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Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa

<jats:title>ABSTRACT</jats:title> <jats:p>When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 Congolese children with severe <jats:italic>falciparum</jats:italic> malaria to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg of body weight) followed 12 h later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested <jats:italic>in vivo</jats:italic> IC<jats:sub>50</jats:sub> and IC<jats:sub>90</jats:sub> values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC<jats:sub>50</jats:sub> and IC<jats:sub>90</jats:sub> was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively (<jats:italic>P</jats:italic> = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe <jats:italic>falciparum</jats:italic> malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.)</jats:p>

Development and validation of an in silico decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients

<jats:p>Most deaths from severe falciparum malaria occur within 24 hours of presentation to hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections Bayesian pharmacokinetic-pharmacodynamic modelling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% parasites within 24 hours (PC24≥99%) for standard (2.4 mg/kg i.v. artesunate at 0 and 12 hours) and simplified (4 mg/kg i.v. artesunate at 0 hours) regimens were 65% (52.5%-74.5%) versus 44% (25%-61.5%) for adults, 62% (51.5%-74.5%) versus 39% (20.5%-58.5%) for larger children (≥20 kg) and 60% (48.5%-70%) versus 36% (20%-53.5%) for smaller children (&lt;20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. Rapid clearance of parasites, where there is loss of ring stage sensitivity to artemisinin, in patients with severe falciparum malaria is compromised with the currently recommended and proposed simplified i.v. artesunate dosing regimens.</jats:p>

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.

Structure-switching aptamer sensors for the specific detection of piperaquine and mefloquine

<jats:p>Tracking antimalarial drug use and efficacy is essential for monitoring the current spread of antimalarial drug resistance. However, available methods for determining tablet quality and patient drug use are often inaccessible, requiring well-equipped laboratories capable of performing liquid chromatography–mass spectrometry (LC-MS). Here, we report the development of aptamer-based fluorescent sensors for the rapid, specific detection of the antimalarial compounds piperaquine and mefloquine—two slow-clearing partner drugs in current first-line artemisinin-based combination therapies (ACTs). Highly selective DNA aptamers were identified that bind piperaquine and mefloquine with dissociation constants (<jats:italic>K</jats:italic><jats:sub>d</jats:sub>’s) measured in the low nanomolar range via two independent methods. The aptamers were isolated from a library of single-stranded DNA molecules using a capture–systematic evolution of ligands by exponential enrichment (SELEX) technique and then adapted into structure-switching aptamer fluorescent sensors. Sensor performance was optimized for the detection of drug from human serum and crushed tablets, resulting in two sensing platforms. The patient sample platform was validated against an LC-MS standard drug detection method in samples from healthy volunteers and patients with malaria. This assay provides a rapid and inexpensive method for tracking antimalarial drug use and quality for the containment and study of parasite resistance, a major priority for malaria elimination campaigns. This sensor platform allows for flexibility of sample matrix and can be easily adapted to detect other small-molecule drugs.</jats:p>

Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria

<jats:title>ABSTRACT</jats:title> <jats:p>Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative PCR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with <jats:named-content content-type="genus-species">P. falciparum</jats:named-content> malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (<jats:italic>E</jats:italic><jats:sub>max</jats:sub>) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥10<jats:sup>2</jats:sup> per life cycle (38.8 h) with a duration of action of ≥2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.)</jats:p>

Theory of change: Drama and arts-based community engagement for malaria research and elimination in Cambodia

<ns3:p><ns3:bold>Background</ns3:bold>: Across the Greater Mekong Sub-region, malaria persists in isolated communities along international borders. Arts and drama have been used to reach to communities in Cambodia to engage them in malaria research, prevention and control. The “Village Drama Against Malaria” (VDAM) project was conducted in north eastern and western Cambodia: Stung Treng; Battambang and Pailin provinces during 2016 to 2019.  In total, VDAM reached 55 rural villages, 2,378 student participants and 43,502 audience members.</ns3:p><ns3:p> <ns3:bold>Methods</ns3:bold>: This article presents the results of two stakeholder-led evaluation workshops in which participants collaboratively developed theories of change to better understand the potential and actual impact of arts and drama-based activities on malaria in these communities. The workshops had a particular focus on identifying areas for monitoring and evaluation so that impact can be measured. Workshop participants included village malaria workers, community leaders, professional and student drama performers, and representatives from the local health authorities and the national malaria control programme.</ns3:p><ns3:p> <ns3:bold>Results</ns3:bold>: Five broad areas were identified as relevant for monitoring and evaluation: logistical and practical challenges; embeddedness and reach of engagement; health knowledge and confidence of young people; community-level malaria outcomes; impact on malaria. These areas align well with the monitoring and evaluation conducted to date and point to additional opportunities for data collection.</ns3:p><ns3:p> <ns3:bold>Conclusions</ns3:bold>: The findings from these workshops will inform future engagement strategies, for example, we may engage a smaller number of young people but over a longer period and more in-depth.</ns3:p>

Perspectives on public health interventions in the management of the COVID-19 pandemic in Thailand

<ns3:p> <h4>Background: </h4> Any government needs to react quickly to a pandemic and make decisions on healthcare interventions locally and internationally with little information regarding the perceptions of people and the reactions they may receive during the implementation of restrictions.</ns3:p><ns3:p> <h4>Methods: </h4> We report an anonymous online survey in Thailand conducted in May 2020 to assess public perceptions of three interventions in the Thai context: isolation, quarantine and social distancing. A total of 1,020 participants, of whom 52% were women, responded to the survey.</ns3:p><ns3:p> <h4>Results: </h4></ns3:bold>: Loss of income was the main concern among respondents (>80% for all provinces in Thailand). Traditional media and social media were important channels for communication during the pandemic. A total of 92% of respondents reported that they changed their social behaviour even before the implementation of government policy with 94% reporting they performed social distancing, 97% reported using personal protective equipment such as masks and 95% reported using sanitizer products.</ns3:p><ns3:p> <h4>Conclusions: </h4> This study showed a high level of compliance from individuals with government enforced or voluntarily controls such as quarantine, isolation and social distancing in Thailand. The findings from this study can be used to inform future government measures to control the pandemic and to shape communication strategies.</ns3:p>

Effect of delays in concordant antibiotic treatment on mortality in patients with hospital-acquired Acinetobacter spp. bacteremia in Thailand: a 13-year retrospective cohort

Targeted capture and sequencing of Orientia tsutsugamushi genomes from chiggers and humans.

Scrub typhus is a febrile disease caused by Orientia tsutsugamushi, transmitted by larval stage Trombiculid mites (chiggers), whose primary hosts are small mammals. The phylogenomics of O. tsutsugamushi in chiggers, small mammals and humans remains poorly understood. To combat the limitations imposed by the low relative quantities of pathogen DNA in typical O. tsutsugamushi clinical and ecological samples, along with the technical, safety and cost limitations of cell culture, a novel probe-based target enrichment sequencing protocol was developed. The method was designed to capture variation among conserved genes and facilitate phylogenomic analysis at the scale of population samples. A whole-genome amplification step was incorporated to enhance the efficiency of sequencing by reducing duplication rates. This resulted in on-target capture rates of up to 93% for a diverse set of human, chigger, and rodent samples, with the greatest success rate in samples with real-time PCR Ct values below 35. Analysis of the best-performing samples revealed phylogeographic clustering at local, provincial and international scales. Applying the methodology to a comprehensive set of samples could yield a more complete understanding of the ecology, genomic evolution and population structure of O. tsutsugamushi and other similarly challenging organisms, with potential benefits in the development of diagnostic tests and vaccines.

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years Results From the INTERBIO-21st Newborn Study

Guidelines should not pool evidence from uncomplicated and severe COVID-19.

Anti-malarial drug effects on parasite dynamics in vivax malaria

Improving Treatment and Outcomes for Melioidosis in Children, Northern Cambodia, 2009-2018.

We report trends in manifestations, treatment, and outcomes of 355 children with culture-confirmed melioidosis over 10 years at a pediatric hospital in northern Cambodia. Bacteremia and presentation with pneumonia were risk factors for death. A total of 39 children recovered after being given only oral antimicrobial drug treatment.

Chloroquine/ hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; protocol for a randomised, placebo-controlled prophylaxis study (COPCOV)

<ns3:p>There is no proven preventative therapy or vaccine against COVID-19. Theinfection has spread rapidly and there has already been a substantial adverse impact on the global economy. Healthcare workers have been affected disproportionately in the continuing pandemic. Significant infection rates in this critical group have resulted in a breakdown of health services in some countries. Chloroquine, and the closely related hydroxychloroquine, are safe and well tolerated medications which can be given for years without adverse effects. Chloroquine and hydroxychloroquine have significant antiviral activity against SARS-CoV-2, and despite the lack of benefit of hydroxychloroquine treatment in patients hospitalised with severe COVID-19, these drugs could still work in prevention. The emerging infection paradigm of an early viral peak, and late inflammation where there is benefit from corticosteroids. If these direct actiing antivirals are to work, they have the best chance given either early in infection and before infection occurs. We describe the study protocol for a multi-centre, multi-country randomised, double blind, placebo controlled trial to answer the question- can chloroquine/ hydroxychloroquine prevent COVID-19. 40,000 participants working in healthcare facilities or involved in the management of COVID-19 will be randomised 1:1 to receive chloroquine/ hydroxychloroquine or matched placebo as daily prophylaxis for three months. The primary objective is the prevention of symptomatic, virological or serologically proven coronavirus disease (COVID-19). The study could detect a 23% reduction from an incidence of 3% in the placebo group for either drug with 80% power. Secondary objectives are to determine if chloroquine/hydroxychloroquine prophylaxis attenuates severity, prevents asymptomaticCOVID-19 and symptomatic acute respiratory infections of another aetiology (non-SARS-CoV-2).</ns3:p>

Vaginal Microbiota and Cytokine Levels Predict Preterm Delivery in Asian Women

<jats:p>Preterm birth (PTB) is the most common cause of neonatal morbidity and mortality worldwide. Approximately half of PTBs is linked with microbial etiologies, including pathologic changes to the vaginal microbiota, which vary according to ethnicity. Globally more than 50% of PTBs occur in Asia, but studies of the vaginal microbiome and its association with pregnancy outcomes in Asian women are lacking. This study aimed to longitudinally analyzed the vaginal microbiome and cytokine environment of 18 Karen and Burman pregnant women who delivered preterm and 36 matched controls delivering at full term. Using 16S ribosomal RNA gene sequencing we identified a predictive vaginal microbiota signature for PTB that was detectable as early as the first trimester of pregnancy, characterized by higher levels of <jats:italic>Prevotella buccalis</jats:italic>, and lower levels of <jats:italic>Lactobacillus crispatus and Finegoldia</jats:italic>, accompanied by decreased levels of cytokines including IFNγ, IL-4, and TNFα. Differences in the vaginal microbial diversity and local vaginal immune environment were associated with greater risk of preterm birth. Our findings highlight new opportunities to predict PTB in Asian women in low-resource settings who are at highest risk of adverse outcomes from unexpected PTB, as well as in Burman/Karen ethnic minority groups in high-resource regions.</jats:p>

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.

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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Shigella</jats:italic> 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 <jats:italic>S. flexneri</jats:italic> and <jats:italic>S. sonnei</jats:italic>. We show that <jats:italic>S. sonnei</jats:italic> and each major <jats:italic>S. flexneri</jats:italic> 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 <jats:italic>S. sonnei</jats:italic> and the major <jats:italic>S. flexneri</jats:italic> 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 <jats:italic>Shigella</jats:italic> in Southeast Asia.</jats:p>

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera

A haemagglutination test for rapid detection of antibodies to SARS-CoV-2.

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.

The WHO guideline on drugs to prevent COVID-19: small numbers- big conclusions

<ns3:p>The World Health Organization living guideline on drugs to prevent COVID-19 has recently advised that ongoing trials evaluating hydroxychloroquine in chemoprophylaxis should stop. The WHO guideline cites “high certainty” evidence from randomised controlled trials (RCTs) that hydroxychloroquine prophylaxis does not reduce mortality and does not reduce hospital admission, and “moderate certainty” evidence of poor tolerability because of a significantly increased rate of adverse events leading to drug discontinuation. Yet there is no such evidence. In the three pre-exposure chemoprophylaxis RCTs evaluated in the guideline there were no deaths and only two COVID-19-related hospital admissions, and there was a mistake in the analysis of the number of discontinuations (after correction there is no longer a statistically significant difference between those taking the drug and the controls). Guidelines on the prevention and treatment of COVID-19 should be based on sufficient verified evidence, understanding of the disease process, sound statistical analysis and interpretation, and an appreciation of global needs.</ns3:p>