Klik på linket nedenfor, tryk derefter Ctrl + C eller højreklik for at kopiere det.
Nedenfor kan du finde abstracts fra de nyeste artikler indenfor udvalgte internationale tidsskrifter med infektionsmedicinsk relevans. Du kan under "Yderligere søgekriterier" vælge tidsskrifter, hvor langt tilbage i tiden og rækkefølge.
Vælg eventuelt et eller flere søgeord til at afgrænse søgningen. Match, hvis mindst 1 ord er fundet. Benyt semikolon mellem hvert ord.
Vælg et eller flere tidsskrifter fra listen.
Alle | Ingen
Vælg hvor mange dage tilbage i tiden, der skal vælges artikler fra.
Vælg, hvordan resultaterne skal sorteres.
Ingen søgeord valgt. Opdateret for 2 dage siden.26 emner vises.
Arnaud Tarantola, Laurent Gautier
We commend Srinivas Mantha1 for the much needed clarification of the differences between risks, ratios, and rates, and of the latter's underlying notion of time. There is, however, an additional and important difference.
Ho H, Peluso M, Margus C, et al.
AbstractWe performed a retrospective study of Covid-19 in people with HIV (PWH). PWH with Covid-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin-6, interleukin-8, and TNF-alpha were commonly elevated. In all, 19/72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of Covid-19 despite ART and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes.
Serrano-Villar S, Sanchez-Carrillo S, Talavera-Rodríguez A, et al.
AbstractHIV infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by ART. Using 16S rDNA targeted sequencing and shotgun proteomics, we show that HIV increases bacterial translocation from the gut to the blood. HIV increased α-diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular crosstalk between the host and the translocated bacterial products could influence ART-mediated immune recovery.
Kullar R, Marcelin J, Swartz T, et al.
AbstractThe COVID-19 pandemic has unveiled unsettling disparities in the outcome of the disease among African Americans. These disparities are not new, but are rooted in structural inequities that must be addressed to adequately care for communities of color. We describe the historical context of these structural inequities, their impact on the progression of COVID-19 in the African American (Black) community, and suggest a multifaceted approach to addressing these healthcare disparities. Of note, terminology from survey data cited for this article varied from Blacks, African Americans or both; for consistency, we use African Americans throughout.
Mastroeni, P., Rossi, O.
Salmonella causes grave systemic infections in humans and other animals and provides a paradigm for other diseases where the bacteria have both intracellular and extracellular lifestyles.New generations of vaccines rely on the essential contribution of the antibody responses for their protection. The quality, antigen specificity and functions associated with antibody responses to this pathogen have been elusive for a long time. Recent approaches that combine studies in humans and genetically manipulated experimental models, and exploit awareness of the location and within-host life cycle of the pathogen, are shedding light on how humoral immunity to Salmonella operates. However, this area of research remains full of controversy and discrepancies.The overall scenario indicates that antibodies are essential for resistance against systemic Salmonella infections and can express the highest protective function when operating in conjunction with cell-mediated immunity. Antigen specificity, isotype profile, Fc-gamma receptor usage and complement activation are all intertwined factors that still arcanely influence antibody-mediated protection to Salmonella.
McQueen, B. E., Kiatthanapaiboon, A., Fulcher, M. L., Lam, M., Patton, K., Powell, E., Kollipara, A., Madden, V., Suchland, R. J., Wyrick, P., O'Connell, C. M., Reidel, B., Kesimer, M., Randell, S. H., Darville, T., Nagarajan, U. M.
Chlamydia trachomatis infection of the human Fallopian tubes can lead to damaging inflammation and scarring, ultimately resulting in infertility. To study the human cellular responses to chlamydial infection, researchers have frequently used transformed cell lines that can have limited translational relevance. We developed a primary human Fallopian tube epithelial cell model based on a method previously established for culture of primary human bronchial epithelial cells. After protease digestion and physical dissociation of excised Fallopian tubes, epithelial cell precursors were expanded in growth factor-containing medium. Expanded cells were cryopreserved to generate a biobank of cells from multiple donors and cultured at an air-liquid interface. Culture conditions stimulated cellular differentiation into polarized mucin-secreting and multi-ciliated cells, recapitulating the architecture of human Fallopian tube epithelium. The polarized and differentiated cells were infected with a clinical isolate of C. trachomatis, and inclusions containing chlamydial developmental forms were visualized by fluorescence and electron microscopy. Apical secretions from infected cells contained increased amounts of proteins associated with chlamydial growth and replication, including transferrin receptor protein 1, the amino acid transporters SLC3A2 and SLC1A5, and the T cell chemoattractants CXCL10, CXCL11, and RANTES. Flow cytometry revealed that chlamydial infection induced cell surface expression of T cell homing and activation proteins including ICAM-1, VCAM-1, HLA class I and II, and IFNR. This human Fallopian tube epithelial cell culture model is an important tool with translational potential for studying cellular responses to Chlamydia and other sexually-transmitted pathogens.
Christoph Schultheiß, Lisa Paschold, Donjete Simnica, Malte Mohme, Edith Willscher, Lisa von Wenserski, Rebekka Scholz, Imke Wieters, Christine Dahlke, Eva Tolosa, Daniel G. Sedding, Sandra Ciesek, Marylyn Addo, Mascha Binder
It is unclear how immune responses to Sars-CoV-2 differ in patients with mild versus severe COVID-19 disease. Schultheiß et al. define specific immune receptor sequences associated with different disease courses and established an actively updated sequence repository for public use.
C. Tan and K. Wong
A. Kumar et al.
N. E. Brown et al.
Van den Kerkhof, M., Mabille, D., Hendrickx, S., Leprohon, P., Mowbray, C. E., Braillard, S., Ouellette, M., Maes, L., Caljon, G.
Introduction: Current antileishmanial treatment is hampered by limitations such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles - a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development.Methodology: Resistance selection was performed by successive exposure of Leishmania infantum promastigotes (in vitro) and intracellular amastigotes (both in vitro and in golden Syrian hamsters). The stability of resistant phenotypes was assessed after passage in mice and Lutzomyia longipalpis sand flies. Whole genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs) and somy changes. The potential role of efflux pumps (MDR/MRP) in the development of resistance was assessed by co-incubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine A and probenecid).Results: Repeated drug exposure of amastigotes did not result in the emergence of drug resistance, either in vitro or in vivo. Selection on the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index: 5-24). This phenotype proved to be unstable after in vivo passage in mice and sand flies, suggesting that non-fixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may account for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested.Conclusion: The selection performed does not suggest rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.
Sarink, M. J., Tielens, A. G. M., Verbon, A., Sutak, R., van Hellemond, J. J.
Primary Amoebic Meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living amoeba Naegleria fowleri. The amoeba migrates along the olfactory nerve to the brain, resulting in seizures, coma and eventually death. Previous research has shown that Naegleria gruberi, a close relative of N. fowleri, prefers lipids over glucose as an energy source. Therefore, we tested several already approved inhibitors of fatty acid oxidation alongside the currently used drugs amphotericin B and miltefosine. Our data demonstrate that etomoxir, orlistat, perhexiline, thioridazine and valproic acid inhibited growth of N. gruberi. We then tested these compounds on N. fowleri and found etomoxir, perhexiline and thioridazine to be effective growth inhibitors. Hence, lipids are not only the preferred food source for N. gruberi, but oxidation of fatty acids also seems to be essential for growth of N. fowleri. Inhibition of fatty acid oxidation could result in new treatment options, as thioridazine inhibits N. fowleri growth in concentrations that can be reached at the site of infection. It could also potentiate currently used therapy, as checkerboard assays revealed synergy between miltefosine and etomoxir. Animal testing should be performed to confirm the added value of these inhibitors. Although the development of new drugs and randomized controlled trials for this rare disease are nearly impossible, inhibition of fatty acid oxidation seems a promising strategy as we showed effectivity of several drugs that are or have been in use and thus could be repurposed to treat PAM in the future.
Hopkins, J., Yadavalli, T., Suryawanshi, R., Qatanani, F., Volety, I., Koganti, R., Iqbal, A., Shukla, D.
Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the ano-genital area that may be transmitted through sexual encounters. Nucleoside analogs such as acyclovir (ACV) are currently prescribed clinically to curb this infection. But in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule, BX795 which was originally used as an inhibitor of TANK-binding kinase 1 (TBK1). In this study, we report the antiviral efficacy of BX795 on HSV-2 infection in vaginal epithelial cells in vitro at 10 μM and in vivo at 50 μM. Additionally, through biochemical assays in vitro and histopathology in vivo, we show the tolerability of BX795 in vaginal epithelial cells at concentrations as high as 80 μM. Our investigations also revealed that the mechanism of action of BX795's antiviral activity stems from the reduction of viral protein translation via inhibition of protein kinase B phosphorylation. Finally, using a murine model of vaginal infection, we show that topical therapy using 50 μM BX795 is well tolerated and efficacious in controlling HSV-2 replication.
Bulman, Z. P., Cirz, R., Hildebrandt, D., Kane, T., Rosario, Z., Wlasichuk, K., Park, M., Andrews, L. D.
The gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture. A Liquid Chromatography-Mass Spectroscopy analysis revealed that the relative abundances of each gentamicin congener in commercial formulations can vary up to 1.9-fold depending on the commercial source of the gentamicin. To determine if the gentamicin used for antibiotic susceptibility testing (AST) would be predictive of the microbiological activity of the product used to dose patients, the relative abundances of the four congeners contained on commercial AST disks were measured. It was found that the congener abundances on the commercial AST disks varied up to 4.1-fold. After purification of the four gentamicin congeners, similar potencies against bacterial strains lacking aminoglycoside modifying enzymes (AMEs) were observed. However, the potency of the congeners differed by up to 128-fold against strains harboring a common AME. Nephrotoxicity of the individual gentamicin congeners also differed significantly in cell-based and repeat-dose rat nephrotoxicity studies. Variations in the composition of commercial gentamicin products combined with toxicity differences between gentamicin congeners suggests that some gentamicin formulations may be more nephrotoxic. Our results also raise the concern that gentamicin susceptibility test results may not be predictive of patient outcomes and could lead to unexpected clinical treatment failures.
de Araujo, J. S., da Silva, C. F., Batista, D. d. G. J., Nefertiti, A., Fiuza, L. F. d. A., Fonseca-Berzal, C. R., da Silva, P. B., Batista, M. M., Sijm, M., Kalejaiye, T. D., de Koning, H. P., Maes, L., Sterk, G. J., Leurs, R., Soeiro, M. d. N. C.
Pyrazolones are heterocyclic compounds with interesting biological properties. Some derivatives inhibit phosphodiesterases (PDEs) and thereby increase the cellular concentration of cyclic AMP (cAMP), which plays a vital role in the control of metabolism in eukaryotic cells, including the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease (CD), a major Neglected Tropical Disease. In vitro phenotypic screening identified a 4-bromophenyl-dihydropyrazole dimer as anti-T. cruzi hit and 17 novel pyrazolone analogues with variations on the phenyl ring were investigated in a panel of phenotypic laboratory models. Potent activity against the intracellular forms (Tulahuen and Y strains) was obtained with EC50 values within the 0.17 - 3.3 μM range. Although most were not active against bloodstream trypomastigotes, an altered morphology and loss of infectivity were observed. Pretreatment of the mammalian host cells with pyrazolones did not interfere with infection and proliferation, showing that the drug activity was not the result of changes to host cell metabolism. The pyrazolone NPD-227 increased the intracellular cAMP levels and was able to sterilize of T. cruzi-infected cell cultures. Thus, due to its high potency and selectivity in vitro, and its additive interaction with benznidazole (Bz), NPD-227 was next assessed in the acute mouse model. Oral dosing for 5 days of NPD-227 at 10 mg/kg + BZ at 10 mg/kg not only reduced parasitaemia (>87 %) but also protected against mortality (>83% survival), hence demonstrating superiority to the monotherapy schemes. These data support these pyrazolone molecules as potential novel therapeutic alternatives for Chagas disease.
Borsuk-De Moor, A., Sysiak-Sławecka, J., Rypulak, E., Borys, M., Piwowarczyk, P., Raszewski, G., Onichimowski, D., Czuczwar, M., Wiczling, P.
Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic AUC0–24/MIC ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 ICU patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies including ECMO and CRRT. Caspofungin was administered as empirical antifungal therapy 70 mg i.v. on the first day and 50 mg i.v. on the consecutive days once daily and the concentrations were measured after 3 subsequent doses. Population pharmacokinetic data were analysed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by 2-compartment model. A particular drift of individual CL and V1 values with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at day one, two and three were 0.563 L/h (6.7 %RSE), 0.737 L/h (6.1 %RSE) and 1.01 L/h (9.1 %RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients.
Sheth, S., Miller, M., Prouse, A. B., Baker, S.
Background: Bloodstream infections (BSI) are associated with increased morbidity and mortality, especially when caused by gram-negative or fungal pathogens. The objective of this study was to assess the impact of fast ID/AST with the Accelerate Pheno ™ system (AXDX) from May 2018 to December 2018 on antibiotic therapy and patient outcomes.Methods: A pre-post quasi-experimental study of 200 patients (100 pre-AXDX implementation and 100 post-AXDX implementation) was conducted. The primary endpoints measured were time to first antibiotic intervention, time to most targeted antibiotic therapy, and 14-day hospital mortality. Secondary endpoints included hospital and intensive care unit (ICU) length of stay (LOS), antibiotic intensity score at 96 hours, and 30-day readmission rates.Results: Of 100 patients with gram-negative bacteremia or candidemia in each cohort, 84 in the pre-implementation group and 89 in the AXDX group met all inclusion criteria. The AXDX group had a decreased time to first antibiotic intervention (26.3 vs 8.0 p=0.003), hours to most targeted therapy (14.4 vs 9, p=0.03), hospital LOS (6 vs 8, p=0.002), and average antibiotic intensity score at 96 hours (16 vs 12, p=0.002). Both groups had a comparable 14-day mortality (0% vs 3.6%, p = 0.11).Conclusion: In this analysis of patients with gram-negative bacteremia or candidemia, fast ID/AST implementation was associated with decreased hospital LOS, decreased use of broad-spectrum antibiotics, shortened time to targeted therapy, and an improved utilization of antibiotics within the first 96 hours of therapy.
Al-Shaer, M. H., Neely, M. N., Liu, J., Cherabuddi, K., Venugopalan, V., Rhodes, N. J., Klinker, K., Scheetz, M. H., Peloquin, C. A.
Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time the free cefepime concentration above the minimum inhibitory concentration (fT>MIC) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients using population pharmacokinetic (PK) modeling and simulations. Two datasets were included in this study. The first was a prospective study in pediatric patients who received cefepime 50 mg/kg and had extensive PK sampling. The second was retrospective data for adult ICU patients admitted to UFHealth–Shands hospital, received cefepime, and had cefepime concentration measured. The population PK model was developed and simulations were performed using Pmetrics. The target exposures were 100% fT>MIC and fT>4xMIC. A total of 266 patients and the mean age was 3.9 years in pediatric and 55 years in adult group. More than half of patients were males. The mean (SD) creatinine clearance (CrCl) was 125 mL/min (93). The mean (SD) daily dose in adults was 4.9 g (1.6). Cefepime was well described by a two-compartment model with weight as a covariate on volume of distribution and elimination rate constant (ke) and CrCl and age group on ke. At MIC of 8 mg/L, cefepime 4g loading dose as extended infusion followed by 6g continuous infusion was needed to achieve good target attainment. In conclusion, prolonged or continuous infusions will be needed to achieve optimal cefepime exposure in ICU patients. Given the observed variability, therapeutic drug monitoring can help individualize therapy.
Smith, S. J., Zhao, X. Z., Passos, D. O., Lyumkis, D., Burke, T. R., Hughes, S. H.
The current recommended first-line therapy for HIV-1 infected patients is a second generation integrase (IN) strand transfer inhibitor (INSTI), either Dolutegravir (DTG) or Bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by first-generation INSTIs. BIC has not been reported to select for resistance in treatment-naïve patients and DTG has selected for a small number of resistant viruses in treatment-naïve patients. However, some patients who had viruses with substitutions selected by first-generation INSTIs responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI Cabotegravir (CAB), which is in late stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.
Lazzarini, C., Haranahalli, K., McCarthy, J. B., Mallamo, J., Ojima, I., Del Poeta, M.
The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and more importantly for the consistent rise of fungal species that are intrinsically resistant or develop resistance due to the prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, BHBM and D13, we performed a SAR study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified as the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N'-(5-bromo-2-hydroxybenzylidene) benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis and aspergillosis. Specifically, animals treated with SB-AF-1002 survive the infection, but also show a clearing of key organs from fungal cells. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to the parent compound D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents, which warrants further development for the treatment of invasive fungal infections.
Jenson, R. E., Baines, S. L., Howden, B. P., Mishra, N. N., Farah, S., Lew, C., Berti, A. D., Shukla, S. K., Bayer, A. S., Rose, W. E.
Daptomycin-nonsusceptible (DAP-NS) S. aureus often exhibit gain-in-function mutations in the mprF gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against MRSA, may prevent emergence of mprF mutations and DAP-NS. We determined if β-lactams might also impact DAP-NS isolates already possessing an mprF mutation to revert them to DAP-susceptible (DAP-S) phenotypes, and if so, whether this is associated with specific penicillin-binding protein (PBP) targeting.This study included 25 DAP-S/DAP-NS isogenic, clinically-derived MRSA bloodstream isolates. MICs were performed to DAP; nafcillin (NAF; PBP-promiscuous), cloxacillin (LOX; PBP-1), ceftriaxone (CRO; PBP-2) and cefoxitin (FOX; PBP-4). Three DAP-NS isolates were selected for 28-day serial passage in subinhibitory β-lactams. DAP MICs and time-kill assays, host defense peptide (LL-37) susceptibilities and whole genome sequencing were performed to associate genetic changes to key phenotypic profiles.Pronounced decreases in baseline MICs were observed for NAF and LOX (but not for CRO or FOX) among DAP-NS vs DAP-S isolates ("see-saw" effect). Prolonged (28d) β-lactam passage of three DAP-NS isolates significantly reduced DAP MICs. LOX was most impactful (~16-fold decrease in DAP MIC; 2-to-0.125 mg/L). In these DAP-NS isolates with preexisting mprF polymorphisms, accumulation of additional mprF mutations occurred with prolonged LOX exposures. This was associated with enhanced LL-37 killing activity and reduced surface charge (both mprF-dependent phenotypes). β-lactams which either promiscuously or specifically target PBP-1 have significant DAP ‘re-sensitizing' effects against DAP-NS S. aureus strains. This may relate to acquisition of multiple mprF SNPs which, in turn, affect cell envelope function and metabolism.
Georgi, F., Andriasyan, V., Witte, R., Murer, L., Hemmi, S., Yu, L., Grove, M., Meili, N., Kuttler, F., Yakimovich, A., Turcatti, G., Greber, U. F.
Adenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. The human AdV (HAdV) species B and C, such as HAdV-C2, C5 and B14, cause respiratory disease, and constitute a health threat for immuno-compromised individuals. HAdV-Cs are well known for lysing cells, owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening frame-work and identified an inhibitor of HAdV-C2 multi-round infection, Nelfinavir mesylate. Nelfinavir is the active ingredient of Viracept, an FDA-approved inhibitor of the human immuno-deficiency virus (HIV) aspartyl protease, and used to treat acquired immuno-deficiency syndrome (AIDS). It is not effective against single round HAdV infections. Here, we show that Nelfinavir inhibits the lytic cell-free transmission of HAdV, indicated by the suppression of comet-shaped infection foci in cell culture. Comet-shaped foci occur upon convection-based trans-mission of cell-free viral particles from an infected cell to neighbouring uninfected cells. HAdV lacking ADP was insensitive to Nelfinavir, but gave rise to comet-shaped foci indicating that ADP enhances but is not required for cell lysis. This was supported by the notion that HAdV-B14 and B14p1 lacking ADP were highly sensitive to Nelfinavir, although HAdV-A31, B3, B7, B11, B16, B21, D8, D30 or D37 were less sensitive. Conspicuously, Nelfinavir unco-vered slow-growing round-shaped HAdV-C2 foci, independent of neutralizing antibodies in the medium, indicative of non-lytic cell-to-cell transmission. Our study demonstrates the repurposing potential of Nelfinavir with post-exposure efficacy against different HAdVs, and describes an alternative non-lytic cell-to-cell transmission mode of HAdV.
Hao, S., Abdelghany, M., Lyden, A., Sit, R., Tan, M., Tato, C. M., DeRisi, J. L., Miller, S., Doernberg, S. B., Langelier, C.
Staphylococcus argenteus is a novel staphylococcal species associated with invasive disease. We report the first case of daptomycin/vancomycin-resistant S. argenteus, initially speciated as S. aureus, that developed from repeated treatment with daptomycin for a complex vascular graft infection. Whole genome sequencing of longitudinally collected isolates identified acquisition of MprF S337L, a mutation predicted to increase surface charge and repel cationic molecules.
Nguyen, K., Bensman, T. J., Wei, X., Moore, J. N.
Effective bacterial infection eradication requires not only potent antibacterial agents, but also proper dosing strategies. Current practices generally utilize point estimates of the effect of the therapeutic agents even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed in vitro effects to develop a semi-mechanistic pharmacokinetic-pharmacodynamic model for eravacycline against multiple Gram-negative bacterial pathogens. This model incorporates components such as pharmacokinetics, bacterial life-cycle, and drug effects to quantitatively describe the time course of antibacterial killing and emergence of resistance. Model discrimination was performed by comparing goodness of fit, convergence diagnostics, and objection function value. Models were validated by assessing their ability to describe bacterial count time courses in visual predictive checks. The final model describes 576 bacterial counts (log10 CFU/mL) from 144 in vitro time-kill experiments with low residual error and high precision. We characterize antibacterial susceptibility as a function of minimal inhibitory concentration and adaptive resistance. In doing so, we show that minimal inhibitory concentration is proportional to initial susceptibility at 0 hour and the development of resistance over the course of 16 hours. Altogether, this model may be useful in supporting dose selection as it incorporates in vitro pharmacodynamics and clinically observed individual drug susceptibilities.
Ferreira, L. T., Rodrigues, J., Cassiano, G. C., Tavella, T. A., Tomaz, K. C. P., Baia-da-Silva, D. C., Souza, M. F., Lima, M. N. d. N., Mottin, M., Almeida, L. D., Calit, J., Puca, M. C. S. d. B., Melo, G. C., Bargieri, D. Y., Lopes, S. C. P., Lacerda, M. V. G., Bilsland, E., Sunnerhagen, P., Neves, B. J., Andrade, C. H., Cravo, P. V. L., Costa, F. T. M.
Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks and time-to-market. Herein we have used this strategy to identify novel antimalarial hits. We performed a comparative in silico chemogenomics approach to select Plasmodium falciparum and P. vivax proteins as potential drug targets and analyzed these using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of P. yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights on epirubicin's mechanism of action. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity not only against P. falciparum but also P. vivax in different stages of the parasite lifecycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.
Ojkic, N., Lilja, E., Direito, S., Dawson, A., Allen, R. J., Waclaw, B.
Fluoroquinolones - antibiotics that cause DNA damage by inhibiting DNA topoisomerases - are clinically important, but their mechanism of action is not yet fully understood. In particular, the dynamical response of bacterial cells to fluoroquinolone exposure has hardly been investigated, although the SOS response, triggered by DNA damage, is often thought to play a key role. Here we investigate growth inhibition of the bacterium Escherichia coli by the fluoroquinolone ciprofloxacin at low concentrations. We measure the long-term and short-term dynamical response of the growth rate and DNA production rate to ciprofloxacin, at both population- and single-cell level. We show that despite the molecular complexity of DNA metabolism, a simple ‘roadblock-and-kill’ model focusing on replication fork blockage and DNA damage by ciprofloxacin-poisoned DNA topoisomerase II (gyrase) quantitatively reproduces long-term growth rates in the presence of ciprofloxacin. The model also predicts dynamical changes in DNA production rate in wild type E. coli and in a recombination deficient mutant, following a step-up of ciprofloxacin. Our work highlights that bacterial cells show a delayed growth rate response following fluoroquinolone exposure. Most importantly, our model explains why the response is delayed: it takes many doubling times to fragment the DNA sufficiently to inhibit gene expression. We also show that the dynamical response is controlled by the timescale of DNA replication and gyrase binding/unbinding to the DNA, rather than by the SOS response, challenging the accepted view. Our work highlights the importance of including detailed biophysical processes in biochemical-systems models to quantitatively predict the bacterial response to antibiotics.
International AIDS Conference (AIDS) 2020
6.07.2020 - 10.07.2020
International Liver Congress (ILC) 2020
27.08.2020 - 29.08.2020
World Sepsis Day
Det 8. videnskabelige nationale møde om infektiøs endokarditis
International Congress for Tropical Medicine and Malaria (ICTMM) 2020
20.09.2020 - 24.09.2020
COVID-19 retningslinje (2020)
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Infections in Patients Colonized with Extended-Spectrum Beta-Lactamase-Producing Enterobacterales – a Retrospective Cohort Study
30.07.2020Clinical Infectious Diseases Advance Access
Zoonoses: beyond the human–animal–environment interface
Ambulatory management of primary spontaneous pneumothorax: when less is more
Surgery for benign prostatic obstruction
Investing in surgery: a value proposition for African leaders
Hvorfor synes Professor Jens Lundgren, at du bør læse"Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV."?
Hvorfor anbefaler Professor Troels Lillebæk artiklen"The global prevalence of latent tuberculosis: a systematic review and meta-analysis."?
Hvad synes Professor Lars Østergaard om"Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial."?
Hvorfor synes Professor Thomas Benfield, at du bør læse"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvorfor synes Professor Niels Obel, at du bør læse"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
© 2020 Dansk Selskab for Infektionsmedicin
version: 2.7.1 ● design: C P Fischer
Side indlæst på 0,156 s
Cookies og privatliv