496 research outputs found
Artemisinin resistant falciparum malaria in Myanmar: Artemisinin resistant malaria
No full textArtemisinin-based combination therapy (ACT) is first-line treatment for Plasmodium falciparum malaria globally but artemisinin resistance is now prevalent across Southeast Asia. Myanmar has the highest malaria burden in the region, and determining the prevalence of artemisinin resistance and current therapeutic efficacy of first-line antimalarial drugs is critical for both clinicians and policy makers planning malaria control and elimination programmes. The aim of this research was to study the geographical extent, prevalence, degree and optimum treatment of artemisinin-resistant falciparum malaria in Myanmar through a countrywide molecular survey and two multicentre clinical trials supported by parasitological and pharmacological investigations. In a molecular survey of clinical falciparum malaria cases carried out in 55 sites across 10 administrative regions and border sites in neighbouring countries 39% of cases (371/940) were associated with parasites carrying a kelch13 propeller mutation. Kelch13 mutation prevalence exceeded 10% in much of the east and north of the country and was 47% in an area 25 km from the border with India. In a trial conducted in central and northern Myanmar treatment efficacy of dihydroartemisinin-piperaquine (DP) was 100% but there was delayed parasite clearance associated with the kelch13 mutation F446I (median clearance half-life 4.7 hours, IQR, 3.7 to 6.2). In a randomised controlled trial of 3-days versus 5-days artemether-lumefantrine (AL) treatment efficacy was 100% (95%CI, 94.9-100) and 97% (95%CI, 90-99.7) respectively and the two arms showed equal clearance rates (measured by an ultrasensitive quantitative polymerase chain reaction assay, uqPCR)..There was no association between the presence of kelch13 propeller mutations and residual parasite density at day 21, measured using uqPCR. Gametocyte carriage rates were high reinforcing the need to implement single low-dose primaquine (0.25 mg/kg) with ACTs to kill gametocytes in this area of artemisinin resistance. In conclusion, artemisinin resistant falciparum malaria is widespread in Myanmar. While DP and AL remain efficacious, the partner drugs are vulnerable and if resistance develops treatment efficacy is likely to decline rapidly. Greater efforts are urgently needed to monitor treatment efficacy of first-line antimalarial drugs and develop alternative treatment regimens
Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies.
No full textBACKGROUND: Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. METHODS: A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. RESULTS: The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures. CONCLUSION: This paper has demonstrated the use of a comprehensive mathematical model to describe malaria transmission and the spread of drug resistance. The model is strongly linked to the empirical evidence obtained from extensive data available from various sources. This model can be a useful tool to inform the design of treatment policies, particularly at a time when ACT has been endorsed by WHO as first-line treatment for falciparum malaria worldwide
Malaria elimination modelling in the context of antimalarial drug resistance
No full textIntroduction Antimalarial resistance, particularly artemisinin resistance, is a major threat to P. falciparum malaria elimination efforts worldwide. Urgent intervention is required to tackle artemisinin resistance but field data on which to base planning of strategies are limited. The aims were to collect available field data and develop population level mathematical models of P. falciparum malaria treatment and artemisinin resistance in order to determine the optimal strategies for elimination of artemisinin resistant malaria in Cambodia and treatment of pre-hospital and severe malaria in Cambodia and Bangladesh. Methods Malaria incidence and parasite clearance data from Cambodia and Bangladesh were collected and analysed and modelling parameters derived. Population dynamic mathematical models of P. falciparum malaria were produced. Results The modelling demonstrated that elimination of artemisinin resistant P. falciparum malaria would be achievable in Cambodia in the context of artemisinin resistance using high coverages with ACT treatment, ideally combined with LLITNs and adjunctive single dose primaquine. Sustained efforts would be necessary to achieve elimination and effective surveillance is essential, both to identify the baseline malaria burden and to monitor parasite prevalence as interventions are implemented. A modelled policy change to rectal and intravenous artesunate in the context of pre-existing artemisinin resistance would not compromise the efficacy of ACT for malaria elimination. Conclusions By being developed rapidly in response to specific questions the models presented here are helping to inform planning efforts to combat artemisinin resistance. As further field data become available, their planned on-going development will produce increasingly realistic and informative models which can be expected to play a central role in planning efforts for years to come
Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial.
No full textBACKGROUND: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.
METHODS: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).
RESULTS: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.
CONCLUSIONS: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment
Scrub typhus in Indonesia
No full textScrub typhus is a neglected and understudied disease. In 1902, Schüffner first described scrub typhus in Indonesia. However, until today, data are lacking and we do not understand its public health significance yet. In this DPhil project, I aimed to (1) characterise scrub typhus epidemiology in Indonesia and its public health importance, and (2) address knowledge gaps in scrub typhus by optimising available data. I mapped and ranked the available evidence on scrub typhus in Indonesia based on the likelihood of sustaining infectious reservoirs. Despite limited data, it appears that scrub typhus does exist and is widespread within the Indonesian archipelago. North Sumatra has the highest number of data points. South Sumatra and Biak have the best evidence in sustaining infective vectors. Serosurvey of archived sera indicated active transmission of scrub typhus in Jambi, Denpasar, and Tabanan. However, the majority of areas in Indonesia did not have any data. To address this, a seroprevalence study to compare exposure to scrub typhus in rural and urban areas of North Sumatra was planned. Diagnosis seems to be the main challenge hindering scrub typhus research. I reviewed the evidence on the accuracy of scrub typhus point-of-care tests. I also performed a meta-analysis on the limited data. The available immunochromatography tests have good specificity – indicating the potential role for ruling in diagnosis. However, they suffer from relatively low sensitivity and are not widely available. A systematic review on scrub typhus treatment studies demonstrated heterogeneity in methods. The optimal treatment dose and duration for scrub typhus is still uncertain. There is an absence of consensus in treatment and research methodologies. There are still gaps in our knowledge on scrub typhus in Indonesia and globally. One way to improve awareness of scrub typhus is to recognise scrub typhus as a neglected tropical disease. Scrub typhus research is also influenced by economic and political factors. Stakeholder engagement and cooperation are therefore essential to fill these knowledge gaps
Community engagement for targeted malaria elimination in Lao PDR (Laos)
No full textThe emergence of artemisinin-resistant malaria in Southeast Asia has prompted malaria control programs to expedite efforts to eliminate malaria. One suggested approach is the mass administration of antimalarials (MDA) to entire target population regardless of malaria infection. MDA is one of the central components of Targeted Malaria Elimination (TME), an approach recently piloted in Laos. For MDA to be successful (leading to interruption of local malaria transmission), a high population coverage is critical. Among myriad factors, community engagement has been recognized as critical to promoting high coverage. The main aim of this study was to design, execute and assess a locally suitable community engagement strategy that can promote the uptake of and adherence to MDA. This study utilized a longitudinal mixed method approach. In addition to the local social and cultural factors, five main elements of community engagement that contributed to high population coverage were identified: 1. Stakeholder and authority engagement: a stepwise approach from central to the local level; 2. Local human resources: recruitment and training of local community members to execute TME; 3. Formative research: an exploration of the local social and cultural context to guide the community engagement; 4. Responsiveness: flexible and adaptable approach based on the demands and needs of the community and 5. Sharing control/leadership with the community: joint decision making with the community members. Various factors contributed to the high population coverage recorded in the Lao TME study (above 85%): community engagement to promote the concept of asymptomatic malaria and the rationale for MDA, baseline understanding of malaria as a health concern, perceptions that TME was worthwhile, provision of free primary health care, partnering of the research with local volunteers and authorities, building social relationship with community members and the cohesive nature of the communities that boosted the trust and participation in MDA.</p
Epidemiology and health burdens of antimicrobial resistant bacterial infection in Southeast Asia and impact of antibiotic use on patient survival
No full textAntimicrobial-resistance (AMR) is a global health concern. Data to support estimates of the AMR health burden are important to guide policy makers in developing appropriate interventions. The objective of this thesis is to improve the understanding of the epidemiology of AMR in low and middle-income countries (LMICs), where data is scarce.
A prospective surveillance study on hospital-acquired infection (HAI) was conducted to estimate excess mortality attributable to AMR infection in a LMIC. Evaluating all types of infections and seven priority bacteria, I estimated that 16.0% of deaths involving bacterial infections were attributable to AMR. This is higher than is observed in high-income countries (HICs).
One of the barriers in sharing AMR data in LMICs is a lack of expertise, time, and resources to analyse the data and write reports. I developed an open-access, offline, and easy-to-use application to fill in this gap. The tool was tested in seven hospitals in seven countries. AMR surveillance reports from those hospitals were shared on an open-access data repository platform and each has a digital object identifier that can be appropriately cited when re-used.
It is known that low blood culture usage can bias the estimates of health burden of AMR. However, the magnitude of this effect is largely unknown. I performed a retrospective study with bootstrap sampling to illustrate the potential magnitude of biases in the estimates of AMR prevalence and incidence rates due to low blood culture utilisation rates.
Finally, using a large retrospective data set, I applied a counterfactual framework to estimate the impact of delays in concordant antibiotic treatments. Attempts were made using observational data to emulate randomised controlled trials that are otherwise unethical to perform.
This thesis describes work which generated data, provided evidence, and created a new tool for quantifying the health burden of AMR infections in LMICs
Effect of delays in concordant antibiotic treatment on mortality in patients with hospital-acquired Acinetobacter species bacteremia: emulating a target randomized trial with a 13-year retrospective cohort
No full textDelays in treating bacteremias with antibiotics to which the causative organism is susceptible are expected to adversely affect patient outcomes. Quantifying the impact of such delays to concordant treatment is important for decision-making about interventions to reduce the delays and for quantifying the burden of disease due to antimicrobial resistance. There are, however, potentially important biases to be addressed, including immortal time bias. We aimed to estimate the impact of delays in appropriate antibiotic treatment of patients with Acinetobacter species hospital-acquired bacteremia in Thailand on 30-day mortality by emulating a target trial using retrospective cohort data from Sunpasitthiprasong Hospital in 2003–2015. For each day, we defined treatment as concordant if the isolated organism was susceptible to at least 1 antibiotic given. Among 1,203 patients with Acinetobacter species hospital-acquired bacteremia, 682 had 1 or more days of delays to concordant treatment. Surprisingly, crude 30-day mortality was lower in patients with delays of ≥3 days compared with those who had 1–2 days of delays. Accounting for confounders and immortal time bias resolved this paradox. Emulating a target trial, we found that these delays were associated with an absolute increase in expected 30-day mortality of 6.6% (95% confidence interval: 0.2, 13.0), from 33.8% to 40.4%
Simultaneous and enantiospecific quantification of primaquine and carboxyprimaquine in human plasma using liquid chromatography-tandem mass spectrometry
No full textBACKGROUND: The enantiomers of the 8-aminoquinoline anti-malarial primaquine have different pharmacological properties. Development of an analytical method for simultaneous quantification of the enantiomers of primaquine and its metabolite, carboxyprimaquine, will support clinical pharmacometric assessments. METHODS: A simple and sensitive method consisting of liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) was developed for simultaneous and enantiospecific determination of primaquine and its metabolite, carboxyprimaquine, in human plasma. Stable isotopes were used as internal standards to compensate for potential interference and matrix effects. Plasma samples (100 µL) were precipitated with 1% formic acid in acetonitrile followed by phospholipid removal solid phase extraction. Primaquine and carboxyprimaquine enantiomers were separated on a Chiralcel OD-3R (150 mm × 4.6 mm; I.D. 3 μm) column using a LC gradient mode. For separation of racemic primaquine and carboxyprimaquine, the LC method was modified and validated using a reverse phase column (Hypersil Gold 100 mm × 4.6 mm; I.D. 3 µm) and a mobile phase composed of 10 mM ammonium acetate buffer, pH 3.5 and acetonitrile in the isocratic mode. Method validation was performed according to regulatory guidelines. RESULTS: The calibration range was set to 0.571–260 ng/mL and 2.44–2,500 ng/mL for primaquine and carboxyprimaquine enantiomers, respectively, resulting in a correlation coefficient (r(2)) ≥ 0.0998 for all calibration curves. The intra- and inter-day assay precisions were < 10% and the accuracy was between 94.7 to 103% for all enantiomers of primaquine and carboxyprimaquine. The enantiospecific method was also modified and validated to quantify racemic primaquine and carboxyprimaquine, reducing the total run time from 30 to 8 min. The inter-, intra-day assay precision of the racemic quantification method was < 15%. The absolute recoveries of primaquine and carboxyprimaquine were between 70 and 80%. Stability was demonstrated for up to 2 years in − 80 °C. Both the enantiomeric and racemic LC–MS/MS methods were successfully implemented in pharmacokinetic studies in healthy volunteers. CONCLUSIONS: Simple, sensitive and accurate LC–MS/MS methods for the quantification of enantiomeric and racemic primaquine and carboxyprimaquine in human plasma were validated successfully and implemented in clinical routine drug analysis
- …
