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Melioidosis is an often-fatal neglected tropical disease caused by an environmental bacterium Burkholderia pseudomallei. However, our understanding of the disease-causing bacterial lineages, their dissemination, and adaptive mechanisms remains limited. To address this, we conduct a comprehensive genomic analysis of 1,391 B. pseudomallei isolates collected from nine hospitals in northeast Thailand between 2015 and 2018, and contemporaneous isolates from neighbouring countries, representing the most densely sampled collection to date. Our study identifies three dominant lineages, each with unique gene sets potentially enhancing bacterial fitness in the environment. We find that recombination drives lineage-specific gene flow. Transcriptome analyses of representative clinical isolates from each dominant lineage reveal increased expression of lineage-specific genes under environmental conditions in two out of three lineages. This underscores the potential importance of environmental persistence for these dominant lineages. The study also highlights the influence of environmental factors such as terrain slope, altitude, and river direction on the geographical dispersal of B. pseudomallei. Collectively, our findings suggest that environmental persistence may play a role in facilitating the spread of B. pseudomallei, and as a prerequisite for exposure and infection, thereby providing useful insights for informing melioidosis prevention and control strategies.
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Burkholderia pseudomallei , Variação Genética , Melioidose , Burkholderia pseudomallei/genética , Burkholderia pseudomallei/isolamento & purificação , Burkholderia pseudomallei/classificação , Melioidose/microbiologia , Melioidose/epidemiologia , Tailândia/epidemiologia , Humanos , Filogenia , Fluxo Gênico , Genoma Bacteriano/genéticaRESUMO
BACKGROUND: The presence of antimicrobial-resistant (AMR) bacteria in edible ice in tropical countries is largely unknown. METHODS: We evaluate the presence of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales in 100 edible ice samples from drink carts in 20 markets in four provinces (five markets/province) in Thailand. Ten samples of commercially sold edible ice in sealed packages were tested as controls. RESULTS: Of 100 samples, 29 (29%) were culture positive for ESBL-producing Enterobacterales, with a median quantitative count of 2 colony-forming units (CFU)/100 mL (range, 1 to 40 CFU/100 mL). All control samples were culture negative for ESBL-producing Enterobacterales. CONCLUSIONS: AMR bacteria is commonly found in edible ice from drink carts.
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In preparation for mass vaccinations with R21/Matrix-M™ combined with mass administrations of dihydroartemisinin, piperaquine, and a single low dose primaquine we assessed the tolerability, safety, and potential interactions of this combination affecting immunogenicity or pharmacokinetics. 120 healthy Thai volunteers were randomised to receive either antimalarials combined with vaccinations (n = 50), vaccinations alone (n = 50), or antimalarials only (n = 20). Three rounds of vaccines and antimalarials were administered one month apart. The vaccine was well tolerated alone and in combination with the antimalarials. None of the participants failed completion of the 3-dose vaccine course. There was no significant difference in the vaccine immunogenicity or in the pharmacokinetics of piperaquine given individually or in combination. This study supports proceeding to a large trial of mass vaccinations with R21/Matrix-M™ combined with mass antimalarial administration in Bangladesh.
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A strong and effective COVID-19 and future pandemic responses rely on global efforts to carry out surveillance of infections and emerging SARS-CoV-2 variants and to act accordingly in real time. Many countries in Southeast Asia lack capacity to determine the potential threat of new variants, or other emerging infections. Funded by Wellcome, the Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium aims to develop and apply a multidisciplinary research platform in Southeast Asia (SEA) for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby informing coordinated local, regional and global responses to the COVID-19 pandemic. Our proposal is delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in Indonesia, Thailand and Vietnam with partners in Singapore, the UK and the USA. Herein we outline five work packages to deliver strengthened regional scientific capacity that can be rapidly deployed for future outbreak responses.
Our project strengthens local scientific capacity in South East Asia (SEA) and therefore enables the rapid assessment of SARS-CoV-2 variants as they emerge within the region. While COVID-19 remains a global pandemic, future emerging infections caused by a novel virus is an inevitable event, with SEA being a global hot-spot for pathogen emergence. Consequently, the research capacity built, the scientists trained and the research network formed as part of this project will lay the foundation for future locally-led outbreak responses. Our project will demonstrate that novel research platforms can be set up in other low and middle income countries to address the unprecedented challenges presented by emerging infections.
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Investment in community health workers is essential.
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Antimaláricos , Artemisininas , Agentes Comunitários de Saúde , Resistência a Medicamentos , Malária Falciparum , Plasmodium falciparum , Humanos , África/epidemiologia , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artemisininas/farmacologia , Agentes Comunitários de Saúde/economia , Resistência a Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genéticaRESUMO
OBJECTIVES: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. We aimed to provide the first comprehensive review on the seroprevalence, incidence, mortality of and risk factors for scrub typhus. METHODS: We searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases. Trended incidence and median mortality were calculated and pooled seroprevalence and risk factors for scrub typhus were evaluated using the random-effects meta-analysis. RESULTS: We included 663 articles from 29 countries/regions. The pooled seroprevalence was 10.73% (95%CI 9.47-12.13%) among healthy individuals and 22.58% (95%CI: 20.55%-24.76%) among febrile patients. Mainland China reported the highest number of cases and South Korea and Thailand had the highest incidence rates. Median mortalities were 5.00% (range: 0.00-56.00%) among hospital inpatients, 6.70% (range: 0.00-33.33%) among patients without specified admission status and 2.17% (range: 0.00-22.22%) among outpatients. The significant risk factors included agricultural work, specific vegetation exposure, other outdoor activities, risky personal health habits, and proximity to rodents, livestock, or poultry. CONCLUSIONS: Our comprehensive review elucidates the significant yet variable burden of scrub typhus across different regions, underscoring its emergence as a critical public health concern globally.
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Tifo por Ácaros , Tifo por Ácaros/epidemiologia , Tifo por Ácaros/mortalidade , Humanos , Estudos Soroepidemiológicos , Fatores de Risco , Incidência , Orientia tsutsugamushi/imunologia , Saúde Global , AnimaisRESUMO
There are few studies comparing proportion, frequency, mortality and mortality rate following antimicrobial-resistant (AMR) infections between tertiary-care hospitals (TCHs) and secondary-care hospitals (SCHs) in low and middle-income countries (LMICs) to inform intervention strategies. The aim of this study is to demonstrate the utility of an offline tool to generate AMR reports and data for a secondary data analysis. We conducted a secondary-data analysis on a retrospective, multicentre data of hospitalised patients in Thailand. Routinely collected microbiology and hospital admission data of 2012 to 2015, from 15 TCHs and 34 SCHs were analysed using the AMASS v2.0 (www.amass.website). We then compared the burden of AMR bloodstream infections (BSI) between those TCHs and SCHs. Of 19,665 patients with AMR BSI caused by pathogens under evaluation, 10,858 (55.2%) and 8,807 (44.8%) were classified as community-origin and hospital-origin BSI, respectively. The burden of AMR BSI was considerably different between TCHs and SCHs, particularly of hospital-origin AMR BSI. The frequencies of hospital-origin AMR BSI per 100,000 patient-days at risk in TCHs were about twice that in SCHs for most pathogens under evaluation (for carbapenem-resistant Acinetobacter baumannii [CRAB]: 18.6 vs. 7.0, incidence rate ratio 2.77; 95%CI 1.72-4.43, p<0.001; for carbapenem-resistant Pseudomonas aeruginosa [CRPA]: 3.8 vs. 2.0, p = 0.0073; third-generation cephalosporin resistant Escherichia coli [3GCREC]: 12.1 vs. 7.0, p<0.001; third-generation cephalosporin resistant Klebsiella pneumoniae [3GCRKP]: 12.2 vs. 5.4, p<0.001; carbapenem-resistant K. pneumoniae [CRKP]: 1.6 vs. 0.7, p = 0.045; and methicillin-resistant Staphylococcus aureus [MRSA]: 5.1 vs. 2.5, p = 0.0091). All-cause in-hospital mortality (%) following hospital-origin AMR BSI was not significantly different between TCHs and SCHs (all p>0.20). Due to the higher frequencies, all-cause in-hospital mortality rates following hospital-origin AMR BSI per 100,000 patient-days at risk were considerably higher in TCHs for most pathogens (for CRAB: 10.2 vs. 3.6,mortality rate ratio 2.77; 95%CI 1.71 to 4.48, p<0.001; CRPA: 1.6 vs. 0.8; p = 0.020; 3GCREC: 4.0 vs. 2.4, p = 0.009; 3GCRKP, 4.0 vs. 1.8, p<0.001; CRKP: 0.8 vs. 0.3, p = 0.042; and MRSA: 2.3 vs. 1.1, p = 0.023). In conclusion, the burden of AMR infections in some LMICs might differ by hospital type and size. In those countries, activities and resources for antimicrobial stewardship and infection control programs might need to be tailored based on hospital setting. The frequency and in-hospital mortality rate of hospital-origin AMR BSI are important indicators and should be routinely measured to monitor the burden of AMR in every hospital with microbiology laboratories in LMICs.
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Bacteriemia , Centros de Atenção Terciária , Humanos , Centros de Atenção Terciária/estatística & dados numéricos , Estudos Retrospectivos , Tailândia/epidemiologia , Bacteriemia/mortalidade , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Feminino , Masculino , Infecção Hospitalar/mortalidade , Infecção Hospitalar/microbiologia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Pessoa de Meia-Idade , Idoso , Adulto , Mortalidade HospitalarRESUMO
Current guidelines advise against primaquine treatment for breastfeeding mothers to avoid the potential for haemolysis in infants with G6PD deficiency. To predict the haemolytic risk, the amount of drug received from the breast milk and the resulting infant drug exposure need to be characterised. Here, we develop a pharmacokinetic model to describe the drug concentrations in breastfeeding women using venous, capillary, and breast milk data. A mother-to-infant model is developed to mimic the infant feeding pattern and used to predict their drug exposures. Primaquine and carboxyprimaquine exposures in infants are <1% of the exposure in mothers. Therefore, even in infants with the most severe G6PD deficiency variants, it is highly unlikely that standard doses of primaquine (0.25-1 mg base/kg once daily given to the mother for 1-14 days) would cause significant haemolysis. After the neonatal period, primaquine should not be restricted for breastfeeding women (Clinical Trials Registration: NCT01780753).
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Antimaláricos , Aleitamento Materno , Lactação , Leite Humano , Primaquina , Humanos , Feminino , Primaquina/farmacocinética , Primaquina/administração & dosagem , Antimaláricos/farmacocinética , Antimaláricos/administração & dosagem , Lactente , Leite Humano/química , Leite Humano/metabolismo , Adulto , Recém-Nascido , Hemólise/efeitos dos fármacos , Modelos BiológicosRESUMO
BACKGROUND: Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations. METHODS: Serial viral density data were analysed from symptomatic, previously healthy, adult patients (within 4 days of symptom onset) enrolled in a large multicentre, randomised, adaptive, pharmacodynamic, platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over 1 week were estimated under a hierarchical Bayesian linear model with B-splines used to characterise temporal changes in enrolment viral densities and clearance rates. Bootstrap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal was defined as maximising the expected Z score when comparing effective antivirals with no treatment. PLATCOV is registered at ClinicalTrials.gov, NCT05041907. FINDINGS: Between Sept 29, 2021, and Oct 20, 2023, 1262 patients were randomly assigned in the PLATCOV trial. Unblinded data were available from 800 patients (who provided 16â818 oropharyngeal viral quantitative PCR [qPCR] measurements), of whom 504 (63%) were female. 783 (98%) patients had received at least one vaccine dose and 703 (88%) were fully vaccinated. SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase (α) was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected Z score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the 2-year period studied, median viral clearance half-lives estimated over 7 days shortened from 16·6 h (IQR 15·3 to 18·2) in September, 2021, to 9·2 h (8·0 to 10·6) in October, 2023, in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% (95% credible interval [CrI] 19 to 64). A parallel reduction in viral clearance half-lives over time was observed in patients receiving antiviral drugs. For example, in the 158 patients assigned to ritonavir-boosted nirmatrelvir (3380 qPCR measurements), the median viral clearance half-life reduced from 6·4 h (IQR 5·7 to 7·3) in June, 2022, to 4·8 h (4·2 to 5·5) in October, 2023, a relative reduction of 26% (95% CrI -4 to 42). INTERPRETATION: SARS-CoV-2 viral clearance kinetics in symptomatic, vaccinated individuals accelerated substantially over 2 years of the pandemic, necessitating a change to how new SARS-CoV-2 antivirals are compared (ie, shortening the period of pharmacodynamic assessment). As of writing (October, 2023), antiviral efficacy in COVID-19 can be efficiently assessed in vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. FUNDING: Wellcome Trust.
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Over the past year, P. falciparum infections have declined in Thailand, yet nonhuman primate malaria infections have correspondingly increased, including Plasmodium knowlesi and P. cynomolgi. Nevertheless, little is known about simian malaria in its natural macaque hosts, Macaca mulatta and Macaca fascicularis. This study aims to address several research questions, including the prevalence and distribution of simian malaria in these two Thai wild macaque species, variations in infection between different macaque species and between M. fascicularis subspecies, and the genetic composition of these pathogens. Blood samples were collected from 82 M. mulatta and 690 M. fascicularis across 15 locations in Thailand, as well as two locations in Vietnam and Myanmar. We employed quantitative real-time PCR targeting the Plasmodium genus-specific 18S ribosomal RNA (rRNA) gene to detect malaria infection, with a limit of detection set at 1,215.98 parasites per mL. We genotyped eight microsatellite markers, and the P. cynomolgi dihydrofolate reductase gene (DHFR) was sequenced (N = 29). In total, 100 of 772 samples (13 %) tested positive for malaria, including 45 (13 %) for P. cynomolgi, 37 (13 %) for P. inui, 16 (5 %) for P. coatneyi, and 2 (0.25 %) for Hepatocystis sp. in Saraburi, central and Ranong, southern Thailand. Notably, simian malaria infection was observed exclusively in M. fascicularis and not in M. mulatta (P = 0.0002). Particularly, P. cynomolgi was detected in 21.7 % (45/207) of M. f. fascicularis living in Wat Tham Phrapothisat, Saraburi Province. The infection with simian malaria was statistically different between M. fascicularis and M. mulatta (P = 0.0002) but not within M. fascicularis subspecies (P = 0.78). A haplotype network analysis revealed that P. cynomolgi shares a lineage with reference strains obtained from macaques. No mutation in the predicted binding pocket of PcyDHFR to pyrimethamine was observed. This study reveals a significant prevalence of simian malaria infection in M. fascicularis. The clonal genotypes of P. cynomolgi suggest in-reservoir breeding. These findings raise concerns about the potential spread of nonhuman primate malaria to humans and underscore the need for preventive measures.
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Variação Genética , Macaca fascicularis , Malária , RNA Ribossômico 18S , Animais , Tailândia/epidemiologia , Malária/epidemiologia , Malária/parasitologia , Malária/veterinária , Macaca fascicularis/parasitologia , Prevalência , RNA Ribossômico 18S/genética , Macaca mulatta/parasitologia , Genótipo , Repetições de Microssatélites/genética , Doenças dos Macacos/parasitologia , Doenças dos Macacos/epidemiologia , Humanos , Mianmar/epidemiologia , Tetra-Hidrofolato Desidrogenase/genética , Plasmodium knowlesi/genética , Plasmodium knowlesi/isolamento & purificação , Plasmodium/genética , Plasmodium/classificação , Plasmodium/isolamento & purificação , Vietnã/epidemiologia , DNA de Protozoário/genética , Plasmodium cynomolgi/genética , Plasmodium cynomolgi/classificação , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Diminished hip labral size and tissue quality may be a predictor of poor patient outcomes when a non-augmented primary labral repair is performed. Labral augmentation is an option for patients with hypoplastic or degenerative labral tissue. The optimal graft for augmentation has yet to be identified, and biomechanical research shows no difference in force to suction-seal disruption between dermal allograft and iliotibial band allograft when used to augment the labrum. However, time-zero biomechanical studies do not reflect the biological ability of the graft to heal to surrounding structures, revascularization of the graft, durability of the graft, hip capsular status, and response to functional demands of the patient.
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BACKGROUND: Little is known about diagnostic and antibiotic use practices in low and middle-income countries (LMICs) before and during COVID-19 pandemic. This information is crucial for monitoring and evaluation of diagnostic and antimicrobial stewardships in healthcare facilities. METHODS: We linked and analyzed routine databases of hospital admission, microbiology laboratory and drug dispensing of Indonesian National Referral Hospital from 2019 to 2020. Patients were classified as COVID-19 cases if their SARS-CoV-2 RT-PCR result were positive. Blood culture (BC) practices and time to discontinuation of parenteral antibiotics among inpatients who received a parenteral antibiotic for at least four consecutive days were used to assess diagnostic and antibiotic use practices, respectively. Fine and Grey subdistribution hazard model was used. RESULTS: Of 1,311 COVID-19 and 58,917 non-COVID-19 inpatients, 333 (25.4%) and 18,837 (32.0%) received a parenteral antibiotic for at least four consecutive days. Proportion of patients having BC taken within ±1 calendar day of parenteral antibiotics being started was higher in COVID-19 than in non-COVID-19 patients (21.0% [70/333] vs. 18.7% [3,529/18,837]; p<0.001). Cumulative incidence of having a BC taken within 28 days was higher in COVID-19 than in non-COVID-19 patients (44.7% [149/333] vs. 33.2% [6,254/18,837]; adjusted subdistribution-hazard ratio [aSHR] 1.71, 95% confidence interval [CI] 1.47-1.99, p<0.001). The median time to discontinuation of parenteral antibiotics was longer in COVID-19 than in non-COVID-19 patients (13 days vs. 8 days; aSHR 0.73, 95%Cl 0.65-0.83, p<0.001). CONCLUSIONS: Routine electronic data could be used to inform diagnostic and antibiotic use practices in LMICs. In Indonesia, the proportion of timely blood culture is low in both COVID-19 and non-COVID-19 patients, and duration of parenteral antibiotics is longer in COVID-19 patients. Improving diagnostic and antimicrobial stewardship is critically needed.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , Indonésia/epidemiologia , SARS-CoV-2 , Antibacterianos/uso terapêutico , Pandemias , Hospitais , Teste para COVID-19RESUMO
[This corrects the article DOI: 10.1371/journal.pone.0204509.].
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INTRODUCTION: In low-income and middle-income countries in Southeast Asia, the burden of diseases among rural population remains poorly understood, posing a challenge for effective healthcare prioritisation and resource allocation. Addressing this knowledge gap, the South and Southeast Asia Community-based Trials Network (SEACTN) will undertake a survey that aims to determine the prevalence of a wide range of non-communicable and communicable diseases, as one of the key initiatives of its first project-the Rural Febrile Illness project (RFI). This survey, alongside other RFI studies that explore fever aetiology, leading causes of mortality, and establishing village and health facility maps and profiles, will provide an updated epidemiological background of the rural areas where the network is operational. METHODS AND ANALYSIS: During 2022-2023, a cross-sectional household survey will be conducted across three SEACTN sites in Bangladesh, Cambodia and Thailand. Using a two-stage cluster-sampling approach, we will employ a probability-proportional-to-size sample method for village, and a simple random sample for household, selection, enrolling all members from the selected households. Approximately 1500 participants will be enrolled per country. Participants will undergo questionnaire interview, physical examination and haemoglobin point-of-care testing. Blood samples will be collected and sent to central laboratories to test for chronic and acute infections, and biomarkers associated with cardiovascular disease, and diabetes. Prevalences will be presented as an overall estimate by country, and stratified and compared across sites and participants' sociodemographic characteristics. Associations between disease status, risk factors and other characteristics will be explored. ETHICS AND DISSEMINATION: This study protocol has been approved by the Oxford Tropical Research Ethics Committee, National Research Ethics Committee of Bangladesh Medical Research Council, the Cambodian National Ethics Committee for Health Research, the Chiang Rai Provincial Public Health Research Ethical Committee. The results will be disseminated via the local health authorities and partners, peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05389540.
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Efeitos Psicossociais da Doença , População Rural , Humanos , Bangladesh/epidemiologia , Camboja/epidemiologia , Estudos Transversais , Inquéritos Epidemiológicos , TailândiaRESUMO
BACKGROUND: Melioidosis is a neglected but often fatal tropical disease. The disease has broad clinical manifestations, which makes diagnosis challenging and time consuming. To improve diagnosis, we aimed to evaluate the performance of the CRISPR-Cas12a system (CRISPR-BP34) to detect Burkholderia pseudomallei DNA across clinical specimens from patients suspected to have melioidosis. METHODS: We conducted a prospective, observational cohort study of adult patients (aged ≥18 years) with melioidosis at Sunpasitthiprasong Hospital, a tertiary care hospital in Thailand. Participants were eligible for inclusion if they had culture-confirmed B pseudomallei infection from any clinical samples. Data were collected from patient clinical records and follow-up telephone calls. Routine clinical samples (blood, urine, respiratory secretion, pus, and other body fluids) were collected for culture. We documented time taken for diagnosis, and mortality at day 28 of follow-up. We also performed CRISPR-BP34 detection on clinical specimens collected from 330 patients with suspected melioidosis and compared its performance with the current gold-standard culture-based method. Discordant results were validated by three independent qualitative PCR tests. This study is registered with the Thai Clinical Trial Registry, TCTR20190322003. FINDINGS: Between Oct 1, 2019, and Dec 31, 2022, 876 patients with culture-confirmed melioidosis were admitted or referred to Sunpasitthiprasong Hospital, 433 of whom were alive at diagnosis and were enrolled in this study. Median time from sample collection to diagnosis by culture was 4·0 days (IQR 3·0-5·0) among all patients with known survival status at day 28, which resulted in delayed treatment. 199 (23%) of 876 patients died before diagnosis and 114 (26%) of 433 patients in follow-up were treated, but died within 28 days of admission. To test the CRISPR-BP34 assay, we enrolled and collected clinical samples from 114 patients with melioidosis and 216 patients without melioidosis between May 26 and Dec 31, 2022. Application of CRISPR-BP34 reduced the median sample-to-diagnosis time to 1·1 days (IQR 0·7-1·5) for blood samples, 2·3 h (IQR 2·3-2·4) for urine, and 3·3 h (3·1-3·4) for respiratory secretion, pus, and other body fluids. The overall sensitivity of CRISPR-BP34 was 93·0% (106 of 114 samples [95% CI 86·6-96·9]) compared with 66·7% (76 of 114 samples [57·2-75·2]) for culture. The overall specificity of CRISPR-BP34 was 96·8% (209 of 216 samples [95% CI 93·4-98·7]), compared with 100% (216 of 216 samples [98·3-100·0]) for culture. INTERPRETATION: The sensitivity, specificity, speed, and window of clinical intervention offered by CRISPR-BP34 support its prospective use as a point-of-care diagnostic tool for melioidosis. Future development should be focused on scalability and cost reduction. FUNDING: Chiang Mai University Thailand and Wellcome Trust UK.
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Burkholderia pseudomallei , Melioidose , Adulto , Humanos , Benchmarking , Burkholderia pseudomallei/genética , Países em Desenvolvimento , Melioidose/diagnóstico , Patologia Molecular , Sistemas Automatizados de Assistência Junto ao Leito , Sensibilidade e Especificidade , SupuraçãoRESUMO
In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.
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Aminoquinolinas , Antimaláricos , Malária Vivax , Adulto , Humanos , Antimaláricos/uso terapêutico , Hemólise , Malária Vivax/tratamento farmacológico , Primaquina/uso terapêutico , Estudos Prospectivos , Metanálise como AssuntoRESUMO
INTRODUCTION: Rickettsia spp. and Orientia spp. are the causes of neglected infections that can lead to severe febrile and systemic illnesses in humans. Implementing proper biosafety practices when handling these pathogens is crucial to ensure a safe and sustainable work environment. It is essential to assess the current knowledge and identify any potential gaps to develop effective measures that minimise the risk of exposure to these pathogens. By doing so, we can establish a comprehensive framework that promotes safety, mitigates hazards, and safeguards the well-being of personnel and the surrounding community. METHODS AND RESULTS: This review aimed to synthesise and determine the evidence base for biosafety precautions for Rickettsia spp. and Orientia spp. pathogens. Enhancing our understanding of the relative infectious risk associated with different strains of Rickettsia and Orientia spp. requires identifying the infectious dose of these pathogens that can cause human disease. The application of risk groups for Rickettsia and Orientia spp. is inconsistent across jurisdictions. There is also incomplete evidence regarding decontamination methods for these pathogens. With regards to Orientia spp. most of the available information is derived from experiments conducted with Rickettsia spp. CONCLUSIONS: Rickettsia and Orientia spp. are neglected diseases, as demonstrated by the lack of evidence-based and specific biosafety information about these pathogens. In the case of Orientia spp., most of the available information is derived from Rickettsia spp., which may not be appropriate and overstate the risks of working with this pathogen. The advent of effective antibiotic therapy and a better understanding of the true hazards and risks associated with pathogen manipulation should inform decisions, allowing a sustainable and safe work environment.
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Orientia tsutsugamushi , Rickettsia , Tifo por Ácaros , Humanos , Contenção de Riscos Biológicos , BiosseguridadeRESUMO
Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused. Methods: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15-20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given. Results: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1-5.9; relative decline of 26% [range: 15-40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9-4.1; relative fall of 12% [range: 7-30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline. Conclusions: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen. Funding: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z). Clinical trial number: Thai Clinical Trial Registry: TCTR20170830002 and TCTR20220317004.
Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Malária Vivax , Adulto , Humanos , Masculino , Antimaláricos/uso terapêutico , Voluntários Saudáveis , Hemoglobinas , Hemólise , Malária Vivax/tratamento farmacológico , Malária Vivax/prevenção & controle , Primaquina/efeitos adversos , TailândiaRESUMO
BACKGROUND: Scrub typhus is an understudied vector-borne bacterial infection. METHODS: We tested archived fever samples for scrub typhus seropositivity to begin charting its geographic distribution in Indonesia. We analysed 1033 serum samples from three sites. IgM and IgG enzyme-linked immunosorbent assay (ELISA) against Orientia tsutsugamushi was performed using Karp, Kato, Gilliam, TA 716 antigens. To determine the cutoff in the absence of a presumed unexposed population and gold standard tests, we identified the visual inflection point, performed change point analysis, and used finite mixture models. RESULTS: The optical density cutoff values used for IgM and IgG were 0.49 and 0.13, respectively. Across all sites, IgM seropositivity was 4.6% (95% CI: 3.4 to 6.0%) while IgG seropositivity was 4.4% (95% CI: 3.3 to 5.8%). The overall seropositivity across sites was 8.8% (95% CI: 8.1 to 11.7%). The overall seropositivity for Jambi, Denpasar, Tabanan were 9.7% (95% CI: 7.0 to 13.3%), 8.0% (95% CI: 5.7 to 11.0%), 9.0% (95% CI: 6.1 to 13.0%), respectively. CONCLUSIONS: We conclude that O. tsutsugamushi exposure in humans occurred at all sites analysed and could be the cause of illness in some cases. Though it was not the main cause of acute fever in these locations, it is still important to consider scrub typhus in cases not responding to beta-lactam antibiotics. Future seroprevalence surveys and testing for scrub typhus in acute febrile illness studies will be essential to understand its distribution and burden in Indonesia.
Assuntos
Ensaio de Imunoadsorção Enzimática , Imunoglobulina G , Imunoglobulina M , Orientia tsutsugamushi , Tifo por Ácaros , Tifo por Ácaros/epidemiologia , Tifo por Ácaros/diagnóstico , Humanos , Indonésia/epidemiologia , Estudos Transversais , Orientia tsutsugamushi/imunologia , Orientia tsutsugamushi/isolamento & purificação , Imunoglobulina M/sangue , Imunoglobulina G/sangue , Feminino , Masculino , Estudos Soroepidemiológicos , Anticorpos Antibacterianos/sangue , Adulto , Pessoa de Meia-IdadeRESUMO
In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. BACKGROUND: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. METHODS: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13/09/2021. RESULTS: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated. INTERPRETATION: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied patients.