive for Shigella, NTS, or Campylobacter. More than 85% of patients (2697 of 3166) were treated with antimicrobials; fluoroquinolones were the most commonly administered antimicrobials. AMR was highly prevalent among the isolated bacteria, including resistance against fluoroquinolones and third-generation cephalosporins. Antimicrobial treatment and multidrug resistance status of the infecting pathogens were found to have no significant effect on outcome. Antimicrobial treatment was significantly associated with an increase in the duration of hospitalization with particular groups of diarrheal diseases., Conclusions: In a setting with high antimicrobial usage and high AMR, our results imply a lack of clinical benefit for treating diarrhea with antimicrobials; adequately powered randomized controlled trials are required to assess the role of antimicrobials for diarrhea., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection., Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/)., Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone., Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

An accurate and reliable high-performance liquid chromatography with time-programmed fluorescence detection was developed and validated to measure levofloxacin in human plasma and cerebrospinal fluid (CSF). After solid phase extraction process using Evolute ® ABN 96 fixed well plate; levofloxacin and internal standard-enoxacin were separated using a mobile phase consisting of phosphate buffer 10mM with 0.025% triethylamine pH 3.0 - acetonitrile (88:12, v/v) on a Purosphere RP-8e column (5μm, 125×4.0mm) at a flow rate of 1.2mL/min at 35°C. The excitation/emission wavelengths were set to 269/400nm and 294/500nm, for enoxacin and levofloxacin, respectively. The method was linear over the concentration range of 0.02 to 20.0μg/mL with a limit of detection of 0.01μg/mL. The relative standard deviation of intra-assay and inter-assay precision for levofloxacin at four quality controls concentrations (0.02, 0.06, 3.0 and 15.0μg/mL) were less than 7% and the accuracies ranged from 96.75% to 101.9% in plasma, and from 93.00% to 98.67% in CSF. The validated method was successfully applied to quantify levofloxacin in a considerable quantity of plasma (826) and CSF (477) samples collected from 232 tuberculous meningitis patients, and the preliminary intensive pharmacokinetics analysis from 14 tuberculous meningitis patients in Vietnam is described in this paper., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher's exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109 cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

Background: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM., Methods: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations., Results: LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype., Conclusions: LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days., Methods: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks., Results: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy., Conclusions: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

Background: Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB)., Methods: We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB., Results: The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response., Conclusions: These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.