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The addition of a third anti-malarial drug matching the pharmacokinetic characteristics of the slowly eliminated partner drug in artemisinin-based combination therapy (ACT) has been proposed as new therapeutic paradigm for the treatment of uncomplicated falciparum malaria. These triple artemisinin-based combination therapy (TACT) should in theory more effectively prevent the development and spread of multidrug resistance than current ACT. Several clinical trials evaluating TACT-or other multidrug anti-malarial combination therapy (MDACT)-have been reported and more are underway. From a regulatory perspective, these clinical development programmes face a strategic dilemma: pivotal clinical trials evaluating TACT are designed to test for non-inferiority of efficacy compared to standard ACT as primary endpoint. While meeting the endpoint of non-inferior efficacy, TACT are consistently associated with a slightly higher frequency of adverse drug reactions than currently used ACT. Moreover, the prevention of the selection of specific drug resistance-one of the main reasons for TACT development-is beyond the scope of even large-scale clinical trials. This raises important questions: if equal efficacy is combined with poorer tolerability, how can then the actual benefit of these drug combinations be demonstrated? How should clinical development plans be conceived to provide objective evidence for or against an improved management of patients and effective prevention of anti-malarial drug resistance by TACT? What are the objective criteria to ultimately convince regulators to approve these new products? In this Opinion paper, the authors discuss the challenges for the clinical development of triple and multidrug anti-malarial combination therapies and the hard choices that need to be taken in the further clinical evaluation and future implementation of this new treatment paradigm.

Background: During the COVID-19 pandemic, public perceptions and behaviours have had to adapt rapidly to new risk scenarios and radical behavioural restrictions.Aim: To identify major drivers of acceptance of protective behaviours during the 4-week transition from virtually no COVID-19 cases to the nationwide lockdown in Germany (3–25 March 2020).Methods: A serial cross-sectional online survey was administered weekly to ca 1,000 unique individuals for four data collection rounds in March 2020 using non-probability quota samples, representative of the German adult population between 18 and 74 years in terms of age × sex and federal state (n = 3,910). Acceptance of restrictions was regressed on sociodemographic variables, time and psychological variables, e.g. trust, risk perceptions, self-efficacy. Extraction of homogenous clusters was based on knowledge and behaviour.Results: Acceptance of restrictive policies increased with participants’ age and employment in the healthcare sector; cognitive and particularly affective risk perceptions were further significant predictors. Acceptance increased over time, as trust in institutions became more relevant and trust in media became less relevant. The cluster analysis further indicated that having a higher education increased the gap between knowledge and behaviour. Trust in institutions was related to conversion of knowledge into action.Conclusion: Identifying relevant principles that increase acceptance will remain crucial to the development of strategies that help adjust behaviour to control the pandemic, possibly for years to come. Based on our findings, we provide operational recommendations for health authorities regarding data collection, health communication and outreach.

Objectives: Recently, following import by travel and migration, epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has caused nosocomial outbreaks in Europe, sometimes with a fatal outcome. We describe clinico-epidemiological characteristics of CA-MRSA detected by the European Network for the Surveillance of imported S. aureus (www.staphtrav.eu) from May 2011 to November 2016. Methods: Sentinel surveillance at 13 travel clinics enrolling patients with travel-associated skin and soft-tissue infection (SSTI) and analysing lesion and nose swabs at one central laboratory. Results: A total of 564 independent case-patients with SSTI were enrolled and had 374 (67%) S. aureus-positive lesions, of which 14% (51/374) were MRSA. The majority of CA-MRSA isolates from SSTI were Panton-Valentine leucocidin (PVL) -positive (43/51, 84%). The risk of methicillin-resistance in imported S. aureus varied by travel region (p

State-subsidized programs develop medical data integration centers in Germany. To get infection disease (ID) researchers involved in the process of data sharing, common interests and minimum data requirements were prioritized. In 06/2019 we have initiated the German Infectious Disease Data Exchange (iDEx) project. We have developed and performed an online survey to determine prioritization of requests for data integration and exchange in ID research. The survey was designed with three sub-surveys, including a ranking of 15 data categories and 184 specific data items and a query of available 51 data collecting systems. A total of 84 researchers from 17 fields of ID research participated in the survey (predominant research fields: gastrointestinal infections n=11, healthcare-associated and antibiotic-resistant infections n=10, hepatitis n=10). 48% (40/84) of participants had experience as medical doctor. The three top ranked data categories were microbiology and parasitology, experimental data, and medication (53%, 52%, and 47% of maximal points, respectively). The most relevant data items for these categories were bloodstream infections, availability of biomaterial, and medication (88%, 87%, and 94% of maximal points, respectively). The ranking of requests of data integration and exchange is diverse and depends on the chosen measure. However, there is need to promote discipline-related digitalization and data exchange.

INTRODUCTION: Hydroxychloroquine use in COVID-19 patients was widespread and uncontrolled until recently. Patients vulnerable to severe COVID-19 are at risk for hydroxychloroquine interactions with comorbidities and co-medications contributing to detrimental, including fatal adverse treatment effects. METHODS: This is a retrospective survey of health conditions and co-medications of COVID-19 patients who were pre-screened for enrolment into a randomized, double-blind, placebo-controlled hydroxychloroquine multicenter trial. RESULTS: Our survey involved 305 patients (median age 71 (IQR: 59-81) years). The majority of patients (N = 279, 92%) considered for inclusion into the clinical trial were not eligible mainly due to safety concerns caused by health conditions or co-medications. Most common were QT prolonging drugs (N = 188, 62%) and hematologic/hemato-oncologic diseases (N = 39, 13%) which prohibited the administration of hydroxychloroquine in our clinical trial. Additionally, 165 (54%) patients had health conditions and 167 (55%) were on co-medications that did not prohibit hydroxychloroquine treatment but had a risk of adverse interactions with hydroxychloroquine. Most common were diabetes (N = 86, 28%), renal insufficiency (N = 69, 23%) and heart failure (N = 58, 19%). CONCLUSION: The majority of hospitalized COVID-19 patients had health conditions or took co-medications precluding safe treatment with hydroxychloroquine. Therefore, especially in elderly, hydroxychloroquine should be administered with extreme caution and only in clinical trials.

Background. Innovative approaches are needed to limit antimalarial resistance evolution. Understanding the role of intermittent preventive treatment in pregnancy (IPTp) on the selection for resistance and the impact such selection has on pregnancy outcomes can guide future interventions. Methods. Plasmodium fakiparum isolates (n = 914) from 2 randomized clinical trials were screened for pfmdrl copy number variation and pfcrt, pfmdrl, pfdhfr, and pfdhps resistance markers. The trials were conducted between 2010 and 2013 in Benin, Gabon, Kenya, and Mozambique to establish the efficacy of IPTp-mefloquine (MQ) compared with IPTp-sulphadoxine-pyrimethamine (SP) in human immunodeficiency virus (HIV)-uninfected and to IPTp-placebo in HIV-infected women. Results. In HIV-uninfected women, the prevalence of pfcrt mutants, pfdhfr/pfdhps quintuple mutants, and pfmdrl copy number was similar between women receiving IPT-SP and IPTp-MQ. However, prevalence of pfmdr1 polymorphism 86Y was lower in the IPTp-MQ group than in the IPTp-SP group, and within the IPTp-MQ group it was lower at delivery compared with recruitment. No effect of IPTp-MQ on resistance markers was observed among HIV-infected women. The carriage of resistance markers was not associated with pregnancy outcomes. Conclusions. Selection of wild-type pfmdrl polymorphism N86 by IPTp-MQ highlights the strong selective pressure IPTp can exert and the opportunity for using negative cross-resistance in drug choice for clinical treatment and IPTp.

6 páginas, 3 figuras, 1 tabla, Cystic echinococcosis (CE) is a zoonotic parasitic disease endemic in southern and eastern European countries. The true prevalence of CE is difficult to estimate due to the high proportion of asymptomatic carriers who never seek medical attention and to the underreporting of diagnosed cases, factors which contribute to its neglected status. In an attempt to improve this situation, the European Register of Cystic Echinococcosis (ERCE), was launched in October 2014 in the context of the HERACLES project. ERCE is a prospective, observational, multicentre register of patients with probable or confirmed CE. The first ERCE meeting was held in November 2015 at the Italian National Institute of Health (Istituto Superiore di Sanita, ISS) in Rome, to bring together CE experts currently involved in the Register activities, to share and discuss experiences, and future developments. Although the Register is still in its infancy, data collected at the time of writing this report, had outnumbered the total of national cases reported by the European endemic countries and published by the European Centre for Disease Prevention and Control in 2015. This confirms the need for an improved reporting system of CE at the European level. The collection of standardized clinical data and samples is expected to support a more rational, stage-specific approach to clinical management, and to help public authorities harmonize reporting of CE. A better understanding of CE burden in Europe will encourage the planning and implementation of public health policies toward its control., This research received funding from the European Community’s Seventh Framework Programme under the grant agreement 602051 (Project HERACLES: Human cystic Echinococcosis ReseArch in CentraL and Eastern Societies; http:// www.heracles-fp7.eu/).

Background: Benefits of mobile phone deployment for children

In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms. Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment. Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).

Objectives: In Gabon, a region of high perennial transmission of P. falciparum, national policy for prevention of malaria in pregnancy is intermittent preventive treatment (IPTp) with Sulfadoxine-Pyrimethamine (SP) and use of impregnated bednets. Malaria is thought to be a major cause for premature [for full text, please go to the a.m. URL], 10. Kongress für Infektionskrankheiten und Tropenmedizin (KIT 2010)

The cytokine profile of CD4+, CD8+ T cells, gammadelta+ T cells and natural killer (NK) cells (CD94+CD3-) was studied in a patient with visceral leishmaniasis (VL). The otherwise healthy, human immunodeficiency virus-negative patient acquired the disease in Tuscany, Italy. Diagnosis was made by demonstration of high concentrations of antibodies against Leishmania antigens in serum. Flow cytometry for the detection of intracellular interferon-gamma (IFN-gamma), interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13 and tumour necrosis factor (TNF)-alpha expression in peripheral blood mononuclear cells stimulated with phorbol 12-myristate 13-acetate and ionomycin was performed, followed by treatment with liposomal amphotericin B. CD4+ cells were identified as major cytokine-expressing cells, capable of producing both type 1 and type 2 cytokines. A high frequency of IL-4- and IL-13-expressing CD8+ cells was noted. NK cells and gammadelta+ T cells, thought to be involved in innate host defences against Leishmania, expressed IFN-gamma and TNF-alpha. Ten per cent of gammadelta+ T cells expressed IL-10, predominantly together with IFN-gamma, suggesting additional immune-regulatory roles for this T-cell subset in VL.

Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of low birth weight in sub-Saharan Africa are very young maternal age, first pregnancy, poor gestational nutrition and small stature of the mother. In Gabon, besides malaria, the other two major parasitic infections namely urogenital schistosomiasis and the filarial infection Loa loa, are common in pregnant women. Maternal schistosomiasis like malaria showed to be associated with higher proportions of low birth weight babies. Mefloquine as an alternative preventive treatment, despite showing no difference with sulphadoxine – pyrimethamine in preventing low birth weight, was however more effective in preventing malaria infection and anaemia. Mefloquine administered for the prevention of malaria was effective against concomitant urogenital schistosomiasis, suggesting that mefloquine could seriously be considered as a combined intervention for both malaria and schistosomiasis during pregnancy, and an alternative to praziquantel. Maternal infection with L. loa was associated with expansion in the neonatal cord blood of functionally activate Tregs that kept Th1 and Th17 immune responses in check, providing some insights on the impact of in utero exposure on the offspring’s development and health.