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1.
J Infect Dis ; 229(3): 833-844, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-37403670

RESUMEN

BACKGROUND: Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low- and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures. METHODS: Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of 3 months, and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs. RESULTS: The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE), and the serovar-specific O2 and O9 antigens were greatly elevated over a 3-month follow up period in S. Typhi/S. Paratyphi A patients compared to controls, suggesting seroconversion. CONCLUSIONS: We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies. CLINICAL TRIAL REGISTRATION: ISRCTN63006567.


Asunto(s)
Salmonella enterica , Fiebre Tifoidea , Humanos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Salmonella paratyphi A , Salmonella typhi , Lipopolisacáridos
2.
N Engl J Med ; 381(23): 2209-2218, 2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31800986

RESUMEN

BACKGROUND: Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS: In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS: A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS: A single dose of TCV was immunogenic and effective in reducing S. Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).


Asunto(s)
Salmonella typhi/aislamiento & purificación , Fiebre Tifoidea/prevención & control , Vacunas Tifoides-Paratifoides/inmunología , Vacunas Conjugadas/inmunología , Adolescente , Niño , Preescolar , Método Doble Ciego , Enfermedades Endémicas/prevención & control , Femenino , Humanos , Incidencia , Lactante , Estimación de Kaplan-Meier , Masculino , Vacunas Meningococicas/efectos adversos , Vacunas Meningococicas/inmunología , Nepal/epidemiología , Fiebre Tifoidea/diagnóstico , Fiebre Tifoidea/epidemiología , Vacunas Tifoides-Paratifoides/efectos adversos , Vacunas Conjugadas/efectos adversos
3.
PLoS Pathog ; 16(10): e1008998, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33085725

RESUMEN

Despite recent advances in typhoid fever control, asymptomatic carriage of Salmonella Typhi in the gallbladder remains poorly understood. Aiming to understand if S. Typhi becomes genetically adapted for long-term colonisation in the gallbladder, we performed whole genome sequencing on a collection of S. Typhi isolated from the gallbladders of typhoid carriers. These sequences were compared to contemporaneously sampled sequences from organisms isolated from the blood of acute patients within the same population. We found that S. Typhi carriage was not restricted to any particular genotype or conformation of antimicrobial resistance genes, but was largely reflective of S. Typhi circulating in the general population. However, gallbladder isolates showed a higher genetic variability than acute isolates, with median pairwise SNP distances of 21 and 13 SNPs (p = 2.8x10-9), respectively. Within gallbladder isolates of the predominant H58 genotype, variation was associated with a higher prevalence of nonsense mutations. Notably, gallbladder isolates displayed a higher frequency of non-synonymous mutations in genes encoding hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. Specifically, we identified several gallbladder-specific non-synonymous mutations involved in LPS synthesis and modification, with some isolates lacking the Vi capsular polysaccharide vaccine target due to the 134Kb deletion of SPI-7. S. Typhi is under strong selective pressure in the human gallbladder, which may be reflected phylogenetically by long terminal branches that may distinguish organisms from chronic and acute infections. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generate new antigenic variants and raises questions regarding the role of carriage in the epidemiology of typhoid fever.


Asunto(s)
Vesícula Biliar/microbiología , Salmonella typhi/genética , Fiebre Tifoidea/genética , Adaptación Biológica , Adulto , Anciano , Antibacterianos/uso terapéutico , Femenino , Variación Genética/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Filogenia , Salmonella typhi/patogenicidad , Fiebre Tifoidea/microbiología , Secuenciación Completa del Genoma/métodos
4.
Cell Microbiol ; 23(5): e13306, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33355403

RESUMEN

Salmonella Paratyphi A (SPtA) remains one of the leading causes of enteric (typhoid) fever. Yet, despite the recent increased rate of isolation from patients in Asia, our understanding of its pathogenesis is incomplete. Here we investigated inflammasome activation in human macrophages infected with SPtA. We found that SPtA induces GSDMD-mediated pyroptosis via activation of caspase-1, caspase-4 and caspase-8. Although we observed no cell death in the absence of a functional Salmonella pathogenicity island-1 (SPI-1) injectisome, HilA-mediated overexpression of the SPI-1 regulon enhances pyroptosis. SPtA expresses FepE, an LPS O-antigen length regulator, which induces the production of very long O-antigen chains. Using a ΔfepE mutant we established that the very long O-antigen chains interfere with bacterial interactions with epithelial cells and impair inflammasome-mediated macrophage cell death. Salmonella Typhimurium (STm) serovar has a lower FepE expression than SPtA, and triggers higher pyroptosis, conversely, increasing FepE expression in STm reduced pyroptosis. These results suggest that differential expression of FepE results in serovar-specific inflammasome modulation, which mirrors the pro- and anti-inflammatory strategies employed by STm and SPtA, respectively. Our studies point towards distinct mechanisms of virulence of SPtA, whereby it attenuates inflammasome-mediated detection through the elaboration of very long LPS O-polysaccharides.


Asunto(s)
Inflamasomas/metabolismo , Macrófagos/microbiología , Macrófagos/fisiología , Antígenos O/fisiología , Fiebre Paratifoidea/microbiología , Piroptosis , Salmonella paratyphi A/patogenicidad , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Caspasas/metabolismo , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/inmunología , Antígenos O/química , Proteínas de Unión a Fosfato/metabolismo , Salmonella paratyphi A/inmunología , Células THP-1 , Sistemas de Secreción Tipo III/metabolismo , Virulencia , Factores de Virulencia/metabolismo
5.
J Antimicrob Chemother ; 76(12): 3197-3200, 2021 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-34534310

RESUMEN

BACKGROUND: Antimicrobial therapy is essential for the treatment of enteric fever, the infection caused by Salmonella serovars Typhi and Paratyphi A. However, an increase in resistance to key antimicrobials and the emergence of MDR and XDR in Salmonella Typhi poses a major threat for efficacious outpatient treatments. OBJECTIVES: We recently identified tebipenem, an oral carbapenem licensed for use for respiratory tract infections in Japan, as a potential alternative treatment for MDR/XDR Shigella spp. Here, we aimed to test the in vitro antibacterial efficacy of this drug against MDR and XDR typhoidal Salmonella. METHODS: We determined the in vitro activity of tebipenem in time-kill assays against a collection of non-XDR and XDR Salmonella Typhi and Salmonella Paratyphi A (non-XDR) isolated in Nepal and Bangladesh. We also tested the efficacy of tebipenem in combination with other antimicrobials. RESULTS: We found that both XDR and non-XDR Salmonella Typhi and Salmonella Paratyphi A are susceptible to tebipenem, exhibiting low MICs, and were killed within 8-24 h at 2-4×MIC. Additionally, tebipenem demonstrated synergy with two other antimicrobials and could efficiently induce bacterial killing. CONCLUSIONS: Salmonella Paratyphi A and XDR Salmonella Typhi display in vitro susceptibility to the oral carbapenem tebipenem, while synergistic activity with other antimicrobials may limit the emergence of resistance. The broad-spectrum activity of this drug against MDR/XDR organisms renders tebipenem a good candidate for clinical trials.


Asunto(s)
Salmonella typhi , Fiebre Tifoidea , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Humanos , Salmonella , Fiebre Tifoidea/tratamiento farmacológico
6.
BMC Infect Dis ; 21(1): 546, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34107906

RESUMEN

BACKGROUND: Sepsis is an overwhelming and life-threatening response to bacteria in bloodstream and a major cause of neonatal morbidity and mortality. Understanding the etiology and potential risk factors for neonatal sepsis is urgently required, particularly in low-income countries where burden of infection is high and its epidemiology is poorly understood. METHODS: A prospective observational cohort study was conducted between April 2016 and October 2017 in a level three NICU at a tertiary care hospital in Nepal to determine the bacterial etiology and potential risk factors for neonatal sepsis. RESULTS: Among 142 NICU admitted neonates, 15% (21/142) and 32% (46/142) developed blood culture-positive and -negative neonatal sepsis respectively. Klebsiella pneumoniae (34%, 15/44) and Enterobacter spp. (25%, 11/44) were the most common isolates. The antimicrobial resistance of isolates to ampicillin (100%, 43/43), cefotaxime (74%, 31/42) and ampicillin-sulbactam (55%, 21/38) were the highest. BlaTEM (53%, 18/34) and blaKPC (46%, 13/28) were the commonest ESBL and carbapenemase genes respectively. In univariate logistic regression, the odds of sepsis increased with each additional day of use of invasive procedures such as mechanical ventilation (OR 1.086, 95% CI 1.008-1.170), umbilical artery catheter (OR 1.375, 95% CI 1.049-1.803), intravenous cannula (OR 1.140, 95% CI 1.062-1.225); blood transfusion events (OR 3.084, 95% CI 1.407-6.760); NICU stay (OR 1.109, 95% CI 1.040-1.182) and failure to breast feed (OR 1.130, 95% CI 1.060-1.205). Sepsis odds also increased with leukopenia (OR 1.790, 95% CI 1.04-3.082), increase in C-reactive protein (OR 1.028, 95% CI 1.016-1.040) and decrease in platelets count (OR 0.992, 95% CI 0.989-0.994). In multivariate analysis, increase in IV cannula insertion days (OR 1.147, 95% CI 1.039-1.267) and CRP level (OR 1.028, 95% CI 1.008-1.049) increased the odds of sepsis. CONCLUSIONS: Our study indicated various nosocomial risk factors and underscored the need to improve local infection control measures so as to reduce the existing burden of sepsis. We have highlighted certain sepsis associated laboratory parameters along with identification of antimicrobial resistance genes, which can guide for early and better therapeutic management of sepsis. These findings could be extrapolated to other low-income settings within the region.


Asunto(s)
Sepsis Neonatal/epidemiología , Sepsis Neonatal/microbiología , Estudios de Cohortes , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Nepal/epidemiología , Estudios Prospectivos , Factores de Riesgo , Centros de Atención Terciaria
7.
Ann Clin Microbiol Antimicrob ; 19(1): 48, 2020 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-33087115

RESUMEN

BACKGROUND: Multi-drug resistance (MDR) and extensive-drug resistance (XDR) associated with extended-spectrum beta-lactamases (ESBLs) and carbapenemases in Gram-negative bacteria are global public health concerns. Data on circulating antimicrobial resistance (AMR) genes in Gram-negative bacteria and their correlation with MDR and ESBL phenotypes from Nepal is scarce. METHODS: A retrospective study was performed investigating the distribution of ESBL and carbapenemase genes and their potential association with ESBL and MDR phenotypes in E. coli, Klebsiella spp., Enterobacter spp. and Acinetobacter spp. isolated in a major tertiary hospital in Kathmandu, Nepal, between 2012 and 2018. RESULTS: During this period, the hospital isolated 719 E. coli, 532 Klebsiella spp., 520 Enterobacter spp. and 382 Acinetobacter spp.; 1955/2153 (90.1%) of isolates were MDR and half (1080/2153) were ESBL producers. Upon PCR amplification, blaTEM (1281/1771; 72%), blaCTXM-1 (930/1771; 53%) and blaCTXM-8 (419/1771; 24%) were the most prevalent ESBL genes in the enteric bacilli. BlaOXA and blaOXA-51 were the most common blaOXA family genes in the enteric bacilli (918/1771; 25%) and Acinetobacter spp. (218/382; 57%) respectively. Sixteen percent (342/2153) of all isolates and 20% (357/1771) of enteric bacilli harboured blaNDM-1 and blaKPC carbapenemase genes respectively. Of enteric bacilli, Enterobacter spp. was the most frequently positive for blaKPC gene (201/337; 60%). The presence of each blaCTX-M and blaOXA were significantly associated with non-susceptibility to third generation cephalosporins (OR 14.7, p < 0.001 and OR 2.3, p < 0.05, respectively).The presence of each blaTEM, blaCTXM and blaOXA family genes were significantly associated with ESBL positivity (OR 2.96, p < 0.001; OR 14.2, p < 0.001 and OR 1.3, p < 0.05 respectively) and being MDR (OR 1.96, p < 0.001; OR 5.9, p < 0.001 and OR 2.3, p < 0.001 respectively). CONCLUSIONS: This study documents an alarming level of AMR with high prevalence of MDR ESBL- and carbapenemase-positive ESKAPE microorganisms in our clinical setting. These data suggest a scenario where the clinical management of infected patients is increasingly difficult and requires the use of last-resort antimicrobials, which in turn is likely to intensify the magnitude of global AMR crisis.


Asunto(s)
Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana Múltiple/genética , Bacterias Gramnegativas/genética , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , beta-Lactamasas/genética , Acinetobacter/genética , Antibacterianos/farmacología , Enterobacter/genética , Escherichia coli/genética , Humanos , Klebsiella/genética , Pruebas de Sensibilidad Microbiana , Nepal/epidemiología , Prevalencia , Estudios Retrospectivos , Centros de Atención Terciaria
8.
Clin Infect Dis ; 68(Suppl 2): S67-S73, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30845329

RESUMEN

BACKGROUND: Enteric fever is estimated to affect 11-20 million people worldwide each year. Morbidity and mortality from enteric fever primarily occur in lower-income countries, with children under 5 years of age experiencing a significant portion of the burden. Over the last few decades, the control of enteric fever has focused primarily on improved water and sanitation, with the available vaccines unsuitable for children and primarily used by travelers. A new typhoid conjugate vaccine (Vi-TCV), prequalified by the World Health Organization (WHO) and highly immunogenic in children under 5, has the potential to reduce the typhoid burden in endemic countries. METHODS: This study is a double-blinded, randomized, controlled trial with a 2-year follow-up to assess the protective impact of the Vi-TCV vaccine, compared with a control vaccine, in children from 9 months to 16 years of age. The primary outcome of interest is the reduction in the number of culture-confirmed typhoid cases attributable to Vi-TCV. Approximately 20 000 children living in the Lalitpur district, within the Kathmandu valley, will be enrolled in the study and followed to measure both safety and efficacy data, which will include adverse events, hospitalizations, antibiotic use, and fever frequency. RESULTS: Both the intervention and control vaccines are WHO prequalified vaccines, which provide a health benefit to all participants. Children have been chosen to participate because they bear a substantial burden of both typhoid morbidity and mortality in this population. The results of this study will be disseminated through a series of published articles. The findings will also be made available to the participants and the broader community, as well as local stakeholders, within Nepal. CONCLUSIONS: This is the first large-scale, individually randomized, controlled trial of Vi-TCV in children in an endemic setting, and will provide new data on Vi-TCV field efficacy. With Vi-TCV introduction being considered in high-burden countries, this study will support important policy decisions. CLINICAL TRIALS REGISTRATION: The trial is registered on the ISRCTN registry (for details, see https://doi.org/10.1186/ISRCTN43385161; registry number: ISRCTN 43385161).


Asunto(s)
Fiebre Tifoidea/prevención & control , Vacunas Tifoides-Paratifoides/inmunología , Adolescente , Anticuerpos Antibacterianos/sangre , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Femenino , Estudios de Seguimiento , Humanos , Inmunogenicidad Vacunal , Lactante , Masculino , Nepal , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de Registros , Vacunas Tifoides-Paratifoides/administración & dosificación , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/inmunología
9.
Clin Infect Dis ; 68(Suppl 2): S138-S145, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30845335

RESUMEN

Typhoid fever is estimated to affect over 20 million people per year worldwide, with infants, children, and adolescents in south-central and southeast Asia experiencing the greatest burden of disease. The Typhoid Vaccine Acceleration Consortium (TyVAC) aims to support the introduction of typhoid conjugate vaccines into Gavi-eligible countries in an effort to reduce morbidity and mortality from typhoid. TyVAC-Nepal is a large-scale, participant- and observer-blind, individually randomized, controlled trial evaluating the efficacy of a newly developed typhoid conjugate vaccine in an urban setting in Nepal. In order to effectively deliver the trial, a number of key elements required meticulous planning. Public engagement strategies were considered early, and involved the implementation of a tiered approach. Approximately 300 staff were employed and trained in order to achieve the mass vaccination of 20 000 children aged 9 months to ≤16 years old over a 4-month period. There were 19 vaccination clinics established across the Lalitpur metropolitan city in the Kathmandu valley. Participants will be followed for 2 years post-vaccination to measure the rate reduction of blood culture-confirmed typhoid fever in the vaccination arm as compared to the control arm. The experience of conducting this large-scale vaccine trial suggests that comprehensive planning, continuous monitoring, and an ability to adapt plans in response to feedback are key.


Asunto(s)
Implementación de Plan de Salud/métodos , Vacunación Masiva/métodos , Fiebre Tifoidea/prevención & control , Vacunas Tifoides-Paratifoides/administración & dosificación , Adolescente , Niño , Preescolar , Implementación de Plan de Salud/legislación & jurisprudencia , Implementación de Plan de Salud/organización & administración , Humanos , Lactante , Vacunación Masiva/legislación & jurisprudencia , Vacunación Masiva/organización & administración , Nepal , Organización y Administración , Ensayos Clínicos Controlados Aleatorios como Asunto , Vacunas Conjugadas/administración & dosificación
10.
Clin Infect Dis ; 64(11): 1522-1531, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28329181

RESUMEN

BACKGROUND.: Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. METHODS.: Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. RESULTS.: Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. CONCLUSION.: The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.


Asunto(s)
Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Fiebre Paratifoidea/tratamiento farmacológico , Salmonella paratyphi A/efectos de los fármacos , Salmonella typhi/efectos de los fármacos , Fiebre Tifoidea/tratamiento farmacológico , Adolescente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Azitromicina/administración & dosificación , Azitromicina/farmacología , Azitromicina/uso terapéutico , Ceftriaxona/administración & dosificación , Ceftriaxona/farmacología , Ceftriaxona/uso terapéutico , Niño , Femenino , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Gatifloxacina , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Nepal/epidemiología , Ofloxacino/administración & dosificación , Ofloxacino/farmacología , Ofloxacino/uso terapéutico , Fiebre Paratifoidea/microbiología , Salmonella paratyphi A/aislamiento & purificación , Salmonella typhi/aislamiento & purificación , Insuficiencia del Tratamiento , Resultado del Tratamiento , Fiebre Tifoidea/sangre , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/microbiología , Adulto Joven
12.
Antimicrob Agents Chemother ; 59(5): 2756-64, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25733500

RESUMEN

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 µg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 µg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-µg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 µg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 µg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 µg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.


Asunto(s)
Azitromicina/farmacología , Azitromicina/uso terapéutico , Salmonella enterica/efectos de los fármacos , Salmonella enterica/patogenicidad , Fiebre Tifoidea/tratamiento farmacológico , Adolescente , Niño , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Serogrupo , Adulto Joven
13.
PLoS Negl Trop Dis ; 18(6): e0011864, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38889189

RESUMEN

Salmonella Paratyphi A, one of the major etiologic agents of enteric fever, has increased in prevalence in recent decades in certain endemic regions in comparison to S. Typhi, the most prevalent cause of enteric fever. Despite this increase, data on the prevalence and molecular epidemiology of S. Paratyphi A remain generally scarce. Here, we analysed the whole genome sequences of 216 S. Paratyphi A isolates originating from Kathmandu, Nepal between 2005 and 2014, of which 200 were from patients with acute enteric fever and 16 from the gallbladder of people with suspected chronic carriage. By exploiting the recently developed genotyping framework for S. Paratyphi A (Paratype), we identified several genotypes circulating in Kathmandu. Notably, we observed an unusual clonal expansion of genotype 2.4.3 over a four-year period that spread geographically and systematically replaced other genotypes. This rapid genotype replacement is hypothesised to have been driven by both reduced susceptibility to fluoroquinolones and genetic changes to virulence factors, such as functional and structural genes encoding the type 3 secretion systems. Finally, we show that person-to-person is likely the most common mode of transmission and chronic carriers seem to play a limited role in maintaining disease circulation.

14.
J Trop Pediatr ; 59(4): 317-20, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23598894

RESUMEN

The Vi capsular polysaccharide (ViPS) protects Salmonella enterica subspecies enterica serotype Typhi (S.Typhi) in vivo by multiple mechanisms. Recent microbiological reports from typhoid endemic countries suggest that acapsulate S.Typhi may occur in nature and contribute to clinical typhoid fever that is indistinguishable from disease caused by capsulate strains. The prevalence and genetic basis of ViPS-negative S.Typhi isolates in children from Kathmandu, Nepal, were tested in 68 isolates. Although 5.9% of isolates tested negative for capsular expression by slide agglutination tests, a novel multiplex PCR assay and individual PCR analyses demonstrated the presence of all 14 genes responsible for the synthesis, transportation and regulation of the ViPS. These data suggest that phenotypically acapsulate S.Typhi may not have a genetic basis for the same.


Asunto(s)
Genes Bacterianos , Salmonella typhi/genética , Salmonella typhi/aislamiento & purificación , Fiebre Tifoidea/epidemiología , Niño , Genoma Bacteriano , Humanos , Lactante , Mutación , Nepal/epidemiología , Fenotipo , Reacción en Cadena de la Polimerasa , Polisacáridos Bacterianos/metabolismo , Prevalencia , Salmonella typhi/inmunología , Fiebre Tifoidea/sangre , Fiebre Tifoidea/microbiología
15.
PLoS One ; 18(5): e0285287, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37134062

RESUMEN

BACKGROUND: Unregulated antimicrobial use is common in both hospital and community settings of low- and middle-income countries (LMICs). However, discrete data regarding the use/misuse of antimicrobials at pharmacies in LMICs are limited. This study was conducted to understand knowledge, attitude, and practice of pharmacy employees on antimicrobial dispensing in Nepal. METHODS: We conducted a cross-sectional survey using a structured questionnaire on 801 pharmacy employees working in community and hospital pharmacies located in Lalitpur metropolitan city (LMC) of Kathmandu, Nepal between April 2017 and March 2019. RESULTS: A majority (92%) of respondents agreed that demand for non-prescription antimicrobials was common. Asking for prescription before dispensing was ranked as the first preference by majority (69%) of participants. Suspected respiratory tract infection was the most common reason demanding for non-prescription antimicrobials with the highest mean rank of 1.5. Azithromycin was the most commonly prescribed and sold antimicrobial, as reported by 46% and 48% of participants respectively. A majority (87%) of respondents agreed on antimicrobial resistance (AMR) to be a global public health threat; and misuse/overuse of antimicrobials was perceived as the most common cause of AMR with a mean rank of 1.93. CONCLUSION: Our study revealed that unfounded dispensing and use of antimicrobials is prevalent among pharmacies in Kathmandu, Nepal. This over reliance on antimicrobials, notably azithromycin, may escalate burden of AMR. We identified several drivers of inappropriate antimicrobial dispensing practice in pharmacies, which will aid public health authorities in addressing these issues. Further studies considering role of other stakeholders, such as doctors, veterinarians, general public, and policy makers are required to obtain a more holistic perspectives on practices of antimicrobial use so to curb the extant AMR crisis.


Asunto(s)
Antiinfecciosos , Servicios Comunitarios de Farmacia , Farmacias , Farmacia , Humanos , Azitromicina , Nepal , Estudios Transversales , Antiinfecciosos/uso terapéutico , Antibacterianos/uso terapéutico
16.
Commun Biol ; 6(1): 804, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37532769

RESUMEN

RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood samples from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.


Asunto(s)
Genética de Población , Humanos , Estudios Retrospectivos , Genotipo , Secuencia de Bases , Análisis de Secuencia de ARN
17.
Antimicrob Agents Chemother ; 56(5): 2761-2, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22371897

RESUMEN

As a consequence of multidrug resistance, clinicians are highly dependent on fluoroquinolones for treating the serious systemic infection typhoid fever. While reduced susceptibility to fluoroquinolones, which lessens clinical efficacy, is becoming ubiquitous, comprehensive resistance is exceptional. Here we report ofloxacin treatment failure in typhoidal patient infected with a novel, highly fluoroquinolone-resistant isolate of Salmonella enterica serovar Typhi. The isolation of this organism has serious implications for the long-term efficacy of ciprofloxacin and ofloxacin for typhoid treatment.


Asunto(s)
Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Girasa de ADN/genética , Fluoroquinolonas/uso terapéutico , Salmonella typhi/genética , Fiebre Tifoidea/tratamiento farmacológico , Adolescente , Secuencia de Aminoácidos , Azitromicina/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutación , Nepal , Ofloxacino/uso terapéutico , Salmonella typhi/efectos de los fármacos , Salmonella typhi/aislamiento & purificación , Salmonella typhi/patogenicidad , Insuficiencia del Tratamiento , Fiebre Tifoidea/microbiología
18.
JAC Antimicrob Resist ; 4(3): dlac050, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35663828

RESUMEN

Objectives: Community-onset bloodstream infections (BSIs) caused by carbapenemase-producing Enterobacter cloacae complex (ECC) species are increasing internationally. This observation suggests that ECC are emerging pathogens, requiring for detailed understanding on their genomic epidemiology including transmission dynamics and antimicrobial resistance profiles. Patients and methods: We performed WGS on 79 Enterobacter spp. isolated from the patients with clinically significant BSIs and admitted to emergency department of a major tertiary hospital in Nepal between April 2016 and October 2017. Results: We identified 5 species and 13 STs of ECC. Enterobacter xiangfangensis ST171, one of the globally emerging carbapenem resistant ECC clones with epidemic potential, was the most prevalent (42%). Phylogenetic analysis showed a large (>19 400 SNPs) core genome SNP distance across major STs, which was minimal (<30 SNPs) among the isolates of each prevalent ST, suggesting the relatively recent importation of major STs followed by local clonal expansions. Genomic evidence for resistance to all major antimicrobial classes except for colistin and macrolides was detected. A limited number of isolates also carried bla NDM-1 (n = 2) and bla OXA-48 (n = 1) carbapenemase genes. Virulence factors encoding siderophores (24%), T6SSD (25%) and fimbriae (54%) were detected. Conclusions: Our study highlighted that MDR ECC clones are important pathogens of BSIs in community. Though of low prevalence, carbapenem resistance observed in our ECC isolates raised concern about further community dissemination, underscoring the need for community surveillance to identify MDR ECC clones with epidemic potential.

19.
PLoS One ; 16(11): e0259634, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34788314

RESUMEN

Epidemiologic data regarding health care acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) from Nepal are negligible. We conducted a prospective observational cohort study in the intensive care unit (ICU) of a major tertiary hospital in Nepal between April 2016 and March 2018, to calculate the incidence of VAP, and to describe clinical variables, microbiological etiology, and outcomes. Four hundred and thirty-eight patients were enrolled in the study. Demographic data, medical history, antimicrobial administration record, chest X-ray, biochemical, microbiological and haematological results, acute physiology and chronic health evaluation II score and the sequential organ failure assessment scores were recorded. Categorical variables were expressed as count and percentage and analyzed using the Fisher's exact test. Continuous variables were expressed as median and interquartile range and analyzed using Kruskal-Wallis rank sum test and the pairwise Wilcoxon rank-sum test. 46.8% (205/438) of the patients required intubation. Pneumonia was common in both intubated (94.14%; 193/205) and non-intubated (52.36%; 122/233) patients. Pneumonia developed among intubated patients in the ICU had longer days of stay in the ICU (median of 10, IQR 5-15, P< 0.001) when compared to non-intubated patients with pneumonia (median of 4, IQR 3-6, P< 0.001). The incidence rate of VAP was 20% (41/205) and incidence density was 16.45 cases per 1,000ventilator days. Mortality was significantly higher in patients with pneumonia requiring intubation (44.6%, 86/193) than patients with pneumonia not requiring intubation (10.7%, 13/122, p<0.001, Fisher's exact test). Gram negative bacteria such as Klebsiella and Acinetobacter species were the dominant organisms from both VAP and non-VAP categories. Multi-drug resistance was highly prevalent in bacterial isolates associated with VAP (90%; 99/110) and non-VAP categories (81.5%; 106/130). HAP including VAP remains to be the most prevalent hospital-acquired infections (HAIs) at Patan hospital. A local study of etiological agents and outcomes of HAP and VAP are required for setting more appropriate guidelines for management of such diseases.


Asunto(s)
Neumonía Asociada al Ventilador/epidemiología , Neumonía Asociada al Ventilador/etiología , Adulto , Anciano , Antibacterianos/uso terapéutico , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Nepal/epidemiología , Neumonía Asociada al Ventilador/diagnóstico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Estudios Prospectivos
20.
J Glob Antimicrob Resist ; 27: 123-131, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34482019

RESUMEN

OBJECTIVES: This study aimed to develop and evaluate a novel air-dried high-resolution melt (HRM) assay to detect eight major extended-spectrum ß-lactamase (ESBL) (blaSHV and blaCTX-M groups 1 and 9) and carbapenemase (blaNDM, blaIMP, blaKPC, blaVIM and blaOXA-48-like) genes that confer resistance to cephalosporins and carbapenems. METHODS: The assay was evaluated using 439 DNA samples extracted from bacterial isolates from Nepal, Malawi and the UK and 390 clinical isolates from Nepal with known antimicrobial susceptibility. Assay reproducibility was evaluated across five different real-time quantitative PCR (qPCR) instruments [Rotor-Gene® Q, QuantStudioTM 5, CFX96, LightCycler® 480 and Magnetic Induction Cycler (Mic)]. Assay stability was also assessed under different storage temperatures (6.2 ± 0.9°C, 20.4 ± 0.7°C and 29.7 ± 1.4°C) at six time points over 8 months. RESULTS: The sensitivity and specificity (with 95% confidence intervals) for detecting ESBL and carbapenemase genes was 94.7% (92.5-96.5%) and 99.2% (98.8-99.5%) compared with the reference gel-based PCR and sequencing and 98.3% (97.0-99.3%) and 98.5% (98.0-98.9%) compared with the original HRM wet PCR mix format. Overall agreement was 91.1% (90.0-92.9%) when predicting phenotypic resistance to cefotaxime and meropenem among Enterobacteriaceae isolates. We observed almost perfect inter-machine reproducibility of the air-dried HRM assay, and no loss of sensitivity occurred under all storage conditions and time points. CONCLUSION: We present a ready-to-use air-dried HRM PCR assay that offers an easy, thermostable, fast and accurate tool for the detection of ESBL and carbapenemase genes in DNA samples to improve antimicrobial resistance detection.


Asunto(s)
Antibacterianos , beta-Lactamasas , Antibacterianos/farmacología , Proteínas Bacterianas , Pruebas de Sensibilidad Microbiana , Reproducibilidad de los Resultados , beta-Lactamasas/genética
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