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1.
Antimicrob Agents Chemother ; 64(3)2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-31907183

RESUMEN

Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.).

2.
Malar J ; 18(1): 252, 2019 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-31349834

RESUMEN

BACKGROUND: Large-scale surveillance of molecular markers of anti-malarial drug resistance is an attractive method of resistance monitoring, to complement therapeutic efficacy studies in settings where the latter are logistically challenging. METHODS: Between 2014 and 2017, this study sampled malaria rapid diagnostic tests (RDTs), used in routine clinical care, from two health centres in Bissau, Guinea-Bissau. In order to obtain epidemiological insights, RDTs were collected together with patient data on age and sex. A subset of positive RDTs from one of the two sites (n = 2184) were tested for Plasmodium DNA content. Those testing positive for Plasmodium DNA by PCR (n = 1390) were used for library preparation, custom designed dual indexing and next generation Miseq targeted sequencing of Plasmodium falciparum genes pfcrt, pfmdr1, pfdhfr, pfdhps and pfk13. RESULTS: The study found a high frequency of the pfmdr1 codon 86N at 88-97%, a significant decrease of the pfcrt wildtype CVMNK haplotype and elevated levels of the pfdhfr/pfdhps quadruple mutant ranging from 33 to 51% between 2014 and 2017. No polymorphisms indicating artemisinin tolerance were discovered. The demographic data indicate a large proportion of young adults (66%, interquartile range 11-28 years) presenting with P. falciparum infections. While a total of 5532 gene fragments were successfully analysed on a single Illumina Miseq flow cell, PCR-positivity from the library preparation varied considerably from 13 to 87% for different amplicons. Furthermore, pre-screening of samples for Plasmodium DNA content proved necessary prior to library preparation. CONCLUSIONS: This study serves as a proof of concept for using leftover clinical material (used RDTs) for large-scale molecular surveillance, encompassing the inherent complications regarding to methodology and analysis when doing so. Factors such as RDT storage prior to DNA extraction and parasitaemia of the infection are likely to have an effect on whether or not parasite DNA can be successfully analysed, and are considered part of the reason the data yield is suboptimal. However, given the necessity of molecular surveillance of anti-malarial resistance in settings where poor infrastructure, poor economy, lack of educated staff and even surges of political instability remain major obstacles to performing clinical studies, obtaining the necessary data from used RDTs, despite suboptimal output, becomes a feasible, affordable and hence a justifiable method.


Asunto(s)
Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Monitoreo Epidemiológico , Malaria Falciparum/diagnóstico , Plasmodium falciparum/genética , Prueba de Estudio Conceptual , Adolescente , Adulto , Niño , Preescolar , Femenino , Guinea Bissau , Humanos , Lactante , Recién Nacido , Masculino , Adulto Joven
3.
Int J Microbiol ; 2019: 7395127, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31354831

RESUMEN

Background: Patients with recurrent Clostridium difficile infections (CDIs) constitute an increasing treatment problem. Fecal microbiota transplantation (FMT) has shown promising results of treating recurrent CDI, where treatment with antibiotics fails repeatedly. Our study describes retrospective cohort treated with FMT at two major hospitals in Stockholm. Methods: Medical records of all patients with recurrent CDI treated with FMT during the period 2013-2017 were reviewed. We evaluated cure of CDI-related diarrhea without relapse 10 weeks after FMT. Results: 47 patients were included. One treatment cured 25 patients (53%), and more than one treatment cured 32 patients (68%). Treatment outcome did not vary significantly with treatment with fresh donor feces or frozen fecal culture, days of use of antibiotics or days of hospitalization prior to CDI, and renal function or time from the first CDI to therapy. Treatment failure was associated with a significantly lower Karnofsky performance status score (70 points vs 90, p=0.02). Conclusion: Fecal instillation, for the treatment of relapsing CDI, is a promising approach, with 68% success rate reported in this study. The success rate of FMT is high, regardless of multiple comorbidities, extended use of antibiotics, or long time hospitalization. Although generally FMT is performed with fresh donor feces, our data show that the usage of frozen fecal culture could be an effective treatment alternative in recurrent CDI.

4.
Artículo en Inglés | MEDLINE | ID: mdl-31901492

RESUMEN

OBJECTIVE: To evaluate the effectiveness and tolerability of secnidazole combined with high-dose mebendazole for treatment of 5-nitroimidazole resistant giardiasis. METHOD: Adults with microscopically verified Giardia intestinalis monoinfection attending a secondary level hospital in Matanzas City, Cuba were prospectively included into a cohort. A recently introduced treatment ladder consisting of metronidazole as first line, followed by secnidazole, tinidazole, secnidazole plus mebendazole and quinacrine as 2nd to 5th line treatment was used. Adverse events and treatment success were determined by questioning and microscopy on concentrated stool samples, respectively on days 3, 5 and 7 after end of treatment. If G. intestinalis were detected on day 3, 5 or 7 the infection was classified as refractory and no further microscopy was done. RESULTS: 456 patients were included. Metronidazole, 500 mg three times daily for 5 days, cured 248/456 (54%) patients. A single two gram secnidazole dose as second line treatment cured 50/208 (24%) patients. A single two gram tinidazole dose as third line treatment cured 43/158 (27%) patients. Three rounds of 5-nitroimidazole therapy thus cured 341/456 (75%) patients. Secnidazole plus mebendazole (200 mg every 8 hours for 3 days) cured 100/115 (87%) of nitroimidazole refractory infections. Quinacrine cured the remaining 15 patients. All treatments were well tolerated. CONCLUSIONS: 5-Nitroimidazole refractory giardiasis was common indicating that an alternative first line treatment may be needed. Retreatment of metronidazole refractory giardiasis with an alternative 5-nitroimidazole was suboptimal indicating cross-resistance. Mebendazole plus secnidazole were well tolerated and effective for the treatment of 5-nitroimidazole refractory G. intestinalis infection in this setting.

5.
PLoS Med ; 15(6): e1002579, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29894518

RESUMEN

BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.


Asunto(s)
Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Combinación Arteméter y Lumefantrina/farmacología , Combinación Arteméter y Lumefantrina/uso terapéutico , Antimaláricos/farmacocinética , Combinación Arteméter y Lumefantrina/farmacocinética , Preescolar , Relación Dosis-Respuesta a Droga , Etanolaminas/metabolismo , Etanolaminas/farmacocinética , Etanolaminas/farmacología , Femenino , Fluorenos/metabolismo , Fluorenos/farmacocinética , Fluorenos/farmacología , Humanos , Lactante , Recién Nacido , Malaria Falciparum/tratamiento farmacológico , Masculino , Modelos Químicos , Embarazo
6.
Malar J ; 17(1): 91, 2018 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-29471822

RESUMEN

BACKGROUND: Plasmodium falciparum malaria remains a major health burden and genomic research represents one of the necessary approaches for continued progress towards malaria control and elimination. Sample acquisition for this purpose is troublesome, with the majority of malaria-infected individuals living in rural areas, away from main infrastructure and the electrical grid. The aim of this study was to describe a low-tech procedure to sample P. falciparum specimens for direct whole genome sequencing (WGS), without use of electricity and cold-chain. METHODS: Venous blood samples were collected from malaria patients in Bandim, Guinea-Bissau and leukocyte-depleted using Plasmodipur filters, the enriched parasite sample was spotted on Whatman paper and dried. The samples were stored at ambient temperatures and subsequently used for DNA-extraction. Ratios of parasite:human content of the extracted DNA was assessed by qPCR, and five samples with varying parasitaemia, were sequenced. Sequencing data were used to analyse the sample content, as well as sample coverage and depth as compared to the 3d7 reference genome. RESULTS: qPCR revealed that 73% of the 199 samples were applicable for WGS, as defined by a minimum ratio of parasite:human DNA of 2:1. WGS revealed an even distribution of sequence data across the 3d7 reference genome, regardless of parasitaemia. The acquired read depths varied from 16 to 99×, and coverage varied from 87.5 to 98.9% of the 3d7 reference genome. SNP-analysis of six genes, for which amplicon sequencing has been performed previously, confirmed the reliability of the WGS-data. CONCLUSION: This study describes a simple filter paper based protocol for sampling P. falciparum from malaria patients for subsequent direct WGS, enabling acquisition of samples in remote settings with no access to electricity.


Asunto(s)
Desecación , Eritrocitos/parasitología , Plasmodium falciparum/genética , Manejo de Especímenes/métodos , Secuenciación Completa del Genoma/métodos , ADN Protozoario/química , ADN Protozoario/genética , ADN Protozoario/aislamiento & purificación , Guinea Bissau , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Temperatura Ambiental
7.
Lakartidningen ; 1142017 06 16.
Artículo en Sueco | MEDLINE | ID: mdl-28632298

RESUMEN

Rapid improvement of tick-borne encephalitis after treatment with corticosteroids Tick-borne encephalitis (TBE) is a viral disease transmitted by ticks. The virus is divided into three subtypes named Western, Siberian and Far Eastern TBE virus (TBEV). Western TBEV is endemic in parts of Europe and Sweden and typically causes a biphasic illness with influenza-like symptoms followed by neurological symptoms ranging from mild meningitis to severe meningoencephalitis and death. Despite an effective vaccine, TBE is increasing in Sweden and Europe. The pathogenesis of TBE is poorly understood; direct infection of neurons as well as immunological reactions mediated by T-cells have been implicated. In some endemic areas, such as Lithuania, patients with TBE are given corticosteroids based on the clinical experience that it results in rapid improvement. However, existing retrospective studies have failed to show beneficial effects of corticosteroids compared to symptomatic treatment in patients with TBE. This case report describes how an elderly man with meningoencephalitis and cranial nerve palsy due to TBE  rapidly improved after administration of high dose corticosteroids.


Asunto(s)
Encefalitis Transmitida por Garrapatas/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Hemisuccinato de Metilprednisolona/uso terapéutico , Anciano , Encefalitis Transmitida por Garrapatas/diagnóstico , Medicina Basada en la Evidencia , Humanos , Masculino
8.
Sci Rep ; 7(1): 2398, 2017 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-28546554

RESUMEN

Genetic polymorphisms in P. falciparum can be used to indicate the parasite's susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custom designed dual indexing and Miseq sequencing for high throughput SNP-profiling of 457 malaria infections from Guinea-Bissau, at the cost of 10 USD per sample. By amplifying and sequencing 15 genetic fragments, we cover 20 resistance-conferring SNPs occurring in pfcrt, pfmdr1, pfdhfr, pfdhps, as well as the entire length of pfK13, and the mitochondrial barcode for parasite origin. SNPs of interest were sequenced with an average depth of 2,043 reads, and bases were called for the various SNP-positions with a p-value below 0.05, for 89.8-100% of samples. The SNP data indicates that artemisinin resistance-conferring SNPs in pfK13 are absent from the studied area of Guinea-Bissau, while the pfmdr1 86 N allele is found at a high prevalence. The mitochondrial barcodes are unanimous and accommodate a West African origin of the parasites. With this method, very reliable high throughput surveillance of antimalarial drug resistance becomes more affordable than ever before.


Asunto(s)
Antimaláricos/farmacología , Resistencia a Medicamentos , Secuenciación de Nucleótidos de Alto Rendimiento , Malaria Falciparum/parasitología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Antimaláricos/uso terapéutico , ADN Protozoario/genética , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Mutación , Polimorfismo de Nucleótido Simple , Prevalencia , Proteínas Protozoarias/genética , Tetrahidrofolato Deshidrogenasa/genética
9.
Infect Dis (Lond) ; 49(9): 655-663, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28446068

RESUMEN

BACKGROUND: In developing countries, diarrhoea is the most common cause of death for children under five years of age, with Giardia lamblia, Cryptosporidium and Entamoeba histolytica as the most frequent pathogenic parasites. Traditional microscopy for stool parasites has poor sensitivity and specificity, while new molecular methods may provide more accurate diagnostics. In poor regions with sample storage hampered by uncertain electricity supply, research would benefit from a method capable of analysing dried stools. METHODS: A real-time multiplex PCR method with internal inhibition control was developed for detecting Giardia lamblia, Cryptosporidium hominis/parvum and Entamoeba histolytica directly from stool specimens. Applicability to dried samples was checked by comparing with fresh ones in a small test material. Finally, the assay was applied to dried specimens collected from Guinea-Bissauan children with diarrhoea. RESULTS: The PCR's analytical sensitivity limit was 0.1 ng/ml for G. lamblia DNA, 0.01 ng/ml for E. histolytica DNA and 0.1 ng/ml for Cryptosporidium sp. In the test material, the assay performed similarly with fresh and dried stools. Of the 52 Guinea-Bissauan samples, local microscopy revealed a parasite in 15%, while PCR detected 62% positive for at least one parasite: 44% of the dried samples had Giardia, 23% Cryptosporidium and 0% E. histolytica. CONCLUSIONS: Our new multiplex real-time PCR for protozoa presents a sensitive method applicable to dried samples. As proof of concept, it worked well on stools collected from Guinea-Bissauan children with diarrhoea. It provides an epidemiological tool for analysing dried specimens from regions poor in resources.


Asunto(s)
Cryptosporidium/aislamiento & purificación , Diarrea/parasitología , Entamoeba histolytica/aislamiento & purificación , Heces/parasitología , Giardia lamblia/aislamiento & purificación , Reacción en Cadena de la Polimerasa Multiplex/métodos , Preescolar , Criptosporidiosis/epidemiología , Criptosporidiosis/parasitología , Cryptosporidium/genética , Cartilla de ADN , Sondas de ADN , Entamoeba histolytica/genética , Entamebiasis/epidemiología , Entamebiasis/parasitología , Femenino , Giardia lamblia/genética , Giardiasis/epidemiología , Giardiasis/parasitología , Guinea/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sensibilidad y Especificidad , Viaje
10.
Malar J ; 16(1): 113, 2017 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-28288632

RESUMEN

BACKGROUND: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naïve Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P. falciparum resistance after 2 years of treatment are reported. METHODS: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods. RESULTS: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069ACT→ACG synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001). CONCLUSIONS: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069ACG and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.


Asunto(s)
Antimaláricos/administración & dosificación , Cloroquina/administración & dosificación , Resistencia a Medicamentos , Plasmodium falciparum/efectos de los fármacos , Polimorfismo Genético , Proguanil/análogos & derivados , Pirimetamina/administración & dosificación , Niño , Preescolar , Humanos , Liberia , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/genética , Reacción en Cadena de la Polimerasa , Proguanil/administración & dosificación , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Selección Genética
11.
PLoS One ; 11(9): e0161495, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27649561

RESUMEN

BACKGROUND: Artemether-lumefantrine (AL) was introduced for treatment of uncomplicated malaria in Guinea-Bissau in 2008. Malaria then resurged and recurrent malaria after treatment with AL and stock-outs of AL were common. This study therefore aimed to assess the efficacy of AL and identify an alternative second line antimalarial. Dihydroartemisinin-piperaquine (DP) was chosen as it has been shown to be safe and efficacious and to reduce the incidence of recurrent malaria. METHODS AND FINDINGS: In a multicentre randomised open-label non-inferiority clinical trial, AL or DP were given over 3 days to children aged 6 months-15 years with uncomplicated P. falciparum mono-infection. Intake was observed and AL was given with milk. Children were seen on days 0, 1, 2 and 3 and then weekly days 7-42. Recurring P. falciparum were classified as recrudescence or new infections by genotyping. Between November 2012 and July 2015, 312 children were randomised to AL (n = 155) or DP (n = 157). The day 42 PCR adjusted per protocol adequate clinical and parasitological responses were 95% and 100% in the AL and DP groups respectively, Mantel-Haenszel weighted odds ratio (OR) 0.22 (95% CI 0-0.68), p = 0.022. In a modified intention to treat analysis in which treatment failures day 0 and reinfections were also considered as treatment failures adequate clinical and parasitological responses were 94% and 97% (OR 0.42 [95% CI, 0.13-1.38], p = 0.15). Parasite clearance and symptom resolution were similar with both treatments. CONCLUSIONS: Both treatments achieved the WHO recommended efficacy for antimalarials about to be adopted as policy. DP was not inferior to AL for treatment of uncomplicated P. falciparum malaria in Guinea-Bissau. TRIAL REGISTRATION: ClinicalTrials.gov NTC01704508.


Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Etanolaminas/uso terapéutico , Fluorenos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Quinolinas/uso terapéutico , Arteméter , Niño , Guinea Bissau/epidemiología , Humanos , Lumefantrina , Malaria Falciparum/epidemiología , Resultado del Tratamiento
12.
J Infect Dis ; 213(8): 1315-21, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26656124

RESUMEN

BACKGROUND: Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. METHODS: Standard or double-dose chloroquine was given to 892 children aged <15 years with uncomplicated malaria during 3 clinical trials (2001-2008) with ≥ 35 days follow-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (<5, 5-9, and 10-14 years) because concentrations increase with age when chloroquine is prescribed according to body weight. RESULTS: Adequate clinical and parasitological responses were 14%, 38%, and 39% after standard-dose and 66%, 84%, and 91% after double-dose chloroquine in children aged <5, 5-9, and 10-14 years, respectively, and infected with P. falciparum genotypes conferring chloroquine resistance (n = 195, P < .001). In parallel, median chloroquine concentrations were 471, 688, and 809 nmol/L for standard-dose and 1040, 1494, and 1585 nmol/L for double-dose chloroquine. CONCLUSIONS: Chloroquine resistance is dose dependent and can be overcome by higher, still well-tolerated doses.


Asunto(s)
Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Cloroquina/administración & dosificación , Cloroquina/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Niño , Preescolar , Cloroquina/farmacología , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Proteínas de Transporte de Membrana/genética , Carga de Parásitos , Plasmodium falciparum/genética , Proteínas Protozoarias/genética
13.
Microb Cell ; 2(2): 57-58, 2015 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-28357276

RESUMEN

The antimalarial drug chloroquine (CQ) has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of 'outdated' drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD) pathway may be exploited through the reformulation of CQ to address this need.

14.
Lancet Infect Dis ; 15(1): 55-64, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25477022

RESUMEN

BACKGROUND: Travel is important in the acquisition and dissemination of infection. We aimed to assess European surveillance data for travel-related illness to profile imported infections, track trends, identify risk groups, and assess the usefulness of pre-travel advice. METHODS: We analysed travel-associated morbidity in ill travellers presenting at EuroTravNet sites during the 5-year period of 2008-12. We calculated proportionate morbidity per 1000 ill travellers and made comparisons over time and between subgroups. We did 5-year trend analyses (2008-12) by testing differences in proportions between subgroups using Pearson's χ(2) test. We assessed the effect of the pre-travel consultation on infection acquisition and outcome by use of proportionate morbidity ratios. FINDINGS: The top diagnoses in 32 136 patients, ranked by proportionate morbidity, were malaria and acute diarrhoea, both with high proportionate morbidity (>60). Dengue, giardiasis, and insect bites had high proportionate morbidity (>30) as well. 5-year analyses showed increases in vector borne infections with significant peaks in 2010; examples were increased Plasmodium falciparum malaria (χ(2)=37·57, p<0·001); increased dengue fever (χ(2)=135·9, p<0·001); and a widening geographic range of acquisition of chikungunya fever. The proportionate morbidity of dengue increased from 22 in 2008 to 36 in 2012. Five dengue cases acquired in Europe contributed to this increase. Dermatological diagnoses increased from 851 in 2008 to 1102 in 2012, especially insect bites and animal-related injuries. Respiratory infection trends were dominated by the influenza H1N1 pandemic in 2009. Illness acquired in Europe accounted for 1794 (6%) of all 32 136 cases-mainly, gastrointestinal (634) and respiratory (357) infections. Migration within Europe was associated with more serious infection such as hepatitis C, tuberculosis, hepatitis B, and HIV/AIDS. Pre-travel consultation was associated with significantly lower proportionate morbidity ratios for P falciparum malaria and also for acute hepatitis and HIV/AIDS. INTERPRETATION: The pattern of travel-related infections presenting in Europe is complex. Trend analyses can inform on emerging infection threats. Pre-travel consultation is associated with reduced malaria proportionate morbidity ratios and less severe illness. These findings support the importance and effectiveness of pre-travel advice on malaria prevention, but cast doubt on the effectiveness of current strategies to prevent travel-related diarrhoea. FUNDING: European Centre for Disease Prevention and Control, University Hospital Institute Méditerranée Infection, US Centers for Disease Control and Prevention, and the International Society of Travel Medicine.


Asunto(s)
Control de Enfermedades Transmisibles/métodos , Enfermedades Transmisibles/epidemiología , Derivación y Consulta/estadística & datos numéricos , Viaje , Adulto , Animales , Monitoreo Epidemiológico , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad
15.
Antimicrob Agents Chemother ; 59(2): 872-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25421474

RESUMEN

In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) children<15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P<0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76+pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P=0.001). The pfmdr1 86+184 NF frequency increased from 39% to 66% (from 2003 to 2011; P=0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P<0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).


Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Etanolaminas/uso terapéutico , Fluorenos/uso terapéutico , Quinina/uso terapéutico , Adolescente , Antimaláricos/efectos adversos , Niño , Preescolar , Cloroquina/efectos adversos , Etanolaminas/efectos adversos , Femenino , Fluorenos/efectos adversos , Guinea Bissau , Humanos , Lumefantrina , Malaria Falciparum/tratamiento farmacológico , Masculino , Quinina/efectos adversos
16.
PLoS One ; 9(7): e101167, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24984039

RESUMEN

INTRODUCTION: As Plasmodium falciparum prevalence decreases in many parts of Sub-Saharan Africa, so does immunity resulting in larger at risk populations and increased risk of malaria resurgence. In Bissau, malaria prevalence decreased from ∼50% to 3% between 1995 and 2003. The epidemiological characteristics of P. falciparum malaria within Bandim health and demographic surveillance site (population ∼100,000) between 1995 and 2012 are described. METHODS AND FINDINGS: The population was determined by census. 3603 children aged <15 years that were enrolled in clinical trials at the Bandim health centre (1995-2012) were considered incident cases. The mean annual malaria incidence per thousand children in 1995-1997, 1999-2003, 2007, 2011, 2012 were as follows; age <5 years 22→29→4→9→3, age 5-9 years 15→28→4→33→12, age 10-14 years 9→15→1→45→19. There were 4 campaigns (2003-2010) to increase use of insecticide treated bed nets (ITN) amongst children <5 years. An efficacious high-dose chloroquine treatment regime was routinely used until artemisinin based combination therapy (ACT) was introduced in 2008. Long lasting insecticide treated bed nets (LLIN) were distributed in 2011. By 2012 there was 1 net per 2 people and 97% usage. All-cause mortality decreased from post-war peaks in 1999 until 2012 in all age groups and was not negatively affected by malaria resurgence. CONCLUSION: The cause of decreasing malaria incidence (1995-2007) was probably multifactorial and coincident with the use of an efficacious high-dose chloroquine treatment regime. Decreasing malaria prevalence created a susceptible group of older children in which malaria resurged, highlighting the need to include all age groups in malaria interventions. ACT did not hinder malaria resurgence. Mass distribution of LLINs probably curtailed malaria epidemics. All-cause mortality was not negatively affected by malaria resurgence.


Asunto(s)
Malaria Falciparum/transmisión , Adolescente , Niño , Preescolar , Femenino , Guinea Bissau/epidemiología , Humanos , Malaria Falciparum/epidemiología , Malaria Falciparum/mortalidad , Masculino , Prevalencia , Lluvia
17.
Malar J ; 13: 182, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24885535

RESUMEN

BACKGROUND: Since 2011, artesunate + sulphadoxine-pyrimethamine (ASP), instead of chloroquine, has been recommended for treatment of uncomplicated malaria in India. In Ujjain, central India, with an annual parasite index <0.1, the prevalence of drug-resistant Plasmodium falciparum is unknown. In other parts of India chloroquine and sulphadoxine-pyrimethamine-resistant P. falciparum is prevalent. The aim of this study was to determine the prevalence of anti-malarial drug resistance-associated genetic polymorphisms in P. falciparum collected in Ujjain in 2009 and 2010, prior to the introduction of ASP. METHODS: Blood samples from 87 patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons Pfcrt 72-76, pfmdr1 1034-1246, pfdhfr 16-185, pfdhps 436-632 and pfnhe1 ms4760 haplotypes were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism, and pfmdr1 gene copy number by real-time PCR. RESULTS: Sulphadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 75/78 (96%) and 70/78 (90%) samples, respectively, and pfdhps 437G was found in 7/77 (9%) samples. Double mutant pfdhfr 59R + 108 N were found in 62/76 (82%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/76 (8%) samples. Chloroquine-resistance-associated pfcrt 76 T was found in 82/87 (94%). The pfcrt 72-76 haplotypes found were: 80/84 (95%) SVMNT, 3/84 (4%) CVMNK and 1/84 (1%) CVMNT. Pfmdr1 N86 and 86Y were identified in 70/83 (84%) and 13/83 (16%) samples, respectively. Pfmdr1 S1034 + N1042 + D1246 were identified together in 70/72 (97%) of successfully sequenced samples. One pfmdr1 gene copy was found in 74/75 (99%) successfully amplified samples. CONCLUSION: This is the first characterization of key anti-malarial drug resistance-associated genetic markers among P. falciparum collected in Ujjain, Madhya Pradesh, India. The results indicate that the efficacy of standard dose chloroquine at the time of the study was likely to be poor, whereas ASP was likely to be efficacious, supporting the changed drug treatment policy. However, P. falciparum with reduced susceptibility to sulphadoxine-pyrimethamine is highly prevalent, highlighting the need for continuous surveillance of ASP efficacy in the study area.


Asunto(s)
Antimaláricos/farmacología , Resistencia a Medicamentos , Malaria Falciparum/parasitología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Polimorfismo Genético , Adolescente , Adulto , Femenino , Haplotipos , Humanos , India , Masculino , Plasmodium falciparum/clasificación , Plasmodium falciparum/aislamiento & purificación , Polimorfismo de Longitud del Fragmento de Restricción , Proteínas Protozoarias/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Adulto Joven
18.
J Travel Med ; 21(4): 248-54, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24750378

RESUMEN

BACKGROUND: Limited data exist on infectious diseases imported to various locations in Europe, particularly after travel within the continent. METHODS: To investigate travel-related disease relevant to Europe that is potentially preventable through pre-travel intervention, we analyzed the EuroTravNet database of 5,965 ill travelers reported by 16 centers in "Western" Europe in 2011. RESULTS: There were 54 cases of vaccine-preventable disease, mostly hepatitis A (n = 16), typhoid fever (n = 11), and measles (n = 8); 6 cases (including 3 measles cases) were associated with travel within "Western" Europe. Malaria was the most commonly diagnosed infection (n = 482, 8.1% of all travel-related morbidity). Among patients with malaria, the military most commonly received pre-travel advice (95%), followed by travelers for missionary, volunteer, research, or aid work (81%) but travelers visiting friends and relatives (VFRs) were least likely to receive pre-travel advice (21%). The vast majority (96%) of malaria patients were resident in "Western" Europe, but over half (56%) were born elsewhere. Other significant causes of morbidity, which could be reduced through advice and behavioral change, include Giardia (n = 221, 3.7%), dengue (n = 146, 2.4%), and schistosomiasis (n = 131, 2.2%). Of 206 (3.5%) travelers with exposure in "Western" Europe, 75% were tourists; the highest burden of disease was acute gastrointestinal infection (35% cases). Travel from "Eastern" Europe (n = 132, 2.2%) was largely associated with migration-related travel (53%); among chronic infectious diseases, tuberculosis was frequently diagnosed (n = 20). Travelers VFRs contributed the largest group of malaria patients (46%), but also had the lowest documented rate of pre-travel health advice in this subset (20%). Overall, 44% of nonimmigrant ill travelers did not receive pre-travel advice. CONCLUSION: There is a burden of infectious diseases in travelers attending European health centers that is potentially preventable through comprehensive pre-travel advice, chemoprophylaxis, and vaccination. Targeted interventions for high-risk groups such as travelers VFRs and migration-associated travelers are of particular importance.


Asunto(s)
Enfermedades Transmisibles/epidemiología , Vigilancia de la Población , Viaje/estadística & datos numéricos , Enfermedades Transmisibles/diagnóstico , Dengue/epidemiología , Europa (Continente)/epidemiología , Femenino , Enfermedades Gastrointestinales/epidemiología , Hepatitis A/epidemiología , Humanos , Masculino , Sarampión/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Esquistosomiasis/epidemiología , Enfermedades de la Piel/epidemiología , Fiebre Tifoidea/epidemiología
19.
Infect Genet Evol ; 24: 111-5, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24657918

RESUMEN

BACKGROUND: Chloroquine resistance in Plasmodium falciparum malaria has been associated with pfcrt 76T (chloroquine resistance transporter gene) and pfmdr1 86Y (multidrug resistance gene 1) alleles. Pfcrt 76T enables transport of protonated chloroquine out of the parasites digestive vacuole resulting in a loss of hydrogen ions (H(+)). V type H(+) pyrophosphatase (PfVP2) is thought to pump H(+) into the digestive vacuole. This study aimed to describe the geographic distribution of single nucleotide polymorphisms in pfvp2 and their possible associations with pfcrt and pfmdr1 polymorphisms. METHODS: Blood samples from 384 patients collected (1981-2009) in Honduras (n=35), Colombia (n=50), Liberia (n=50), Guinea Bissau (n=50), Tanzania (n=50), Iran (n=50), Thailand (n=49) and Vanuatu (n=50) were analysed. The pfcrt 72-76 haplotype, pfmdr1 copy numbers, pfmdr1 N86Y and pfvp2 V405I, K582R and P711S alleles were identified using PCR based methods. RESULTS: Pfvp2 was amplified in 344 samples. The pfvp2 allele proportions were V405 (97%), 405I (3%), K582 (99%), 582R (1%), P711 (97%) and 711S (3%). The number of patients with any of pfvp2 405I, 582R and/or 711S were as follows: Honduras (2/30), Colombia (0/46), Liberia (7/48), Guinea-Bissau (4/50), Tanzania (3/48), Iran (3/50), Thailand (1/49) and Vanuatu (0/31). The alleles were most common in Liberia (P=0.01) and Liberia+Guinea-Bissau (P=0.01). The VKP haplotype was found in 189/194 (97%) and 131/145 (90%) samples harbouring pfcrt 76T and pfcrt K76 respectively (P=0.007). CONCLUSIONS: The VKP haplotype was dominant. Most pfvp2 405I, 582R and 711S SNPs were seen where CQ resistance was not highly prevalent at the time of blood sampling possibly due to greater genetic variation prior to the bottle neck event of spreading CQ resistance. The association between the pfvp2 VKP haplotype and pfcrt 76T, which may indicate that pfvp2 is involved in CQ resistance, should therefore be interpreted with caution.


Asunto(s)
Resistencia a Medicamentos/genética , Pirofosfatasa Inorgánica/genética , Proteínas de Transporte de Membrana/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Adulto , Alelos , Antimaláricos , Secuencia de Bases , Niño , Cloroquina/metabolismo , Cloroquina/uso terapéutico , ADN Protozoario/genética , Ligamiento Genético , Haplotipos , Humanos , Malaria Falciparum/parasitología , Plasmodium falciparum/clasificación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN
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