Publications by authors named "Guy Thwaites"

319 Publications

: High Prevalence and Possibly Chronic Shedding in Human Respiratory Tract, But No Zoonotic Transmission.

Viruses 2021 Mar 24;13(4). Epub 2021 Mar 24.

Emerging Infection Group, Oxford University Clinical Research Unit, Ho Chi Minh City 7000, Vietnam.

is a recently discovered DNA virus family consisting of two species, and . Here we used PCR amplification and sequencing to characterize redondoviruses in nasal/throat swabs collected longitudinally from a cohort of 58 individuals working with animals in Vietnam. We additionally analyzed samples from animals to which redondovirus DNA-positive participants were exposed. Redondoviruses were detected in approximately 60% of study participants, including 33% (30/91) of samples collected during episodes of acute respiratory disease and in 50% (29/58) of baseline samples (with no respiratory symptoms). Vientovirus (73%; 24/33) was detected more frequently in samples than brisaviruses (27%; 9/33). In the 23 participants with at least 2 redondovirus-positive samples among their longitudinal samples, 10 (43.5%) had identical redondovirus replication-gene sequences detected (sampling duration: 35-132 days). We found no identical redondovirus replication genes in samples from different participants, and no redondoviruses were detected in 53 pooled nasal/throat swabs collected from domestic animals. Phylogenetic analysis described no large-scale geographical clustering between viruses from Vietnam, the US, Spain, and China, indicating that redondoviruses are highly genetically diverse and have a wide geographical distribution. Collectively, our study provides novel insights into the family in humans, describing a high prevalence, potentially associated with chronic shedding in the respiratory tract with lack of evidence of zoonotic transmission from close animal contacts. The tropism and potential pathogenicity of this viral family remain to be determined.
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http://dx.doi.org/10.3390/v13040533DOI Listing
March 2021

Evolutionary histories and antimicrobial resistance in Shigella flexneri and Shigella sonnei in Southeast Asia.

Commun Biol 2021 Mar 19;4(1):353. Epub 2021 Mar 19.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Conventional disease surveillance for shigellosis in developing country settings relies on serotyping and low-resolution molecular typing, which fails to contextualise the evolutionary history of the genus. Here, we interrogated a collection of 1,804 Shigella whole genome sequences from organisms isolated in four continental Southeast Asian countries (Thailand, Vietnam, Laos, and Cambodia) over three decades to characterise the evolution of both S. flexneri and S. sonnei. We show that S. sonnei and each major S. flexneri serotype are comprised of genetically diverse populations, the majority of which were likely introduced into Southeast Asia in the 1970s-1990s. Intranational and regional dissemination allowed widespread propagation of both species across the region. Our data indicate that the epidemiology of S. sonnei and the major S. flexneri serotypes were characterised by frequent clonal replacement events, coinciding with changing susceptibility patterns against contemporaneous antimicrobials. We conclude that adaptation to antimicrobial pressure was pivotal to the recent evolutionary trajectory of Shigella in Southeast Asia.
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http://dx.doi.org/10.1038/s42003-021-01905-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979695PMC
March 2021

The role of optic nerve sheath diameter ultrasound in brain infection.

eNeurologicalSci 2021 Jun 22;23:100330. Epub 2021 Feb 22.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Brain infections cause significant morbidity and mortality worldwide, especially in resource-limited settings with high HIV co-infection rates. Raised intracranial pressure [ICP] may complicate brain infection and worsen neurological injury, yet invasive ICP monitoring is often unavailable. Optic nerve sheath diameter [ONSD] ultrasound may allow detection of raised ICP at the bedside; however, pathology in brain infection is different to traumatic brain injury, in which most studies have been performed. The use of ONSD ultrasound has been described in tuberculous meningitis, cryptococcal meningitis and cerebral malaria; however correlation with invasive ICP measurement has not been performed. Normal optic nerve sheath values are not yet established for most populations, and thresholds for clinical intervention cannot be assumed to match those used in non-infective brain pathology. ONSD ultrasound may be suitable for use in resource-limited settings by clinicians with limited ultrasound training. Standardisation of scanning technique, consensus on normal ONSD values, and action on abnormal results, are areas for future research. This scoping review examines the role of ONSD ultrasound in brain infection. We discuss pathophysiology, and describe the rationale, practicalities, and challenges of utilising ONSD ultrasound for brain infection monitoring and management. We discuss the existing evidence base for this technique, and identify knowledge gaps and future research priorities.
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http://dx.doi.org/10.1016/j.ensci.2021.100330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935708PMC
June 2021

Clinical characteristics and mortality associated with COVID-19 in Jakarta, Indonesia: A hospital-based retrospective cohort study.

Lancet Reg Health West Pac 2021 Apr 2;9:100108. Epub 2021 Mar 2.

Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia.

Background: Data on COVID-19-related mortality and associated factors from low-resource settings are scarce. This study examined clinical characteristics and factors associated with in-hospital mortality of COVID-19 patients in Jakarta, Indonesia, from March 2 to July 31, 2020.

Methods: This retrospective cohort included all hospitalised patients with PCR-confirmed COVID-19 in 55 hospitals. We extracted demographic and clinical data, including hospital outcomes (discharge or death). We used logistic regression to examine factors associated with mortality.

Findings: Of 4265 patients with a definitive outcome by July 31, 3768 (88%) were discharged and 497 (12%) died. The median age was 46 years (IQR 32-57), 5% were children, and 31% had >1 comorbidity. Age-specific mortalities were 11% (7/61) for <5 years; 4% (1/23) for 5-9; 2% (3/133) for 10-19; 2% (8/638) for 20-29; 3% (26/755) for 30-39; 7% (61/819) for 40-49; 17% (155/941) for 50-59; 22% (132/611) for 60-69; and 34% (96/284) for ≥70. Risk of death was associated with higher age, male sex; pre-existing hypertension, diabetes, or chronic kidney disease; clinical diagnosis of pneumonia; multiple (>3) symptoms; immediate ICU admission, or intubation. Across all ages, risk of death was higher for patients with >1 comorbidity compared to those without; notably the risk was six-fold increased among patients <50 years (adjusted odds ratio 5.87, 95%CI 3.28-10.52; 27% vs 3% mortality).

Interpretation: Overall in-hospital mortality was lower than reported in high-income countries, probably due to younger age distribution and fewer comorbidities. Deaths occurred across all ages, with >10% mortality among children <5 years and adults >50 years.
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http://dx.doi.org/10.1016/j.lanwpc.2021.100108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924904PMC
April 2021

Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, United Kingdom;

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in (), which regulates expression of the proinflammatory mediator leukotriene B (LTB). TT homozygotes, with increased expression of , have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world's population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.
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http://dx.doi.org/10.1073/pnas.2024852118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958233PMC
March 2021

Reducing Antimicrobial Usage in Small-Scale Chicken Farms in Vietnam: A 3-Year Intervention Study.

Front Vet Sci 2020 28;7:612993. Epub 2021 Jan 28.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Indiscriminate antimicrobial use (AMU) in animal production is a driver of antimicrobial resistance globally. There is a need to define sustainable interventions to reduce AMU in small-scale production systems, which currently represent the most widespread farming systems in South East Asia and many low- and middle-income countries. We conducted a before-and-after intervention study on a random sample of small-scale chicken farms in the Mekong Delta of Vietnam from 2016 to 2019. The study included a baseline followed by an intervention phase where farmers were provided with regular veterinary advice on flock health and husbandry, as well as antimicrobial replacement products. Of 102 recruited farms (raising >100 chickens per flock cycle), thirty-five (34.2%) entered the intervention phase, whilst the rest stopped raising chickens, mainly due to suboptimal flock performance. Through the implementation of our intervention, chicken flocks reduced levels of AMU by 66% [adjusted hazard ratio (HR) = 0.34; = 0.002) from a baseline of 343.4 Animal Daily Doses per 1,000 chicken-days and decreased weekly mortality by 40% (adjusted HR = 0.60; = 0.005) from a baseline mortality of 1.60 per 100 birds. Chicken bodyweight increased by 100 g ( = 0.002) in intervention flocks. Our findings demonstrate that the provision of veterinary advice can achieve substantial reductions in AMU in small-scale production systems without compromising flock health and productivity.
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http://dx.doi.org/10.3389/fvets.2020.612993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876082PMC
January 2021

Emerging carbapenem-resistant sequence type 16 causing multiple outbreaks in a tertiary hospital in southern Vietnam.

Microb Genom 2021 Mar 10;7(3). Epub 2021 Feb 10.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

The emergence of carbapenem resistance in represents a major global public health concern. Nosocomial outbreaks caused by multidrug-resistant are commonly reported to result in high morbidity and mortality due to limited treatment options. Between October 2019 and January 2020, two concurrent high-mortality nosocomial outbreaks occurred in a referral hospital in Ho Chi Minh City, Vietnam. We performed genome sequencing and phylogenetic analysis of eight isolates from infected patients and two environmental isolates for outbreak investigation. We identified two outbreaks caused by two distinct lineages of the international sequence type (ST) 16 clone, which displayed extensive drug resistance, including resistance to carbapenem and colistin. Carbapenem-resistant ST16 outbreak strains clustered tightly with previously described ST16 from other hospitals in Vietnam, suggesting local persistence and transmission of this particular clone in this setting. We found environmental isolates from a hospital bed and blood pressure cuff that were genetically linked to an outbreak case cluster, confirming the potential of high-touch surfaces as sources for nosocomial spread of . Further, we found colistin resistance caused by disruption of the gene by an IS-like element, and carbapenem resistance mediated by a transferable IncF/ plasmid carrying the IS-like element. Our study highlights the importance of coordinated efforts between clinical and molecular microbiologists and infection control teams to rapidly identify, investigate and contain nosocomial outbreaks. Routine surveillance with advanced sequencing technology should be implemented to strengthen hospital infection control and prevention measures.
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http://dx.doi.org/10.1099/mgen.0.000519DOI Listing
March 2021

The Application of Sample Pooling for Mass Screening of SARS-CoV-2 in an Outbreak of COVID-19 in Vietnam.

Am J Trop Med Hyg 2021 Jan 22. Epub 2021 Jan 22.

8Department of Health, Da Nang, Vietnam.

We sampled nasal-pharyngeal throat swabs from 96,123 asymptomatic individuals at risk of SARS-CoV-2 infection, and generated 22,290 pools at collection, each containing samples from two to seven individuals. We detected SARS-CoV-2 in 24 pools, and confirmed the infection in 32 individuals after resampling and testing of 104 samples from positive pools. We completed the testing within 14 days. We would have required 64 days to complete the screening for the same number of individuals if we had based our testing strategy on individual testing. There was no difference in cycle threshold (Ct) values of pooled and individual samples. Thus, compared with individual sample testing, our approach did not compromise PCR sensitivity, but saved 77% of the resources. The present strategy might be applicable in settings, where there are shortages of reagents and the disease prevalence is low, but the demand for testing is high.
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http://dx.doi.org/10.4269/ajtmh.20-1583DOI Listing
January 2021

Colonization with and causes infections in a Vietnamese intensive care unit.

Microb Genom 2021 02;7(2)

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Pre-existing colonization with or has been found to increase the risk of infection in intensive care patients. We previously conducted a longitudinal study to characterize colonization of these two organisms in patients admitted to intensive care in a hospital in southern Vietnam. Here, using genomic and phylogenetic analyses, we aimed to assess the contribution these colonizing organisms made to infections. We found that in the majority of patients infected with or , the sequence type of the disease-causing (infecting) isolate was identical to that of corresponding colonizing organisms in the respective patient. Further in-depth analysis revealed that in patients infected by ST188 and by ST17, ST23, ST25 and ST86, the infecting isolate was closely related to and exhibited limited genetic variation relative to pre-infection colonizing isolates. Multidrug-resistant ST188 was identified as the predominant agent of colonization and infection. Colonization and infection by were characterized by organisms with limited antimicrobial resistance profiles but extensive repertoires of virulence genes. Our findings augment the understanding of the link between bacterial colonization and infection in a low-resource setting, and could facilitate the development of novel evidence-based approaches to prevent and treat infections in high-risk patients in intensive care.
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http://dx.doi.org/10.1099/mgen.0.000514DOI Listing
February 2021

Long-Term Humoral Immune Response in Persons with Asymptomatic or Mild SARS-CoV-2 Infection, Vietnam.

Emerg Infect Dis 2021 02;27(2):663-666

Antibody response against nucleocapsid and spike proteins of SARS-CoV-2 in 11 persons with mild or asymptomatic infection rapidly increased after infection. At weeks 18-30 after diagnosis, all remained seropositive but spike protein-targeting antibody titers declined. These data may be useful for vaccine development.
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http://dx.doi.org/10.3201/eid2702.204226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853537PMC
February 2021

A Bayesian analysis of the association between genotype and survival in tuberculous meningitis.

Elife 2021 Jan 8;10. Epub 2021 Jan 8.

Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A hydrolase () gene encoding an enzyme that regulates inflammatory eicosanoids. TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.
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http://dx.doi.org/10.7554/eLife.61722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793626PMC
January 2021

A novel method for measuring phenotypic colistin resistance in populations from chicken flocks.

Appl Environ Microbiol 2020 Dec 18. Epub 2020 Dec 18.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Colistin is extensively used in animal production in many low- and middle-income countries. There is a need to develop methodologies to benchmark and monitor changes in resistance among mixed commensal bacterial populations in farms. We aimed to evaluate the performance of a broth microdilution method based on culturing a pooled suspension (30-50 organisms) obtained from each sample. To confirm the biological basis and sensitivity of the method, we cultured 16 combinations of one colistin-susceptible and one -1 encoded colistin-resistant in the presence of 2mg/L colistin. Optical density (OD) readings over time were used to generate a growth curve, and these values were adjusted to the values obtained in the absence of colistin (adjusted Area Under the Curve, AUC). The median limit of detection was 1 resistant in 10 susceptible colonies [1 - 3 quartile, 10:1 -10:1]. We applied this method to 108 pooled faecal samples from 36 chicken flocks from the Mekong Delta (Vietnam), and determined the correlation between this method and the prevalence of colistin resistance in individual colonies harvested from field samples, determined by the Minimum Inhibitory Concentration. The overall prevalence of colistin resistance at sample and isolate level (estimated from the AUC) was 38.9% [95%CI, 29.8-48.8%] and 19.4% (SD± 26.3%), respectively. Increased colistin resistance was associated with recent (2 weeks) use of colistin (OR=3.67) and other, non-colistin antimicrobials (OR=1.84). Our method is a sensitive and affordable approach to monitor changes in colistin resistance in populations from faecal samples over time. Colistin (polymyxin E) is an antimicrobial with poor solubility in agar-based media, and therefore broth microdilution is the only available method for phenotypic resistance. However, estimating colistin resistance in mixed populations is laborious since it requires individual colony isolation, identification and susceptibility testing. We developed a growth-based microdilution method suitable for pooled faecal samples. We validated the method by comparing it with individual MIC of 909 isolates; we then tested 108 pooled faecal samples from 36 healthy chicken flocks collected over their production cycle. A higher level of resistance was seen in flocks recently treated with colistin in water, although the observed generated resistance was short-lived. Our method is affordable, and may potentially be integrated into surveillance systems aiming at estimating the prevalence of resistance at colony level in flocks/herds. Furthermore, it may also be adapted to other complex biological systems, such as farms and abattoirs.
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http://dx.doi.org/10.1128/AEM.02597-20DOI Listing
December 2020

Viral Metagenomic Analysis of Cerebrospinal Fluid from Patients with Acute Central Nervous System Infections of Unknown Origin, Vietnam.

Emerg Infect Dis 2021 Jan;27(1):205-213

Central nervous system (CNS) infection is a serious neurologic condition, although the etiology remains unknown in >50% of patients. We used metagenomic next-generation sequencing to detect viruses in 204 cerebrospinal fluid (CSF) samples from patients with acute CNS infection who were enrolled from Vietnam hospitals during 2012-2016. We detected 8 viral species in 107/204 (52.4%) of CSF samples. After virus-specific PCR confirmation, the detection rate was lowered to 30/204 (14.7%). Enteroviruses were the most common viruses detected (n = 23), followed by hepatitis B virus (3), HIV (2), molluscum contagiosum virus (1), and gemycircularvirus (1). Analysis of enterovirus sequences revealed the predominance of echovirus 30 (9). Phylogenetically, the echovirus 30 strains belonged to genogroup V and VIIb. Our results expanded knowledge about the clinical burden of enterovirus in Vietnam and underscore the challenges of identifying a plausible viral pathogen in CSF of patients with CNS infections.
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http://dx.doi.org/10.3201/eid2701.202723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774551PMC
January 2021

Severe paradoxical reaction in tuberculous meningitis.

IDCases 2021 17;23:e01009. Epub 2020 Nov 17.

Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Viet Nam.

A 31-year-old female presented with a 3-week history of fever and headache. CSF Ziehl-Neelsen smear microscopy revealed acid-fast bacilli, and CSF GeneXpert MTB/RIF was positive for with no mutations of rifampicin resistance. Tuberculous meningitis (TBM) was diagnosed. Baseline contrast-enhanced brain magnetic resonance imaging (MRI) was unremarkable. Eight weeks later the patient developed markedly reduced visual acuity and clinical signs consistent with left 3rd and 6th cranial nerve palsies. Repeat contrast-enhanced brain MRI revealed extensive tuberculous exudate filling the basal cisterns of the brain consistent with a severe paradoxical reaction of TBM. High dose intravenous dexamethasone was administered, with visual acuity returning to near-normal over 3-4 weeks. In TBM paradoxical inflammatory reactions are common yet difficult to predict. When severe, they may result in substantial neurological morbidity and death. Prompt host directed therapies such as corticosteroids may reduce chances of permanent neurological damage.
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http://dx.doi.org/10.1016/j.idcr.2020.e01009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702007PMC
November 2020

Optic nerve sheath ultrasound for the detection and monitoring of raised intracranial pressure in tuberculous meningitis.

Clin Infect Dis 2020 Dec 7. Epub 2020 Dec 7.

Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.

Background: Neurological complications of tuberculous meningitis (TBM) often lead to raised intracranial pressure (ICP) resulting in high morbidity and mortality. Measurement of optic nerve sheath diameter (ONSD) by point-of-care ultrasound may aid in the identification and management of raised ICP in TBM.

Methods: From June 2017 to December 2019, 107 Vietnamese adults with TBM, enrolled in the ACT HIV or LAST ACT trials (NCT03092817; NCT03100786), underwent ONSD ultrasound at one or more of days 0,3,7,14,21 +/-30 after enrolment. Demographic data, TBM severity grade, HIV co-infection status, and clinical endpoints by 3 months were recorded. ONSD values were correlated with disease severity, baseline brain magnetic resonance imaging or computed tomography imaging, cerebrospinal fluid parameters and clinical endpoints.

Results: 267 ONSD ultrasound scans were performed in 107 participants over the first 30 days of treatment, with measurements from 0.38-0.74cm. Paired baseline ONSD and brain imaging were performed in 63 participants. Higher baseline ONSD was associated with more severe disease and abnormal brain imaging (abnormal imaging 0.55cm vs 0.50cm normal imaging, p=0.01). Baseline median ONSD was significantly higher in participants who died by 3 months (0.56cm [15/72]) vs. participants who survived by 3 months (0.52cm [57/72]), p=0.02. Median ONSD was higher at all follow up time points in participants who died by 3 months.

Conclusions: Higher ONSD was associated with increased disease severity, brain imaging abnormalities, and increased death by 3 months. ONSD ultrasound has a potential role as a non-invasive and affordable bedside tool for predicting brain pathology and death in TBM.
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http://dx.doi.org/10.1093/cid/ciaa1823DOI Listing
December 2020

Most-Probable-Number-Based Minimum Duration of Killing Assay for Determining the Spectrum of Rifampicin Susceptibility in Clinical Mycobacterium tuberculosis Isolates.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

Accurate antibiotic susceptibility testing is essential for successful tuberculosis treatment. Recent studies have highlighted the limitations of MIC-based phenotypic susceptibility methods in detecting other aspects of antibiotic susceptibilities in bacteria. Duration and peak of antibiotic exposure, at or above the MIC required for killing the bacterial population, has emerged as another important factor for determining antibiotic susceptibility. This is broadly defined as antibiotic tolerance. Antibiotic tolerance can further facilitate the emergence of antibiotic resistance. Currently, there are limited methods to quantify antibiotic tolerance among clinical isolates. In this study, we develop a most-probable-number (MPN)-based minimum duration of killing (MDK) assay to quantify the spectrum of rifampicin susceptibility within subpopulations based on the duration of rifampicin exposure required for killing the bacterial population. MDK- and MDK were defined as the minimum duration of antibiotic exposure at or above the MIC required for killing 90 to 99% and 99.99% of the initial (pretreatment) bacterial population, respectively. Results from the rifampicin MDK assay applied to 28 laboratory and clinical isolates showed that there is variation in rifampicin susceptibility among isolates. The rifampicin MDK time for isolates varied from less than 2 to 10 days. MDK was correlated with larger subpopulations of from clinical isolates that were rifampicin tolerant. Our study demonstrates the utility of MDK assays to measure the variation in antibiotic tolerance among clinical isolates and further expands clinically important aspects of antibiotic susceptibility testing.
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http://dx.doi.org/10.1128/AAC.01439-20DOI Listing
February 2021

Variations in Antimicrobial Activities of Human Monocyte-Derived Macrophage and Their Associations With Tuberculosis Clinical Manifestations.

Front Cell Infect Microbiol 2020 23;10:586101. Epub 2020 Oct 23.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Macrophages play a significant role in preventing infection through antimicrobial activities, particularly acidification, and proteolysis. infection can lead to diverse outcomes, from latent asymptomatic infection to active disease involving multiple organs. Monocyte-derived macrophage is one of the main cell types accumulating in lungs following infection. The variation of intracellular activities of monocyte-derived macrophages in humans and the influence of these activities on the tuberculosis (TB) spectrum are not well understood. By exploiting ligand-specific bead-based assays, we investigated macrophage antimicrobial activities real-time in healthy volunteers ( = 53) with 35 cases of latent TB (LTB), and those with active TB (ATB), and either pulmonary TB (PTB, = 70) or TB meningitis (TBM, = 77). We found wide person-to-person variations in acidification and proteolytic activities in response to both non-immunogenic IgG and pathogenic ligands comprising trehalose 6,6'- (TDM) from or β-glucan from . The variation in the macrophage activities remained similar regardless of stimuli; however, IgG induced stronger acidification activity than immunogenic ligands TDM ( = 10, 3 × 10 and 0.01 at 30, 60, and 90 min) and β-glucan ( = 10, 3 × 10 and 0.04 at 30, 60, and 90 min). Variation in proteolysis activity was slightly higher in LTB than in ATB (CV = 40% in LTB vs. 29% in ATB, = 0.03). There was no difference in measured antimicrobial activities in response to TDM and bacterial killing in macrophages from LTB and ATB, or from PTB and TBM. Our results indicate that antimicrobial activities of monocyte-derived macrophages vary among individuals and show immunological dependence, but suggest these activities cannot be solely responsible for the control of bacterial replication or dissemination in TB.
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http://dx.doi.org/10.3389/fcimb.2020.586101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644444PMC
October 2020

A multi centre randomized open label trial of chloroquine for the treatment of adults with SARS-CoV-2 infection in Vietnam.

Wellcome Open Res 2020 12;5:141. Epub 2020 Jun 12.

Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent COVID-19 or therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate chloroquine as a potential therapeutic for the treatment of hospitalised people with COVID-19. We hypothesise that chloroquine slows viral replication in patients with COVID-19, attenuating the infection, and resulting in more rapid decline of viral load in throat/nose swabs. This viral attenuation should be associated with improved patient outcomes. : The study will start with a 10-patient prospective observational pilot study following the same entry and exclusion criteria as for the randomized trial and undergoing the same procedures. The main study is an open label, randomised, controlled trial with two parallel arms of standard of care (control arm) versus standard of care with 10 days of chloroquine (intervention arm) with a loading dose over the first 24 hours, followed by 300mg base orally once daily for nine days. The study will recruit patients in three sites in Ho Chi Minh City, Vietnam: the Hospital for Tropical Diseases, the Cu Chi Field Hospital, and the Can Gio COVID hospital. The primary endpoint is the time to viral clearance from throat/nose swab, defined as the time following randomization until the midpoint between the last positive and the first of the negative throat/nose swabs. Viral presence will be determined using RT-PCR to detect SARS-CoV-2 RNA.  The results of the study will add to the evidence-based guidelines for management of COVID-19. Given the enormous experience of its use in malaria chemoprophylaxis, excellent safety and tolerability profile, and its very low cost, if proved effective then chloroquine would be a readily deployable and affordable treatment for patients with COVID-19. Clinicaltrials.gov NCT04328493 31/03/2020.
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http://dx.doi.org/10.12688/wellcomeopenres.15936.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573712PMC
June 2020

The influence of Strongyloides stercoralis co-infection on the presentation, pathogenesis and outcome of tuberculous meningitis.

J Infect Dis 2020 Oct 26. Epub 2020 Oct 26.

Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.

Background: Helminth infections may modulate the inflammatory response to Mycobacterium tuberculosis and influence disease presentation and outcome. Strongyloides stercoralis is common amongst populations with high tuberculosis prevalence. Our aim was to determine if S. stercoralis co-infection influenced clinical presentation, cerebrospinal fluid (CSF) inflammation, and outcome from tuberculous meningitis (TBM).

Methods: From June 2017 to December 2019, 668 Vietnamese adults with TBM, enrolled in the ACT HIV or LAST ACT trials (NCT03092817; NCT03100786), underwent pre-treatment S. stercoralis testing by serology, stool microscopy, and/or stool PCR. Comparisons of pre-treatment TBM severity, CSF inflammation (including cytokines), and 3-month clinical endpoints were performed in active S. stercoralis infected and uninfected groups.

Results: Overall, 9.4% (63/668) participants tested positive for S. stercoralis. Active S. stercoralis infection was significantly associated with reduced pre-treatment CSF neutrophils (3 cells/mm 3[0-25] vs. 14 (cells/mm 3[1-83], p=0.04), and with reduced CSF IFN-ɣ, IL-2, and TNF-α concentrations (11.4 vs. 56.0pg/mL p=0.01; 33.1 vs. 54.5pg/mL p=0.03; 4.5 vs. 11.9pg/mL p=0.02, respectively), compared with uninfected participants. Neurological complications by 3 months were significantly reduced in active S. stercoralis infection vs. uninfected participants (3.8%[1/26] vs. 30.0%[33/110], respectively, p=0.01).

Conclusions: S. stercoralis co-infection may modulate the intracerebral inflammatory response to M. tuberculosis and improve TBM clinical outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa672DOI Listing
October 2020

A high prevalence of multi-drug resistant Gram-negative bacilli in a Nepali tertiary care hospital and associated widespread distribution of Extended-Spectrum Beta-Lactamase (ESBL) and carbapenemase-encoding genes.

Ann Clin Microbiol Antimicrob 2020 Oct 21;19(1):48. Epub 2020 Oct 21.

Patan Academy of Health Sciences, Oxford University Clinical Research Unit, Kathmandu, Nepal.

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, bla (1281/1771; 72%), bla (930/1771; 53%) and bla (419/1771; 24%) were the most prevalent ESBL genes in the enteric bacilli. Bla and bla were the most common bla 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 bla and bla carbapenemase genes respectively. Of enteric bacilli, Enterobacter spp. was the most frequently positive for bla gene (201/337; 60%). The presence of each bla and bla 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 bla, bla and bla 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.
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http://dx.doi.org/10.1186/s12941-020-00390-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576804PMC
October 2020

Superspreading Event of SARS-CoV-2 Infection at a Bar, Ho Chi Minh City, Vietnam.

Emerg Infect Dis 2021 01 16;27(1). Epub 2020 Oct 16.

We report a superspreading event of severe acute respiratory syndrome coronavirus 2 infection initiated at a bar in Vietnam with evidence of symptomatic and asymptomatic transmission, based on ministry of health reports, patient interviews, and whole-genome sequence analysis. Crowds in enclosed indoor settings with poor ventilation may be considered at high risk for transmission.
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http://dx.doi.org/10.3201/eid2701.203480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774544PMC
January 2021

Automating the Generation of Antimicrobial Resistance Surveillance Reports: Proof-of-Concept Study Involving Seven Hospitals in Seven Countries.

J Med Internet Res 2020 10 2;22(10):e19762. Epub 2020 Oct 2.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Background: Reporting cumulative antimicrobial susceptibility testing data on a regular basis is crucial to inform antimicrobial resistance (AMR) action plans at local, national, and global levels. However, analyzing data and generating a report are time consuming and often require trained personnel.

Objective: This study aimed to develop and test an application that can support a local hospital to analyze routinely collected electronic data independently and generate AMR surveillance reports rapidly.

Methods: An offline application to generate standardized AMR surveillance reports from routinely available microbiology and hospital data files was written in the R programming language (R Project for Statistical Computing). The application can be run by double clicking on the application file without any further user input. The data analysis procedure and report content were developed based on the recommendations of the World Health Organization Global Antimicrobial Resistance Surveillance System (WHO GLASS). The application was tested on Microsoft Windows 10 and 7 using open access example data sets. We then independently tested the application in seven hospitals in Cambodia, Lao People's Democratic Republic, Myanmar, Nepal, Thailand, the United Kingdom, and Vietnam.

Results: We developed the AutoMated tool for Antimicrobial resistance Surveillance System (AMASS), which can support clinical microbiology laboratories to analyze their microbiology and hospital data files (in CSV or Excel format) onsite and promptly generate AMR surveillance reports (in PDF and CSV formats). The data files could be those exported from WHONET or other laboratory information systems. The automatically generated reports contain only summary data without patient identifiers. The AMASS application is downloadable from https://www.amass.website/. The participating hospitals tested the application and deposited their AMR surveillance reports in an open access data repository.

Conclusions: The AMASS is a useful tool to support the generation and sharing of AMR surveillance reports.
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http://dx.doi.org/10.2196/19762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568216PMC
October 2020

Trimethoprim-sulfamethoxazole (SXT) versus azithromycin for the treatment of undifferentiated febrile illness in Nepal: a double-blind, randomized, placebo-controlled trial.

Clin Infect Dis 2020 Sep 29. Epub 2020 Sep 29.

Oxford University Clinical Research Unit Nepal, Patan Academy of Health Sciences, Lalitpur, Nepal.

Background: Azithromycin and trimethoprim-sulfamethoxazole (SXT) are widely used to treat undifferentiated febrile illness (UFI). We hypothesized that azithromycin is superior to SXT for UFI treatment, but the drugs are non-inferior to each other for culture-confirmed enteric fever treatment.

Methods: We conducted a double blind, randomized, placebo-controlled trial of azithromycin (20 mg/kg/day) or SXT (trimethoprim 10 mg/kg/day + sulfamethoxazole 50 mg/kg/day) orally for 7 days for UFI treatment in Nepal. We enrolled patients (aged 3-64 years) presenting to two Kathmandu hospitals with temperature ≥ 38.0°C for ≥4 days without localising signs. The primary endpoint was fever clearance time (FCT); secondary endpoints were treatment failure and adverse events. ClinicalTrials.gov number: NCT02773407.

Results: From June 2016 to May 2019, we randomized 326 participants (163 in each arm); 87 (26.7%) had blood culture-confirmed enteric fever. In all participants, the median FCT was 2.7 days (95% CI 2.6-3.3) in the SXT arm and 2.1 days (95% CI 1.6-3.2) in the azithromycin arm 1.25 (95% CI 0.99-1.58, P=0.059). The hazard ratio of treatment failures by 28 days between azithromycin and SXT was 0.62 (95% CI 0.37-1.05, p=0.073). Planned sub-group analysis showed azithromycin resulted in faster FCT in those with sterile blood cultures and less relapses in culture-confirmed enteric fever. Nausea, vomiting, constipation, and headache were more common in the SXT arm.

Conclusions: Despite similar FCT and treatment failure in the two arms, significantly fewer complications and relapses make azithromycin a better choice for empirical treatment of UFI in Nepal.
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http://dx.doi.org/10.1093/cid/ciaa1489DOI Listing
September 2020

The direct-medical costs associated with interferon-based treatment for Hepatitis C in Vietnam.

Wellcome Open Res 2019 11;4:129. Epub 2020 Sep 11.

Oxford University Clinical Research Unit, Ho Chi Minh, Vietnam.

Injectable interferon-based therapies have been used to treat hepatitis C virus (HCV) infection since 1991. International guidelines have now moved away from interferon-based therapy towards direct-acting antiviral (DAA) tablet regimens, because of their superior efficacy, excellent side-effect profiles, and ease of administration. Initially DAA drugs were prohibitively expensive for most healthcare systems. Access is now improving through the procurement of low-cost, generic DAAs acquired through voluntary licenses. However, HCV treatment costs vary widely, and many countries are struggling with DAA treatment scale-up. This is not helped by the limited cost data and economic evaluations from low- and middle-income countries to support HCV policy decisions. We conducted a detailed analysis of the costs of treating chronic HCV infection with interferon-based therapy in Vietnam. Understanding these costs is important for performing necessary economic evaluations of novel treatment strategies. We conducted an analysis of the direct medical costs of treating HCV infection with interferon alpha (IFN) and pegylated-interferon alpha (Peg-IFN), in combination with ribavirin, from the health sector perspective at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, in 2017. The total cost of the IFN treatment regimen was estimated to range between US$1,120 and US$1,962. The total cost of the Peg-IFN treatment regimen was between US$2,156 and US$5,887. Drug expenses were the biggest contributor to the total treatment cost (54-89%) and were much higher for the Peg-IFN regimen. We found that treating HCV with IFN or Peg-IFN resulted in significant direct medical costs. Of concern, we found that all patients incurred substantial out-of-pocket costs, including those receiving the maximum level of support from the national health insurance programme. This cost data highlights the potential savings and importance of increased access to generic DAAs in low- and middle-income countries and will be useful within future economic evaluations.
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http://dx.doi.org/10.12688/wellcomeopenres.15408.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372532PMC
September 2020

The Virome of Acute Respiratory Diseases in Individuals at Risk of Zoonotic Infections.

Viruses 2020 08 29;12(9). Epub 2020 Aug 29.

Oxford University Clinical Research Unit, Ho Chi Minh City 7000, Vietnam.

The ongoing coronavirus disease 2019 (COVID-19) pandemic emphasizes the need to actively study the virome of unexplained respiratory diseases. We performed viral metagenomic next-generation sequencing (mNGS) analysis of 91 nasal-throat swabs from individuals working with animals and with acute respiratory diseases. Fifteen virus RT-PCR-positive samples were included as controls, while the other 76 samples were RT-PCR negative for a wide panel of respiratory pathogens. Eukaryotic viruses detected by mNGS were then screened by PCR (using primers based on mNGS-derived contigs) in all samples to compare viral detection by mNGS versus PCR and assess the utility of mNGS in routine diagnostics. mNGS identified expected human rhinoviruses, enteroviruses, influenza A virus, coronavirus OC43, and respiratory syncytial virus (RSV) A in 13 of 15 (86.7%) positive control samples. Additionally, rotavirus, torque teno virus, human papillomavirus, human betaherpesvirus 7, cyclovirus, vientovirus, gemycircularvirus, and statovirus were identified through mNGS. Notably, complete genomes of novel cyclovirus, gemycircularvirus, and statovirus were genetically characterized. Using PCR screening, the novel cyclovirus was additionally detected in 5 and the novel gemycircularvirus in 12 of the remaining samples included for mNGS analysis. Our studies therefore provide pioneering data of the virome of acute-respiratory diseases from individuals at risk of zoonotic infections. The mNGS protocol/pipeline applied here is sensitive for the detection of a variety of viruses, including novel ones. More frequent detections of the novel viruses by PCR than by mNGS on the same samples suggests that PCR remains the most sensitive diagnostic test for viruses whose genomes are known. The detection of novel viruses expands our understanding of the respiratory virome of animal-exposed humans and warrant further studies.
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http://dx.doi.org/10.3390/v12090960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552073PMC
August 2020

Clinical, etiological and epidemiological investigations of hand, foot and mouth disease in southern Vietnam during 2015 - 2018.

PLoS Negl Trop Dis 2020 08 17;14(8):e0008544. Epub 2020 Aug 17.

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. In Vietnam, there have been two major outbreaks occurring during 2011-2012 (>200,000 hospitalizations and >200 deaths) and more recently in 2018 (>130,000 hospitalizations and 17 deaths). Given the high burden and the complex epidemic dynamics of HFMD, synthesizing its clinical and epidemiological data remains essential to inform the development of appropriate interventions and design public health measures. We report the results of a hospital-based study conducted during 2015-2018, covering the severe HFMD outbreak recently documented in Vietnam in 2018. The study was conducted at three major hospitals responsible for receiving HFMD patients from southern Vietnam with a population of over 40 million. A total of 19 enterovirus serotypes were detected in 1196 HFMD patients enrolled in the clinical study during 2015-2018, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. Despite the emergence of coxsackieviruses, EV-A71 remains the leading cause of severe HFMD in Vietnam. EV-A71 was consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017-early 2018. Compared with EV-A71 subgenogroup B5, C4 was more likely to be associated with severe HFMD, representing the first report demonstrating the difference in clinical severity between subgenogroup C4 and B5, the two predominant EV-A71 subgenogroups causing HFMD worldwide. Our data have provided significant insights into important aspects of HFMD over four years (2015-2018) in Vietnam, and emphasize active surveillance for pathogen circulation remains essential to inform the local public health authorities in the development of appropriate intervention strategies to reduce the burden of this emerging infections. Multivalent vaccines are urgently needed to control HFMD.
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http://dx.doi.org/10.1371/journal.pntd.0008544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451980PMC
August 2020

Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study.

Lancet Infect Dis 2020 12 4;20(12):1409-1417. Epub 2020 Aug 4.

Service of Infectious Diseases, Hospital Clínic of Barcelona, Barcelona, Spain. Electronic address:

Background: Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia.

Methods: We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1.

Findings: Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51-75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2-4 days, 43% (30 of 69) with 5-7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51-2·46; p<0·0001).

Interpretation: We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(20)30447-3DOI Listing
December 2020

The first 100 days of SARS-CoV-2 control in Vietnam.

Clin Infect Dis 2020 Aug 1. Epub 2020 Aug 1.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK.

Background: One hundred days after SARS-CoV-2 was first reported in Vietnam on January 23rd, 270 cases were confirmed, with no deaths. We describe the control measures used by the Government and their relationship with imported and domestically-acquired case numbers, with the aim of identifying the measures associated with successful SARS-CoV-2 control.

Methods: Clinical and demographic data on the first 270 SARS-CoV-2 infected cases and the timing and nature of Government control measures, including numbers of tests and quarantined individuals, were analysed. Apple and Google mobility data provided proxies for population movement. Serial intervals were calculated from 33 infector-infectee pairs and used to estimate the proportion of pre-symptomatic transmission events and time-varying reproduction numbers.

Results: A national lockdown was implemented between April 1st and 22nd. Around 200 000 people were quarantined and 266 122 RT-PCR tests conducted. Population mobility decreased progressively before lockdown. 60% (163/270) of cases were imported; 43% (89/208) of resolved infections remained asymptomatic for the duration of infection. The serial interval was 3·24 days, and 27·5% (95% confidence interval, 15·7%-40·0%) of transmissions occurred pre-symptomatically. Limited transmission amounted to a maximum reproduction number of 1·15 (95% confidence interval, 0·37-2·36). No community transmission has been detected since April 15th.

Conclusions: Vietnam has controlled SARS-CoV-2 spread through the early introduction of mass communication, meticulous contact-tracing with strict quarantine, and international travel restrictions. The value of these interventions is supported by the high proportion of asymptomatic and imported cases, and evidence for substantial pre-symptomatic transmission.
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http://dx.doi.org/10.1093/cid/ciaa1130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454342PMC
August 2020