bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse
Escherichia coli
and
Klebsiella pneumoniae
Isolates
Authors: Nicasio Anthony M. , Crandon Jared L. , Nicolau David P. 
Published: April 2009

ABSTRACT

Tigecycline is a glycylcycline with activity against
Enterobacteriaceae
, including multidrug-resistant isolates of
Klebsiella pneumoniae
and
Escherichia coli
producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile of tigecycline against genotypically and phenotypically diverse
K. pneumoniae
and
E. coli
isolates. Doses of 3.125 to 300 mg/kg, divided 1 to 6 times daily, were administered subcutaneously against six (two nonresistant, one carbapenemase, and three ESBL producing)
K. pneumoniae
strains and five (two nonresistant and three ESBL producing)
E. coli
strains. The phenotypic profile (reported tigecycline MIC) for all isolates ranged from 0.125 to 2 μg/ml. Mean correlation coefficients of free (
f
) drug exposures (percentage of the dosing interval that free drug concentration remained above the MIC [
fT
>MIC], the ratio of the free drug area under the concentration-time curve/MIC [
f
AUC/MIC], and the ratio of maximum concentration of free drug in serum/MIC) for all 11 isolates were 0.595, 0.969, and 0.897, respectively. The
f
AUC/MIC was the pharmacodynamic parameter that best described the efficacy of tigecycline against both
E. coli
and
K. pneumoniae
. Interestingly, reductions in the number of CFU were noted even though doses achieved an
fT
>MIC of 0%. With respect to
f
AUC/MIC in the neutropenic model, the cumulative 80% and 50% effective pharmacodynamic indexes (EI
80
and EI
50
) for all 11 isolates were 8.4 and 4.7, respectively. An experiment in nonneutropenic mice infected with an ESBL-producing
E. coli
and
K. pneumoniae
isolate resulted in the lowest tigecycline
f
AUC/MIC EI
80
and EI
50
values at 1.8 and 1.0 for
E. coli
and 1.7 and 1.6 for
K. pneumoniae
. While the phenotypic profile of tigecycline appeared to drive efficacy irrespective of ESBL or carbapenemase production, the presence of a competent immune system markedly reduced this required exposure.
Dermcidin-Derived Peptides Show a Different Mode of Action than the Cathelicidin LL-37 against
Staphylococcus aureus
Authors: Senyürek Ilknur , Paulmann Maren , Sinnberg Tobias , Kalbacher Hubert , Deeg Martin , Gutsmann Thomas , Hermes Marina , Kohler Thomas , Götz Fritz , Wolz Christiane , Peschel Andreas , Schittek Birgit 
Published: April 2009

ABSTRACT

Dermcidin (DCD) is an antimicrobial peptide which is constitutively expressed in eccrine sweat glands. By postsecretory proteolytic processing in sweat, the DCD protein gives rise to anionic and cationic DCD peptides with a broad spectrum of antimicrobial activity. Many antimicrobial peptides induce membrane permeabilization as part of their killing mechanism, which is accompanied by a loss of the bacterial membrane potential. In this study we show that there is a time-dependent bactericidal activity of anionic and cationic DCD-derived peptides which is followed by bacterial membrane depolarization. However, DCD-derived peptides do not induce pore formation in the membranes of gram-negative and gram-positive bacteria. This is in contrast to the mode of action of the cathelicidin LL-37. Interestingly, LL-37 as well as DCD-derived peptides inhibit bacterial macromolecular synthesis, especially RNA and protein synthesis, without binding to microbial DNA or RNA. Binding studies with components of the cell envelope of gram-positive and gram-negative bacteria and with model membranes indicated that DCD-derived peptides bind to the bacterial envelope but show only a weak binding to lipopolysaccharide (LPS) from gram-negative bacteria or to peptidoglycan, lipoteichoic acid, and wall teichoic acid, isolated from
Staphylococcus aureus
. In contrast, LL-37 binds strongly in a dose-dependent fashion to these components. Altogether, these data indicate that the mode of action of DCD-derived peptides is different from that of the cathelicidin LL-37 and that components of the bacterial cell envelope play a role in the antimicrobial activity of DCD.
Infectious Complications Associated with Monoclonal Antibodies and Related Small Molecules
Authors: Salvana Edsel Maurice T. , Salata Robert A. 
Published: April 2009

SUMMARYBiologics are increasingly becoming part of routine disease management. As more agents are developed, the challenge of keeping track of indications and side effects is growing. While biologics represent a milestone in targeted and specific therapy, they are not without drawbacks, and the judicious use of these “magic bullets” is essential if their full potential is to be realized. Infectious complications in particular are not an uncommon side effect of therapy, whether as a direct consequence of the agent or because of the underlying disease process. With this in mind, we have reviewed and summarized the risks of infection and the infectious disease-related complications for all FDA-approved monoclonal antibodies and some related small molecules, and we discuss the probable mechanisms involved in immunosuppression as well as recommendations for prophylaxis and treatment of specific disease entities.
Gastric Helicobacters in Domestic Animals and Nonhuman Primates and Their Significance for Human Health
Authors: Haesebrouck Freddy , Pasmans Frank , Flahou Bram , Chiers Koen , Baele Margo , Meyns Tom , Decostere Annemie , Ducatelle Richard 
Published: April 2009

SUMMARYHelicobacters other thanHelicobacter pylorihave been associated with gastritis, gastric ulcers, and gastric mucosa-associated lymphoid tissue lymphoma in humans. These very fastidious microorganisms with a typical large spiral-shaped morphology were provisionally designated “H. heilmannii,” but in fact they comprise at least five differentHelicobacterspecies, all of which are known to colonize the gastric mucosa of animals.H. suis, which has been isolated from the stomachs of pigs, is the most prevalent gastric non-H. pylori Helicobacterspecies in humans. Other gastric non-H. pylorihelicobacters colonizing the human stomach areH. felis, H. salomonis, H. bizzozeronii, and the still-uncultivable “CandidatusHelicobacter heilmannii.” These microorganisms are often detected in the stomachs of dogs and cats. “CandidatusHelicobacter bovis” is highly prevalent in the abomasums of cattle but has only occasionally been detected in the stomachs of humans. There are clear indications that gastric non-H. pylori Helicobacterinfections in humans originate from animals, and it is likely that transmission to humans occurs through direct contact. Little is known about the virulence factors of these microorganisms. The recent successes with in vitro isolation of non-H. pylorihelicobacters from domestic animals open new perspectives for studying these microorganisms and their interactions with the host.
Update on Eosinophilic Meningoencephalitis and Its Clinical Relevance
Authors: Graeff-Teixeira Carlos , da Silva Ana Cristina Arámburu , Yoshimura Kentaro 
Published: April 2009

SUMMARYEosinophilic meningoencephalitis is caused by a variety of helminthic infections. These worm-specific infections are named after the causative worm genera, the most common being angiostrongyliasis, gnathostomiasis, toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, and paragonimiasis. Worm parasites enter an organism through ingestion of contaminated water or an intermediate host and can eventually affect the central nervous system (CNS). These infections are potentially serious events leading to sequelae or death, and diagnosis depends on currently limited molecular methods. Identification of parasites in fluids and tissues is rarely possible, while images and clinical examinations do not lead to a definitive diagnosis. Treatment usually requires the concomitant administration of corticoids and anthelminthic drugs, yet new compounds and their extensive and detailed clinical evaluation are much needed. Eosinophilia in fluids may be detected in other infectious and noninfectious conditions, such as neoplastic disease, drug use, and prosthesis reactions. Thus, distinctive identification of eosinophils in fluids is a necessary component in the etiologic diagnosis of CNS infections.
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses
Authors: Mogensen Trine H. 
Published: April 2009

SUMMARYThe innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.
EnterotoxigenicBacteroides fragilis: a Rogue among Symbiotes
Authors: Sears Cynthia L. 
Published: April 2009

SUMMARYEnterotoxigenicBacteroides fragilis(ETBF) strains are strains ofB. fragilisthat secrete a 20-kDa heat-labile zinc-dependent metalloprotease toxin termed theB. fragilistoxin (BFT). BFT is the only recognized virulence factor specific for ETBF. ETBF strains are associated with inflammatory diarrheal disease in children older than 1 year of age and in adults; limited data suggest an association of ETBF colonization with inflammatory bowel disease flare-ups and colorectal cancer. ETBF secretes one of three highly related BFT isoforms. The relationship between BFT isoform and disease expression is unknown. Although the mechanism of action of BFT is incompletely understood, available data suggest that BFT binds to a specific intestinal epithelial cell receptor, stimulating intestinal cell signal transduction pathways that result in cell morphology changes, cleavage of E-cadherin, reduced colonic barrier function, and increased epithelial cell proliferation and cytokine expression (such as the proinflammatory chemokine interleukin-8). Together, the data suggest that in some hosts, ETBF acts via secretion of BFT to induce colitis. However, the full spectrum of clinical disease related to ETBF and the impact of chronic ETBF colonization on the host remain to be defined.
Identification of a Novel Lipopolysaccharide Core Biosynthesis Gene Cluster in
Bordetella pertussis
, and Influence of Core Structure and Lipid A Glucosamine Substitution on Endotoxic Activity
Authors: Geurtsen Jeroen , Dzieciatkowska Monika , Steeghs Liana , Hamstra Hendrik-Jan , Boleij Johanna , Broen Kelly , Akkerman Grietsje , el Hassan Hassan , Li Jianjun , Richards James C. , Tommassen Jan , van der Ley Peter 
Published: April 2009

ABSTRACT

Lipopolysaccharide (LPS), also known as endotoxin, is one of the main constituents of the gram-negative bacterial outer membrane. Whereas the lipid A portion of LPS is generally considered the main determinant for endotoxic activity, the oligosaccharide moiety plays an important role in immune evasion and the interaction with professional antigen-presenting cells. Here we describe a novel four-gene cluster involved in the biosynthesis of the
Bordetella pertussis
core oligosaccharide. By insertionally inactivating these genes and studying the resulting LPS structures, we show that at least two of the genes encode active glycosyltransferases, while a third gene encodes a deacetylase also required for biosynthesis of full-length oligosaccharide. In addition, we demonstrate that mutations in the locus differentially affect LPS and whole-cell endotoxic activities. Furthermore, while analyzing the mutant LPS structures, we confirmed a novel modification of the lipid A phosphate with glucosamine and found that inactivation of the responsible glycosyltransferase reduces the endotoxic activity of the LPS.
Salmonella enterica
Serovar Enteritidis Pathogenicity Island 1 Is Not Essential for but Facilitates Rapid Systemic Spread in Chickens
Authors: Desin Taseen S. , Lam Po-King S. , Koch Birgit , Mickael Claudia , Berberov Emil , Wisner Amanda L. S. , Townsend Hugh G. G. , Potter Andrew A. , Köster Wolfgang 
Published: April 2009

ABSTRACT

Salmonella enterica
subsp.
enterica
serovar Enteritidis is a leading cause of human food-borne illness that is mainly associated with the consumption of contaminated poultry meat and eggs. To cause infection,
S.
Enteritidis is known to use two type III secretion systems, which are encoded on two salmonella pathogenicity islands, SPI-1 and SPI-2, the first of which is thought to play a major role in invasion and bacterial uptake. In order to study the role of SPI-1 in the colonization of chicken, we constructed deletion mutants affecting the complete SPI-1 region (40 kb) and the
invG
gene. Both ΔSPI-1 and Δ
invG
mutant strains were impaired in the secretion of SipD, a SPI-1 effector protein. In vitro analysis using polarized human intestinal epithelial cells (Caco-2) revealed that both mutant strains were less invasive than the wild-type strain. A similar observation was made when chicken cecal and small intestinal explants were coinfected with the wild-type and ΔSPI-1 mutant strains. Oral challenge of 1-week-old chicken with the wild-type or ΔSPI-1 strains demonstrated that there was no difference in chicken cecal colonization. However, systemic infection of the liver and spleen was delayed in birds that were challenged with the ΔSPI-1 strain. These data demonstrate that SPI-1 facilitates systemic infection but is not essential for invasion and systemic spread of the organism in chickens.
Precolonized Human Commensal
Escherichia coli
Strains Serve as a Barrier to
E. coli
O157:H7 Growth in the Streptomycin-Treated Mouse Intestine
Authors: Leatham Mary P. , Banerjee Swati , Autieri Steven M. , Mercado-Lubo Regino , Conway Tyrrell , Cohen Paul S. 
Published: April 2009

ABSTRACT

Different
Escherichia coli
strains generally have the same metabolic capacity for growth on sugars in vitro, but they appear to use different sugars in the streptomycin-treated mouse intestine (Fabich et al., Infect. Immun. 76:1143-1152, 2008). Here, mice were precolonized with any of three human commensal strains (
E. coli
MG1655,
E. coli
HS, or
E. coli
Nissle 1917) and 10 days later were fed 10
5
CFU of the same strains. While each precolonized strain nearly eliminated its isogenic strain, confirming that colonization resistance can be modeled in mice, each allowed growth of the other commensal strains to higher numbers, consistent with different commensal
E. coli
strains using different nutrients in the intestine. Mice were also precolonized with any of five commensal
E. coli
strains for 10 days and then were fed 10
5
CFU of
E. coli
EDL933, an O157:H7 pathogen.
E. coli
Nissle 1917 and
E. coli
EFC1 limited growth of
E. coli
EDL933 in the intestine (10
3
to 10
4
CFU/gram of feces), whereas
E. coli
MG1655,
E. coli
HS, and
E. coli
EFC2 allowed growth to higher numbers (10
6
to 10
7
CFU/gram of feces). Importantly, when
E. coli
EDL933 was fed to mice previously co-colonized with three
E. coli
strains (MG1655, HS, and Nissle 1917), it was eliminated from the intestine (<10 CFU/gram of feces). These results confirm that commensal
E. coli
strains can provide a barrier to infection and suggest that it may be possible to construct
E. coli
probiotic strains that prevent growth of pathogenic
E. coli
strains in the intestine.
Salmonella enterica
Serovar Typhimurium Pathogenicity Island 1-Encoded Type III Secretion System Translocases Mediate Intimate Attachment to Nonphagocytic Cells
Authors: Lara-Tejero María , Galán Jorge E. 
Published: April 2009

ABSTRACT

Delivery of bacterial proteins into mammalian cells by type III secretion systems (TTSS) is thought to require the intimate association of bacteria with target cells. The molecular bases of this intimate association appear to be different in different bacteria involving TTSS components, as well as surface determinants not associated with TTSS. We show here that the protein translocases SipB, SipC, and SipD of the
Salmonella enterica
serovar Typhimurium pathogenicity island 1 (SPI-1)-encoded TTSS are required for the intimate association of these bacteria with mammalian cells.
S
. Typhimurium mutant strains lacking any of the translocases were defective for intimate attachment. Immunofluorescence microscopy showed that SipD is present on the bacterial surface prior to bacterial contact with host cells. In contrast, SipB and SipC were detected on the bacterial surface only subsequent to bacterial contact with the target cell. We conclude that the coordinated deployment and interaction between the protein translocases mediate the SPI-1 TTSS-dependent intimate association of
S
. Typhimurium with host cells.
Distinct Roles for MyD88 and Toll-Like Receptor 2 during
Leishmania braziliensis
Infection in Mice
Authors: Vargas-Inchaustegui Diego A. , Tai Wendy , Xin Lijun , Hogg Alison E. , Corry David B. , Soong Lynn 
Published: April 2009

ABSTRACT

We have previously reported that
Leishmania braziliensis
infection can activate murine dendritic cells (DCs) and upregulate signaling pathways that are essential for the initiation of innate immunity. However, it remains unclear whether Toll-like receptors (TLRs) are involved in
L. braziliensis
-mediated DC activation. To address this issue, we generated bone marrow-derived DCs from MyD88
−/−
and TLR2
−/−
mice and examined their responsiveness to parasite infection. While wild-type DCs were efficiently activated to produce cytokines and prime naïve CD4
+
T cells,
L. braziliensis
-infected MyD88
−/−
DCs exhibited less activation and decreased production of interleukin-12 (IL-12) p40. Furthermore, MyD88
−/−
mice were more susceptible to infection in that they developed larger and prolonged lesions compared to those in control mice. In sharp contrast, the lack of TLR2 resulted in an enhanced DC activation and increased IL-12 p40 production after infection. As such,
L. braziliensis
-infected TLR2
−/−
DCs were more competent in priming naïve CD4
+
T cells in vitro than were their controls, findings which correlated with an increased gamma interferon production in vivo and enhanced resistance to infection. Our results suggest that while MyD88 is indispensable for the generation of protective immunity to
L. braziliensis
, TLR2 seems to have a regulatory role during infection.
Proteomics-Based Identification of Anchorless Cell Wall Proteins as Vaccine Candidates againstStaphylococcus aureus
Authors: Glowalla Eva , Tosetti Bettina , Krönke Martin , Krut Oleg 
Published: April 2009

ABSTRACTStaphylococcus aureusis an important human pathogen with increasing clinical impact due to the extensive spread of antibiotic-resistant strains. Therefore, development of a protective polyvalent vaccine is of great clinical interest. We employed an intravenous immunoglobulin (IVIG) preparation as a source of antibodies directed against anchorlessS. aureussurface proteins for identification of novel vaccine candidates. In order to identify such proteins, subtractive proteome analysis (SUPRA) ofS. aureusanchorless cell wall proteins was performed. Proteins reacting with IVIG but not with IVIG depleted ofS. aureus-specific opsonizing antibodies were considered vaccine candidates. Nearly 40 proteins were identified by this preselection method using matrix-assisted laser desorption ionization—time of flight analysis. Three of these candidate proteins, enolase (Eno), oxoacyl reductase (Oxo), and hypothetical protein hp2160, were expressed as glutathioneS-transferase fusion proteins, purified, and used for enrichment of corresponding immunoglobulin Gs from IVIG by affinity chromatography. Use of affinity-purified anti-Eno, anti-Oxo, and anti-hp2160 antibodies resulted in opsonization, phagocytosis, and killing ofS. aureusby human neutrophils. High specific antibody titers were detected in mice immunized with recombinant antigens. In mice challenged with bioluminescentS. aureus, reduced staphylococcal spread was measured by in vivo imaging. The recovery ofS. aureusCFU from organs of immunized mice was diminished 10- to 100-fold. Finally, mice immunized with hp2160 displayed statistically significant higher survival rates after lethal challenge with clinically relevantS. aureusstrains. Taken together, our data suggest that anchorless cell wall proteins might be promising vaccine candidates and that SUPRA is a valuable tool for their identification.
Natural Antibody Contributes to Host Defense against an AttenuatedBrucella abortus virBMutant
Authors: Rolán Hortensia G. , Xavier Mariana N. , Santos Renato L. , Tsolis Renée M. 
Published: April 2009

ABSTRACTBrucella abortusis an intracellular pathogen that persists within phagocytic cells of the reticuloendothelial system. To identify in vivo interactions betweenB. abortusand the host that lead to persistent infection, we studied the persistence ofB. abortusand an isogenicvirBmutant deficient in the VirB type IV secretion system (T4SS) in knockout mice. In contrast to control mice, mice lacking B cells (Igh6−/−) were permissive for infection with the attenuatedvirBmutant. To determine the basis for this phenotype, we characterized immune functions ofIgh6−/−mice in the context ofB. abortusinfection.Igh6−/−mice had greater numbers of extracellular bacteria in the spleen and increased early expression of proinflammatory cytokines duringB. abortusinfection. Further, avirBmutant, despite its wild-type level of survival, failed to elicit microgranuloma formation in the spleens ofIgh6−/−mice, suggesting a requirement for the T4SS to elicit this pathological change. Passive transfer of immunoglobulin G from naïve mice restored the ability ofIgh6−/−mice to control the persistence of thevirBmutant by a complement-independent mechanism. Further, adoptive transfer of CD11b+cells from C57BL/6 mice toIgh6−/−mice restored the ability of the knockout mice to limit the replication of thevirBmutant in the spleen, suggesting that theIgh6−/−mutation affects phagocyte function and that phagocyte function can be restored by natural antibody.