1,837 research outputs found

    The future of antibiotics

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    Th1-Th17 Cells Mediate Protective Adaptive Immunity against Staphylococcus aureus and Candida albicans Infection in Mice

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    We sought to define protective mechanisms of immunity to Staphylococcus aureus and Candida albicans bloodstream infections in mice immunized with the recombinant N-terminus of Als3p (rAls3p-N) vaccine plus aluminum hydroxide (Al(OH3) adjuvant, or adjuvant controls. Deficiency of IFN-Ξ³ but not IL-17A enhanced susceptibility of control mice to both infections. However, vaccine-induced protective immunity against both infections required CD4+ T-cell-derived IFN-Ξ³ and IL-17A, and functional phagocytic effectors. Vaccination primed Th1, Th17, and Th1/17 lymphocytes, which produced pro-inflammatory cytokines that enhanced phagocytic killing of both organisms. Vaccinated, infected mice had increased IFN-Ξ³, IL-17, and KC, increased neutrophil influx, and decreased organism burden in tissues. In summary, rAls3p-N vaccination induced a Th1/Th17 response, resulting in recruitment and activation of phagocytes at sites of infection, and more effective clearance of S. aureus and C. albicans from tissues. Thus, vaccine-mediated adaptive immunity can protect against both infections by targeting microbes for destruction by innate effectors

    Effects of Adjunctive rh-transferrin on Susceptibility and Emergence of Resistance in Gram-negative Pathogens

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    Introduction: Human pathogens have experienced selective pressure from antibiotics for nearly 80 years. The high speed of antibiotic resistance formation in nosocomial bacteria together with overuse of antibiotics has promoted the current multidrug resistance crisis. The problem is especially important for Russian healthcare, where the majority of isolated clinical strains of A. baumannii are drug-resistant: 93% of them are resistant to Cefoperazone, 61,2% - to Amicacin, 51,9% - to Levofloxacin [1]. We attempted to decrease the emergence of resistant mutants using a novel combination of antibiotics with recombinant human transferrin (rh-transferrin). We hypothesized that rh- transferrin, which functions by passively starving the bacteria of iron needed for microbial replication [2], would exert less selective pressure as compared to traditional antibiotics. It has been reported in previous studies that transferrin has broad antimicrobial effects in vitro against Gram-positive and Gram-negative bacteria and fungal pathogens [3]. The main goal of this project is to study the in vitro and in vivo effect of adjunctive transferrin on susceptibility and emergence of resistance in the Gram-negative pathogens Acinetobacter baumannii and Klebsiella pneumoniae. Materials and Methods: Time-kill assays were done using ciprofloxacin or meropenem with and without transferrin. Viability was assessed at 1, 2, 4, 6, 8, and 24 hours for A. baumannii and at 1, 4, and 24 hours for K. pneumonia. The assay was done using either resazurin (cellular metabolic readout) or quantitative culturing. Antibiotic-resistant mutants were selected by passaging a high inoculum of bacteria in sub-lethal concentrations of antibiotic for 24 hours or by serial passaging lower inocula of bacteria for 20 days with or without rh-transferrin. C3HeB/FeJ mice were infected IV with 2x10^7 CFU of A. baumannii LAC-4 strain and mice were administered a sub-therapeutic dose of ciprofloxacin (50 mg/kg BID) with and without transferrin (100 mg/kg). Results: The time-kill assays for both bacterial species showed no interaction between the antibiotics and rh-transferrin in vitro for most strains. Mutant selection for 24 hours and 20 days demonstrated a decrease in mutant emergence in the group treated with a combination of rh-transferrin and antibiotics compared to antibiotics alone. The 20-day passage experiment selected for mutants with an extremely high level of resistance. LD100 for all strains in C3HeB/FeJ mice were defined. In vivo efficacy experiments will begin soon with combination therapy. Conclusions: We found that transferrin containing therapeutic regimens suppressed the emergence of resistance in vitro, and is promising as an adjunct to antibiotic therapy

    Impact of Definitive Therapy with Beta-Lactam Monotherapy or Combination with an Aminoglycoside or a Quinolone for Pseudomonas aeruginosa Bacteremia

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    BACKGROUND: Bacteremia by Pseudomonas aeruginosa represents one severe infection. It is not clear whether beta-lactam monotherapy leads to similar rates of treatment success compared to combinations of beta-lactams with aminoglycosides or quinolones. METHODS: Retrospective cohort study from 3 tertiary hospitals (2 in Greece and 1 in Italy). Pseudomonas aeruginosa isolates were susceptible to a beta-lactam and an aminoglycoside or a quinolone. Patients received appropriate therapy for at least 48 hours. Primary outcome of interest was treatment success in patients with definitive beta-lactam combination therapy compared to monotherapy. Secondary outcomes were treatment success keeping the same empirical and definitive regimen, mortality, and toxicity. RESULTS: Out of 92 bacteremias there were 54 evaluable episodes for the primary outcome (20 received monotherapy). Treatment success was higher with combination therapy (85%) compared to beta-lactam monotherapy (65%), however not statistically significantly [Odds ratio (OR) 3.1; 95% Confidence Interval (CI) 0.69-14.7, p = 0.1]. Very long (>2 months) hospitalisation before bacteremia was the only factor independently associated with treatment success (OR 0.73; 95% CI 0.01-0.95, p = 0.046), however this result entailed few episodes. All-cause mortality did not differ significantly between combination therapy [6/31 (19%)] and monotherapy [8/19 (42%)], p = 0.11. Only Charlson comorbidity index was associated with excess mortality (p = 0.03). CONCLUSION: Our study, in accordance with previous ones, indicates that the choice between monotherapy and combination therapy may not affect treatment success significantly. However, our study does not have statistical power to identify small or moderate differences. A large randomized controlled trial evaluating this issue is justified

    On the exoneration of Dr. William H. Stewart: debunking an urban legend

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    Abstract Background It is one of the most infamous quotes in the history of biomedicine: β€œIt is time to close the book on infectious diseases, and declare the war against pestilence won.” Long attributed to the United States Surgeon General, Dr. William H. Stewart (1965-1969), the statement is frequently used as a foil by scientific and lay authors to underscore the ever-increasing problems of antibiotic-resistant and emerging infections. However, the primary source for the quote has never been identified. Methods We undertook a comprehensive search of multiple databases encompassing medical literature, news articles, and congressional records to attempt to identify sources for the quote. Results No source of the quote was identified. However, a trail of source documents was identified that clearly serves as the basis for subsequent, incorrect attribution of the quote to Dr. Stewart. In multiple source documents, Dr. Stewart made statements to the opposite effect, clearly recognizing that infectious diseases had not been conquered. The urban legend was created by a combination of lack of primary witnesses to the originating speech, misunderstanding of points made by Dr. Stewart in the speech, and increasing societal concern about emerging and re-emerging infectious diseases. Conclusions Attribution to Dr. Stewart of a belief that it was time to close the book on infectious diseases is an urban legend; he never made any such statement. Numerous other verifiable sources, however, confirm that other people in academia adopted this belief. Dr. Stewart should no longer be cited in this regard, and should be replaced with verifiable sources
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