Biomedical subjects

Elizabeth A Ashley

Publications and source records attributed to Elizabeth A Ashley.

13 recordsLinked to original sources

PubMed2025

Prospective characterisation of drug-resistant bloodstream infections in Africa and Asia (ACORN2): a surveillance network assessment.

BACKGROUND: Antimicrobial resistance (AMR) is a major global health threat, but there is scarcity of laboratory surveillance data linked to clinical information to determine burden and inform interventions, especially from low-income and middle-income countries. The ACORN2 study sought to address this through prospective case-based surveillance in 19 hospitals across Africa and Asia to characterise drug-resistant infections by origin, clinical syndrome, patient age, outcome, and geographical location. METHODS: Patients were enrolled on selected wards and clinical data were collected daily for community-acquired infections (CAIs). Point prevalence surveys for hospital-acquired infections (HAIs) were conducted weekly. Mortality was assessed at discharge and after 28 days. Linked microbiology data were extracted from local laboratory databases. Primary descriptive analyses focused on WHO Global Antimicrobial Resistance and Use Surveillance System pathogen (target organism) bloodstream infections (BSIs). Comparisons were adjusted for clustering by site using random effects models. FINDINGS: Over 31 months, 41 907 infections were characterised from 41 032 admissions. Two-thirds were children (19 351; 47·2%) or neonates (6649; 16·2%). There were marked differences in pathogen incidence and antibiotic resistance when clinical infections were stratified by patient age category and infection origin (CAI/HAI). The highest rates of target organism AMR BSI were third-generation cephalosporin-resistant (3GC-R) Escherichia coli (718·56/100 000 blood cultured infection episodes), meticillin-resistant Staphylococcus aureus (586·89/100 000 blood cultured infection episodes), and 3GC-R Klebsiella pneumoniae (364·92/100 000 blood cultured infection episodes). In-hospital mortality was 13·1% (166/1265) in patients with target organism BSI versus 6·2% (1357/21 845) in those with negative blood cultures, p<0·0001. INTERPRETATION: ACORN2 has shown practical implementation of collecting linked clinical-laboratory AMR data in low-income and middle-income countries and identified a significant burden of WHO GLASS BSI. Adoption of the ACORN2 approach at scale might enhance use of diagnostic microbiology and improve the volume of clinical data included in national and global AMR surveillance datasets. FUNDING: Wellcome.

Humans↗

PubMed2025

Factors associated with positive blood cultures in children in nine African and Asian countries: the ACORN2 surveillance network.

BACKGROUND: Blood culture (BC) in children has relatively low diagnostic yield and high contamination rates, limiting cost-effectiveness. We aimed to determine readily available baseline characteristics to identify hospitalised children with a likelihood of higher diagnostic yield in low- and middle-income countries. METHODS: We used data from ACORN2, a prospective clinical surveillance network including 19 hospitals across Africa and Asia. We included participants <18 years, hospitalised for a suspected infection, prescribed parenteral antibiotics and with a BC sample. Sociodemographic and clinical data were recorded for each infection episode and linked to routine microbiology data. We described true pathogen (non-contaminant) BC positivity proportion and performed mixed-effects logistic regression, with study site and patient as the random effect, to identify factors associated with BC positivity. RESULTS: Of the 26 407 paediatric infection episodes, 17 815 (67%) had a BC sample and 15 384 were included in the analysis. BC results were: true pathogens in 689 (4.5%), contaminants in 1399 (9%) and uncertain pathogens in 143 (0.9%). In the multivariable model, factors associated with a positive BC were age (29 days-12-month-olds OR 1.33, 95% CI 1.06 to 1.66 and 5-18 year-olds OR 1.62, 95% CI 1.30 to 2.01 vs 1-4 year-olds), number of clinical severity signs (OR 1.29, 95% CI 1.18 to 1.40 per one sign) and hospital acquired infection (OR 3.05, 95% CI 2.30 to 4.06 vs community-acquired). Suspected diagnosis of sepsis (OR 2.09, 95% CI 1.67 to 2.61), gastrointestinal/abdominal (OR 2.36, 95% CI 1.78 to 3.13), skin and soft tissue or bone (OR 3.64, 95% CI 2.57 to 5.14) and genitourinary infection (OR 2.22, 95% CI 1.39 to 3.56) were more likely to have a positive BC, compared with respiratory infections. CONCLUSION: We confirmed the low BC yield among hospitalised children. We identified groups for which diagnostic stewardship efforts to increase BC uptake should be prioritised and others in which it could be limited in times of financial or logistic constraints.

Humans↗

PubMed2006

Intrahost selection of Plasmodium falciparum pfmdr1 alleles after antimalarial treatment on the northwestern border of Thailand.

BACKGROUND: Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. METHODS: In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. RESULTS: Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P<.001). CONCLUSIONS: Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites.

Alleles↗

PubMed2006

The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria.

OBJECTIVE: To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. METHODS: Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. RESULTS: The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. CONCLUSION: Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.

Adolescent↗

PubMed2006

Toxic brainstem encephalopathy after artemisinin treatment for breast cancer.

Explore the source record for details and available documents.

Adult↗

PubMed2006

An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand.

BACKGROUND: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. METHODS: On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. RESULTS: The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. CONCLUSION: This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

Adolescent↗

PubMed2006

Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria.

A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

Adolescent↗

PubMed2006

Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak Malaria Initiative.

BACKGROUND: Early diagnosis and treatment with artesunate-mefloquine combination therapy (MAS) have reduced the transmission of falciparum malaria dramatically and halted the progression of mefloquine resistance in camps for displaced persons along the Thai-Burmese border, an area of low and seasonal transmission of multidrug-resistant Plasmodium falciparum. We extended the same combination drug strategy to all other communities (estimated population 450,000) living in five border districts of Tak province in northwestern Thailand. METHODS AND FINDINGS: Existing health structures were reinforced. Village volunteers were trained to use rapid diagnostic tests and to treat positive cases with MAS. Cases of malaria, hospitalizations, and malaria-related deaths were recorded in the 6 y before, during, and after the Tak Malaria Initiative (TMI) intervention. Cross-sectional surveys were conducted before and during the TMI period. P. falciparum malaria cases fell by 34% (95% confidence interval [CI], 33.5-34.4) and hospitalisations for falciparum malaria fell by 39% (95% CI, 37.0-39.9) during the TMI period, while hospitalisations for P. vivax malaria remained constant. There were 32 deaths attributed to malaria during, and 22 after the TMI, a 51.5% (95% CI, 39.0-63.9) reduction compared to the average of the previous 3 y. Cross-sectional surveys indicated that P. vivax had become the predominant species in Thai villages, but not in populations living on the Myanmar side of the border. In the displaced persons population, where the original deployment took place 7 y before the TMI, the transmission of P. falciparum continued to be suppressed, the incidence of falciparum malaria remained low, and the in vivo efficacy of the 3-d MAS remained high. CONCLUSIONS: In the remote malarious north western border area of Thailand, the early detection of malaria by trained village volunteers, using rapid diagnostic tests and treatment with mefloquine-artesunate was feasible and reduced the morbidity and mortality of multidrug-resistant P. falciparum.

Adult↗

PubMed2005

A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand.

BACKGROUND: The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. METHODS: The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. RESULTS: In 2001-2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. CONCLUSION: Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.

Adolescent↗

PubMed2005

A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy.

BACKGROUND: There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum. METHODS: We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP). RESULTS: Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year. CONCLUSION: AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

Adolescent↗

PubMed2005

A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria.

BACKGROUND: Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness. METHODS: In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3). RESULTS: A total of 499 patients were included in the study. Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 (P=.008 and P=.03, respectively). All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group (P=.05 vs. the MAS3 group). CONCLUSIONS: A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.

Adolescent↗

PubMed2005

Artemisinin-based combinations.

PURPOSE OF REVIEW: Artemisinin-based combination treatments have been the mainstay of treatment for falciparum malaria in Southeast Asia for more than 10 years and are now increasingly recommended as first-line treatment throughout the rest of the world. RECENT FINDINGS: A large multicentre randomised trial conducted in East Asia has shown a 35% reduction in mortality from severe malaria following treatment with parenteral artesunate compared with quinine. There is increasing evidence that artemisinin-based combination treatments are safe and rapidly effective. Artemether-lumefantrine (six doses) has been shown to be very effective in large trials reported from Uganda and Tanzania. A once daily three-dose treatment of dihydroartemisinin piperaquine, a newer fixed combination, was a highly efficacious and well tolerated treatment for multi-drug resistant falciparum malaria in Southeast Asia. SUMMARY: Early diagnosis and treatment of uncomplicated malaria with effective drugs remains a priority as part of a comprehensive malaria control strategy. Artemisinin-based combination treatments have consistently been shown to be highly effective and safe. The challenge is to make them accessible in tropical countries.

Adult↗

PubMed2004

Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand.

BACKGROUND: Dihydroartemisinin-piperaquine (DP) is a new and relatively inexpensive artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroartemisinin (DHA), which is >40% lower than the level in most artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria. METHODS: In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional artemisinin derivative (12 mg/kg; DP+) and with mefloquine plus artesunate (MAS3). RESULTS: A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% (95% CI, 92.6%-99.7%) in the DP group, 98.3% (95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P=.2). Adverse events were few, with an excess of mild abdominal pain in the DP group. CONCLUSIONS: The current dosage of DP (6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA.

Adolescent↗