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Pericopsis elata (afrormosia), bien représentée dans la cuvette centrale congolaise, est une des principales espèces commerciales les plus exploitées en RDC alors qu’elle est inscrite sur la liste rouge des espèces menacées de l’UICN. Afin de garantir sa durabilité, des simulations de sa population ont été réalisées dans les forêts de la concession 010/11 de la Société Africaine de la Forestière (SAFO) à partir des données d’un inventaire d’aménagement. Plusieurs scenarios ont été effectués en variant certains paramètres tel le diamètre minimum d’exploitabilité (DME), la durée de rotation et le taux de prélèvement. Les résultats montrent qu’avec un DME de 60 cm, le taux de reconstitution est de 15 % si on extrait 96 % des tiges exploitables, correspondant au taux de prélèvement fixé par le concessionnaire, et de 31 % si on extrait 75 % des tiges exploitables. En analysant d’autres scénarios, il ressort qu’en fixant le DME à 110 cm et en maintenant le taux de prélèvement à 96 %, il est possible de reconstituer 48 % des tiges exploitables au bout de la durée légale de rotation, soit 25 ans. Enfin, il a été est observé que le fait de remonter le DME à 110 cm ou de réduire le taux de prélèvement à 75 % peut favoriser la régénération et la croissance de P. elata dans la concession étudiée et ainsi assurer le maintien des effectifs de cette espèce. Mots clés: Pericopsis elata, taux de reconstitution, taux de prélèvement, DME

Through their footprint throughout their life cycle, from production to use, medicines have a significant impact on the environment. Reducing this impact is rarely considered from the perspective of the choices that healthcare professionals might have to make when prescribing or dispensing medicines. Should we consider environmental impact, alongside effectiveness and tolerance, one of the dimensions of the proper use of medicines? To address this question, the 5th Forum of the Association for the Proper Use of Medicines highlighted the main sources of pharmaceutical pollution: the carbon footprint linked to production, greenhouse gas emissions, the impact of residues on water and waste from packaging. While the eco-design of medicines should make it possible to limit their environmental impact upstream, there are still few initiatives aimed at their use. The Swedish "Hazard Score" assessment tool, which classifies compounds according to their potential to pollute the aquatic environment, was presented as a tool for guiding prescription choices. Through the exchanges between the various stakeholders (public authorities, doctors, pharmacists, manufacturers, patients) during this forum, recommendations were drawn up both on scientific and ethical grounds., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Given its good tolerance and broad spectrum, isavuconazole is increasingly used off-label as an empirical therapy of invasive fungal infections. We retrospectively reviewed isavuconazole empirical treatment during a 12-month period in four hospitals. During isavuconazole treatment (n=27), none of the patients had a mycological evidence for fungal infection, but 19% (5/27) developed liver test abnormalities without leading to isavuconazole discontinuation. Isavuconazole could be considered as an off-label empirical therapy only if patients cannot receive caspofungin or liposomal amphotericin B., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Invasive candidiasis is still recognized as a major cause of morbidity and mortality. To support clinicians in the optimal use of antifungals for the treatment of invasive candidiasis, a computerized decision support system (CDSS) was developed based on institutional guidelines., Objectives: To evaluate the correlation of this newly developed CDSS with clinical practices, we set-up a retrospective multicentre cohort study with the aim of providing the concordance rate between the CDSS recommendation and the medical prescription (NCT05656157)., Patients and Methods: Adult patients who received caspofungin or fluconazole for the treatment of an invasive candidiasis were included. The analysis of factors associated with concordance was performed using mixed logistic regression models with department as a random effect., Results: From March to November 2022, 190 patients were included from three centres and eight departments: 70 patients from centre A, 84 from centre B and 36 from centre C. Overall, 100 patients received caspofungin and 90 received fluconazole, mostly (59%; 112/190) for empirical/pre-emptive treatment. The overall percentage of concordance between the CDSS and medical prescriptions was 91% (173/190) (confidence interval 95%: 82%-96%). No significant difference in concordance was observed considering the centres (P > 0.99), the department of inclusion (P = 0.968), the antifungal treatment (P = 0.656) or the indication of treatment (P = 0.997). In most cases of discordance (n = 13/17, 76%), the CDSS recommended fluconazole whereas caspofungin was prescribed. The clinical usability evaluated by five clinicians was satisfactory., Conclusions: Our results demonstrated the high correlation between current antifungal clinical practice and this user-friendly and institutional guidelines-based CDSS., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Invasive aspergillosis (IA) is increasing especially in new groups of patients. Despite advances in management, morbidity and mortality related to IA remain high. Thus, Clinical Decision Support System (CDSS) dedicated to IA are needed to promote the optimal antifungal for each group of patients., Patients and Methods: This was a retrospective multicenter cohort study involving intensive care units and medical units. Adult patients who received caspofungin, isavuconazole, itraconazole, liposomal amphotericin B, posaconazole, or voriconazole, for the treatment of IA were eligible for enrollment. The primary objective was the concordance between the clinician's prescription and the prescription recommended by the CDSS. The secondary objective was the concordance according to different hospitals, departments, and indications., Results: Eighty-eight patients (n=88) from three medical hospitals were included. The overall concordance was 97% (85/88) including 100% (41/41) for center A, 92% (23/25) for center B, and 95% (21/22) for center C. There was no significant difference in concordance among the hospitals (P=0.973), the departments (P=1.000), and the indications (P=0.799). The concordance was 70% (7/10) for isavuconazole due to its use as an empirical treatment and 100% (78/78) for the other antifungals., Discussion: The concordance rate was high whatever the hospital, the department, and the indication. The only discrepancy was attributed to the use of isavuconazole as an empirical treatment which is a therapeutic option not included in the CDSS., Conclusions: This new CDSS dedicated to IA is meeting the clinical practice. Its implementation in routine will help to support antifungal stewardship., (Copyright © 2023 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Hemozoin is a byproduct of hemoglobin digestion crucial for parasite survival. It forms crystals that can be of interest as drug targets or biomarkers of malaria infection. However, hemozoin has long been considered as an amorphous crystal of simple morphology. Studying the consequences of biomineralization of this crystal during the parasite growth may provide more comprehensive evidence of its role during malaria., Objectives: This study aimed to investigate the interest of nanoparticles tracker analysis for measuring the concentration and size of hemozoin particles produced from different parasite sources and conditions., Methods: Hemozoin was extracted from several clones of Plasmodium falciparum both asexual and sexual parasites. Hemozoin was also extracted from blood samples of malaria patients and from saliva of asymptomatic malaria carriers. Nanoparticles tracking analysis (NTA) was performed to assess the size and concentration of hemozoin., Results: NTA data showed variation in hemozoin concentration, size, and crystal clusters between parasite clones, species, and stages. Among parasite clones, hemozoin concentration ranged from 131 to 2663 particles/infected red blood cell (iRBC) and size ranged from 149.6 ± 6.3 nm to 234.8 ± 40.1 nm. The mean size was lower for Plasmodium vivax (176 ± 79.2 nm) than for Plasmodium falciparum (254.8 ± 74.0 nm). Sexual NF54 parasites showed a 7.5-fold higher concentration of hemozoin particles (28.7 particles/iRBC) compared to asexual parasites (3.8 particles/iRBC). In addition, the mean hemozoin size also increased by approximately 60 % for sexual parasites. Compared to in vitro cultures of parasites, blood samples showed low hemozoin concentrations., Conclusions: This study highlights the potential of NTA as a useful method for analyzing hemozoin, demonstrating its ability to provide detailed information on hemozoin characterization. However, further research is needed to adapt the NTA for hemozoin analysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The World Health Organization (WHO) recently published a list of fungal priority pathogens, including Candida albicans and C. auris . The increased level of resistance of Candida is raising concern, considering the availability of only four classes of medicine. The WHO is seeking novel agent classes with different targets and mechanisms of action. Targeting Candida metacaspases to control intrinsic cell death could provide new therapeutic opportunities for invasive candidiasis. In this review, we provide the available evidence for Candida cell death, describe Candida metacaspases, and discuss the potential of Candida metacaspases to offer a new specific target. Targeting Candida cell death has good scientific rationale given that the fungicidal activity of many marketed antifungals is mediated, among others, by cell death triggering. But none of the available antifungals are specifically activating Candida metacaspases, making this target a new therapeutic opportunity for non-susceptible isolates. It is expected that antifungals based on the activation of fungi metacaspases will have a broad spectrum of action, as metacaspases have been described in many fungi, including filamentous fungi. Considering this original mechanism of action, it could be of great interest to combine these new antifungal candidates with existing antifungals. This approach would help to avoid the development of antifungal resistance, which is especially increasing in Candida .

Scedosporium and Lomentospora species rank second among the filamentous fungi colonizing the airways of cystic fibrosis (CF) patients. These fungi could be responsible for allergic bronchopulmonary mycosis (ABPM) and bronchitis before lung transplantation and invasive infections after. However, their role in CF lung disease is debated. This study aimed to identify clinical or environmental factors associated with an airway colonization by Scedosporium/Lomentospora species in patients with CF over a period of 7 years. A longitudinal cohort study was conducted from 2008 to 2014 in the CF reference centre in Lyon, France, to compare the characteristics of patients with Scedosporium/Lomentospora colonized and non-colonized patients. During the study period, 283 patients completed the clinical and microbiological follow-up. The analysis revealed that a higher number and duration of hospitalizations, an increased number of courses of parenteral antibiotic therapy, a history of ABPA, and treatment by itraconazole were significantly associated with an airway colonization by Scedosporium/Lomentospora species. The rate of decline of forced expiratory volume in the first second was not statistically different between colonized and non-colonized patients. This study provides evidence that patients colonized by Scedosporium/Lomentospora species require more medical care than non-colonized patients. Additional care could be in part explained by the management of Scedosporium/Lomentospora-related diseases such as ABPM or bronchitis. However, we did not demonstrate a faster rate of decline of respiratory function or body mass index in colonized patients, suggesting, as previously reported, that colonization of the airways by these fungi does not play a significant role in the progression of CF disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Objectives: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter., Patients and Methods: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included., Results: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy., Conclusions: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Malaria elimination is a major goal to be reached in the next decade. Significant progress were made in the past, and the prevalence decreased in many areas while the positive trend stalled in the last years. The exact number of asymptomatic carriers of Plasmodium parasites is unknown since this population is not detected by conventional diagnosis methods and participate in the maintenance of transmission. Molecular methods to detect low parasitemia are not available at point-of-care in low-income countries of malaria endemic areas. Adaptation of molecular methods such as loop-mediated isothermal amplification of DNA may provide effective tools but it required simplification of DNA detection. Square waves voltammetry, easily imbedded in small device such as cell phone, was largely described for DNA detection but support for reaction was an issue to address. Here we used an efficient functionalization method of paper-based material to facilitate the interactions between isothermal amplification product and methylene blue for easy-to-use DNA detection. The proof-of-concept of qualitative detection of very low parasitemia from malaria infected patients using newly chemically treated paper for square waves voltammetry was obtained with a sensitivity and specificity of 100% and a limit-of-detection of 0.1 parasite. μL -1 corresponding to a parasitemia of 0.000002%., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the context of COVID-19 pandemic, antifungal overuse may have occurred in our hospitals as it has been previously reported for antibacterials., Methods: To investigate the impact of COVID-19 on antifungal consumption, a multicenter retrospective study including four medical sites and 14 intensive care units (ICU) was performed. Antifungal consumption and incidences of invasive fungal diseases before and during COVID-19 pandemic, for non-COVID-19 patients and COVID-19 patients, were described., Results: An increase in voriconazole consumption was observed in 2020 compared with 2019 for both the whole hospital and the ICU (+ 40.3% and + 63.7%, respectively), whereas the incidence of invasive aspergillosis significantly increased in slightly lower proportions in the ICU (+ 46%). Caspofungin consumption also increased in 2020 compared to 2019 for both the whole hospital and the ICU (+ 34.9% and + 17.0%, respectively) with an increased incidence of invasive candidiasis in the whole hospital and the ICU but in lower proportions (+ 20.0% and + 10.9%, respectively)., Conclusions: We observed an increased consumption of antifungals including voriconazole and caspofungin in our hospital during the COVID-19 pandemic and explained in part by an increased incidence of invasive fungal diseases in COVID-19 patients. These results are of utmost importance as it raises concern about the urgent need for appropriate antifungal stewardship activities to control antifungal consumption., (© 2022. The Author(s).)

A series of ferrocenyl-containing γ-hydroxy-γ-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 μM, with generally good resistance index. The most active ferrocene in these series exhibited IC 50 equal to 0.09 μM (3D7) and 0.12 μM (W2). The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The production of Plasmodium gametocytes in vitro is a real challenge. Many protocols have been described, but few have resulted in the production of viable and infectious gametocytes in sufficient quantities to conduct research on-but not limited to-transmission-blocking drug and vaccine development. The aim of this review was to identify and discuss gametocyte production protocols that have been developed over the last two decades., Methods: We analyzed the original gametocyte production protocols published from 2000 onwards based on a literature search and a thorough review. A systematic review was performed of relevant articles identified in the PubMed, Web of Sciences and ScienceDirect databases., Results: A total 23 studies on the production of Plasmodium gametocytes were identified, 19 involving in vitro Plasmodium falciparum, one involving Plasmodium knowlesi and three involving ex vivo Plasmodium vivax. Of the in vitro studies, 90% used environmental stressors to trigger gametocytogenesis. Mature gametocytemia of up to 4% was reported., Conclusions: Several biological parameters contribute to an optimal production in vitro of viable and infectious mature gametocytes. The knowledge gained from this systematic review on the molecular mechanisms involved in gametocytogenesis enables reproducible gametocyte protocols with transgenic parasite lines to be set up. This review highlights the need for additional gametocyte production protocols for Plasmodium species other than P. falciparum., (© 2022. The Author(s).)

Metacaspases are caspase-like homologs which undergo a complex maturation process involving multiple intra-chain cleavages resulting in a composite enzyme made of a p10 and a p20 domain. Their proteolytic activity involving a cysteine-histidine catalytic dyad, show peptide bond cleavage specificity in the C-terminal to lysine and arginine, with both maturation- and catalytic processes being calcium-dependent. Here, we present the structure of a metacaspase from the yeast Candida glabrata, CgMCA-I, in complex with a unique calcium along with a structure in which three magnesium ions are bound. We show that the Ca 2+ ion interacts with a loop in the vicinity of the catalytic site. The reorganization of this cation binding loop, by bringing together the two catalytic residues, could be one of the main structural determinants triggering metacaspase activation. Enzymatic exploration of CgMCA-I confirmed that the maturation process implies a trans mechanism with sequential cleavages., (© 2022. The Author(s).)

Background: Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment., Methods: The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry., Results: The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively., Conclusion: Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment., (© 2022. The Author(s).)

Background: The Indonesian Republic plans to relocate its capital from Jakarta to East Kalimantan, Borneo Island, in the next few years. This relocation may be associated with deforestation, decreased biodiversity, and an increased risk of emerging zoonotic infections, including Plasmodium knowlesi malaria. The Malaysian part of Borneo Island is one of the main hotspots of P. knowlesi malaria., Methods: Considering this risk, we evaluated the transmission dynamics of P. knowlesi in the Indonesian Archipelago based on a literature search and extensive review of data from the Indonesian Ministry of Health., Results: We report that 545 P. knowlesi cases were documented in Indonesia, mainly in the Aceh and North Sumatra provinces, with 95% of these occurring in the last 4 years., Conclusions: The main P. knowlesi vectors are present in the area of the future capital, requiring strengthened surveillance to reduce the risk of emerging cases in a rapidly growing population., (© 2022. The Author(s).)

Antimicrobials including antibiotics, antiparasitic, and antifungals, are subjected to resistance. In this context, Public Health Organizations called for a One Health approach because antimicrobials used to treat different infectious diseases in animals and plants may be the same than those used in humans. Whereas mechanisms of resistance transmission from animals or environment to humans should be considered differently if related to prokaryotic or eukaryotic pathogens, their impact can be considered as a whole. In that respect, we discussed the use of anti-parasitic in animals including anticoccidials, anthelmintics, and insecticides-acaricides, and the use of azoles in the environment that may both favor the development of drug resistance in humans. In light of the current situation, there is an urgent need for a transdisciplinary approach through anti-parasitic and antifungal stewardship programs in humans, animals, and environment, especially in the era of COVID-19 pandemic that will probably aggravate antimicrobial resistance., Competing Interests: The authors have no competing interest to declare., (© 2021 Published by Elsevier B.V.)

Introduction. Antifungal stewardship programmes are needed in healthcare facilities to limit the overuse or misuse of antifungals, which are responsible for an increase in antifungal resistance. Hypothesis/Gap Statement. Core recommendations for antifungal stewardship were published by the Mycoses Study Group Education and Research Consortium, while the Centers for Disease Control and Prevention (CDC) provided a Core Elements of Hospital Antibiotic Stewardship Programs checklist. The recommendations offer global core elements for best practices in antifungal stewardship, but do not provide a framework for the implementation of antifungal stewardship programmes in healthcare facilities. Aim. In line with the recommendations, it is of the utmost importance to establish a practical checklist that may be used to implement antifungal stewardship programmes. Methodology. The practical checklist was established by a national consensus panel of experts involved in antifungal stewardship activities. A preliminary checklist was sent to all experts. The final document was approved by the panel after discussion and the resolution of any disagreements by consensus. Results. The final checklist includes the following items: leadership support; actions to support optimal antifungal use; actions to monitor antifungal prescribing, use and resistance; and an education programme. Conclusion. This antifungal stewardship checklist offers opportunities for antifungal resistance containment, given that antifungal stewardship activities promote the optimal use of antifungals.

Artesunate is the current most potent antimalarial drug widely used for the treatment of malaria. Considering the emergence of artemisinin resistance, several situations may require a simple method for artesunate quantification. We thus developed a quantitative and a semi-quantitative biological method for the determination of artesunate in liquid samples. The tests are based on the measurement of samples' antimalarial activity on Plasmodium falciparum 3D7 using a modified SYBR Green I drug susceptibility test. For the quantitative test, we established a standard curve that resulted from a dose-response curve and evaluated its performances using controls samples. Whereas the linear regression analysis between artesunate concentration and antimalarial activity showed promising results (linearity range 1.5-24.6 ng/mL, r 2 = 0.9373), we found that artesunate content of the controls was significantly overestimated (p = 0.0313). For the semi-quantitative test, we compared the antimalarial activities of samples collected during permeation studies of artesunate to that of a reference (artesunate IC 50 ) by statistical analysis. We demonstrated that antimalarial activities of samples from permeation tests using a powder formulation of artesunate were greater than those of samples from tests using a solution formulation. Bioassays can be simple techniques to assess artesunate in liquid samples, particularly in resource-limited settings. Comparison with reference methods is still recommended when accurate drug quantification is required., (© Y.I. Kouakou et al., published by EDP Sciences, 2022.)

Malaria diagnosis based on microscopy is impaired by the gradual disappearance of experienced microscopists in non-endemic areas. Aside from the conventional diagnostic methods, fluorescence flow cytometry technology using Sysmex XN-31, an automated haematology analyser, has been registered to support malaria diagnosis. The aim of this prospective, monocentric, non-interventional study was to evaluate the diagnostic accuracy of the XN-31 for the initial diagnosis or follow-up of imported malaria cases compared to the reference malaria tests including microscopy, loop mediated isothermal amplification, and rapid diagnostic tests. Over a one-year period, 357 blood samples were analysed, including 248 negative and 109 positive malaria samples. Compared to microscopy, XN-31 showed sensitivity of 100% (95% CI: 97.13-100) and specificity of 98.39% (95% CI: 95.56-100) for the initial diagnosis of imported malaria cases. Moreover, it provided accurate species identification asfalciparumor non-falciparumand parasitaemia determination in a very short time compared to other methods. We also demonstrated that XN-31 was a reliable method for patient follow-up on days 3, 7, and 28. Malaria diagnosis can be improved in non-endemic areas by the use of dedicated haematology analysers coupled with standard microscopy or other methods in development, such as artificial intelligence for blood slide reading. Given that XN-31 provided an accurate diagnosis in 1 min, it may reduce the time interval before treatment and thus improve the outcome of patient who have malaria., (© S. Picot et al., published by EDP Sciences, 2022.)

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment., Competing Interests: The authors have declared that no competing interests exist.

Aim: The aim was to assess the flagging performance of Sysmex XN-10 haematology analyser for malaria detection through the parasitic red blood cell ('pRBC') alarm., Methods: We retrospectively studied 584 blood samples performed on the Sysmex XN-10 analyser that were tested for malaria. Sensitivity, specificity, positive and negative predictive values, and prevalence were established for the pRBC alarm., Results: Sensitivity, specificity, and positive and negative predictive values for the pRBC flag were 7.8%, 100%, 100% and 87.7%, respectively. The prevalence of pRBC flag of 0.026% in the overall population was significantly different from the prevalence of 1.027% in the population tested for malaria., Conclusions: Considering the excellent specificity and the low prevalence of the flag in the overall population, we suggest, in case of the presence of pRBC flag, the implementation of a rapid review of the blood smear looking for Plasmodium , mostly if the patient had fever and had not been tested for malaria., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Diagnosis is a challenging issue for eliminating malaria. Loop-mediated isothermal amplification (LAMP) could be an alternative to conventional methods. This study aimed to evaluate the diagnostic accuracy of LAMP for malaria compared with microscopy, polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs)., Methods and Design: MEDLINE, Web of Science and Scopus were searched from inception to 1 July 2019. Prospective and retrospective, randomised and non-randomised, mono-center and multi-center studies, including symptomatic or asymptomatic patients, that reported one LAMP method and one comparator (microscopy, RDT or PCR) were included. PROSPERO registration number: CRD42017075186., Results: Sixty-six studies published between 2006 and 2019 were included, leading to the analysis of 30,641 LAMP tests. The pooled sensitivity of LAMP remained between 96% and 98%, whichever the comparator. The pooled specificity of LAMP was around 95%, but was a little higher if the best PCR studies were considered. The AUC was found to be >0.98, whichever the subgroup of studies was considered. Diagnostic odds ratio (DOR) was found to be around 1000 for all subgroups, except for Plasmodium vivax., Conclusion: This meta-analysis confirmed that the LAMP method is robust for diagnosing malaria, both in symptomatic and asymptomatic people. Thus, the impact of LAMP for controlling malaria is expected to be important., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Mycetoma and chromoblastomycosis are both chronic subcutaneous infectious diseases that pose an obstacle to socioeconomic development. Besides the therapeutic issue, the diagnosis of most neglected tropical diseases (NTD) is challenging. Confirmation using direct microscopy and culture, recognized as WHO essential diagnostic tests, are limited to specialized facilities. In this context, there is a need for simple user-friendly diagnostic tests to be used in endemic villages., Methods: This review discuss the available biomarkers that could help to improve the diagnostic capacity for mycetoma and chromoblastomycosis in a theoretical and practical perspective., Results: A lack of research in this area has to be deplored, mainly for mycetoma. Biomarkers based on the immune response (pattern of leucocytes, antibody detection), the dermal involvement (extracellular matrix monitoring, protein expression), and the presence of the infectious agent (protein detection) are potential candidates for the detection or follow-up of infection., Conclusion: Confirmatory diagnosis based on specific diagnostic biomarkers will be the basis for the optimal treatment of mycetoma and chromoblastomycosis. It will be part of the global management of NTDs under the umbrella of stewardship activities.

Purpose : Candida endophthalmitis represents a therapeutic challenge, considering the inability of many antifungals to achieve adequate concentrations in the vitreous. Intravitreal injection (IVI) of antifungals (amphotericin b deoxycholate or voriconazole) is therefore recommended. Whereas amphotericin b IVI is well documented, clinical data on voriconazole IVI are limited. Methods : This was a retrospective review IRB approved of patients receiving voriconazole IVI for Candida endophthalmitis. Complete ophthalmological examination was completed at baseline and during follow-up. Results : Five patients were treated with a mean four injections [range: 2-9] of voriconazole (100 µg/0.1 mL saline). Improvement of visual acuity and disappearance of signs of infection were obtained in all patients. Safety concern including photoreceptor toxicity was not attributed to voriconazole IVI. Conclusions : Voriconazole IVI demonstrated to be safe and led to a favorable clinical outcome. Thus, voriconazole IVI must be performed if Candida endophthalmitis is suspected to increase the chance of clinical success.

Background: Candidemia is a major cause of mortality in the intensive care unit (ICU). According to the Infectious Diseases Society of America (IDSA), an echinocandin is recommended as initial therapy and fluconazole as an alternative. In a context of echinocandin resistance development, the question arising is whether azoles are a suitable alternative to echinocandins for the treatment of candidemia in critically ill patients., Methods: A 3-year (2015-2017) retrospective multicentric cohort study was conducted. Adult patients with a diagnosis of candidemia during the ICU stay and treated with echinocandins or azoles were included. Demographic, clinical data, mycological data, and antifungal treatments were collected. Kaplan-Meier survival analysis, univariate analysis, and a multivariate logistic regression analysis using a propensity score with the inverse probability of treatment weighting method were performed., Findings: Seventy-nine patients (n = 79) were analyzed. Treatment success, as well as survival on day 90 (Kaplan-Meier survival analysis, log rank test, p = 0.542), were comparable between patients who received echinocandins (caspofungin (n = 47)) or azoles (fluconazole (n = 29) or voriconazole (n = 3)). A multivariable analysis demonstrated that higher SOFA score on the day of candidemia diagnosis and absence of adequate Candida source control were independently associated with a greater risk of 90-day mortality, whereas azoles treatment was not associated with an excess 90-day mortality., Interpretation: This study confirms that the use of azoles recommended for candidemia, mostly fluconazole, as a first-line therapy is a reasonable alternative to caspofungin for ICU patients in our institution. This needs to be included in local guidelines through antifungal stewardship programs., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Artesunate (ART) is an artemisinin derivative used as monotherapy for the treatment of severe malaria and in combination with a partner drug for non-severe malaria. Resistance of malaria parasites to artemisinins have emerged in Southeast Asia. Adjustment of drug regimen may be an option to prevent therapeutic failures considering the relative favourable safety profile of ART high doses., Methods: For that purpose, a systematic review was done using PubMed, Scopus and Web of Science databases. All studies on ART and DHA pharmacokinetic post-administration of artesunate in human patients or volunteers were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 2009 was used., Findings: Fifty studies exploring oral, intravenous, rectal, and intramuscular route (1470 persons, volunteers and patients) were included. Correlations between artesunate doses and C max or AUC 0-∞ of dihydroartemisinin (DHA) and DHA+ART were evaluated. This correlation was good (R 2 >0.9) using intravenous (IV) route. DHA and ART+DHA average concentrations (Cav) were well above estimated in vivo half-maximal effective concentration (EC 50 ) for intravenous route, but this was not the case for oral route., Interpretation: The favorable Cav/EC 50 ratio for IV route provides evidence that IV ART will remain efficient even in the case of increased resistance level, whereas for the oral route, a two-fold increase in EC 50 may lead to therapeutic failures, thus providing a rationale for oral dose escalation. Considering the inter-individual variability of ART pharmacokinetic, Therapeutic Drug Monitoring through antimalarial stewardship activities is needed to optimize drug exposure and avoid resistance development., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Candida resistance to antifungals impaired invasive candidiasis outcome. In a context of echinocandin resistance development, we aimed to evaluate the association between phenotypic resistance to micafungin and fks mutations of Candida glabrata. For this systematic review and meta-analysis, we searched MEDLINE, Scopus and Web of Science for reports published up to December 2017. Studies of C glabrata candidiasis with minimum inhibitory concentrations (MIC) determination of micafungin and fks genotyping were included. Reviews, studies not using reference methods, non-glabrata Candida, experimental isolates and undetailed mutations were excluded. Two authors independently assessed the eligibility of articles and extracted data. The main outcome was the diagnostic accuracy of fks mutations compared to micafungin MIC for C glabrata, measured as fixed-effect odd ratio. Heterogeneity was calculated with the I 2 statistic. This study is registered with PROSPERO (CRD42018082023). Twenty-four studies were included in the meta-analysis. Pooled analysis found that S663P (OR 7.25, 95% CI 3.50-15.00; P < 0.00001), S629P (OR 3.70, 1.64-8.33; P = 0.002) and F659del (OR 5.66, 1.22-26.18; P = 0.03) were associated with increased risk of having a resistant isolate according to authors' interpretation of MICs. In sensitivity analysis based on new CLSI clinical breakpoints, the ORs for S663P and S629P remained significant. Genotyping of isolates of C glabrata for S663P and S629P mutations is an effective alternative to micafungin susceptibility tests. Relevant molecular markers of drug resistance will significantly improve the management of C glabrata infections., (© 2019 Blackwell Verlag GmbH.)

Objectives: Following the removal of temporary treatment protocol procedures, we developed a thesaurus for off-label indications for systemic antifungals at our facility to update clinical practices and to control off-label prescriptions., Materials and Methods: Clinical practice guidelines and literature data were analyzed. This work was part of an antifungal stewardship program., Results: Off-label wording (prophylaxis, preemptive, empirical, curative) and corresponding antifungals and references were validated by the multidisciplinary group for antifungal agents under the aegis of the Commission for the use of drugs and sterile medical devices and of the anti-infective committee., Conclusion: Considering the complexity of invasive fungal infection management, this thesaurus needs to be shared and used as a helping tool to review off-label situations., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Global malaria cases have not been significantly reduced over the last three years although more than USD 3 billion was invested in malaria control and elimination. The reasons for this stagnation are highly complex and multi-factorial. It remains that almost three billion treatment courses were supplied over the period 2010-2017: 30% of them without malaria tests, and some with suboptimal doses leading to the risk of selection of resistant parasites. An antimalarial stewardship program should be implemented at the healthcare provider, physician, pharmacist, medical student, and population levels. This would significantly reinforce the impact of international guidelines and national malaria program policies and fill the gap between recommendations and actual practices., (© A.-L. Bienvenu et al., published by EDP Sciences, 2019.)

Objectives: Recent studies have reported the emerging worldwide problem of azole drug resistance of A. fumigatus isolates. The aim of this study was to evaluate the antifungal susceptibilities of A. fumigatus isolates recovered from air and clinical samples collected in a French University hospital (Lyon), which underwent major deconstruction works over a one year-period., Methods: A daily surveillance of fungal contamination was implemented during 11-months. Environmental survey was realized by air samplings, outdoor and indoor, with an automatic agar sampler. In parallel, surveillance of IA infection cases was conducted by epidemiological investigation. Environmental and clinical isolates of A. fumigatus were identified by conventional methods and β-tubulin sequencing. Susceptibility testing of A. fumigatus isolates against Itraconazole (ITZ), Voriconazole (VCZ) was performed using Etest method., Results: A total of 3885 air samples (1744 outdoor samples and 2141 indoor samples) were collected. From the 3073 identified colonies of A. fumigatus, 400 A. fumigatus isolates were tested for their susceptibility to ITZ and VCZ, including 388 isolates coming from the environment (indoor n:157, outdoor n:231) and 12 isolates coming from clinical samples. All the 400 isolates were susceptible to azoles (≤1μg/mL)., Conclusions: No environmental reservoir of A. fumigatus azole resistant strains was found in our hospital which was undergoing major demolition works. Further studies with larger number of A. fumigatus clinical isolates and environmental isolates from agricultural areas and healthcare establishments are needed to better appreciate the occurrence and prevalence of azole resistance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Malaria is a potentially severe disease affecting nearly 200 million people per year. Early detection of the parasite even in unsuspected patients remains the challenging aim for effective patient care. Automated complete blood counts that are usually performed for any febrile patient might represent a tool to ascertain malaria infection., Aims: To evaluate the ability of the new generation of the Sysmex hematology analyzer (XN-series) to detect malaria., Methods: We retrospectively studied 100 blood samples performed with the recent Sysmex XN analyzer that were positive for Plasmodium and explored its ability to detect the parasite. 100 samples from patients uninfected by malaria were used as control group., Results: Specific abnormalities such as additional events in the mature neutrophil/eosinophil area of the white blood cells differential (WDF) scattergram were noted for 1.1% of Plasmodium falciparum samples and 56.2% of other Plasmodium species samples. Mature parasite stages (schizonts or gametocytes) were observed on blood smears among those samples. WDF scattergrams were able to detect 80.0% (12/15) of Plasmodium mature stages. Furthermore, the differential in white blood counts between WDF and white cell nucleated (WNR) channels was a predictive signal of Plasmodium mature stages in 73.3% (11/15) of samples and may be explained by a differential destruction of particles with the analyzer reagent., Conclusion: Associated to thrombocytopaenia, a Sysmex XN Plasmodium pattern may represent a useful warning for Plasmodium detection in unsuspected patients, particularly when mature parasite stages are present., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures., Methods: We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term 'antifungal stewardship' on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures., Results: A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality., Conclusions: All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The role of some nutrient-derived metabolites on the innate and adaptive immune responses is now established. Global research approach investigating the interplay between environment, lifestyle and the host's immune responses is crucial in the understanding of malaria susceptibility. Advanced Glycation end products (AGE), which are food-derived metabolites result from the link between reducing sugar and amino group of proteins, lipids or nucleic acids. The level of exposure to AGEs varies depending on the type of diet. The dysfunction of the immune system induced by AGE and the cellular receptors for AGEs (RAGE) in susceptibility to bacterial infection has been described. But no study has yet explored their role in susceptibility to malaria. Therefore, we aimed to evaluate systemic AGE and RAGE gene polymorphism in two sympatric populations with previously described difference of susceptibility to malaria. We measured by ELISA the plasma levels of AGEs, and their soluble receptors (sRAGE) from 170 volunteers (68 Fulani and 102 Dogon). We also determined by real-time quantitative PCR the expression of RAGE, and the -374 T/A, -429 T/C polymorphisms and 63 bp deletion by fragment length restriction polymorphism. The prevalence rate of Plasmodium in Fulani and Dogon were respectively 42.64% and 51.30% for P. falciparum, 5.88% and 6.5% for P. malariae, 0% and 2.6% for P. ovale. The average AGE was 12.65 μg/ml, and 496.48pg/ml for sRAGE. Highest levels of sRAGE were observed in Fulani (563,07pg/ml, 95% CI [547.81-580.13] vs 465.68pg/ml, 95% CI [331.19-467.51]) for Dogon, p = 0.00001. Fulani had the lowest mean of AGE (10.21μg/ml, 95% CI [8.02-10.92]) compared to Dogon (16.88μg/ml, 95% CI [13.92-17.96]; p = 0.00001. RAGE was more expressed in Dogon than Fulani (0.08 vs 0.04), P = 0.08. The -374A polymorphism vas more frequent in Fulani (32%) compared to Dogon (20%). The chronic exposure to dietary AGE could lead to immune responses impairment and polymorphism with implications in malaria susceptibility. More studies are necessary to better investigate this hypothesis.

Background: Since several malaria parasite species are usually present in a particular area, co-infections with more than one species of Plasmodium are more likely to occur in humans infected in these areas. In many mixed infections, parasite densities of the cryptic species may be low and often not recognized in clinical practice., Case Presentation: Two children (3 and 6 years old) adopted recently from Central African Republic were admitted to hospital because of intermittent fever. Thin blood smears stained with Giemsa showed Plasmodium falciparum and Plasmodium malariae co-infection for both children at admission. They were both treated with atovaquone-proguanil combination for 3 days. At day 7, both thin blood smears examination remained negative but at day 28, thin blood smear was positive for P. malariae trophozoites and for Plasmodium ovale for the girl and her brother, respectively. Samples collected at day 1 and day 28 were submitted to real-time PCR showing the presence of the three parasite species (P. falciparum, P malariae and P. ovale) in admission blood samples from the two children and only P. ovale at day 28., Conclusions: Twenty-eight days follow-up after treatment led to detection of a third parasite species in the blood of these two patients suggesting covert co-infection and a delayed appearance of one cryptic species following treatment. Concurrently infecting malaria species could be mutually suppressive, with P. falciparum tending to dominate other species. These observations provide more evidence that recommendations for treatment of imported malaria should take into account the risk of concurrent or cryptic infection with Plasmodium species. Clinicians and biologists should be aware of the underestimated frequency of mixed infections with cryptic species and of the importance of patient follow-up at day 28. Future guidelines should shed more light on the treatment of mixed infection and on the interest of using artemisinin-based combinations for falciparum and non-falciparum species.

Background: Plasmodium vivax is the second most important human malaria parasite, widely spread across the world. This parasite is associated with important issues in the process toward malaria elimination, including potential for relapse and increased resistance to chloroquine. Plasmodium vivax multi-drug resistant (pvmdr1) is suspected to be a marker of resistance although definitive evidence is lacking. Progress has been made in knowledge of biological factors affecting parasite growth, including mechanisms of regulated cell death and the suspected role of metacaspase. Plasmodium vivax metacaspase1 (PvMCA1-cd) has been described with a catalytic domain composed of histidine (H372) and cysteine (C428) residues. The aim of this study was to test for a link between the conserved histidine and cysteine residues in PvMCA1-cd, and the polymorphism of the P. vivax multi-drug resistant gene (pvmdr1)., Results: Thirty P. vivax isolates were collected from Mauritania, Sudan, and Oman. Among the 28 P. vivax isolates successfully sequenced, only 4 samples showed the conserved His (372)-Cys (428) residues in PvMCA1-cd. Single nucleotide polymorphisms observed were H372T (46.4%), H372D (39.3%), and C428R (85.7%). A new polymorphic catalytic domain was observed at His (282)-Cys (305) residues. Sequences alignment analysis of pvmdr1 showed SNP in the three codons 958, 976 and 1076. A single SNP was identified at the codon M958Y (60%), 2 SNPs were found at the position 976: Y976F (13%) and Y976V (57%), and 3 SNPs were identified at the position 1076: F1076L (40%), F1076T (53%) and F1076I (3%). Only one isolate was wildtype in all three codons (MYF), 27% were single MYL mutants, and 10% were double MFL mutants. Three new haplotypes were also identified: the triple mutant YVT was most prevalent (53.3%) distributed in the three countries, while triple YFL and YVI mutants (3%), were only found in samples from Sudan and Mauritania., Conclusions: Triple or quadruple mutants for metacaspase genes and double or triple mutants for Pvmdr1 were observed in 24/28 and 19/28 samples. There was no difference in the frequency of mutations between PvMCA1-cd and Pvmdr1 (P > 0.2). Histidine and cysteine residues in PvMCA1-cd are highly polymorphic and linkage disequilibrium with SNPs of Pvmdr1 gene may be expected from these three areas with different patterns of P. vivax transmission.

Background: Sensitive and easy-to-perform methods for the diagnosis of malaria are not yet available. Improving the limit of detection and following the requirements for certification are issues to be addressed in both endemic and non-endemic settings. The aim of this study was to test whether loop-mediated isothermal amplification of DNA (LAMP) may be an alternative to microscopy or real-time PCR for the screening of imported malaria cases in non-endemic area., Results: 310 blood samples associated with 829 suspected cases of imported malaria were tested during a one year period. Microscopy (thin and thick stained blood slides, reference standard) was used for the diagnosis. Real-time PCR was used as a standard of truth, and LAMP (Meridian Malaria Plus) was used as an index test in a prospective study conducted following the Standards for Reporting Diagnosis Accuracy Studies. In the 83 positive samples, species identification was P. falciparum (n = 66), P. ovale (n = 9), P. vivax (n = 3) P. malariae (n = 3) and 2 co-infections with P. falciparum + P.malariae. Using LAMP methods, 93 samples gave positive results, including 4 false-positives. Sensitivity, specificity, positive predictive value and negative predictive value for LAMP tests were 100%, 98.13%, 95.51%, and 100% compared to PCR., Conclusion: High negative predictive value, and limit of detection suggest that LAMP can be used for screening of imported malaria cases in non-endemic countries when expert microscopists are not immediately available. However, the rare occurrence of non-valid results and the need for species identification and quantification of positive samples preclude the use of LAMP as a single reference method., (© C. Ponce et al., published by EDP Sciences, 2017.)

Plasmodium vivax is the most widely distributed human malaria parasite. Outside sub-Saharan Africa, the proportion of P. vivax malaria is rising. A major cause for concern is the re-emergence of Plasmodium vivax in malaria-free areas. Oman, situated in the south-eastern corner of the Arabian Peninsula, has long been an area of vivax malaria transmission but no locally acquired cases were reported in 2004. However, local transmission has been registered in small outbreaks since 2007. In this study, a local outbreak of 54 cases over 50 days in 2014 was analyzed retrospectively and stained blood slides have been obtained for parasite identification and genotyping. The aim of this study was to identify the geographical origin of these cases, in an attempt to differentiate between imported cases and local transmission. Using circumsporozoite protein (csp), merozoite surface protein 1 (msp1), and merozoite surface protein 3 (msp3) markers for genotyping of parasite DNA obtained by scrapping off the surface of smears, genetic diversity and phylogenetic analysis were performed. The study found that the samples had very low genetic diversity, a temperate genotype, and a high genetic distance, with most of the reference strains coming from endemic countries. We conclude that a small outbreak of imported malaria is not associated with re-emergence of malaria transmission in Oman, as no new cases have been seen since the outbreak ended., (© B. Simon et al., published by EDP Sciences, 2017.)

In this Letter we report on an efficient and short 2-3 steps synthesis of γ-hydroxy-γ-lactam derived-tetramates bearing a 7-chloro-4-aminoquinoline skeleton and their evaluation as potent antimalarials. These molecules were obtained through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of 7-chloro-4-aminoquinoline-derived amines. In vitro antimalarial activity of these new γ-lactams was evaluated against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) and they were found to be active in the range of 14-827nM with generally good resistance index. A preliminary SAR study is also presented to explain these results. Finally, the most active compounds did not show in vitro cytotoxicity when tested against Human Umbilical Vein Endothelial Cells (HUVEC) up to concentration of 50μM and they were stable at pH 7.4 for at least 48h., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition., Objective: We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods., Methods: The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn., Results: Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63)., Conclusion: The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pneumocystis pneumonia (PCP) is one of the most devastating fungal diseases in patients with impaired immunity. Effective antiviral therapies have reduced the burden of PCP among AIDS patients, but an increase in the prevalence of this disease among persons receiving immunosuppressive therapies has been reported., Methods: We retrospectively reviewed HIV and non-HIV PCP patients diagnosed in our department during a nine year period. Data were collected from the local database completed during the diagnosis procedure. For each patient, demographic, clinical, radiological, biological and therapeutic data were analyzed., Results: A total of 21,274 bronchoalveolar samples were received from patients suspected of pneumocystosis during the study period, leading to a discharge diagnosis of PCP for 604 patients (143 HIV-positive and 461 HIV-negative). The ratio of non-HIV versus HIV patients presenting PCP increased from 1.7 to 5.6 during the study period. The mortality rate at day 14 was 16%, occurring mostly in non-HIV patients (20.6% compared to 1.4%, P<0.0001), while non-HIV patients were less symptomatic at diagnosis than AIDS patients., Conclusions: This study presents one of the higher number of HIV and non-HIV patients presenting with PCP in a single center. Pneumocystosis is now a crucial health challenge for patients receiving immunosuppressive therapy, with a high mortality rate. This study highlights the need for international guidelines for prophylaxis of PCP in non-HIV patients., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cryptococcus neoformans var. neoformans (serotype D) represents about 30% of the clinical isolates in Europe and is present less frequently in the other continents. It is the prevalent etiological agent in primary cutaneous cryptococcosis as well as in cryptococcal skin lesions of disseminated cryptococcosis. Very little is known about the genotypic diversity of this Cryptococcus subtype. The aim of this study was to investigate the genotypic diversity among a set of clinical and environmental C. neoformans var. neoformans isolates and to evaluate the relationship between genotypes, geographical origin and clinical manifestations. A total of 83 globally collected C. neoformans var. neoformans isolates from Italy, Germany, France, Belgium, Denmark, Greece, Turkey, Thailand, Japan, Colombia, and the USA, recovered from different sources (primary and secondary cutaneous cryptococcosis, disseminated cryptococcosis, the environment, and animals), were included in the study. All isolates were confirmed to belong to genotype VNIV by molecular typing and they were further investigated by MLST analysis. Maximum likelihood phylogenetic as well as network analysis strongly suggested the existence of a recombinant rather than a clonal population structure. Geographical origin and source of isolation were not correlated with a specific MLST genotype. The comparison with a set of outgroup C. neoformans var. grubii isolates provided clear evidence that the two varieties have different population structures., (Copyright © 2016 Elsevier Inc. All rights reserved.)