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Peters A, Borzykowski T, Tartari E, et al.
infection prevention and controlinfection controlhand hygieneuniversal health coverageWorld Health Organization
Lun, S., Tasneen, R., Chaira, T., Stec, J., Onajole, O. K., Yang, T. J., Cooper, C. B., Mdluli, K., Converse, P. J., Nuermberger, E. L., Raj, V. S., Kozikowski, A., Bishai, W. R.
Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall associated mycolic acid transporter of Mycobacterium tuberculosis (Mtb). In the present study, we characterized indoleamide effects on bacterial cell morphology and re-evaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated Mtb cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, a second-generation indoleamide, compound 2, showed significantly improved PK parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant Mtb, these findings demonstrate the therapeutic potential of this novel scaffold for treatment of both drug-susceptible and drug-resistant tuberculosis.
Ersoy, S. C., Abdelhady, W., Li, L., Chambers, H. F., Xiong, Y. Q., Bayer, A. S.
Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as ‘resistant' to β-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin and cefazolin (‘NaHCO3-responsive’) and one resistant to such agents (‘NaHCO3-nonresponsive’). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.
Hunt-Serracin, A. C., Parks, B. J., Boll, J., Boutte, C.
Mycobacterium abscessus (Mab) is a biofilm-forming, multi-drug resistant, non-tuberculous mycobacterial (NTM) pathogen increasingly found in Cystic Fibrosis patients. Antibiotic treatment for these infections is often unsuccessful, partly due to Mab's high intrinsic antibiotic resistance. It is not clear whether antibiotic tolerance caused by biofilm formation also contributes to poor treatment outcomes. We studied the surface glycolipids and antibiotic tolerance of Mab biofilms grown in Artificial Cystic Fibrosis Sputum (ACFS) media in order to determine how they are affected by nutrient conditions that mimic infection. We found that Mab displays more of the virulence lipid trehalose dimycolate when grown in ACFS compared to standard lab media. In ACFS media, biofilm-associated cells are more antibiotic tolerant than planktonic cells in the same well. This contrasts with standard lab medias, where biofilm and planktonic cells are both highly antibiotic tolerant. These results indicate that Mab cell physiology in biofilms depends on environmental factors, and that nutrient conditions found within Cystic Fibrosis infections could contribute to both increased virulence and antibiotic tolerance.
Rapaka, R. R., Dai, G., Zheng, M., Kolls, J. K.
Pneumocystis pneumonia is a life-threatening opportunistic fungal infection observed in individuals with severe immunodeficiencies, such as AIDS. Molecules with the ability to bind β-glucan and signal at Fc- receptors enhance defense against Pneumocystis f. sp. murina, though it is unclear whether antibodies reactive with fungal cell wall carbohydrates are induced during Pneumocystis infection. We observed that systemic and lung mucosal immunoglobulins cross-reactive with β-glucan and chitosan/chitin are generated after Pneumocystis infection, with increased quantities within the lung mucosal fluid after challenge. While IgG responses against Pneumocystis protein antigens are markedly CD4+ T cell dependent, CD4+ T cell depletion did not impact quantities of IgG cross-reactive with β-glucan or chitosan/chitin in the serum or mucosa after challenge. Notably, lung mucosal quantities of IgA cross-reactive with β-glucan or chitosan/chitin are decreased in the setting of CD4+ T cell deficiency, occurring in the setting of concurrent reduced quantities of active TGF-β, while mucosal IgM is significantly increased in the setting of CD4+ T cell deficiency. IL-21 receptor deficiency does not lead to reduction in mucosal IgA reactive with fungal carbohydrate antigens after Pneumocystis challenge. These studies demonstrate differential CD4+ T cell dependent regulation of mucosal antibody responses against β-glucan and chitosan/chitin after Pneumocystis challenge, suggesting that different B cell subsets may be responsible for the generation of these antibody responses, and suggest a potential immune response against fungi that may be operative in the setting of CD4+ T cell related immunodeficiency.
Kim, D., Lee, H., Yoon, E.-J., Hong, J. S., Shin, J. H., Uh, Y., Shin, K. S., Shin, J. H., Kim, Y. A., Park, Y. S., Jeong, S. H.
Introduction: To evaluate the clinical impacts of ampicillin-susceptible but penicillin-resistant (ASPR) phenotypes of Enterococcus faecalis on clinical outcomes in patients with a bloodstream infection (BSI).Methods: A total of 295 patients with an E. faecalis BSI from six sentinel hospitals during a two-year period (from May 2016 to April 2018) were enrolled in this study. Putative risk factors, including host-, treatment-, and pathogen-related variables, were assessed to determine the associations with the 30-day mortality rate of patients with an E. faecalis BSI.Results: The proportion of ASPR E. faecalis isolates was 22.7% (67/295). ASPR isolates (adjusted odds ratio, 2.27; 95% confidence interval, 1.01-5.02) exhibited a significant association with an increased 30-day mortality rate, and a significant difference in survival was identified in a group of patients treated with ampicillin- and/or piperacillin-based regimens who were stratified according to the penicillin susceptibility of the causative pathogen (log-rank test, P = 0.011).Conclusions: ASPR E. faecalis BSIs resulted in a >2-fold higher 30-day mortality rate (26.9%, 18/67) than the BSIs caused by penicillin-susceptible strains (12.3%, 28/228). The differences in mortality rates of patients stratified by penicillin susceptibility were likely due to the treatment failures of ampicillin and/or piperacillin in patients with an ASPR E. faecalis BSI.
Oishi, T., Takahashi, K., Wakabayashi, S., Nakamura, Y., Ono, S., Kono, M., Kato, A., Saito, A., Kondo, E., Tanaka, Y., Teranishi, H., Akaike, H., Tanaka, T., Miyata, I., Ogita, S., Ohno, N., Nakano, T., Ouchi, K.
We compared the antimicrobial susceptibility of Mycoplasma pneumoniae isolated from pediatric patients in Japan in 2011–2012 and 2015–2016 when epidemics occurred. The antimicrobial activity of macrolides and tetracyclines against M. pneumoniae tended to be restored in 2015–2016. There was no change in the antimicrobial activity of quinolones against M. pneumoniae.
In malaria-endemic settings, a small proportion of children suffer repeated malaria infections, contributing to most of the malaria cases, yet underlying factors are not fully understood. This study was aimed to determine whether undernutrition predicts this over-dispersion of malaria infections in children aged 6–18 months in settings of high malaria and undernutrition prevalence.
Prospective cohort study, conducted in Mangochi, Malawi. Six-months-old infants were enrolled and had length-for-age z-scores (LAZ), weight-for-age z-scores (WAZ), and weight-for-length z-scores (WLZ) assessed. Data were collected for ‘presumed’, clinical, and rapid diagnostic test (RDT)-confirmed malaria until 18 months. Malaria microscopy was done at 6 and 18 months. Negative binomial regression was used for malaria incidence and modified Poisson regression for malaria prevalence.
Of the 2723 children enrolled, 2561 (94%) had anthropometry and malaria data. The mean (standard deviation [SD]) of LAZ, WAZ, and WLZ at 6 months were − 1.4 (1.1), − 0.7 (1.2), and 0.3 (1.1), respectively. The mean (SD) incidences of ‘presumed’, clinical, and RDT-confirmed malaria from 6 to 18 months were: 1.1 (1.6), 0.4 (0.8), and 1.3 (2.0) episodes/year, respectively. Prevalence of malaria parasitaemia was 4.8% at 6 months and 9.6% at 18 months. Higher WLZ at 6 months was associated with lower prevalence of malaria parasitaemia at 18 months (prevalence ratio [PR] = 0.80, 95% confidence interval [CI] 0.67 to 0.94, p = 0.007), but not with incidences of ‘presumed’ malaria (incidence rate ratio [IRR] = 0.97, 95% CI 0.92 to 1.02, p = 0.190), clinical malaria (IRR = 1.03, 95% CI 0.94 to 1.12, p = 0.571), RDT-confirmed malaria (IRR = 1.00, 95% CI 0.94 to 1.06, p = 0.950). LAZ and WAZ at 6 months were not associated with malaria outcomes. Household assets, maternal education, and food insecurity were significantly associated with malaria. There were significant variations in hospital-diagnosed malaria by study site.
In children aged 6–18 months living in malaria-endemic settings, LAZ, WAZ, and WLZ do not predict malaria incidence. However, WLZ may be associated with prevalence of malaria. Socio-economic and micro-geographic factors may explain the variations in malaria, but these require further study.
Trial registration NCT00945698. Registered July 24, 2009, https://clinicaltrials.gov/ct2/show/NCT00945698, NCT01239693. Registered Nov 11, 2010, https://clinicaltrials.gov/ct2/show/NCT01239693
Kirby, B. D., Al Ahmar, R., Withers, T. R., Valentine, M. E., Valentovic, M., Long, T. E., Gaskins, J. R., Yu, H. D.
Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation. Using a NIH small compounds drug library approved for safe use in humans, we identified rifaximin (RFX), a semisynthetic, rifamycin family, non-systemic antibiotic that inhibits alginate production and growth in P. aeruginosa. Inhibition of alginate production was further analyzed using the uronic acid carbazole assay and a promoter reporter assay that measures the transcription of the alginate biosynthetic operon. Compared to TOB, RFX significantly reduced alginate production in laboratory and CF sputum isolates of P. aeruginosa. In addition, RFX showed a narrow range of minimum inhibitory concentrations when measured with multidrug-resistant bacterial species of clinical relevance, synergistic activities with TOB or amikacin against clinical isolates, as well as reduction towards in vitro pre-formed biofilms. In C57BL/6 mice, penetration of nebulized TOB into the lungs was shown at a higher level compared to RFX. Further in vivo assessment using a DBA/2 mouse lung-infection model found increased survival rates with a single-dose treatment of nebulized RFX and decreased P. aeruginosa PAO1 bio-burden with multiple-dose treatment of RFX plus TOB. In addition, mice treated with a single exposure to dimethyl sulfoxide (DMSO), a solvent that dissolves RFX, showed no apparent toxicity. In summary, RFX may be used to supplement the TOB inhalation therapy to increase the efficacy against P. aeruginosa biofilm infections.
Moayedi Y, Walmsley S.
Zanni M, Awadalla M, Toribio M, et al.
AbstractHIV imparts increased heart failure risk to women. Among WHIV, immune pathways relating to heart failure precursors may intimate targets for heart failure prevention strategies. Twenty asymptomatic, ART-treated WHIV and fourteen non-HIV-infected women matched on age/BMI underwent cardiac MRI and immune phenotyping. WHIV (vs. non-HIV-infected women) exhibited increased myocardial fibrosis (extracellular volume fraction, 0.34±0.06 vs 0.29±0.04;P=0.002), reduced diastolic function (diastolic strain rate, 1.10±0.23 vs. 1.39±0.27 s-1;P=0.003), and heightened systemic monocyte activation. Among WHIV, sCD163 levels correlated with myocardial fibrosis (r=0.53;P=0.02), while circulating inflammatory CD14+CD16+ monocyte CCR2 expression related directly to myocardial fibrosis (r=0.48;P=0.04) and inversely to diastolic function (r= -0.49;P=0.03).
Rogawski_McQuade E, Platts-Mills J, Gratz J, et al.
AbstractBackgroundWe assessed the impact of water, sanitation, and hygiene (WASH) and infant and young child feeding (IYCF) interventions on enteric infections in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.MethodsWe tested stool samples collected at 1, 3, 6, and 12 months of age and during diarrhea using quantitative molecular diagnostics for 29 pathogens. We estimated the effects of the WASH, IYCF, and combined WASH+IYCF on individual enteropathogen prevalence and quantity, total numbers of pathogens detected, and incidence of pathogen-attributable diarrhea.ResultsWASH interventions decreased the number of parasites detected (difference in number compared to non-WASH arms: -0.07, 95% CI: -0.14, -0.02), but had no statistically significant effects on bacteria, viruses, or the prevalence and quantity of individual enteropathogens after accounting for multiple comparisons. IYCF interventions had no significant effects on individual or total enteropathogens. Neither intervention had significant effects on pathogen-attributable diarrhea.ConclusionThe WASH interventions implemented in SHINE (improved pit latrine, hand-washing stations, liquid soap, point-of-use water chlorination, and clean play space) did not prevent enteric infections. Transformative WASH interventions are needed that are more efficacious in interrupting fecal-oral microbial transmission in children living in highly contaminated environments.ClinicalTrials.gov IdentifierNCT01824940 (https://clinicaltrials.gov/ct2/show/NCT01824940)
Brann, K. R., Fullerton, M. S., Onyilagha, F. I., Prince, A. A., Kurten, R. C., Rom, J. S., Blevins, J. S., Smeltzer, M. S., Voth, D. E.
Pulmonary pathogens encounter numerous insults while establishing infection in the human lung, including phagocytic cells designed to degrade bacteria. Staphylococcus aureus is a versatile, opportunistic pathogen that can cause severe pneumonia, and methicillin-resistant isolates are of particular concern. Recent reports present conflicting data regarding the ability of S. aureus to survive and replicate within macrophages. However, due to use of multiple strains and macrophage sources, making comparisons between reports remains difficult. Here, we established a disease-relevant platform to study innate interactions between S. aureus and human lungs. Human Precision-Cut Lung Slices (hPCLS) were subjected to S. aureus LAC (methicillin-resistant) or UAMS-1 (methicillin-sensitive) isolates. Additionally, primary human alveolar macrophages (hAMs) were infected with S. aureus and antibacterial activity assessed. Although both S. aureus isolates survived within hAM phagosomes, neither strain replicated efficiently in these cells. S. aureus was prevalent within the epithelial and interstitial regions of hPCLS, with limited numbers present in a subset of hAMs, suggesting the pathogen may not target phagocytic cells for intracellular growth during natural pulmonary infection. S. aureus-infected hAMs mounted a robust inflammatory response that reflects natural human disease. S. aureus LAC was significantly more cytotoxic to hAMs than UAMS-1, potentially due to isolate-specific virulence factors. The bi-component toxin, Panton-Valentine Leukocidin, was not produced during intracellular infection, while α-hemolysin was produced but was not hemolytic, suggesting hAMs alter toxin activity. Overall, this study has defined a new disease-relevant infection platform to study S. aureus interaction with human lungs and define virulence factors that incapacitate pulmonary cells.
Raz, A., Serrano, A., Hernandez, A., Euler, C. W., Fischetti, V. A.
Multi-drug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogen Pseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens, however the outer membrane of Gram-negative bacteria prevents most lysins from reaching the peptidoglycan, making them less effective as therapeutics. Nevertheless, a few lysins from gram-negative phage can penetrate the bacterial outer membrane, aided by an amphipathic tail found in the molecule's termini. In this work we took a phylogenetic approach to systematically identify those lysins from P. aeruginosa phage that would be most effective therapeutically. We isolated and performed preliminary characterization of 16 lysins, and chose two lysins, PlyPa03 and PlyPa91, which exhibited >5-log killing activity against P. aeruginosa and other Gram-negative pathogens (particularly Klebsiella and Enterobacter). These lysins showed rapid killing kinetics and were active in the presence of high concentrations of salt and urea and in pH conditions ranging from 5.0 to 10.0. Activity was not inhibited in the presence of the pulmonary surfactant Survanta. While neither enzyme was active in 100% human serum, PlyPa91 retained activity in low serum concentrations. The lysins were effective in the treatment of a P. aeruginosa skin infection in a mouse model, and PlyPa91 protected mice in a lung infection model, making these lysins potential drug candidates for Gram-negative infections of the skin or respiratory mucosa.
Ghodousi, A., Tagliani, E., Karunaratne, E., Niemann, S., Perera, J., Köser, C. U., Cirillo, D. M.
MIC testing using the BACTEC 960 MGIT system of 70 phylogenetically diverse, isoniazid-resistant clinical strains of Mycobacterium tuberculosis revealed a complex pattern of overlapping MIC distributions. Whole-genome sequencing could explain most of the level of resistance observed. The MIC distribution of strains with only inhA promoter mutations was split by the current concentration that is endorsed by the Clinical Laboratory Standards Institute to detect low-level resistance to isoniazid and is, consequently, likely not optimally set.
Soucy, J.-P. R., Schmidt, A. M., Frenette, C., Dolce, P., Boudreault, A. A., Buckeridge, D. L., Quach, C.
Empirical treatment of urinary tract infections should be based on susceptibility profiles specific to the locale and patient population. Additionally, these susceptibility profiles should account for correlations between resistance to different types of antimicrobials. We used hierarchical logistic regression models to investigate geographic, temporal, and demographic trends in resistance to six antimicrobials in community-acquired and nosocomial urinary E. coli isolates from three communities in the province of Quebec, Canada procured between April 2010 and December 2017. A total of 74,986 community-acquired (age ≥ 18) and 4,384 nosocomial isolates (age ≥ 65) were analyzed. In both community-acquired and nosocomial isolates, we found geographic variation in the prevalence of resistance. Male sex (community-acquired hierarchical mean OR = 1.24, 95% credible interval: 1.02–1.50; nosocomial hierarchical mean OR = 1.16, 95% CI: 0.92–1.41) and recent hospitalization (community-acquired hierarchical mean OR = 1.49, 95% CI: 1.33–1.66; nosocomial hierarchical mean OR = 1.31, 95% CI: 0.99–1.78) were associated with a higher risk of resistance to most types of antimicrobials. We found distinct seasonal trends in both community-acquired and nosocomial isolates, but only community-acquired isolates showed a consistent annual pattern. Ciprofloxacin resistance increased sharply with patient age. We found clinically relevant differences in antimicrobial resistance in urinary E. coli isolates between locales and patient populations in the province of Quebec. These results could help inform empirical treatment decisions for urinary tract infections. In the future, similar models integrating local, provincial, and national resistance data could be incorporated into decision-support systems for clinicians.
van den Elsen, S. H. J., Sturkenboom, M. G. G., Akkerman, O. W., Manika, K., Kioumis, I. P., van der Werf, T. S., Johnson, J. L., Peloquin, C., Touw, D. J., Alffenaar, J.-W. C.
Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest; the area under the concentration time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampicin (MFX+RIF) in TB patients.Population pharmacokinetic (popPK) models were developed for MFX (n=77) and MFX+RIF (n=24). Additionally, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (1-3 samples; 6 h timespan post-dose; 1 h interval) were tested.Moxifloxacin exposure was slightly underestimated in the one compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed a mean overestimation of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively.LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX 0 and 4 h, MFX+RIF 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.
Denys, G. A., Devoe, N. C., Gudis, P., May, M., Allen, R. C., Stephens, J. T.
E-101 Solution is a first in class myeloperoxidase-mediated antimicrobial developed for topical application. It is composed of porcine myeloperoxidase (pMPO), glucose oxidase (GO), glucose, sodium chloride, and specific amino acids in an aqueous solution. Once activated, the reactive species hydrogen peroxide (H2O2), hypochlorous acid and singlet oxygen are generated. We evaluated the treatment effect of E-101 solution and its oxidative products on ultrastucture changes and microbicidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli. Time kill and transmission electron microscopy studies were also performed using formulations with pMPO or GO omitted. The glutathione membrane protection assay was used to study the neutralization of reactive oxygen species. The potency of E-101 solution was also measured in the presence of serum and whole blood by MIC and MBC determinations. E-101 solution demonstrated rapid bactericidal activity and ultracellular changes in MRSA and E. coli cells. When pMPO was omitted, high levels of H2O2 generated from GO and glucose demonstrated slow microbicidal activity with minimal cellular damage. When GO was omitted from the formulation no antimicrobial activity or cellular damage was observed. Protection from exposure to E-101 solution reactive oxygen species in the glutathione protection assay was competitive and temporary. E-101 solution maintained its antimicrobial activity in the presence of inhibitory substances such as serum and whole blood. E-101 solution is a potent myeloperoxidase enzyme system with multiple oxidative mechanisms of action. Our findings suggest the primary site that E-101solution exerts microbicidal action is the cell membrane by inactivation of essential cell membrane components.
Rees, C. A., Bao, R., Zegans, M. E., Cramer, R. A.
The in vitro activities of two antifungal drugs in combination with four non-antifungal ophthalmic agents were evaluated using a micro-broth dilution method and a collection of eight Fusarium ocular isolates that exhibited resistance to both natamycin (MICs: 14-32 μg/mL) and voriconazole (4->128 μg/mL). Synergistic interactions were observed for natamycin with 5-fluorouracil (FICIs: 0.34-0.61) and natamycin with timolol (0.41-0.52). Synergistic or indifferent interactions were observed for natamycin with EDTA (0.38-1.00), natamycin with dorzolamide (0.53-1.00), voriconazole with EDTA (0.38-1.00), voriconazole with timolol (0.39-0.94), and voriconazole with 5-fluorouracil (0.53-0.75). Taken together, these data suggest commonly used ophthalmic agents enhance the in vitro activity of antifungal drugs against drug recalcitrant ocular fungal pathogens.
Truong-Bolduc, Q. C., Wang, Y., Hooper, D. C.
Using an affinity column retention assay we showed that the purified Tet38 membrane transporter of Staphylococcus aureus bound specifically to host cell CD36 and to the complex CD36-TLR-2, but not to TLR-2 alone or TLR-2 and S. aureus lipoteichoic acid (LTA). We tested the effect of LTA on the internalization of S. aureus tet38 mutant QT7 versus RN6390 by A549 epithelial cells. Addition of anti-LTA antibody to the bacteria prior to adding to A549, reduced internalization of QT7 by twofold compared to non-specific antibody treatment. QT7 internalized four- to sixfold less than RN6390 with or without anti-LTA antibody. These data suggested that Tet38 and LTA were independently involved in the invasion process. The wall teichoic acid (WTA) inhibitor tunicamycin had an eightfold decrease in activity with overexpression of tet38 and a twofold increase in activity in QT7 (tet38). Reserpine (an inhibitor of efflux pumps) reduced the effect of tet38 overexpression on tunicamycin resistance by fourfold. In addition, tet38 affected growth in the presence of LTA inhibitor Congo Red, with overexpression increasing growth and deletion of tet38 reducing growth.In conclusion, Tet38 contributes to S. aureus invasion of A549 via direct binding to CD36 of the complex CD36-TLR-2, and LTA independently bound to TLR-2. The reduction of tunicamycin resistance in the presence of reserpine, and the survival ability of the tet38-overexpressor in the presence of Congo Red suggest that Tet38 can also protect the synthesis of LTA and WTA in S. aureus against their inhibitors, possibly functioning as an efflux pump.
Iacobino, A., Giannoni, F., Pardini, M., Piccaro, G., Fattorini, L.
The activities of rifampin, nitazoxanide, PA-824, sutezolid, were tested against dormant Mycobacterium tuberculosis under conditions mimicking caseous granulomas (hypoxia at pH 7.3), in comparison with the combination rifampin-isoniazid-pyrazinamide-ethambutol (R-I-Z-E), used for human therapy. Mycobacterial viability was monitored by CFU and regrowth in MGIT 960 tubes. As shown by lack of regrowth in MGIT, rifampin-nitazoxanide containing combinations, but not R-I-Z-E, killed dormant cells in 28-35 days. These observations might be important in designing new tuberculosis therapies.
Blumenthal M, Schutz C, Barr D, et al.
AbstractBackgroundDespite increasing numbers of human immunodeficiency virus (HIV)-infected South Africans receiving antiretroviral therapy (ART), tuberculosis remains the leading cause of mortality. Approximately 25% of patients treated for tuberculosis have microbiologically unconfirmed diagnoses. We assessed whether elevated Kaposi’s sarcoma-associated Herpes Virus (KSHV) viral load (VL) contributes to mortality in hospitalized HIV-infected patients investigated for tuberculosis.Methods682 HIV-infected patients admitted to Khayelitsha Hospital, South Africa, were recruited, investigated for tuberculosis, and followed for 12-weeks. KSHV-serostatus, peripheral blood KSHV-VL, and KSHV-associated clinical correlates were evaluated.ResultsMedian CD4 count was 62 cells/μL (range: 0-526); KSHV-seropositivity was 30.7% (95%CI: 27-34%); 5.8% had detectable KSHV-VL (median 199.1; range: 13.4-2.2x106 copies/106 cells); 22% died. Elevated KSHV-VL was associated with mortality (adjusted OR=6.5 [95%CI: 1.3, 32.4]) in patients without tuberculosis or other microbiologically confirmed co-infections (n=159). Six patients had “possible KSHV-inflammatory cytokine syndrome (KICS)”: five died, representing significantly worse survival (p
Diekema, D. J., Hsueh, P.-R., Mendes, R. E., Pfaller, M. A., Rolston, K. V., Sader, H. S., Jones, R. N.
Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequent pathogen overall in the 1997–2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus resistant to oxacillin (MRSA) increased until 2005–08, then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (
Lima, B., Bodeau, S., Quinton, M.-C., Leven, C., Lemaire-Hurtel, A.-S., Bennis, Y.
Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum including potent activity against methicillin-resistant Staphylococcus aureus. As for the other cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected. We describe here the first simple and rapid analytical method intended for ceftobiprole serum concentration monitoring. We report the data of 5 patients treated with ceftobiprole, among who 2 developed reversible neurological disorders with high ceftobiprole serum concentration.
J. Voermans et al.
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
Resistance of Influenza Virus to Antiviral Medications
20.09.2019Clinical Infectious Diseases Advance Access
Erratum to: Chlamydia trachomatis and the Risk of Pelvic Inflammatory Disease, Ectopic Pregnancy, and Female Infertility: A Retrospective Cohort Study Among Primary Care Patients
19.09.2019Clinical Infectious Diseases Advance Access
Comparison of repeated doses of ivermectin versus ivermectin plus albendazole for treatment of onchocerciasis – a randomized open-label clinical trial
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Association between Toxoplasma gondii infection and thyroid dysfunction: a case-control seroprevalence study
18.09.2019Latest Results for BMC Infectious Diseases
Antimicrobial Stewardship in a Hematological Malignancy Unit: Carbapenem Reduction and Decreased Vancomycin-resistant Enterococcus Infection
18.09.2019Clinical Infectious Diseases Advance Access
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Hvad mener Professor Niels Obel om artiklen"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
Hvad tænker Professor Thomas Benfield om"Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial."?
Hvorfor synes Professor Morten Sodemann, at du bør læse"Evidence-based clinical guidelines for immigrants and refugees."?
Hvorfor synes Professor Niels Obel, at du bør læse"Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy."?
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