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In India, Accredited Social Health Activists (ASHAs) deliver services for diagnosis and treatment of malaria, although unlicensed medical practitioners (UMPs) (informal health providers) are most preferred in communities. A cross sectional survey was conducted to: (i) assess knowledge and treatment-seeking practices in the community, and (ii) explore the diagnosis and treatment practices related to malaria of UMPs working in rural and tribal-dominated high malaria endemic areas of central India, and whether they adhere to the national guidelines.
A multi-stage sampling method and survey technique was adopted. Heads of the households and UMPs were interviewed using a structured interview schedule to assess knowledge and malaria treatment practices.
Knowledge regarding malaria symptoms was generally accurate, but misconceptions emerged related to malaria transmission and mosquito breeding places. Modern preventive measures were poorly accessed by the households. UMPs were the most preferred health providers (49%) and the first choice in households for seeking treatment. UMPs typically lacked knowledge of the names of malaria parasite species and species-specific diagnosis and treatment. Further, irrational use of anti-malarial drugs was common.
UMPs were the most preferred type of health care providers in rural communities where health infrastructure is poor. The study suggests enhancing training of UMPs on national guidelines for malaria diagnosis and treatment to strengthen their ability to contribute to achievement of India’s malaria elimination goals.
The intraerythrocytic development cycle (IDC) of the rodent malaria Plasmodium chabaudi is coordinated with host circadian rhythms. When this coordination is disrupted, parasites suffer a 50% reduction in both asexual stages and sexual stage gametocytes over the acute phase of infection. Reduced gametocyte density may not simply follow from a loss of asexuals because investment into gametocytes (“conversion rate”) is a plastic trait; furthermore, the densities of both asexuals and gametocytes are highly dynamic during infection. Hence, the reasons for the reduction of gametocytes in infections that are out-of-synch with host circadian rhythms remain unclear. Here, two explanations are tested: first, whether out-of-synch parasites reduce their conversion rate to prioritize asexual replication via reproductive restraint; second, whether out-of-synch gametocytes experience elevated clearance by the host’s circadian immune responses.
First, conversion rate data were analysed from a previous experiment comparing infections of P. chabaudi that were in-synch or 12 h out-of-synch with host circadian rhythms. Second, three new experiments examined whether the inflammatory cytokine TNF varies in its gametocytocidal efficacy according to host time-of-day and gametocyte age.
There was no evidence that parasites reduce conversion or that their gametocytes become more vulnerable to TNF when out-of-synch with host circadian rhythms.
The factors causing the reduction of gametocytes in out-of-synch infections remain mysterious. Candidates for future investigation include alternative rhythmic factors involved in innate immune responses and the rhythmicity in essential resources required for gametocyte development. Explaining why it matters for gametocytes to be synchronized to host circadian rhythms might suggest novel approaches to blocking transmission.
Lynn W. Enquist
Journal of Medical Virology, Volume 0, Issue ja, -Not available-.
Nayak, A., Schüler, W., Seidel, S., Gomez, I., Meinke, A., Comstedt, P., Lundberg, U.
The development of vaccines for prevention of diseases caused by pathogenic species can encounter major obstacles if high sequence diversity is observed between individual strains. Therefore, the development might be restricted either to conserved antigens, which often are rare, or to multivalent vaccines, which renders the production more costly and cumbersome. In light of this complexity, we applied a structure-based surface shaping approach for the development of a Lyme borreliosis (LB) vaccine suitable for the USA and Europe. The surface of the C-terminal fragment of outer surface protein A (OspA) was divided into distinct regions mainly based on binding sites of monoclonal antibodies. In order to target the six clinically most relevant OspA serotypes (ST) in a single protein, exposed amino acids of the individual regions were exchanged to corresponding amino acids of a chosen OspA serotype. Six chimeric proteins were constructed and based on their immunogenicity four of these chimeras were tested in mouse challenge models. Significant protection could be demonstrated for all four proteins following challenge with infected ticks (OspA ST1, OspA ST2, and OspA ST4), as well as with in vitro grown spirochetes (OspA ST1 and OspA ST5). Two of the chimeric proteins were linked to form a fusion protein, which provided significant protection against in vitro grown spirochetes (OspA ST1) and infected ticks (OspA ST2). This article presents the proof-of-concept study for a multivalent OspA vaccine targeting a wide range of pathogenic LB Borrelia species with a single recombinant antigen for prevention of Lyme borreliosis.
Wang, S., Lyu, C., Duan, G., Meng, F., Yang, Y., Yu, Y., He, X., Wang, Z., Gottschalk, M., Li, G., Cai, X., Wang, G.
Streptococcus suis serotype 2 is an important bacterial pathogen of swine and also an emerging zoonotic agent that may be harmful to human health. Although the virulence genes of S. suis have been extensively studied, the mechanisms by which they damage the central immune organs have rarely been studied. In the current work, we wanted to uncover more details about the impact and mechanisms of S. suis on specific populations of thymic and immune cells in infected mice. Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling (TUNEL) assays revealed that S. suis infection induced apoptosis in CD3+, CD14+ and epithelial cells from the thymus. S. suis infection resulted in a rapid depletion of mitochondrial permeability and release of cytochrome c (CytC) and apoptosis-inducing factor (AIF) through up-regulation of Bax and down-regulation of Bcl-xl and Bcl2 expression in thymocytes. Moreover, S. suis infection increased cleavage of caspase-3, -8, -9. Thus, S. suis induced thymocyte apoptosis through a p53- and caspase-dependent pathway, which led to a decrease of CD3+ cells in the thymus, subsequently decreasing the numbers of CD4+ and CD8+ cells in the peripheral blood. Finally, expression dysregulation of pro-inflammatory cytokines in the serum including interleukin (IL)-2, IL-6, IL-12 (p70), tumor necrosis factor (TNF), and IL-10 was observed in mice after S. suis type 2 infection. Taken together, these results suggest that S. suis infection can cause atrophy of the thymus and induces apoptosis of thymocytes in mice, thus likely suppressing host immunity.
Nichols, F. C., Clark, R. B., Liu, Y., Provatas, A. A., Dietz, C. J., Zhu, Q., Wang, Y.-H., Smith, M. B.
The serine-glycine dipeptide lipid classes, including Lipid 430 and Lipid 654, are produced by the periodontal pathogen, Porphyromonas gingivalis, and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans. Both serine-glycine lipid classes were previously shown to engage human and mouse Toll-like receptor 2 (TLR2) and to inhibit mouse osteoblast differentiation and function through engagement of TLR2. It is not clear if other lipids related to serine-glycine lipids are also produced by P. gingivalis. The goal of this investigation was to determine whether P. gingivalis produces additional lipid classes similar to the serine-glycine lipids that possess biological properties. P. gingivalis (ATCC 33277) was grown in broth culture and lipids were extracted and fractionated by HPLC. Lipids were separated using semipreparative HPLC and specific lipid classes were identified using LC-MS/MS and LC-MRM mass spectrometric approaches. Two glycine lipid classes were identified, termed Lipid 567 and Lipid 342, and these lipid classes are structurally related to the serine-glycine dipeptide lipids. Both glycine lipid classes were shown to promote TLR2-dependent TNF-α release from bone marrow macrophages and both were shown to activate human embryonic kidney (HEK) cells through TLR2 and TLR6, but not TLR1. These results demonstrate that P. gingivalis synthesizes glycine lipids and that these lipids engageTLR2 similar to the previously reported serine-glycine dipeptide lipids.
McDaniel, M. S., Schoeb, T., Swords, W. E.
Stenotrophomonas maltophilia is a Gram-negative bacterium found ubiquitously in the environment that has historically been regarded as nonpathogenic. S. maltophilia is increasingly observed in patient sputa in cystic fibrosis (CF), and while existing epidemiology indicates that patients with S. maltophilia have poorer diagnoses, its clinical significance remains unclear. Moreover, as multidrug resistance is common among S. maltophilia isolates, treatment options for these infections may be limited. Here we investigated the pathogenicity of S. maltophilia alone and during polymicrobial infection with Pseudomonas aeruginosa. Colonization, persistence, and virulence of S. maltophilia were assessed in experimental respiratory infections of mice. The results of this study indicate that S. maltophilia transiently colonizes the lung accompanied by significant weight loss and immune cell infiltration, and the expression of early inflammatory markers including IL-6, IL-1α, and TNF-α. Importantly, polymicrobial infection with P. aeruginosa elicited significantly higher S. maltophilia counts in bronchoalveolar lavages and lung tissue homogenates. This increase in bacterial load was directly correlated with the density of the P. aeruginosa population, and required viable P. aeruginosa bacteria. Microscopic analysis of biofilms formed in vitro revealed that S. maltophilia formed well-integrated biofilms with P. aeruginosa, and these organisms colocalize in the lung during dual species infection. Based on these results, we conclude that active cellular processes by P. aeruginosa afford significant benefit to S. maltophilia during polymicrobial infections. Further, these results indicate that S. maltophilia may have clinical significance in respiratory infections.
Khalaf, O. H., Chaki, S. P., Garcia-Gonzalez, D. G., Suva, L. J., Gaddy, D., Arenas-Gamboa, A. M.
Osteoarticular disease is a frequent complication of human brucellosis. Vaccination remains a critical component of brucellosis control but there are currently no vaccines for use in humans and no in vitro models for assessing safety of candidate vaccines in reference to development of bone lesions currently exist. While the effect of Brucella infection on osteoblasts has been extensively evaluated, little is known about the consequences of osteoclast infection. Murine bone marrow-derived macrophages were derived into mature osteoclasts and infected with B. abortus 2308, the vaccine strain S19, and attenuated mutants S19vjbR and B. abortus virB2. While B. abortus 2308 and S19 replicated inside mature osteoclasts, the attenuated mutants were progressively killed, behavior that mimics infection kinetics in macrophages. Interestingly, B. abortus 2308 impaired the growth of osteoclasts without reducing resorptive activity while osteoclasts infected with B. abortus S19 and S19vjbR were significantly larger and exhibited enhanced resorption. None of the Brucella strains induced apoptosis or stimulated nitric oxide or lactose dehydrogenase production in mature osteoclasts. Finally, infection of macrophages or osteoclast precursors with B. abortus 2308 resulted in generation of smaller osteoclasts with decreased resorptive activity. Overall, Brucella exhibits similar growth characteristics in mature osteoclasts compared to the primary target cell, the macrophage, but is able to impair the maturation and alter the resorptive capacity of these cells. These results suggest that osteoclasts play an important role in osteoarticular brucellosis and could serve as a useful in vitro model for both analyzing host-pathogen interactions and assessing vaccine safety.
Schultz, C. M., Goel, A., Dunn, A., Knauss, H., Huss, C., Launder, D., Wuescher, L. M., Conti, H. R., Worth, R. G.
Candida albicans is a pervasive commensal fungus that is the most common pathogen responsible for invasive fungal infection (IFI). With incidence of IFI on the rise due to increasing susceptible populations, it is imperative that we investigate how Candida albicans interacts with blood components. When stimulating either human or mouse whole blood with thrombin we saw a significant decrease in C. albicans survival. We then repeated Candida killing assays with thrombin-stimulated or unstimulated washed platelets and saw a similar decrease in CFU. To investigate whether killing was mediated through surface components or releasable products, platelets were pretreated with an inhibitor of actin polymerization (CytochalasinD, CytoD). CytoD was able to abrogate C. albicans killing. Moreover, dilution of releasates from thrombin-stimulated platelets showed that the toxicity of the releasates on C. albicans is concentration dependent. We then investigated C. albicans actions on platelet activation, granule release, and aggregation. While C. albicans does not appear to affect alpha or dense granule release, C. albicans exerts a significant attenuation of platelet aggregation to multiple agonists. These results illustrate for the first time that platelets can directly kill C. albicans through release of their granular contents. Additionally, C. albicans can also exert inhibitory effects on platelet aggregation.
Paik, W., Alonzo, F., Knight, K. L.
Staphylococcus aureus is a gram-positive opportunistic pathogen that causes a variety of diseases. Bloodstream infection is the most severe, with mortality rates reaching 20-50%. Exopolysaccharide (EPS) from the probiotic, Bacillus subtilis, reduces bacterial burden and inflammation during S. aureus bloodstream infection in mice. Protection is due, in part, to hybrid macrophages that restrict S. aureus growth through reactive oxygen species, and to limiting superantigen-induced T cell activation, and IFN- production during infection. The decrease in IFN- production was observed within 24 hr after infection, and here, we investigated how EPS abrogates its production. We discovered that S. aureus uses a rapid, superantigen-independent mechanism to induce host IFN- and that this is mediated by IL-12 activation of NK cells. Furthermore, we found that EPS limits IFN- production by modulating host immunity in a TLR4-dependent manner, a signaling pathway that is required for EPS-mediated protection from S. aureus infection in vivo. We conclude that EPS protects hosts from acute bloodstream S. aureus infection not only by inducing macrophages that restrict S. aureus growth and inhibit superantigen-activated T cells, but also by limiting NK cell production of IFN- after S. aureus infection, in a TLR4-dependent manner.
Group B Streptococcal (GBS) infections in the United States are a leading cause of meningitis and sepsis in newborns. The CDC therefore recommends GBS screening for all pregnant women at 35–37 weeks of gestation and administration of intrapartum prophylaxis (in those that tested positive) as an effective means of controlling disease transmission. Several FDA approved molecular diagnostic tests are available for rapid and accurate detection of GBS in antepartum women.
In this study, we report a clinical comparison of the Xpert GBS LB assay and a novel FDA-cleared test, Revogene GBS LB assay. A total of 250 vaginal-rectal swabs from women undergoing prenatal screening were submitted to the University of Wisconsin’s clinical microbiology laboratory for GBS testing.
We found 96.8% of samples were concordant between the two tests, while 3.2% were discordant with a positive percent agreement of 98.0% and a negative percent agreement of 96.5% between the Revogene GBS LB assay and the GeneXpert GBS LB assay.
Overall, we report that both assays perform well for the detection of GBS colonization in pregnant women.
Reitzel, R. A., Rosenblatt, J., Gerges, B. Z., Vargas-Cruz, N., Raad, I. I.
Candida auris is an emerging pathogen that can cause virulent central line associated bloodstream infections. Catheter salvage through eradicating biofilm is a desirable therapeutic option. We compared taurolidine and minocycline-EDTA-ethanol (MEE) catheter lock solutions in vitro for eradication of biofilm of 10 C. auris strains. MEE fully eradicated all C. auris biofilms while taurolidine lock partially eradicated all of the C. auris biofilms. The superiority was significant for all C. auris strains tested (p=0.002).
Jorgensen, S. C. J., Trinh, T. D., Zasowski, E. J., Lagnf, A. M., Simon, S. P., Bhatia, S., Melvin, S. M., Steed, M. E., Finch, N. A., Morrisette, T., Estrada, S. J., Rosenberg, J. R., Davis, S. L., Rybak, M. J.
Objective: To describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) gram-negative infections.Methods: Multicenter, retrospective, cohort study at eight U.S. medical centers (2015-2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR gram-negative infection. The primary efficacy outcome, evaluated amongst patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure: 30-day all-cause mortality, 30-day recurrence and/or failure to resolve or improve infection signs or symptoms on C/T.Results: In total, 259 patients were included. P. aeruginosa was isolated in 236(91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (RTI, 62.9%). High dose C/T was used in 71.2% of patients with a RTI overall, but in only 39.6% of patients with a RTI who required C/T renal dose adjustment. In the primary efficacy population (n=226), clinical failure and 30-day mortality occurred in 85(37.6) and 39(17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in three of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and APACHE II score were independently associated with clinical failure (aOR 2.472, 95% CI 1.322-4.625 and aOR 1.068, 95% CI 1.031-1.106, respectively). Twenty-five (9.7%) patients experienced ≥ one adverse effect (nine acute kidney injury, 13 Clostridioides difficile infection, one hepatotoxicity, two encephalopathy and two gastrointestinal intolerance)Conclusions: C/T addresses an unmet medical need in patients with MDR gram-negative infections.
Biagi, M., Shajee, A., Vialichka, A., Jurkovic, M., Tan, X., Wenzler, E.
The Serratia marcescens enzyme (SME) is a chromosomally encoded carbapenemase with no known optimal treatment. Various β-lactam/β-lactamase inhibitors and comparators were evaluated against 8 SME-producers via broth microdilution. Four isolates were subsequently tested via time-kill analyses. All isolates were resistant to imipenem, imipenem-relebactam, and meropenem, but susceptible to ceftazidime, ceftazidime-avibactam, and meropenem-vaborbactam. Ceftazidime, imipenem-relebactam, and meropenem-vaborbactam were bactericidal against 3/4, 0/4, and 4/4 isolates, respectively. Meropenem-vaborbactam may be a potential option for severe SME-producing infections.
O'Brien, B., Chaturvedi, S., Chaturvedi, V.
Since 2016, New York hospitals and healthcare facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over one thousand C. auris isolates from affected facilities and found high-resistance to fluconazole (MIC > 256 mg/L), and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris. Broth micro-dilution antifungal combination plates were custom-manufactured by TREK Diagnostic System. We used 100% inhibition endpoints for the drug combination as reported earlier for the intra- and inter-laboratory agreements against Candida species. The results were derived from 12,960 readings, for fifteen C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/L potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB, MIC ≥ 2.0 mg/L]), AMB/5FC (0.25/1.0 mg/L) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG, MIC ≥ 4.0 mg/L], caspofungin [CAS, MIC ≥ 2.0 mg/L], and micafungin [MFG, MIC ≥ 4.0 mg/L]), were 100% inhibited by AFG/5FC and CAS/5FC (0.0078/1 mg/L), and MFG/5FC (0.12/1 mg/L). None of the combinations were effective for C. auris 18-1 and 18-13 (FLC > 256 mg/L, 5FC > 32 mg/L) except MFG/5FC (0.1/0.006 mg/L). Thirteen isolates with high voriconazole MIC (VRC, > 2 mg/L) were 100% inhibited by the VRC/5FC (0.015/1 mg/L). The simplified two-drug combination susceptibility test format would permit laboratories to provide clinicians and public health experts with additional data to manage multidrug-resistant C. auris.
Wasserman, S., Huo, S., Ky, K., Malig, Y. N., Esmail, A., Dheda, K., Bacchetti, P., Gerona, R., Maartens, G., Gandhi, M., Metcalfe, J.
Plasma drug quantification has a potential role as a biomarker of TB treatment adherence, but utility of short half-life drugs such as linezolid (1) for adherence monitoring may be limited due to rapid plasma clearance and inability to capture long-term dosing....
Fikatas, A., Vervaeke, P., Martinez-Gualda, B., Marti-Mari, O., Noppen, S., Meyen, E., Camarasa, M.-J., San-Felix, A., Pannecouque, C., Schols, D.
Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection in vitro. These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups, thus their carboxylic acid groups are free and exposed to the periphery. Structure activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 positions of the indole side-chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines. Moreover, they were active against laboratory and clinical strains of all four serotypes of dengue virus as well as a selected group of Zika virus strains. Additional mechanistic studies performed with the two most potent compounds (AL439 and AL440) demonstrated an interaction with the viral envelope glycoprotein (domain III) of dengue 2 virus, thus preventing virus attachment to the host cell membrane. Since no antiviral agent is approved at the moment against these two flaviviruses, further pharmacokinetic studies with these molecules are needed for their development as future therapeutic/prophylactic drugs.
Simonetti, O., Lucarini, G., Morroni, G., Orlando, F., Lazzarini, R., Zizzi, A., Brescini, L., Provinciali, M., Giacometti, A., Offidani, A., Cirioni, O.
Dalbavancin is an effective antibiotic widely used to treat skin infection. Our aim was to determinate the effects of dalbavancin administration on wound healing compared to vancomycin, and to elucidate if EGFR, MMP-1, MMP-9 and VEGF could be involved in its therapeutic mechanism.A mouse model of MRSA skin infection was established. Mice were treated daily with vancomycin (10mg/kg) and weekly with dalbavancin, at day 1 (20 mg/kg) and day 8 (10 mg/kg). After 14 days wounds were excised and bacterial counts were perfomed. Wound healing was assessed by histological and immunohistochemical staining, followed by protein extraction and immunoblotting.Our microbiological results confirmed that both dalbanvancin and vancomycin are effective in reducing the bacterial load in wounds. Dalbavancin had a strong effect compared with infected untreated animals and vancomycin treated group. The wounds treated with dalbavancin showed robust epidermal coverage with a reconstitution of the regular and keratinized epidermal lining and a well-organized granulation tissue with numerous blood vessels, although slightly less than in the uninfected group, while in vancomycin treated group the epithelium appeared in general still hypertrophic, the granulation tissue appears even less organized.We observed elevated EGFR and VEGF expression in both treated groups, although it was higher in dalbavancin treated mice. MMP-1 and MMP-9 were decreased in uninfected and in both treated tissue when compared with untreatd infected wounds.This study showed faster healing with dalbavancin treatment that might be associated with a higher EGFR and VEGF levels.
Kieffer, N., Poirel, L., Descombes, M.-C., Nordmann, P.
Fosfomycin is gaining renewed interest for treating urinary tract infections. Monitoring fosfomycin resistance is therefore important in order to detect the emergence of novel resistance mechanisms. Here we used the Rapid Fosfomycin NP test to screen a collection of extended-spectrum ß-lactamase-producing Escherichia coli isolates from Switzerland and found a fosfomycin-resistant isolate in which a novel plasmid-mediated fosfomycin resistance gene, named fosL1, was identified. The FosL1 protein is a putative glutathione-S-transferase enzyme conferring high-level resistance to fosfomycin and sharing between 57 to 63 % amino-acid identity with other FosA-like family members. Genetic analyses showed that the fosL1 gene was embedded in a mobile insertion cassette and had likely been acquired by transposition through a Tn7-related mechanism. In-silico analysis over Genbank databases identified the FosL1 encoding gene in addition to another variant (fosL1-2) respectively in two Salmonella enterica isolates from the US. Our study further highlights the necessity of monitoring fosfomycin resistance in Enterobacteriaceae to identify the emergence of novel mechanisms of resistance.
Kontou, A., Sarafidis, K., Begou, O., Gika, H. G., Tsiligiannis, A., Ogungbenro, K., Dokoumetzidis, A., Agakidou, E., Roilides, E.
OBJECTIVES: To develop a population pharmacokinetic (PK) model in order to evaluate currently recommended dosing regimen in term and preterm neonates.METHODS: By using optimal design approach, a prospective PK study was designed and implemented in 60 neonates with post-menstrual age of 26-43wks. A loading dose 16mg/kg was administered at day 1 followed by a maintenance dose of 8mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on pharmacodynamic index AUC/MIC≥400.RESULTS: A two-compartment model with linear elimination best described the data by these equations: CL(clearance)=0.0227x(WT/1765)0.75x(eCRCL/22)0.672, V1(central compartment volume of distribution)=0.283(WT/1765), Q (inter-compartmental clearance)=0.151(WT/1765)0.75, V2(peripheral compartment volume)=0.541(WT/1765). Inter-individual variability estimates for CL, V1 and V2 was 36.5%, 45.7% and 51.4%, respectively. Current weight (WT) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that with the current dosing regimen AUC/MIC≥400 was reached only by 68.5% of neonates with WT
Jin, Y., Guo, Y., Zhan, Q., Shang, Y., Qu, D., Yu, F.
Previous studies have shown that the administration of antibiotics at sub-inhibitory concentrations stimulates biofilm formation by the majority of MRSA strains. Here, we investigated the effect of sub-inhibitory mupirocin concentrations on biofilm formation by the community-associated (CA) mupirocin-sensitive MRSA strain USA300 and highly mupirocin-resistant clinical S. aureus SA01-SA05 isolates. We found that mupirocin increased the ability of MRSA cells to attach to surfaces and form biofilms. Confocal laser scanning microscopy (CLSM) demonstrated that mupirocin treatment promoted thicker biofilm formation, which also correlated with the production of extracellular DNA (eDNA). Furthermore, RT-qPCR results revealed that this effect was largely due to the involvement of holin-/antiholin-like proteins (encoded by the cidA gene), which are responsible for modulating cell death and lysis during biofilm development. We found that cidA expression levels significantly increased 6.05-35.52 fold (P < 0.01) on mupirocin administration. We generated a cidA-deficient mutant of the USA300 S. aureus strain. Exposure of the cidA mutant to mupirocin did not result in thicker biofilm formation compared with that in the parent strain. We therefore hypothesize that the mupirocin-induced stimulation of S. aureus biofilm formation may involve the upregulation of cidA.
Sinxadi, P., Donini, C., Johnstone, H., Langdon, G., Wiesner, L., Allen, E., Duparc, S., Chalon, S., McCarthy, J. S., Lorch, U., Chibale, K., Möhrle, J., Barnes, K. I.
MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single ascending dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the P. falciparum induced blood stage malaria (IBSM) model. Due to the high pharmacokinetic variability with the powder-in-bottle formulation used in both these studies, a third study was undertaken to select a tablet formulation of MMV390048 to take forward into future studies. MMV390048 was generally well tolerated when administered as a single oral dose up to 120 mg, with rapid absorption and a long elimination half-life. Twelve adverse events were considered to be potentially related to MMV390048 in the first-in-human study, but with no obvious correlation between these and MMV390048 dose or exposure. Although antimalarial activity was evident in the IBSM study, rapid recrudescence occurred in most subjects after treatment with 20 mg MMV390048, a dose expected to be sub-therapeutic. Reformulation of MMV390048 into two tablet formulations (tartaric acid and syloid) resulted in significantly reduced inter-subject pharmacokinetic variability. Overall, the results of this study suggest that MMV390048 is well tolerated in humans and the pharmacokinetic properties of the compound indicate that it has the potential to be used for antimalarial prophylaxis or inclusion in a single-dose cure. MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or vivax malaria mono-infection.
Delaune, D., Iseni, F.
Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus de novo, implying that VARV could, in theory, be resurrected. Because of this new perspective the WHO Advisory Committee on VARV Research released new recommendations concerning research on poxviruses that strongly encourages pursuing the development of new antiviral drugs against orthopoxviruses. In 2018, the US FDA advised in favor of two molecules for smallpox treatment: Tecovirimat and Brincidofovir. This review highlights the difficulties to develop new drugs targeting an eradicated disease, especially as it requires working under the FDA "animal efficacy rule" with the few, and imperfect, animal models available.
Ricardo, E., Grenouillet, F., Miranda, I. M., Silva, R. M., Eglin, G., Devillard, N., Rodrigues, A. G., Pina-Vaz, C.
Five C. krusei isolates (susceptible and resistant) recovered from the urine of a kidney transplant patient treated with VRC 200mg/2x day for 20 days were studied. Eight unrelated clinical isolates of C. krusei were exposed in vitro to VRC 0.001 μg/ml, during 30 days. Development of VRC transient resistance occurred in vivo and induction of permanent resistance occurred in vitro. Mostly ABC1 and ERG11 genes were overexpressed and a homozygous T418C mutation in ERG11 gene was found.
Miller, C. R., Dey, S., Smolenski, P. D., Kulkarni, P. S., Monk, J. M., Szubin, R., Sakoulas, G., Berti, A. D.
We present a case of endocarditis wherein organisms cultured from different valve leaflets yielded different daptomycin susceptibility from each other, and from organisms obtained from peripheral blood culture. Genomic analyses showed mutations in mprF, purR and agrA. Pharmacokinetic simulations showed consistent activity of daptomycin+beta-lactam against all subpopulations. This represents an opportunity to understand S. aureus evolution and fitness in vivo on daptomycin therapy, and the role of beta-lactams to prevent selection of daptomycin resistant subpopulations.
Jones, S., Plucinski, M., Kay, K., Hodel, E. M., Hastings, I. M.
Anti-malarial drugs have long half-lives, so clinical trials to monitor their efficacy require long durations of follow-up to capture drug failure that may only become patent weeks after treatment. Reinfections often occur during follow-up so robust methods of distinguishing drug failures (recrudescence) from emerging new infections are needed to produce accurate failure rate estimates. "Molecular correction" aims to achieve this by comparing the genotypes between a patient's pre-treatment (initial) blood sample and any infection that occurs during follow-up, ‘matching’ genotypes indicating a drug failure. We use an in-silico approach to show that the widely used "match counting" method of molecular correction with microsatellite markers is likely to be highly unreliable and may lead to gross under- or over-estimates of true failure rates depending on the choice of matching criterion. A Bayesian algorithm for molecular correction has been previously developed and utilized for analysis of in vivo efficacy trials. We validated this algorithm using in silico data and showed it had high specificity and generated accurate failure rate estimates. This conclusion was robust for multiple drugs, different levels of drug failure rate, different levels of transmission intensity in the study sites, and microsatellite genetic diversity. The Bayesian algorithm was inherently unable to accurately identify low-density recrudescence that occurred in a small number of patients, but this did not appear to compromise its utility as a highly effective molecular correction method for analysing microsatellite genotypes. Strong consideration should be given to using Bayesian methodology for obtaining accurate failure rate estimates during routine monitoring trials of antimalarial efficacy that use microsatellite markers.
Bonnin, R. A., Jousset, A. B., Gauthier, L., Emeraud, C., Girlich, D., Sauvadet, A., Cotellon, G., Jove, T., Dortet, L., Naas, T.
A carbapenem-resistant Citrobacter spp. was recovered from routine screening of multidrug resistant bacteria. This isolate co-produced OXA-48 and OXA-198. OXA-48 was carried by the prototypical incL plasmid whereas OXA-198 was carried by a peculiar IncHI-type plasmid. This carbapenemase gene was inserted within a class 1 integron located on a conjugative plasmid. This report described the first occurrence of OXA-198 in Enterobacterales.
Mensah, B. A., Aydemir, O., Myers-Hansen, J. L., Opoku, M., Hathaway, N. J., Marsh, P. W., Anto, F., Bailey, J., Abuaku, B., Ghansah, A.
A key drawback to monitoring the emergence and spread of antimalarial drug resistance in sub-Saharan Africa is early detection and containment. Next-generation sequencing methods offer the resolution, sensitivity and scale required to fill this gap by surveilling for molecular markers of drug resistance. We performed targeted sequencing using molecular inversion probes to interrogate five Plasmodium falciparum genes (pfcrt, pfmdr1, pfdhps, pfdhfr and pfk13) implicated in chloroquine, sulphadoxine-pyrimethamine (SP) and artemisinin resistance, in two sites in Ghana. A total of 803 dried blood spots were prepared on filter-paper, from children aged between 6 months-14 years presenting with uncomplicated P. falciparum malaria at the Begoro district hospital in Begoro and the Ewim polyclinic in Cape Coast from 2014 to 2017. Thirteen years after the removal of drug pressure, chloroquine sensitive parasite strains, pfcrt K76 have increased nearly to fixation in Begoro in the forest area (prevalence = 95%), but at a slower rate in Cape Coast in the coastal region (prevalence = 71%, z=-3.5, P
Rotondo, C. M., Sychantha, D., Koteva, K., Wright, G. D.
The rise of Gram-negative pathogens expressing metallo-β-lactamases (MBLs) is a growing concern, threatening the efficacy of β-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use. Aspergillomarasmine A (AMA) is an MBL inhibitor isolated from Aspergillus versicolor with both in vitro and in vivo ability to rescue meropenem activity in MBL-producing bacteria. Here we systematically explored the pairing of AMA with six β-lactam antibiotic partners against nineteen MBLs from each subclass (B1, B2, B3). Cell-based assays with Escherichia coli and Klebsiella pneumoniae showed that bacteria producing NDM-1 and VIM-2 of subclass B1 were the most susceptible to AMA inhibition, whereas bacteria producing CphA2 and AIM-1 of subclasses B2 and B3, respectively, were the least sensitive. Intracellular antibiotic accumulation assays and in vitro enzyme assays demonstrated that the efficacy of AMA/β-lactam combinations did not correlate with outer membrane permeability or drug efflux. We determined that the optimal β-lactam partners for AMA are the carbapenem antibiotics, and the efficacy of AMA is linked to the Zn2+ affinity of specific MBLs.
Specialespecifikt kursus om immundefekt og feber af ukendt årsag
28.01.2020 - 29.01.2020
International Congress on Infectious Diseases (ICID) 2020
Kuala Lumpur, Malaysia
20.02.2020 - 23.02.2020
Dansk Selskab for Intern Medicin (DSIM) årsmøde og overrækkelse af Hagedorn prisen 2020
Novo Nordisk Fonden, Tuborg Havnevej 19, 2900 Hellerup
Conference on Retroviruses and Opportunistic Infections (CROI) 2020
Boston, Massachusetts, USA
8.03.2020 - 11.03.2020
Når CROI går i fisk - med transmissioner fra CROI 2020
10.03.2020 - 11.03.2020
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
Cryptococcal meningitis and immune reconstitution inflammatory syndrome in a pediatric patient with HIV after switching to second line antiretroviral therapy: a case report
21.01.2020Latest Results for BMC Infectious Diseases
Impaired cytokine responses to live Staphylococcus epidermidis in preterm infants precede Gram-positive late-onset sepsis
21.01.2020Clinical Infectious Diseases Advance Access
“Rapid Start” treatment to End the (Other) Epidemic: Walking the Tight-rope without a Net
21.01.2020Clinical Infectious Diseases Advance Access
Outcomes Associated with Medications for Opioid Use Disorder Among Persons Hospitalized for Infective Endocarditis
21.01.2020Clinical Infectious Diseases Advance Access
Sensory nociceptive neurons contribute to host protection during enteric infection with Citrobacter rodentium
21.01.2020The Journal of Infectious Diseases Advance Access
Hvad tænker Professor Jens Lundgren om"Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV."?
Hvad mener Professor Troels Lillebæk om artiklen"The global prevalence of latent tuberculosis: a systematic review and meta-analysis."?
Hvad mener Professor Lars Østergaard om artiklen"Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial."?
Hvad mener Professor Thomas Benfield om artiklen"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvad mener Professor Niels Obel om artiklen"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
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