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The role of point‐of‐care tests in antibiotic stewardship for urinary tract infections in a resource‐limited setting on the Thailand–Myanmar border

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      ObjectivePublished literature from resource‐limited settings is infrequent, although urinary tract infections (UTI) are a common cause of outpatient presentation and antibiotic use. Point‐of‐care test (POCT) interpretation relates to antibiotic use and antibiotic resistance. We aimed to assess the diagnostic accuracy of POCT and their role in UTI antibiotic stewardship.MethodsOne‐year retrospective analysis in three clinics on the Thailand–Myanmar border of non‐pregnant adults presenting with urinary symptoms. POCT (urine dipstick and microscopy) were compared to culture with significant growth classified as pure growth of a single organism >105 CFU/ml.ResultsIn 247 patients, 82.6% female, the most common symptoms were dysuria (81.2%), suprapubic pain (67.8%) and urinary frequency (53.7%). After excluding contaminated samples, UTI was diagnosed in 52.4% (97/185); 71.1% (69/97) had a significant growth on culture, and >80% of these were Escherichia coli (20.9% produced extended‐spectrum β‐lactamase (ESBL)). Positive urine dipstick (leucocyte esterase ≥1 and/or nitrate positive) compared against positive microscopy (white blood cell >10/HPF, bacteria ≥1/HPF, epithelial cells <5/HPF) had a higher sensitivity (99% vs. 57%) but a lower specificity (47% vs. 89%), respectively. Combined POCT resulted in the best sensitivity (98%) and specificity (81%). Nearly one in ten patients received an antimicrobial to which the organism was not fully sensitive.ConclusionOne rapid, cost‐effective POCT was too inaccurate to be used alone by healthcare workers, impeding antibiotic stewardship in a high ESBL setting. Appropriate prescribing is improved with concurrent use and concordant results of urine dipstick and microscopy.

      Translated abstract

      ObjectifLa littérature publiée provenant des régions à ressources limitées est rare, bien que les infections des voies urinaires (IVU) soient une cause fréquente de présentation ambulatoire et d'utilisation d'antibiotiques. L'interprétation des tests au point des soins (TPS) est liée à l'utilisation d'antibiotiques et à la résistance aux antibiotiques. Nous avons cherché à évaluer la précision diagnostique des TPS et leur rôle dans la prise en charge antibiotiques des IVU.MéthodesAnalyse rétrospective sur un an dans trois cliniques à la frontière entre la Thaïlande et le Myanmar sur des adultes non enceintes avec des symptômes urinaires. Les TPS (bandelettes urinaires et microscopie) ont été comparés à la culture avec une croissance significative, classée comme croissance pure d'un organisme unique >105 cfu/mL.RésultatsChez 247 patients, 82,6% de femmes, les symptômes les plus fréquents étaient la dysurie (81.2%), la douleur suspubienne (67.8%) et la fréquence urinaire (53.7%). Après exclusion des échantillons contaminés, les IVU ont été diagnostiquées chez 52.4% (97/185); 71.1% (69/97) ont révélé une croissance significative sur la culture et pour >80% d'entre eux, il s'agissait d’Escherichia coli (20.9% à spectre étendu de β‐lactamase (BLSE)). La positivité de la bandelette urinaire (estérase leucocytaire ≥1 et/ou de nitrate positive) comparée à la positivité de la microscopie (globule blanc >10/HPF, bactéries ≥1/HPF, cellules épithéliales <5/HPF), avait une sensibilité plus élevée (99% vs 57%), mais une plus faible spécificité (47% vs 89%). La combinaison des TPS menait à la meilleure sensibilité (98%) et spécificité (81%). Près d'un patient sur dix ont reçu un antimicrobien auquel l'organisme n’était pas totalement sensible.ConclusionUn TPS rapide et rentable était trop imprécis pour être utilisé seul par les agents de la santé, ce qui entrave la prise en charge antibiotique dans un cadre à taux élevé de BLSE. Des TPS améliorés sont urgemment nécessaires pour faire face à cette résistance mondiale croissante.

      Translated abstract

      ObjetivoSi bien las infecciones del tracto urinario (ITU) son una causa común de las consultas externas y del uso de antibióticos en lugares con recursos limitados, la literatura publicada al respecto es escasa. La intrepretación de las pruebas de diagnóstico en el punto de atención (PoC) se relaciona con el uso de los antibióticos y la resistencia a los mismos. Nuestro objetivo era evaluar la precisión diagnóstica de las PoC y su papel en la administración de antibióticos para ITU.MétodosAnálisis retrospectivo de un año en tres clínicas en la frontera entre Tailandia‐Myanmar para adultos no embarazados que con síntomas urinarios. Las pruebas diagnósticas PoC (tira reactiva de orina y microscopía) se compararon con el cultivo, clasificando un crecimiento significativo como un crecimiento puro de un único organismo si >105cfu/mL.ResultadosEn 247 pacientes, 82,6% mujeres, los síntomas más comunes eran disuria (81,2%), dolor suprapúbico (67,8%) y frecuencia urinaria (53,7%). Después de excluir las muestras contaminadas, se diagnosticó ITU en un 52,4% (97/185); 71,1% (69/97) tenían un crecimiento significativo en cultivo y >80% de ellos eran Escherichia coli (20,9% producían β‐lactamasas de amplio espectro (BLAEs)). Un resultado positivo con la tira reactiva de orina (esterasa leucocitaria ≥1 y/o nitrato positiva), comparado con una microscopía positiva (leucocitos >10/HPF, bacterias ≥1/HPF, células epiteliales <5/HPF), tenían una mayor sensibilidad (99% vs 57%) pero menor especificidad (47% vs 89%), respectivamente. Pruebas PoC combinadas tenían la mejor sensibilidad (98%) y especificidad (81%). Casi uno de diez pacientes recibió un antimicrobiano para el cual el patógeno no era totalmente susceptible.ConclusiónUna sola prueba PoC rápida y coste‐efectiva era demasiado inexacta para ser utilizada por si sola por los trabajadores sanitarios, dificultando la administración de antibióticos en zonas con una alta prevalencia de BLAEs. Se requiere con urgencia unas pruebas PoC mejoradas para abordar la cada vez mayor resistencia a antibióticos a nivel global.

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      Interventions to improve antibiotic prescribing practices for hospital inpatients.

      The first publication of this review in Issue 3, 2005 included studies up to November 2003. This update adds studies to December 2006 and focuses on application of a new method for meta-analysis of interrupted time series studies and application of new Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias criteria to all studies in the review, including those studies in the previously published version. The aim of the review is to evaluate the impact of interventions from the perspective of antibiotic stewardship. The two objectives of antibiotic stewardship are first to ensure effective treatment for patients with bacterial infection and second support professionals and patients to reduce unnecessary use and minimize collateral damage. To estimate the effectiveness of professional interventions that, alone or in combination, are effective in antibiotic stewardship for hospital inpatients, to evaluate the impact of these interventions on reducing the incidence of antimicrobial-resistant pathogens or Clostridium difficile infection and their impact on clinical outcome. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE from 1980 to December 2006 and the EPOC specialized register in July 2007 and February 2009 and bibliographies of retrieved articles. The main comparison is between interventions that had a restrictive element and those that were purely persuasive. Restrictive interventions were implemented through restriction of the freedom of prescribers to select some antibiotics. Persuasive interventions used one or more of the following methods for changing professional behaviour: dissemination of educational resources, reminders, audit and feedback, or educational outreach. Restrictive interventions could contain persuasive elements. We included randomized clinical trials (RCTs), controlled clinical trials (CCT), controlled before-after (CBA) and interrupted time series studies (ITS). Interventions included any professional or structural interventions as defined by EPOC. The intervention had to include a component that aimed to improve antibiotic prescribing to hospital inpatients, either by increasing effective treatment or by reducing unnecessary treatment. The results had to include interpretable data about the effect of the intervention on antibiotic prescribing or microbial outcomes or relevant clinical outcomes. Two authors extracted data and assessed quality. We performed meta-regression of ITS studies to compare the results of persuasive and restrictive interventions. Persuasive interventions advised physicians about how to prescribe or gave them feedback about how they prescribed. Restrictive interventions put a limit on how they prescribed; for example, physicians had to have approval from an infection specialist in order to prescribe an antibiotic. We standardized the results of some ITS studies so that they are on the same scale (percent change in outcome), thereby facilitating comparisons of different interventions. To do this, we used the change in level and change in slope to estimate the effect size with increasing time after the intervention (one month, six months, one year, etc) as the percent change in level at each time point. We did not extrapolate beyond the end of data collection after the intervention. The meta-regression was performed using standard weighted linear regression with the standard errors of the coefficients adjusted where necessary. For this update we included 89 studies that reported 95 interventions. Of the 89 studies, 56 were ITSs (of which 4 were controlled ITSs), 25 were RCT (of which 5 were cluster-RCTs), 5 were CBAs and 3 were CCTs (of which 1 was a cluster-CCT).Most (80/95, 84%) of the interventions targeted the antibiotic prescribed (choice of antibiotic, timing of first dose and route of administration). The remaining 15 interventions aimed to change exposure of patients to antibiotics by targeting the decision to treat or the duration of treatment. Reliable data about impact on antibiotic prescribing data were available for 76 interventions (44 persuasive, 24 restrictive and 8 structural). For the persuasive interventions, the median change in antibiotic prescribing was 42.3% for the ITSs, 31.6% for the controlled ITSs, 17.7% for the CBAs, 3.5% for the cluster-RCTs and 24.7% for the RCTs. The restrictive interventions had a median effect size of 34.7% for the ITSs, 17.1% for the CBAs and 40.5% for the RCTs. The structural interventions had a median effect of 13.3% for the RCTs and 23.6% for the cluster-RCTs. Data about impact on microbial outcomes were available for 21 interventions but only 6 of these also had reliable data about impact on antibiotic prescribing.Meta-analysis of 52 ITS studies was used to compare restrictive versus purely persuasive interventions. Restrictive interventions had significantly greater impact on prescribing outcomes at one month (32%, 95% confidence interval (CI) 2% to 61%, P = 0.03) and on microbial outcomes at 6 months (53%, 95% CI 31% to 75%, P = 0.001) but there were no significant differences at 12 or 24 months. Interventions intended to decrease excessive prescribing were associated with reduction in Clostridium difficile infections and colonization or infection with aminoglycoside- or cephalosporin-resistant gram-negative bacteria, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. Meta-analysis of clinical outcomes showed that four interventions intended to increase effective prescribing for pneumonia were associated with significant reduction in mortality (risk ratio 0.89, 95% CI 0.82 to 0.97), whereas nine interventions intended to decrease excessive prescribing were not associated with significant increase in mortality (risk ratio 0.92, 95% CI 0.81 to 1.06). The results show that interventions to reduce excessive antibiotic prescribing to hospital inpatients can reduce antimicrobial resistance or hospital-acquired infections, and interventions to increase effective prescribing can improve clinical outcome. This update provides more evidence about unintended clinical consequences of interventions and about the effect of interventions to reduce exposure of patients to antibiotics. The meta-analysis supports the use of restrictive interventions when the need is urgent, but suggests that persuasive and restrictive interventions are equally effective after six months.
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        Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study

        Introduction The past decade has seen encouraging progress in the control of malaria worldwide. According to the World Health Organization's World Malaria Report 2011 [1], several countries in sub-Saharan Africa have registered very significant decreases in the number of Plasmodium falciparum malaria cases. In other continents, malaria has receded too, particularly in Southeast Asia, although the precise number of cases in some countries of the subcontinent may have been grossly underestimated [2]. Economic development, urbanisation, and unprecedented financial support have all contributed to these successes against malaria. Renewed efforts in vector control, insecticide-treated net distribution, and the deployment of artemisinin-based combination treatments (ACTs) have also contributed to the reduction of morbidity and mortality associated with P. falciparum, and this trend is particularly prominent in areas of low transmission such as in Southeast Asia. These trends have boosted efforts towards malaria elimination. However, these gains are now threatened by the emergence in Southeast Asia of P. falciparum isolates that exhibit resistance to artesunate [3]. This resistance is characterised by a slow parasite clearance rate observed in patients treated with artesunate, but the precise mechanism remains unknown. Whether or not this particular form of resistance has spread beyond Southeast Asia is currently uncertain, but confirmed resistance surrounding the Thai–Myanmar border is attributable to changes in the parasite's genetic make-up [4]. It is not known whether the resistant parasites on the Thai–Myanmar border are related to those in Cambodia or whether resistance to artemisinin has emerged independently, but there is considerable concern that if this resistance to artemisinin spreads or emerges elsewhere because of widespread use, it will seriously compromise malaria control programs and threaten the lives of millions worldwide. During the previous decades, the spread of chloroquine- and sulphadoxine-pyrimethamine-resistant parasites from Southeast Asia to Africa resulted in a dramatic rise in mortality from increased perennial or epidemic transmission [5],[6]. Resistance to artemisinin could trigger a catastrophic resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria [7],[8]. With substantial international support, containment efforts have started in Cambodia and bordering Thailand. The strategy is based on active detection of parasite carriers using molecular tools, but the impact is difficult to measure in the absence of a molecular marker of artemisinin resistance. The largest focus of P. falciparum malaria in this region is situated in Myanmar, with a reported annual caseload of 70,941 in 2010 [1]. It is therefore essential to suppress malaria transmission as much as possible on the border between Myanmar and Thailand to avoid the spread of resistance to artemisinin to neighbouring countries and beyond. Between 1994 and 1999 we observed the impact of early detection and treatment (EDT) with ACT in populations of refugees living on the Thai–Myanmar border [9]. Ten years later we reported a similar impact in a larger population living in the region, including villagers, migrant workers, and refugees [10]. In the meantime, as per national policies, Thailand (in 1995), Vietnam (in 1995), Cambodia (in 2000), and Myanmar (in 2002) all adopted ACT as first-line therapy for P. falciparum infections. Malaria control in border areas is particularly challenging, especially if effective control measures are not deployed on both sides of the border. The combination of a constant reservoir of malaria in Myanmar, where the disease burden is higher than in Thailand, and frequent population movement mean that providing control measures based on EDT alone to migrants on the Myanmar side of the border might be expected to have a lower impact on local malaria transmission and incidence than in a more enclosed population, such as in large refugee camps or in villages on the Thai side of the border, where similar measures have been highly successful. We evaluated malaria prevalence and incidence in the mobile and migrant population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to EDT with ACT for this population was associated with a decline in the malaria burden. Methods Setting The border between Thailand and Myanmar (Burma) is 2,107 km long and is mostly forested and mountainous. It is inhabited by a mosaic of ethnic groups and is characterised by intense migration fluxes between the two countries. Decades of internal conflicts in Myanmar have resulted in massive population displacements, and over 150,000 refugees now live in camps in Thailand. Economic stagnation has also prompted the migration of millions of people to Thailand in search of work, especially since the mid-1990s. This region is endemic for malaria (all four types, namely, P. falciparum, P. vivax, P. ovale, and P. malariae), and P. falciparum is highly drug resistant. The migration of gem miners from western Cambodia to Myanmar in the 1960s is thought to have played a major role in the spread of resistance to chloroquine [11]. The main vectors of malaria are the mosquitoes Anopheles minimus, A. dirus, and A. maculatus, and the transmission is low but unstable. The population has very little naturally acquired immunity against malaria, and all age groups are affected. In 1985, malaria was the main cause of consultations and mortality in the Karen refugee camps [12]. Population The catchment area of the five Shoklo Malaria Research Unit (SMRU) clinics extends over 120 km of the border (see Figure 1). The population living along the border is diverse and is composed of three main groups: a relatively stable population living in established villages inside Myanmar for a number of years; a much more mobile group, mainly adult workers migrating according to work availability; and newly arrived people either displaced or in search of employment. 10.1371/journal.pmed.1001398.g001 Figure 1 Location of SMRU clinics and cross-border health posts run by village health workers. Blue crosses indicate SMRU clinics; inverted red triangles indicate SMRU health posts. The Thai–Myanmar border is represented by a black line, and the main roads by grey lines. Based on village population lists, the population living in villages on the Myanmar side has been estimated to be 42,000 people, with numbers updated during malariometric surveys and bed net distributions. This population size has grown steadily through the years. The ratio of men to women is estimated at 1, and ∼40% of the population is under 15 y of age, a population structure similar to that of the refugee camps. Villages in the catchment area are mainly located along the Moei river (the border between Myanmar and Thailand) but occasionally are as far as 30–40 km inside Myanmar. The size of the mobile population is more difficult to assess; in 2004, the Thai Ministry of Interior estimated the number of registered migrants living in Tak province at ∼125,000. Another 50,000–100,000 migrants are thought to be living along the border without registration (data from the Tak public health services). The majority of those migrants are living in the three districts where SMRU clinics are located (namely, Mae Ramat, Mae Sot, and Phop Phra districts). In 2010, the Tak Industrial Federation estimated that 154,000 to 190,000 migrants (both registered and unregistered) were living in Tak province. Expanding Cross-Border Access to EDT Access to malaria diagnosis and treatment on the Myanmar side of the border is poor, because of travel limitations and insecurity. Health care is provided by local organisations, and coverage is limited. In general, patients with more severe illness seek treatment in Thailand. From 1999 to 2005, two “health posts” were run by locally selected health workers; they were trained by the SMRU staff to use rapid diagnostic tests (RDTs) and microscopy and to provide appropriate treatment following the protocols used in the SMRU clinics. After 2008, nine health posts were established on the Myanmar side but without microscopy. (see Figure 1). The health posts are operated and supported as follows. Severe cases are referred to the nearest medical facility. Antimalarial drugs (artemisinin-based combinations as well as chloroquine for the treatment of non-falciparum malaria) and antipyretics are supplied on a regular basis to avoid shortages or stock-outs. Supervision of the work is done routinely, and quality control (QC) of malaria diagnosis is performed at the SMRU laboratory in Mae Sot. Pregnant women seeking care at the health posts are encouraged to attend antenatal care at the nearest SMRU clinic on the Thai side. Insecticide-impregnated bed nets are distributed to all patients with confirmed malaria seen in SMRU clinics, as per the requirements of the clinic's funding agencies. Study Design In order to evaluate changes in the malaria burden since access to EDT was expanded, we recorded the number of consultations in all clinics with confirmed malaria diagnosis, changes in the prevalence of malaria in the populations on the Myanmar side of the border by means of cross-sectional surveys, and the incidence of malaria in a cohort of pregnant women living on both sides of the border but followed in clinics on the Thai side. Other factors that can affect malaria incidence were monitored, i.e., in vivo and in vitro antimalarial drug efficacy, bed net distribution, and climatic conditions. The observation period extended from 1 October 1999 to 30 September 2011. Monitoring the Number of Malaria Cases In the cross-border health posts (Myanmar side), malaria cases were detected by village health workers. Data were obtained weekly, and compiled on site by age group and malaria species. No gender distribution was available. All cases of P. falciparum reported were confirmed by either RDT (nine health posts) or microscopy (two health posts). For each individual malaria case detected in the SMRU clinics (Thai side), demographic characteristics and type of malaria test and its result were recorded. Species were confirmed systematically by slide microscopy only for children under 5 y and pregnant women because some of the RDTs used can only detect P. falciparum. However, one week each month, all patients presenting at the SMRU clinics with malaria symptoms were tested by blood smear microscopy, allowing the calculation of changes in the P. falciparum/P. vivax ratio over time. The presence of gametocytes was reported routinely for each malaria smear done in the SMRU clinics. Hospitalisations due to severe malaria have been systematically recorded since 2003. QC of the malaria diagnostic tests was implemented at all sites. All RDTs performed in the field by village health workers, mostly Paracheck-Pf, an HRP-II-based RDT detecting only P. falciparum, and Optimal-IT, a pLDH-based test detecting falciparum and non-falciparum species, were retained in zip-sealed plastic bags on site and reread later by a senior technician in Mae Sot. Although, this QC method has limitations, as RDT results do not always remain stable over time, it enables a check on the accuracy of data recording and can detect major errors in test result interpretation in the field that warrant further investigation or refresher training. For SMRU clinics and health posts with a field laboratory performing microscopy, a standardised protocol for internal QC has been in place since 1997. Briefly, each field laboratory stores all slides in zip-sealed plastic bags, separating positive from negative slides. These are sampled several times a year and sent to the central laboratory in Mae Sot for cross-checking and quality assessment of the sensitivity, specificity, and negative and positive predictive values of the tests. Any discrepancies between results required a third and final reading by the head of the laboratory department. Malaria Incidence: Follow-Up of the Cohort of Pregnant Women Pregnant women attended weekly antenatal care clinics until delivery. In addition to routine antenatal care, a malaria smear was done at each consultation, whether the woman was symptomatic or not, and her haematocrit was measured every fortnight. Pregnant women were also encouraged to seek care immediately in case of fever or symptoms suggestive of malaria. Women found to be parasitaemic were treated for malaria, regardless of their symptoms. Malariometric Cross-Sectional Surveys Cross-sectional surveys in villages and migrant communities were conducted annually in order to detect changes in the transmission of P. falciparum and P. vivax. We surveyed one or two villages each year between 2000 and 2003; in 2006–2008, prior to expanding malaria control on the Myanmar side, we surveyed up to five villages annually. Most of the surveys were done during the rainy season, when malaria is at its peak. Exhaustive population surveys were done in villages with fewer than 500 inhabitants; for larger villages, 25% of the houses were randomly selected, and all residents in those houses were screened. Participation to the survey was voluntary. Each participant was given a unique identifier, was asked basic demographic information, and had a malaria smear performed. Anyone presenting with fever or a history of fever in the previous days also underwent an RDT for malaria, and if the test was positive, the individual was immediately treated. Malaria smears were considered negative if the technician did not find any parasites in 100 oil-immersion fields (1,000×) on a thick blood film. Results of the malaria smear screening were obtained within 24–48 h, and all people with a positive malaria smear result were treated. In Vivo Efficacy of Mefloquine-Artesunate We monitored the efficacy of mefloquine (8 mg/kg/d) and artesunate (4 mg/kg/d) over 3 d for the treatment of patients with uncomplicated P. falciparum malaria confirmed microscopically annually. After giving written consent, patients were followed daily until resolution of their parasitaemia and then weekly for 6 wk. Recrudescence between days 5 and 42 was differentiated from a new infection using parasite genotyping by PCR [13]. Patients with indeterminate genotyping results and new infections were censored at the date of the reappearance of P. falciparum parasites. Delayed parasite clearance was considered to be present if patients were still parasitaemic 72 h (day 3) after the baseline positive malaria smear. In Vitro Antimalarial Drug Studies Parasite isolates were obtained from non-pregnant patients with uncomplicated acute P. falciparum malaria primary infection attending the SMRU clinics if they had at least five parasites per 1,000 red blood cells and consented to give 5 ml of blood. Drug susceptibility was tested using the hypoxanthine uptake method. The reproducibility of IC50 measurements was assessed using cloned K1 isolates of P. falciparum. Climate Monthly climatic conditions (rainfall and mean temperature) were obtained from Mae Sot (central area) and Umphang (southern area) meteorological stations and from the Tha Song Yang health department (northern area). Annual trends were obtained by averaging monthly rainfall (in millimetres) and mean temperature (in degrees Celsius) from the different meteorological stations. Statistical Analysis Annual incidence rates in pregnancy for P. falciparum and for P. vivax were calculated separately. Only the first positive malaria smear of each species was considered and counted to calculate the number of new malaria episodes per pregnant woman. Women with negative malaria smears throughout their pregnancy were considered free of malaria; the period between the first antenatal care visit and the pregnancy outcome was considered the period “at risk” and was measured in weeks. In addition to incidence, the annual cumulative proportion of women who experienced at least one malaria episode during their pregnancy was calculated for both P. falciparum and P. vivax. Anaemia was reported as present if the haematocrit was 15 y Male Female Male Female Male Female 2000 210 (4%) 213 (4%) 653 (13%) 491 (10%) 2,669 (53%) 788 (16%) 5,024 2.4 2001 259 (4%) 238 (3%) 984 (14%) 656 (9%) 3,825 (54%) 1,137 (16%) 7,099 2.5 2002 174 (4%) 162 (4%) 591 (14%) 418 (10%) 2,105 (51%) 644 (16%) 4,094 2.3 2003 133 (4%) 136 (4%) 481 (13%) 321 (9%) 2,057 (56%) 552 (15%) 3,680 2.6 2004 168 (4%) 145 (4%) 538 (13%) 389 (10%) 2,061 (51%) 714 (18%) 4,015 2.2 2005 327 (4%) 256 (3%) 1,171 (13%) 935 (10%) 4,813 (53%) 1,611 (18%) 9,113 2.3 2006 485 (4%) 398 (3%) 1,787 (13%) 1,220 (9%) 7,749 (56%) 2,125 (15%) 13,764 2.7 2007 382 (3%) 285 (2%) 1,719 (14%) 1,087 (9%) 6,955 (57%) 1,862 (15%) 12,290 2.8 2008 344 (3%) 325 (2%) 1,736 (13%) 1,189 (9%) 7,538 (57%) 2,067 (16%) 13,199 2.7 2009 266 (3%) 234 (2%) 1,282 (13%) 828 (8%) 5,685 (58%) 1,500 (15%) 9,795 2.8 2010 90 (2%) 92 (2%) 573(12%) 347 (7%) 2,836 (61%) 741 (16%) 4,679 3.0 2011 117 (3%) 86 (2%) 510 (14%) 273 (8%) 2,023 (57%) 560 (16%) 3,569 2.9 Total annual numbers of P. falciparum cases reported in this table are smaller than those reported in Table 2 because of some missing data on either age or sex. Number of P. vivax Infections The annual numbers of P. vivax (and P. falciparum) infections in children under 5 y that presented at the SMRU clinics are shown in Table 4. The percentage of consultations due to malaria decreased over time (from 1,048/1,344, 78% [95% CI 76–80], to 767/11,542, 7% [95% CI 6.2–7.1]; chi-square test for trend, p 15 y 2000 0.7 1.0 1.8 1.4 2001 0.7 1.2 1.7 1.7 2002 0.1 0.4 1.1 0.7 2003 0.4 0.5 1.0 0.8 2004 0.5 0.8 1.5 1.1 2005 0.6 1.3 2.1 1.6 2006 0.5 1.0 1.5 1.2 2007 0.4 0.7 1.1 0.9 2008 0.3 0.6 1.1 0.8 2009 0.3 0.4 0.7 0.6 2010 0.1 0.2 0.4 0.3 2011 0.5 0.7 0.8 0.7 One week each month, all patients presenting at the SMRU clinics with malaria symptoms were tested by microscopy, allowing the calculation of the ratio of P. falciparum to P. vivax infection; a ratio above 1 indicates a predominance of P. falciparum, and a ratio below 1 a predominance of P. vivax. Hospitalised Cases and Mortality Table 6 shows the number of patients hospitalised for malaria during the study period and the case fatality rate. The proportion of patients hospitalised for either uncomplicated hyperparasitaemia or severe disease was stable, 4.0% (95% CI 3.9–4.2) (3,022 hospitalisations/75,126 total patients with falciparum malaria). The number of deaths remained very low: the overall case fatality rate was 0.05% (95% CI 0.04–0.07), ranging across years from 0.01% (95% CI 0.00–0.06) to 0.11% (95% CI 0.05–0.25). Overall, only two patients (0.003% [95% CI 0.000–0.010] of 72,104 patients treated in ambulatory care in the outpatient department) died after receiving an oral artemisinin-based treatment for an uncomplicated P. falciparum infection. Forty-eight patients were hospitalised with a P. vivax infection and a concomitant condition between 2007 and 2011, but none were fatal or associated with signs of severe malaria. 10.1371/journal.pmed.1001398.t006 Table 6 Hyperparasitaemia and severe malaria cases hospitalised in SMRU clinics, and case fatality rate among non-pregnant patients, from 2003 to 2011. Year OPD+IPD Malaria: Total PF OPD Malaria: Total PF IPD Malaria Malaria Deaths Case Fatality Rate Total PFa PF Hyperparasitaemiab Severe PF Malariab 2003 4,235 4,061 174 (4.1%) 115 (66%) 59 (34%) 1 0.02% 2004 3,945 3,760 185 (4.7%) 104 (56%) 81 (44%) 1 0.03% 2005 8,937 8,752 185 (2.1%) 113 (61%) 72 (39%) 6 0.07% 2006 13,648 13,306 342 (2.5%) 200 (58%) 142 (42%) 11 0.08% 2007 12,599 12,013 586 (4.7%) 469 (80%) 117 (20%) 5 0.04% 2008 13,412 12,836 576 (4.3%) 416 (72%) 160 (28%) 7 0.05% 2009 10,117 9,553 564 (5.6%) 380 (67%) 184 (33%) 1 0.01% 2010 4,746 4,514 232 (4.9%) 151 (65%) 81 (35%) 5 0.11% 2011 3,487 3,309 178 (5.1%) 140 (79%) 38 (21%) 2 0.06% a Percentages in parentheses indicate the percent of all malaria cases treated in the inpatient department for a given year. b Percentages in parentheses indicate the percent of each category among those treated in the inpatient department for a given year. IPD, hospitalisation in inpatient department; OPD, ambulatory care in outpatient department, PF, P. falciparum malaria. Laboratory Quality Control Between 1 January 2000 and 31 December 2011 a total of 42,806 malaria smears were rechecked. This figure corresponds to an average of 3.6 unannounced rounds of QC per site per year. The mean sensitivity, specificity, positive predictive value, negative predictive value, and Kappa value for species differentiation were 95.7%, 99.8%, 99.7%, 98.0%, and 0.95, respectively. Out of 14,426 Paracheck-Pf tests that could be verified, 2.3% (95% CI 2.1–2.6) (335/14,426) had an interpretation error. Out of 9,569 Optimal-IT tests verified, 1.1% (95% CI 1.0–1.4) (109/9,569) were wrongly interpreted. However, delays in double-checking the RDTs may have affected the reliability of these results. Malaria in Pregnancy The incidence of P. falciparum and P. vivax infection in pregnant women is shown in Figure 3. There was a marked decline in the incidence of P. falciparum, from 1.09 to 0.14 infections·woman−1·year−1 (Student's t test, p 15 y; chi-square test, p 3 d] clearance of parasitaemia in 2000, but 8 of 29 [28% (95% CI 15–46)] did in 2011; chi-square test for trend, p = 0.003). 10.1371/journal.pmed.1001398.g007 Figure 7 Day-42 PCR-adjusted MAS3 parasitological efficacy and proportion of patients still parasitaemic at day 3. This graph shows the changes in day-42 PCR-adjusted MAS3 parasitological efficacy (black dashed line) and proportion of patients still parasitaemic at day 3 (red line) from 2000 to 2011. Bars indicate 95% CIs. In Vitro Sensitivity The in vitro sensitivity (IC50) of P. falciparum isolates to mefloquine, artesunate, and dihydroartemisinin is shown in Figure 8. There were no specific trends over the study period. 10.1371/journal.pmed.1001398.g008 Figure 8 P. falciparum isolate in vitro sensitivity to mefloquine, artesunate, and di-hydroartemisinin from 2000 to 2010. Red lines indicate in vitro sensitivity of P. falciparum isolates to (A) mefloquine, (B) artesunate, and (C) dihydroartemisinin. Bars indicate 95% CIs. No data were available for 2011. Climate The annual rainfall and the mean annual temperature are shown in Figure 9. There was a steady increase in the mean annual temperature of 0.1°C between October 1999 and September 2011, but expected seasonal variations in temperature and rainfall. Over the study period, the mean annual rainfall ranged from 1,600 mm to 2,600 mm. The mean temperature ranged from 22.2°C in December to 28.3°C in April, and annual relative humidity was above 75%. The start of the rains was delayed in 2010, resulting in an overall reduction of annual mean rainfall by half. However, rainfall increased again in 2011. 10.1371/journal.pmed.1001398.g009 Figure 9 Annual rainfall and mean annual temperature between 2000 and 2011. Black line indicates mean annual temperature in degrees Celsius, and grey bars indicate annual rainfall in millimetres. Discussion Since 2000 the transmission of P. falciparum has declined substantially in the population in Myanmar living on the border with Thailand in Tak province (the most populated part of the border, with intense migration), despite being a well-known focus of highly drug-resistant P. falciparum malaria and an area of documented emergence of P. falciparum resistance to artesunate [4]. The decline is evident from the number of cases detected and treated in the SMRU clinics situated on the Thai side of the border. Longitudinal studies in a cohort of pregnant women confirm this decline. The decline has mainly been attributed to improved access to early detection of malaria and treatment with highly effective artemisinin-based antimalarial therapies. This approach used by SMRU as well as other health providers in the area had proven effectiveness first in the refugee camps on the Thai border in the 1990s, then in Thai villages of Tak province and elsewhere in the region [14], and even in low transmission areas of Africa [15]. This effectiveness is explained by the rapid killing of sexual stages of P. falciparum and the activity of artemisinins on gametocytes [16]. Expanding EDT to the mobile and migrant population on the Myanmar side of the border also appears to have been successful in reducing malaria transmission, as evidenced by the decrease in the number of consultations for malaria and the results of the cross-sectional prevalence surveys. The financial investment was relatively modest, consisting mainly of drug and diagnostic test provision. There are other factors that may have contributed to this reduction in the transmission of P. falciparum. There was a sharp decline in rainfall in 2010, and this may have contributed to lower vector abundance. However, the levels of precipitation in 2011 were higher than average, and this finding did not translate into a significant rise in caseload. In general, there was not much seasonal climatic variation from year to year over the period of study, so we do not believe that climate was a major confounding factor for changes in malaria prevalence or incidence observed over time (see detailed climate information in Figure S1). Over 46,000 insecticide-impregnated bed nets were also distributed between 2000 and 2011; however, the vectors in this area (A. minimus, A.dirus, and A. maculatus) are forest mosquitoes feeding early in the evening and outdoors, such that the impact of impregnated nets is limited [17]. These vector characteristics also explain the high proportion of cases in young adult males, because they are exposed while working in the forested areas. Vector control measures would also not explain the differences observed between P. falciparum and P. vivax case reductions. The latter species has become dominant, and the ratio of P. falciparum to P. vivax infections has declined in all areas where the patients had access to EDT (Figure 6). The slow decline in the number of P. vivax infections may be explained by the decline in P. falciparum infections, as many P. vivax parasitaemic episodes are relapses from previous infections, and P. falciparum infection is associated with P. vivax relapse [18]. So the reduction in the number of clinical episodes of P. falciparum may have contributed to lower numbers of P. vivax relapses [19]. Antimalarial drugs are the cornerstone of EDT, and this situation puts the parasite population under selection pressure for resistance. Indeed, we have shown that the proportion of patients with multiple copies of the gene Pfmdr1 (known to mediate resistance to mefloquine) is increasing, which may have contributed to the decline in the in vivo efficacy of the MAS3 combination recently reported, although the number of participants recruited in 2011 was very small (n = 32) [10]. If this sharp drop in efficacy is confirmed, an alternative ACT will have to be registered and deployed. The effectiveness of the current treatment for failures (7 d of quinine and tetracyclines) is poor. More worryingly, resistance to artemisinin is also emerging. This situation translates into a reduction of the parasite clearance rate following treatment with artesunate and may be explained by parasite genetics [20]. Unfortunately, resistance to artemisinin is not detected by conventional in vitro susceptibility testing methods, as shown in this study. The observation of increasing gametocyte carriage in patients presenting with P. falciparum infection is of great concern. The mechanisms that confer resistance to artemisinin are unknown, but it has been suggested that the use of substandard drugs and monotherapies may be contributing factors [3]. However, in the border population described here, self-treatment and monotherapies are uncommon. Alternatively, the use of quality drugs, free of charge, even in combination, may have selected parasite clones resistant to artesunate. This situation does not question the rationale behind using ACTs [16] but may be related to the phenomenon of dormancy [21]. When ring stages of P. falciparum are exposed to artesunate (or its metabolite, dihydroartemisinin), a small proportion becomes metabolically inactive and insensitive to drugs, and these are not removed by the spleen, unlike those affected by the drug [22] and unlike what is normally seen in patients [23],[24]. Whether the two observations (dormancy and the slow clearance phenotype) are related is unknown but cannot be excluded [25],[26]. To complicate matters further, P. vivax is becoming more resistant to chloroquine in this area [27], and this finding may explain the increasing proportion of patients presenting with vivax gametocytes (Figure 2). It may be necessary to adopt a unified ACT for both species, as in Papua province, Indonesia [28]. The observational nature of some of these data is an obvious limitation, and there are potential biases. The unstable nature of the population and the difficulties of working across an international border mean that the cases detected may not be representative of the overall population. Pregnant women, the group in whom we defined malaria incidence, may have a different risk of exposure and may not reflect the disease burden in the general population. However, it should be acknowledged that in most malarious regions (in particular in border areas), data are either nonexistent or much less detailed than in this study. We cannot eliminate all sources of bias, but the decline in P. falciparum cases in all age groups and both genders remains robust. The benefit of increased access to EDT for the population is obvious, as illustrated by the decrease in maternal malaria-related anaemia. Efforts are underway to try to contain the spread of artemisinin resistance from western Cambodia. Our results and results from elsewhere indicate that an aggressive strategy based on EDT of cases, combined with vector control and information to the population, is the way forward to eliminate malaria. However, it is uncertain whether this strategy alone could achieve complete elimination over time. Adjunctive approaches should be evaluated, such as the use of low-dose primaquine to reduce transmission further, mass drug administrations, more sensitive detection of sub-microscopic infections using molecular methods, or targeted use of the new malaria vaccine, if it is approved. Addition of all these interventions may not be cost-effective, and so this approach should also be assessed. Considerable support and strong leadership are urgently needed to step up the malaria control program in Myanmar and elsewhere. In practice, this means increasing the population coverage and training of village health workers in the use of RDTs and ACTs plus primaquine. Eliminating P. falciparum or dramatically reducing the number of cases is feasible, but the main obstacle is the difficulty of accessing populations living in remote, sometimes dangerous areas and across international borders. Supporting Information Figure S1 Monthly mean temperature in districts of Tak province bordering Myanmar. 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          The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy

          Background Many studies have evaluated the accuracy of dipstick tests as rapid detectors of bacteriuria and urinary tract infections (UTI). The lack of an adequate explanation for the heterogeneity of the dipstick accuracy stimulates an ongoing debate. The objective of the present meta-analysis was to summarise the available evidence on the diagnostic accuracy of the urine dipstick test, taking into account various pre-defined potential sources of heterogeneity. Methods Literature from 1990 through 1999 was searched in Medline and Embase, and by reference tracking. Selected publications should be concerned with the diagnosis of bacteriuria or urinary tract infections, investigate the use of dipstick tests for nitrites and/or leukocyte esterase, and present empirical data. A checklist was used to assess methodological quality. Results 70 publications were included. Accuracy of nitrites was high in pregnant women (Diagnostic Odds Ratio = 165) and elderly people (DOR = 108). Positive predictive values were ≥80% in elderly and in family medicine. Accuracy of leukocyte-esterase was high in studies in urology patients (DOR = 276). Sensitivities were highest in family medicine (86%). Negative predictive values were high in both tests in all patient groups and settings, except for in family medicine. The combination of both test results showed an important increase in sensitivity. Accuracy was high in studies in urology patients (DOR = 52), in children (DOR = 46), and if clinical information was present (DOR = 28). Sensitivity was highest in studies carried out in family medicine (90%). Predictive values of combinations of positive test results were low in all other situations. Conclusions Overall, this review demonstrates that the urine dipstick test alone seems to be useful in all populations to exclude the presence of infection if the results of both nitrites and leukocyte-esterase are negative. Sensitivities of the combination of both tests vary between 68 and 88% in different patient groups, but positive test results have to be confirmed. Although the combination of positive test results is very sensitive in family practice, the usefulness of the dipstick test alone to rule in infection remains doubtful, even with high pre-test probabilities.
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            Author and article information

            Affiliations
            [ 1 ] Shoklo Malaria Research Unit Faculty of Tropical MedicineMahidol University Mae SotThailand
            [ 2 ] Mahidol‐Oxford Tropical Medicine Research Unit Faculty of Tropical MedicineMahidol University BangkokThailand
            [ 3 ] Centre for Tropical Medicine and Global Health Nuffield Department of Clinical MedicineUniversity of Oxford OxfordUK
            Author notes
            [* ] Corresponding Author: Lauren Chalmers, Shoklo Malaria Research Unit (SMRU), Mahidol‐Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, PO Box 46, Mae Sot, Tak 63110, Thailand. Tel.: +66 55 545021, E‐mail: lauren.chalmers86@ 123456gmail.com
            Journal
            Trop Med Int Health
            Trop. Med. Int. Health
            10.1111/(ISSN)1365-3156
            TMI
            Tropical Medicine & International Health
            John Wiley and Sons Inc. (Hoboken )
            1360-2276
            1365-3156
            11 June 2015
            October 2015
            : 20
            : 10 ( doiID: 10.1111/tmi.2015.20.issue-10 )
            : 1281-1289
            25963224
            4758398
            10.1111/tmi.12541
            TMI12541
            © 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

            This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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            Pages: 9
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            Original Article
            Original Research Papers
            Custom metadata
            2.0
            tmi12541
            October 2015
            Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:22.04.2016

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