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1.
J Clin Microbiol ; 62(4): e0128723, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38466092

RESUMO

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.


Assuntos
Mycobacterium tuberculosis , Tuberculose Meníngea , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Humanos , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/líquido cefalorraquidiano , Mycobacterium tuberculosis/genética , Pirazinamida , Sensibilidade e Especificidade , Rifampina/farmacologia , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Líquido Cefalorraquidiano , Testes de Sensibilidade Microbiana
2.
Clin Infect Dis ; 73(7): e2338-e2341, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33051650

RESUMO

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.


Assuntos
Síndrome da Imunodeficiência Adquirida , Meningite Criptocócica , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Humanos , Meningite Criptocócica/tratamento farmacológico
3.
Clin Infect Dis ; 71(9): e465-e470, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-32107527

RESUMO

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.


Assuntos
Antimaláricos , Artemisininas , Bacteriemia , Malária Falciparum , Malária , Adulto , África , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Bacteriemia/complicações , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Criança , Humanos , Malária/tratamento farmacológico , Malária Falciparum/complicações , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Plasmodium falciparum , Vietnã/epidemiologia
4.
J Clin Microbiol ; 58(12)2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-32907994

RESUMO

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.


Assuntos
Anti-Infecciosos , Gastroenterite , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Criança , Criança Hospitalizada , Farmacorresistência Bacteriana , Farmacorresistência Bacteriana Múltipla/genética , Gastroenterite/epidemiologia , Genômica , Humanos , Testes de Sensibilidade Microbiana , Sorotipagem , Vietnã/epidemiologia
5.
BMC Microbiol ; 20(1): 192, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620076

RESUMO

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.


Assuntos
Diarreia/microbiologia , Escherichia coli Enteropatogênica/classificação , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adolescente , Criança , Pré-Escolar , Diarreia/epidemiologia , Escherichia coli Enteropatogênica/genética , Escherichia coli Enteropatogênica/isolamento & purificação , Escherichia coli Enteropatogênica/patogenicidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex , Prevalência , Sensibilidade e Especificidade , Vietnã/epidemiologia , Fatores de Virulência de Bordetella
6.
J Infect Dis ; 219(2): 295-304, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30321351

RESUMO

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.


Assuntos
Anticorpos Antibacterianos/imunologia , Imunidade Materno-Adquirida/imunologia , Imunidade , Infecções por Salmonella/imunologia , Adulto , Anticorpos Antibacterianos/sangue , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Lipopolissacarídeos/imunologia , Masculino , Análise Multivariada , Antígenos O , Fatores de Risco , Salmonella enteritidis , Salmonella typhimurium , Estudos Soroepidemiológicos , Sorogrupo , Vietnã
7.
Clin Infect Dis ; 66(4): 523-532, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29029055

RESUMO

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.


Assuntos
Coinfecção/mortalidade , Infecções por HIV/complicações , Modelos Teóricos , Tuberculose Meníngea/mortalidade , Adulto , Fatores Etários , Coinfecção/microbiologia , Coinfecção/virologia , Feminino , Infecções por HIV/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Nomogramas , Estudos Observacionais como Assunto , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de Tempo , Vietnã
8.
Clin Infect Dis ; 66(4): 504-511, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29029149

RESUMO

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.


Assuntos
Antibacterianos/uso terapêutico , Diarreia/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Fezes/microbiologia , Adolescente , Campylobacter/efeitos dos fármacos , Criança , Pré-Escolar , Estudos Transversais , Diarreia/microbiologia , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Prevalência , Estudos Prospectivos , Salmonella/efeitos dos fármacos , Shigella/efeitos dos fármacos , Resultado do Tratamento , Vietnã
9.
Virol J ; 15(1): 69, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650033

RESUMO

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.


Assuntos
Infecções do Sistema Nervoso Central/epidemiologia , Infecções do Sistema Nervoso Central/virologia , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Enterovirus/classificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Adolescente , Adulto , Infecções do Sistema Nervoso Central/diagnóstico , Infecções do Sistema Nervoso Central/história , Criança , Pré-Escolar , Enterovirus/genética , Enterovirus/isolamento & purificação , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/história , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , História do Século XX , História do Século XXI , Humanos , Lactente , Masculino , Filogenia , Vigilância da População , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/história , Estações do Ano , Análise de Sequência de DNA , Sorogrupo , Vietnã/epidemiologia , Adulto Jovem
10.
Clin Infect Dis ; 64(12): 1784-1787, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28158507

RESUMO

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.


Assuntos
Angiostrongylus cantonensis/isolamento & purificação , Eosinofilia/parasitologia , Meningite/parasitologia , Infecções por Strongylida/parasitologia , Adolescente , Adulto , Angiostrongylus cantonensis/genética , Animais , Estudos de Coortes , Eosinofilia/epidemiologia , Feminino , Humanos , Masculino , Meningite/epidemiologia , Reação em Cadeia da Polimerase , Estudos Prospectivos , Infecções por Strongylida/diagnóstico , Infecções por Strongylida/epidemiologia , Centros de Atenção Terciária , Vietnã/epidemiologia , Adulto Jovem
12.
Antimicrob Agents Chemother ; 60(8): 4511-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27161633

RESUMO

Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those with impaired blood-brain barrier integrity.


Assuntos
Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Alcinos , Barreira Hematoencefálica , Ciclopropanos , Genótipo
13.
J Clin Microbiol ; 52(1): 226-33, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24197880

RESUMO

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (P = 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.


Assuntos
Antituberculosos/farmacologia , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Tuberculose Meníngea/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Cefalorraquidiano/microbiologia , Reações Falso-Positivas , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Sensibilidade e Especificidade , Vietnã , Adulto Jovem
14.
Commun Biol ; 6(1): 1007, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37789208

RESUMO

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 blaCTX-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.


Assuntos
Anti-Infecciosos , Salmonella enterica , Humanos , Criança , Salmonella enterica/genética , Sorogrupo , Farmacorresistência Bacteriana Múltipla/genética , Plasmídeos/genética , Salmonella , Sudeste Asiático/epidemiologia
15.
medRxiv ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36711829

RESUMO

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 tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-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. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. 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).

16.
Elife ; 122023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37158692

RESUMO

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).


Assuntos
Infecções por HIV , Meningite Criptocócica , Tuberculose Meníngea , Adulto , Humanos , Tuberculose Meníngea/tratamento farmacológico , Triptofano/metabolismo , Cinurenina , Infecções por HIV/tratamento farmacológico , Inflamação/microbiologia
17.
Crit Care Med ; 40(2): 477-83, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21946658

RESUMO

OBJECTIVE: Dengue continues to cause significant global morbidity and mortality. Severe disease is characterized by cardiovascular compromise from capillary leakage. Cardiac involvement in dengue has also been reported but has not been adequately studied. SETTING: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. SUBJECTS AND DESIGN: Seventy-nine patients aged 8-6 yrs with different dengue severity grades were studied using echocardiography including tissue Doppler imaging. The patients were split into severity grades: dengue, dengue with warning signs, and severe dengue. Changes in cardiac functional parameters and hemodynamic indices were monitored over the hospital stay. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients with severe dengue had worse cardiac function compared with dengue in the form of left ventricular systolic dysfunction with increased left myocardial performance index (0.58 [0.26-0.80] vs. 0.38 [0.22-0.70], p = .006). Septal myocardial systolic velocities were reduced (6.4 [4.8-10] vs. 8.1 [6-13] cm/s, p = .01) as well as right ventricular systolic (11.4 [7.5-17] vs. 13.5 [10-17] cm/s, p = .016) and diastolic velocities (13 [8-23] vs. 17 [12-25] cm/s, p = .0026). In the severe group, these parameters improved from hospital admission to discharge; septal myocardial systolic velocities to 8.8 (7-11) cm/s (p = .002), right ventricular myocardial systolic velocities to 15.0 (11.8-23) cm/s, (p = .003), and diastolic velocity to 21 (11-25) cm/s (p = .002). Patients with cardiac impairment were more likely to have significant pleural effusions. CONCLUSIONS: Patients with severe dengue have evidence of systolic and diastolic cardiac impairment with septal and right ventricular wall being predominantly affected.


Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Dengue/epidemiologia , Doenças Endêmicas/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Doenças Cardiovasculares/fisiopatologia , Criança , Estudos de Coortes , Comorbidade , Dengue/diagnóstico por imagem , Dengue/fisiopatologia , Ecocardiografia Doppler/métodos , Ecocardiografia Doppler de Pulso , Eletrocardiografia/métodos , Feminino , Testes de Função Cardíaca , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Dengue Grave/diagnóstico por imagem , Dengue Grave/epidemiologia , Dengue Grave/fisiopatologia , Índice de Gravidade de Doença , Distribuição por Sexo , Volume Sistólico , Taxa de Sobrevida , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/fisiopatologia , Vietnã/epidemiologia , Adulto Jovem
18.
Microb Genom ; 8(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35511231

RESUMO

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_1 and IncHI1B(R27)_1_R27 replicons (33%), and those containing IncHI2_1 and IncHI2A_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.


Assuntos
Antibacterianos , Febre Tifoide , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Humanos , Salmonella , Sorogrupo , Vietnã
19.
Clin Infect Dis ; 52(11): 1374-83, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21596680

RESUMO

BACKGROUND: The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses. RESULTS: A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). CONCLUSIONS: Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Tuberculose Meníngea/complicações , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Antituberculosos/administração & dosagem , Benzoxazinas/administração & dosagem , Ciclopropanos , Dexametasona/administração & dosagem , Método Duplo-Cego , Feminino , Infecções por HIV/mortalidade , Humanos , Lamivudina/administração & dosagem , Masculino , Placebos/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/mortalidade , Zidovudina/administração & dosagem
20.
Antimicrob Agents Chemother ; 55(7): 3624-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21576427

RESUMO

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.


Assuntos
Aciclovir/análogos & derivados , Antivirais/farmacocinética , Encefalite por Herpes Simples/tratamento farmacológico , Valina/análogos & derivados , Aciclovir/sangue , Aciclovir/líquido cefalorraquidiano , Aciclovir/farmacocinética , Aciclovir/uso terapêutico , Antivirais/sangue , Antivirais/líquido cefalorraquidiano , Antivirais/uso terapêutico , Encefalite por Herpes Simples/sangue , Feminino , Humanos , Masculino , Valaciclovir , Valina/sangue , Valina/líquido cefalorraquidiano , Valina/farmacocinética , Valina/uso terapêutico
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