bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pyridodiazepine Amines Are Selective Therapeutic Agents for Helicobacter pylori by Suppressing Growth through Inhibition of Glutamate Racemase but Are Predicted To Require Continuous Elevated Levels in Plasma To Achieve Clinical Efficacy
Authors: de Jonge Boudewijn L. M. , Kutschke Amy , Newman Joseph V. , Rooney Michael T. , Yang Wei , Cederberg Christer 
Published: February 2015

ABSTRACT

A pyridodiazepine amine inhibitor of
Helicobacter pylori
glutamate racemase (MurI) was characterized. The compound was selectively active against
H. pylori
, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed against
H. pylori
if once-a-day dosing is required.
Propensity-Matched Analysis To Compare the Therapeutic Efficacies of Cefuroxime versus Cefotaxime as Initial Antimicrobial Therapy for Community-Onset Complicated Nonobstructive Acute Pyelonephritis Due to Enterobacteriaceae Infection in Women
Authors: Chang U-Im , Kim Hyung Wook , Wie Seong-Heon 
Published: February 2015

ABSTRACT

This study was performed to compare the therapeutic efficacy of cefuroxime with that of cefotaxime as initial antimicrobial therapies in women with complicated nonobstructive acute pyelonephritis (APN) caused by
Enterobacteriaceae
infections. The clinical characteristics and outcomes of a cefuroxime-treated group (
n
= 156) were compared with those of a cefotaxime-treated group (
n
= 166). Of these 322 women, 90 from each group were matched by propensity scores. The defervescence rates were not significantly different in the cefuroxime and cefotaxime groups at 72 h after the start of antimicrobial therapy (81.1% versus 78.9%,
P
= 0.709). The clinical and microbiological cure rates during the follow-up visits that were 4 to 14 days after the end of the antimicrobial therapies were not significantly different in the cefuroxime versus cefotaxime groups, which were 97.8% (87/89) versus 97.8% (87/89) (
P
> 0.999) and 89.5% (68/76) versus 90.7% (68/75) (
P
= 0.807), respectively. The median hospital stay duration and the median times to defervescence in the cefuroxime versus cefotaxime groups were 8 days (interquartile range [IQR], 7 to 10 days) versus 9 days (IQR, 7 to 11 days), respectively, and 55 h (IQR, 37 to 70 h) versus 55 h (IQR, 35 to 69 h), respectively. Bacteremia, extended-spectrum-β-lactamase-producing
Enterobacteriaceae
, C-reactive protein levels of ≥15 mg/dl, and white blood cell counts of ≥15,000/mm
3
of blood had independent effects on the rates of early clinical failure. Our data suggest that the effects of cefuroxime are not different from those of cefotaxime when they are used as an initial antimicrobial treatments for community-onset complicated nonobstructive APN in women.
Efficacy of ETI-204 Monoclonal Antibody as an Adjunct Therapy in a New Zealand White Rabbit Partial Survival Model for Inhalational Anthrax
Authors: Biron Bethany , Beck Katie , Dyer David , Mattix Marc , Twenhafel Nancy , Nalca Aysegul 
Published: February 2015

ABSTRACT

Inhalational anthrax is characterized by extensive bacteremia and toxemia as well as nonspecific to mild flu-like symptoms, until the onset of hypotension, shock, and mortality. Without treatment, the mortality rate approaches 100%. Antibiotic treatment is not always effective, and alternative treatments are needed, such as monotherapy for antibiotic-resistant inhalational anthrax or as an adjunct therapy in combination with antibiotics. The
Bacillus anthracis
antitoxin monoclonal antibody (MAb) ETI-204 is a high-affinity chimeric deimmunized antibody which targets the anthrax toxin protective antigen (PA). In this study, a partial protection New Zealand White (NZW) rabbit model was used to evaluate the protective efficacy of the adjunct therapy with the MAb. Following detection of PA in the blood, NZW rabbits were administered either an antibiotic (doxycycline) alone or the antibiotic in conjunction with ETI-204. Survival was evaluated to compare the efficacy of the combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals.
Ceftaroline Activity against Bacterial Pathogens Frequently Isolated in U.S. Medical Centers: Results from Five Years of the AWARE Surveillance Program
Authors: Sader Helio S. , Flamm Robert K. , Streit Jennifer M. , Farrell David J. , Jones Ronald N. 
Published: February 2015

ABSTRACT

A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all
Staphylococcus aureus
isolates at ≤2 μg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC
90
], 1 μg/ml; 97.6% susceptible). Among
Streptococcus pneumoniae
isolates, the highest ceftaroline MIC was 0.5 μg/ml, and ceftaroline activity against the most common
Enterobacteriaceae
species (MIC
50
, 0.12 μg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC
50
, ≤0.25 μg/ml; 86.8% susceptible).
Pharmacokinetics and Penetration of Ceftazidime and Avibactam into Epithelial Lining Fluid in Thigh- and Lung-Infected Mice
Authors: Berkhout Johanna , Melchers Maria J. , van Mil Anita C. , Seyedmousavi Seyedmojtaba , Lagarde Claudia M. , Nichols Wright W. , Mouton Johan W. 
Published: February 2015

ABSTRACT

Ceftazidime and the β-lactamase inhibitor avibactam constitute a new, potentially highly active combination in the battle against extended-spectrum-β-lactamase (ESBL)-producing bacteria. To determine possible clinical use, it is important to know the pharmacokinetic profiles of the compounds related to each other in plasma and the different compartments of infection in experimentally infected animals and in humans. We used a neutropenic murine thigh infection model and lung infection model to study pharmacokinetics in plasma and epithelial lining fluid (ELF). Mice were infected with ca. 10
6
CFU of
Pseudomonas aeruginosa
intramuscularly into the thigh or intranasally to cause pneumonia and were given 8 different (single) subcutaneous doses of ceftazidime and avibactam in various combined concentrations, ranging from 1 to 128 mg/kg of body weight in 2-fold increases. Concomitant samples of serum and bronchoalveolar lavage fluid were taken at up to 12 time points until 6 h after administration. Pharmacokinetics of both compounds were linear and dose proportional in plasma and ELF and were independent of the infection type, with estimated half-lives (standard deviations [SD]) in plasma of ceftazidime of 0.28 (0.02) h and of avibactam of 0.24 (0.04) h and volumes of distribution of 0.80 (0.14) and 1.18 (0.34) liters/kg. The ELF-plasma (area under the concentration-time curve [AUC]) ratios (standard errors [SE]) were 0.24 (0.03) for total ceftazidime and 0.27 (0.03) for unbound ceftazidime; for avibactam, the ratios were 0.20 (0.02) and 0.22 (0.02), respectively. No pharmacokinetic interaction between ceftazidime and avibactam was observed. Ceftazidime and avibactam showed linear plasma pharmacokinetics that were independent of the dose combinations used or the infection site in mice. Assuming pharmacokinetic similarity in humans, this indicates that similar dose ratios of ceftazidime and avibactam could be used for different types and sites of infection.
Candida Infective Endocarditis: an Observational Cohort Study with a Focus on Therapy
Authors: Arnold Christopher J. , Johnson Melissa , Bayer Arnold S. , Bradley Suzanne , Giannitsioti Efthymia , Miró José M. , Tornos Pilar , Tattevin Pierre , Strahilevitz Jacob , Spelman Denis , Athan Eugene , Nacinovich Francisco , Fortes Claudio Q. , Lamas Cristiane , Barsic Bruno , Fernández-Hidalgo Nuria , Muñoz Patricia , Chu Vivian H. 
Published: February 2015

ABSTRACT

Candida
infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for
Candida
infective endocarditis. This prospective cohort study was based on 70 cases of
Candida
infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion,
Candida
infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.
Antipseudomonal Agents Exhibit Differential Pharmacodynamic Interactions with Human Polymorphonuclear Leukocytes against Established Biofilms of Pseudomonas aeruginosa
Authors: Chatzimoschou Athanasios , Simitsopoulou Maria , Antachopoulos Charalampos , Walsh Thomas J. , Roilides Emmanuel 
Published: February 2015

ABSTRACT

Pseudomonas aeruginosa
is the most common pathogen infecting the lower respiratory tract of cystic fibrosis (CF) patients, where it forms tracheobronchial biofilms.
Pseudomonas
biofilms are refractory to antibacterials and to phagocytic cells with innate immunity, leading to refractory infection. Little is known about the interaction between antipseudomonal agents and phagocytic cells in eradication of
P. aeruginosa
biofilms. Herein, we investigated the capacity of three antipseudomonal agents, amikacin (AMK), ceftazidime (CAZ), and ciprofloxacin (CIP), to interact with human polymorphonuclear leukocytes (PMNs) against biofilms and planktonic cells of
P. aeruginosa
isolates recovered from sputa of CF patients. Three of the isolates were resistant and three were susceptible to each of these antibiotics. The concentrations studied (2, 8, and 32 mg/liter) were subinhibitory for biofilms of resistant isolates, whereas for biofilms of susceptible isolates, they ranged between sub-MIC and 2 × MIC values. The activity of each antibiotic alone or in combination with human PMNs against 48-h mature biofilms or planktonic cells was determined by XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2
H
-tetrazolium-5-carboxanilide] assay. All combinations of AMK with PMNs resulted in synergistic or additive effects against planktonic cells and biofilms of
P. aeruginosa
isolates compared to each component alone. More than 75% of CAZ combinations exhibited additive interactions against biofilms of
P. aeruginosa
isolates, whereas CIP had mostly antagonistic interaction or no interaction with PMNs against biofilms of
P. aeruginosa
. Our findings demonstrate a greater positive interaction between AMK with PMNs than that observed for CAZ and especially CIP against isolates of
P. aeruginosa
from the respiratory tract of CF patients.
A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator
Authors: Dragset Marte S. , Poce Giovanna , Alfonso Salvatore , Padilla-Benavides Teresita , Ioerger Thomas R. , Kaneko Takushi , Sacchettini James C. , Biava Mariangela , Parish Tanya , Argüello José M. , Steigedal Magnus , Rubin Eric J. 
Published: February 2015

ABSTRACT

Efficient iron acquisition is crucial for the pathogenesis of
Mycobacterium tuberculosis
. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against
M. tuberculosis
have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.
A Novel New Delhi Metallo-β-Lactamase Variant, NDM-14, Isolated in a Chinese Hospital Possesses Increased Enzymatic Activity against Carbapenems
Authors: Zou Dayang , Huang Yong , Zhao Xiangna , Liu Wei , Dong Derong , Li Huan , Wang Xuesong , Huang Simo , Wei Xiao , Yan Xiabei , Yang Zhan , Tong Yigang , Huang Liuyu , Yuan Jing 
Published: February 2015

ABSTRACT

A novel New Delhi metallo-β-lactamase (NDM) variant, NDM-14, was identified in clinical isolate
Acinetobacter lwoffii
JN49-1, which was recovered from an intensive care unit patient at a local hospital in China. NDM-14, which differs from other existing enzymes by an amino acid substitution at position 130 (Asp130Gly), possesses enzymatic activity toward carbapenems that is greater than that of NDM-1. Kinetic data indicate that NDM-14 has a higher affinity for imipenem and meropenem.
The N Terminus of Type III Secretion Needle Protein YscF from Yersinia pestis Functions To Modulate Innate Immune Responses
Authors: Osei-Owusu Patrick , Jessen Condry Danielle L. , Toosky Melody , Roughead William , Bradley David S. , Nilles Matthew L. 
Published: February 2015

ABSTRACT

The type III secretion system is employed by many pathogens, including the genera
Yersinia
,
Shigella
,
Pseudomonas
, and
Salmonella
, to deliver effector proteins into eukaryotic cells. The injectisome needle is formed by the polymerization of a single protein, e.g., YscF (
Yersinia pestis
), PscF (
Pseudomonas aeruginosa
), PrgI (
Salmonella enterica
SPI-1), SsaG (
Salmonella enterica
SPI-2), or MxiH (
Shigella flexneri
). In this study, we demonstrated that the N termini of some needle proteins, particularly the N terminus of YscF from
Yersinia pestis
, influences host immune responses. The N termini of several needle proteins were truncated and tested for the ability to induce inflammatory responses in a human monocytic cell line (THP-1 cells). Truncated needle proteins induced proinflammatory cytokines to different magnitudes than the corresponding wild-type proteins, except SsaG. Notably, N-terminally truncated YscF induced significantly higher activation of NF-κB and/or AP-1 and higher induction of proinflammatory cytokines, suggesting that a function of the N terminus of YscF is interference with host sensing of YscF, consistent with
Y. pestis
pathogenesis. To directly test the ability of the N terminus of YscF to suppress cytokine induction, a YscF-SsaG chimera with 15 N-terminal amino acids from YscF added to SsaG was constructed. The chimeric YscF-SsaG induced lower levels of cytokines than wild-type SsaG. However, the addition of 15 random amino acids to SsaG had no effect on NF-κB/AP-1 activation. These results suggest that the N terminus of YscF can function to decrease cytokine induction, perhaps contributing to a favorable immune environment leading to survival of
Y. pestis
within the eukaryotic host.
The Levels of Brachyspira hyodysenteriae Binding to Porcine Colonic Mucins Differ between Individuals, and Binding Is Increased to Mucins from Infected Pigs with
De Novo
MUC5AC Synthesis
Authors: Quintana-Hayashi Macarena P. , Mahu Maxime , De Pauw Nele , Boyen Filip , Pasmans Frank , Martel An , Premaratne Pushpa , Fernandez Harvey R. , Teymournejad Omid , Vande Maele Lien , Haesebrouck Freddy , Lindén Sara K. 
Published: February 2015

ABSTRACT

Brachyspira hyodysenteriae
colonizes the pig colon, resulting in mucohemorrhagic diarrhea and growth retardation. Fecal mucus is a characteristic feature of swine dysentery; therefore, we investigated how the mucin environment changes in the colon during infection with
B. hyodysenteriae
and how these changes affect this bacterium's interaction with mucins. We isolated and characterized mucins, the main component of mucus, from the colon of experimentally inoculated and control pigs and investigated
B. hyodysenteriae
binding to these mucins. Fluorescence microscopy revealed a massive mucus induction and disorganized mucus structure in the colon of pigs with swine dysentery. Quantitative PCR (qPCR) and antibody detection demonstrated that the mucus composition of pigs with swine dysentery was characterized by
de novo
expression of MUC5AC and increased expression of MUC2 in the colon. Mucins from the colon of inoculated and control pigs were isolated by two steps of isopycnic density gradient centrifugation. The mucin densities of control and inoculated pigs were similar, whereas the mucin quantity was 5-fold higher during infection. The level of
B. hyodysenteriae
binding to mucins differed between pigs, and there was increased binding to soluble mucins isolated from pigs with swine dysentery. The ability of
B. hyodysenteriae
to bind, measured in relation to the total mucin contents of mucus in sick versus healthy pigs, increased 7-fold during infection. Together, the results indicate that
B. hyodysenteriae
binds to carbohydrate structures on the mucins as these differ between individuals. Furthermore,
B. hyodysenteriae
infection induces changes to the mucus niche which substantially increase the amount of
B. hyodysenteriae
binding sites in the mucus.
Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Activates the NLRP3 Inflammasome in Human Macrophages, Leading to the Release of Proinflammatory Cytokines
Authors: Shenker Bruce J. , Ojcius David M. , Walker Lisa P. , Zekavat Ali , Scuron Monika Damek , Boesze-Battaglia Kathleen 
Published: February 2015

ABSTRACTThe cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies withActinobacillus actinomycetemcomitansCdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive oxygen species (ROS) generation and Cdt-induced increases in extracellular ATP levels. Increases in extracellular ATP levels contribute to the activation of the P2X7purinergic receptor, leading to K+efflux. The relationship between the abilities of the active toxin subunit CdtB to function as a lipid phosphatase, activate the NLRP3 inflammasome, and induce a proinflammatory cytokine response is discussed. These studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such asAggregatibacter actinomycetemcomitans.
Citrulline Protects Streptococcus pyogenes from Acid Stress Using the Arginine Deiminase Pathway and the F1Fo-ATPase
Authors: Cusumano Zachary T. , Caparon Michael G. 
Published: February 2015

ABSTRACTA common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase (ADI) pathway, which catabolizes arginine to generate two ammonia molecules and one molecule of ATP. While this pathway typically relies on the utilization of arginine, citrulline has also been shown to enter into the pathway and contribute to protection against acid stress. In the pathogenic bacteriumStreptococcus pyogenes, the utilization of citrulline has been demonstrated to contribute to pathogenesis in a murine model of soft tissue infection, although the mechanism underlying its role in infection is unknown. To gain insight into this question, we analyzed a panel of mutants defective in different steps in the ADI pathway to dissect how arginine and citrulline protectS. pyogenesin a low-pH environment. While protection provided by arginine utilization occurred through the buffering of the extracellular environment, citrulline catabolism protection was pH independent, requiring the generation of ATP via the ADI pathway and a functional F1Fo-ATP synthase. This work demonstrates that arginine and citrulline catabolism protect against acid stress through distinct mechanisms and have unique contributions to virulence during an infection.IMPORTANCEAn important aspect of bacterial pathogenesis is the utilization of host-derived nutrients during an infection for growth and virulence. Previously published work from our lab identified a unique role for citrulline catabolism inStreptococcus pyogenesduring a soft tissue infection. The present article probes the role of citrulline utilization during this infection and its contribution to protection against acid stress. This work reveals a unique and concerted action between the catabolism of citrulline and the F1Fo-ATPase that function together to provide protection for bacteria in a low-pH environment. Dissection of these collaborative pathways highlights the complexity of bacterial infections and the contribution of atypical nutrients, such as citrulline, to pathogenesis.