bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antifungal Application of Nonantifungal Drugs
Authors: Stylianou Marios , Kulesskiy Evgeny , Lopes José Pedro , Granlund Margareta , Wennerberg Krister , Urban Constantin F. 
Published: November 2013

ABSTRACT

Candida
species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-
Candida
activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against
Candida albicans
. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against
Candida
spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-
Candida
activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different
Candida
spp., including
Candida glabrata
. Thus, this screen reveals agents that were previously unknown to be anti-
Candida
agents, which allows for the design of novel therapies against invasive candidiasis.
Identification of 50 Class D β-Lactamases and 65 Acinetobacter-Derived Cephalosporinases in Acinetobacter spp
Authors: Périchon Bruno , Goussard Sylvie , Walewski Violaine , Krizova Lenka , Cerqueira Gustavo , Murphy Cheryl , Feldgarden Michael , Wortman Jennifer , Clermont Dominique , Nemec Alexandr , Courvalin Patrice 
Published: November 2013

ABSTRACT

Whole-genome sequencing of a collection of 103
Acinetobacter
strains belonging to 22 validly named species and another 16 putative species allowed detection of genes for 50 new class D β-lactamases and 65 new
Acinetobacter
-derived cephalosporinases (ADC). All oxacillinases (OXA) contained the three typical motifs of class D β-lactamases, STFK, (F/Y)GN, and K(S/T)G. The phylogenetic tree drawn from the OXA sequences led to an increase in the number of OXA groups from 7 to 18. The topologies of the OXA and RpoB phylogenetic trees were similar, supporting the ancient acquisition of
bla
OXA
genes by
Acinetobacter
species. The class D β-lactamase genes appeared to be intrinsic to several species, such as
Acinetobacter baumannii
,
Acinetobacter pittii
,
Acinetobacter calcoaceticus
, and
Acinetobacter lwoffii
. Neither
bla
OXA-40/143
- nor
bla
OXA-58
-like genes were detected, and their origin remains therefore unknown. The phylogenetic tree analysis based on the alignment of the sequences deduced from
bla
ADC
revealed five main clusters, one containing ADC belonging to species closely related to
A. baumannii
and the others composed of cephalosporinases from the remaining species. No indication of
bla
OXA
or
bla
ADC
transfer was observed between distantly related species, except for
bla
OXA-279
, possibly transferred from
Acinetobacter
genomic species 6 to
Acinetobacter parvus
. Analysis of β-lactam susceptibility of seven strains harboring new oxacillinases and cloning of the corresponding genes in
Escherichia coli
and in a susceptible
A. baumannii
strain indicated very weak hydrolysis of carbapenems. Overall, this study reveals a large pool of β-lactamases in different
Acinetobacter
spp., potentially transferable to pathogenic strains of the genus.
Factors Associated with Treatment Failure in Vertebral Osteomyelitis Requiring Spinal Instrumentation
Authors: Arnold Ryan , Rock Clare , Croft Lindsay , Gilliam Bruce L. , Morgan Daniel J. 
Published: November 2013

ABSTRACT
Patients with vertebral osteomyelitis may require instrumentation for spinal stabilization. Determining the optimal duration and type of antimicrobial therapy for these patients is challenging. The aim of this study was to examine risk factors for treatment failure, in particular antimicrobial duration, in a cohort of patients requiring spinal instrumentation for vertebral osteomyelitis. We conducted a retrospective cohort study of all patients with vertebral osteomyelitis who had spinal instrumentation between January 2002 and January 2012 at the University of Maryland Medical Center. The primary outcome measure was treatment failure >4 weeks postoperatively. We identified 131 patients with vertebral osteomyelitis requiring spinal instrumentation, 94 of whom had >4 weeks of follow-up and were included in the primary analysis. Treatment failure occurred in 22 of the 94 patients (23%) at a median of 4 months after surgery. Among patients who failed therapy, 20 of 22 failed within 1 year of surgery. Cervical and thoracic infection sites and the presence of negative cultures were associated with fewer treatment failures. Addition of rifampin and the use of chronic suppressive antimicrobials did not affect treatment failure rate. Twenty-three percent of patients with spinal instrumentation for vertebral osteomyelitis experienced treatment failure. Treatment failure almost always occurred within the first year of spinal instrumentation.
Predictive Value of Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Swab PCR Assay for MRSA Pneumonia
Authors: Dangerfield Benjamin , Chung Andrew , Webb Brandon , Seville Maria Teresa 
Published: November 2013

ABSTRACT

Pneumonia due to methicillin-resistant
Staphylococcus aureus
(MRSA) is associated with poor outcomes and frequently merits empirical antibiotic consideration despite its relatively low incidence. Nasal colonization with MRSA is associated with clinical MRSA infection and can be reliably detected using the nasal swab PCR assay. In this study, we evaluated the performance of the nasal swab MRSA PCR in predicting MRSA pneumonia. A retrospective cohort study was performed in a tertiary care center from January 2009 to July 2011. All patients with confirmed pneumonia who had both a nasal swab MRSA PCR test and a bacterial culture within predefined time intervals were included in the study. These data were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value for clinically confirmed MRSA pneumonia. Four hundred thirty-five patients met inclusion criteria. The majority of cases were classified as either health care-associated (HCAP) (54.7%) or community-acquired (CAP) (34%) pneumonia. MRSA nasal PCR was positive in 62 (14.3%) cases. MRSA pneumonia was confirmed by culture in 25 (5.7%) cases. The MRSA PCR assay demonstrated 88.0% sensitivity and 90.1% specificity, with a positive predictive value of 35.4% and a negative predictive value of 99.2%. In patients with pneumonia, the MRSA PCR nasal swab has a poor positive predictive value but an excellent negative predictive value for MRSA pneumonia in populations with low MRSA pneumonia incidence. In cases of culture-negative pneumonia where initial empirical antibiotics include an MRSA-active agent, a negative MRSA PCR swab can be reasonably used to guide antibiotic de-escalation.
In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections
Authors: Locher Hans H. , Seiler Peter , Chen Xinhua , Schroeder Susanne , Pfaff Philippe , Enderlin Michel , Klenk Axel , Fournier Elvire , Hubschwerlen Christian , Ritz Daniel , Kelly Ciaran P. , Keck Wolfgang 
Published: November 2013

ABSTRACTClostridium difficileis a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment ofC. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report thein vitroandin vivoantibacterial evaluation of cadazolid againstC. difficile. Cadazolid showed potentin vitroactivity againstC. difficilewith a MIC range of 0.125 to 0.5 μg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect againstC. difficileisolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibitedde novotoxin A and B formation in stationary-phase cultures of toxigenicC. difficile. Cadazolid also inhibitedC. difficilespore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.
Evaluation of Vancomycin in Combination with Piperacillin-Tazobactam or Oxacillin against Clinical Methicillin-Resistant Staphylococcus aureus Isolates and Vancomycin-Intermediate S. aureus Isolates
In Vitro
Authors: Dilworth Thomas J. , Sliwinski Jora , Ryan Keenan , Dodd Monique , Mercier Renée-Claude 
Published: November 2013

ABSTRACT

Vancomycin with piperacillin-tazobactam is used as empirical therapy for critically ill patients. Studies of this combination against methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-intermediate
S. aureus
(VISA) are limited, but β-lactams in combination with vancomycin have shown synergistic activity against MRSA and VISA. The goal of this study was to evaluate whether piperacillin-tazobactam and vancomycin were synergistic against MRSA and VISA
in vitro
. Bloodstream MRSA (
n
= 20) and VISA (
n
= 4) strains were selected.
In vitro
antimicrobial activities of piperacillin-tazobactam and oxacillin were evaluated by disk diffusion, and MICs were determined by Etest using Muller-Hinton agar with and without vancomycin at one-half the MIC. Time-kill studies evaluated 14 MRSA and all 4 VISA isolates using piperacillin-tazobactam at 300/35 mg/liter or oxacillin at 40 mg/liter alone and with vancomycin at one-half the MIC. Mean zones of inhibition for piperacillin-tazobactam and oxacillin increased with vancomycin against MRSA and VISA (
P
< 0.001 for all), and the MIC
90
decreased with vancomycin against MRSA and VISA to values meeting susceptibility criteria for
S. aureus
(
P
< 0.001 for both antibiotics against MRSA). In MRSA time-kill studies, the mean 24-h reductions in inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 3.53, 3.69, and 2.62 log
10
CFU/ml, respectively. The mean 24-h reductions in VISA inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 2.85, 2.93, and 3.45 log
10
CFU/ml, respectively. Vancomycin with piperacillin-tazobactam or oxacillin demonstrated synergistic activity against MRSA and VISA. The clinical implications of these combinations against MRSA and VISA should be investigated.
Multicenter Study of Anidulafungin and Micafungin MIC Distributions and Epidemiological Cutoff Values for Eight Candida Species and the CLSI M27-A3 Broth Microdilution Method
Authors: Pfaller M. A. , Espinel-Ingroff A. , Bustamante B. , Canton E. , Diekema D. J. , Fothergill A. , Fuller J. , Gonzalez G. M. , Guarro J. , Lass-Flörl C. , Lockhart S. R. , Martin-Mazuelos E. , Meis J. F. , Ostrosky-Zeichner L. , Pelaez T. , St-Germain G. , Turnidge J. 
Published: November 2013

ABSTRACT

Since epidemiological cutoff values (ECVs) using CLSI MICs from multiple laboratories are not available for
Candida
spp. and the echinocandins, we established ECVs for anidulafungin and micafungin on the basis of wild-type (WT) MIC distributions (for organisms in a species-drug combination with no detectable acquired resistance mechanisms) for 8,210
Candida albicans
, 3,102
C. glabrata
, 3,976
C. parapsilosis
, 2,042
C. tropicalis
, 617
C. krusei
, 258
C. lusitaniae
, 234
C. guilliermondii
, and 131
C. dubliniensis
isolates. CLSI broth microdilution MIC data gathered from 15 different laboratories in Canada, Europe, Mexico, Peru, and the United States were aggregated to statistically define ECVs. ECVs encompassing 97.5% of the statistically modeled population for anidulafungin and micafungin were, respectively, 0.12 and 0.03 μg/ml for
C. albicans
, 0.12 and 0.03 μg/ml for
C. glabrata
, 8 and 4 μg/ml for
C. parapsilosis
, 0.12 and 0.06 μg/ml for
C. tropicalis
, 0.25 and 0.25 μg/ml for
C. krusei
, 1 and 0.5 μg/ml for
C. lusitaniae
, 8 and 2 μg/ml for
C. guilliermondii
, and 0.12 and 0.12 μg/ml for
C. dubliniensis
. Previously reported single and multicenter ECVs defined in the present study were quite similar or within 1 2-fold dilution of each other. For a collection of 230 WT isolates (no
fks
mutations) and 51 isolates with
fks
mutations, the species-specific ECVs for anidulafungin and micafungin correctly classified 47 (92.2%) and 51 (100%) of the
fks
mutants, respectively, as non-WT strains. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin and micafungin due to
fks
mutations.
Activity of Ceftolozane-Tazobactam against a Broad Spectrum of Recent Clinical Anaerobic Isolates
Authors: Snydman David R. , McDermott Laura A. , Jacobus Nilda V. 
Published: November 2013

ABSTRACT

We evaluated
in vitro
activity of ceftolozane-tazobactam (TOL-TAZ), formerly CXA-201, against recent clinical anaerobic isolates with emphasis on the
Bacteroides fragilis
group. Ceftolozane-tazobactam showed good activity against
B. fragilis
species and intermediate to limited activity against other species of
Bacteroides
. Ceftolozane-tazobactam showed very good activity against
Prevotella
spp.,
Fusobacterium
spp., and
Propionibacterium
spp., varying activities against Gram-positive cocci, and limited activity against
Clostridium
spp.
Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing
Authors: Ghosh June , Guha Rajan , Das Shantanabha , Roy Syamal 
Published: November 2013

ABSTRACTLeishmania donovanicauses visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated withL. donovaniinfection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm.
Porphyromonas gingivalis Lipid A Phosphatase Activity Is Critical for Colonization and Increasing the Commensal Load in the Rabbit Ligature Model
Authors: Zenobia Camille , Hasturk Hatice , Nguyen Daniel , Van Dyke Thomas E. , Kantarci Alpdogan , Darveau Richard P. 
Published: November 2013

ABSTRACT

Periodontitis is a disease of polymicrobial etiology characterized by inflammation, degradation of host tissue, and bone that irreversibly destroys the supporting apparatus of teeth.
Porphyromonas gingivalis
contains lipid A with structural heterogeneity that has been postulated to contribute to the initiation of dysbiosis in oral communities by modulating the host response, thereby creating a permissive environment for its growth. We examined two
P. gingivalis
lipid A phosphatase mutants which contain different “locked” lipid A structures that induce different host cellular responses for their ability to induce dysbiosis and periodontitis in rabbits. Lipopolysaccharide (LPS) preparations obtained from these strains were also examined. After repeated applications of all strains and their respective LPS preparations,
P. gingivalis
wild type, but not the lipid A mutants, had a significant impact on both the oral commensal microbial load and composition. In contrast, in rabbits exposed to the mutant strains or the LPS preparations, the microbial load did not increase, and yet significant changes in the oral microbial composition were observed. All strains and their respective LPS preparations induced periodontitis. Therefore, the ability to alter the lipid A composition in response to environmental conditions by lipid A phosphatases is required for both colonization of the rabbit and increases in the microbial load. Furthermore, the data demonstrate that multiple dysbiotic oral microbial communities can elicit periodontitis.
Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging
Authors: Fatoux-Ardore Marie , Peysselon Franck , Weiss Anthony , Bastien Patrick , Pratlong Francine , Ricard-Blum Sylvie 
Published: November 2013

ABSTRACTWe have set up an assay to study the interactions of live pathogens with their hosts by using protein and glycosaminoglycan arrays probed by surface plasmon resonance imaging. We have used this assay to characterize the interactions ofLeishmaniapromastigotes with ∼70 mammalian host biomolecules (extracellular proteins, glycosaminoglycans, growth factors, cell surface receptors). We have identified, in total, 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes of sixLeishmaniaspecies and 18 partners (15 proteins, 3 glycosaminoglycans) of three species of stationary-phase promastigotes for all the strains tested. The diversity of the interaction repertoires ofLeishmaniaparasites reflects their dynamic and complex interplay with their mammalian hosts, which depends mostly on the species and strains ofLeishmania. Stationary-phaseLeishmaniaparasites target extracellular matrix proteins and glycosaminoglycans, which are highly connected in the extracellular interaction network. Heparin and heparan sulfate bind to mostLeishmaniastrains tested, and 6-O-sulfate groups play a crucial role in these interactions. NumerousLeishmaniastrains bind to tropoelastin, and some strains are even able to degrade it. Several strains interact with collagen VI, which is expressed by macrophages. MostLeishmaniapromastigotes interact with several regulators of angiogenesis, including antiangiogenic factors (endostatin, anastellin) and proangiogenic factors (ECM-1, VEGF, and TEM8 [also known as anthrax toxin receptor 1]), which are regulated by hypoxia. Since hypoxia modulates the infection of macrophages by the parasites, these interactions might influence the infection of host cells byLeishmania.
Reversible Lipid Accumulation and Associated Division Arrest of Mycobacterium avium in Lipoprotein-Induced Foamy Macrophages May Resemble Key Events during Latency and Reactivation of Tuberculosis
Authors: Caire-Brändli Irène , Papadopoulos Alexia , Malaga Wladimir , Marais David , Canaan Stéphane , Thilo Lutz , de Chastellier Chantal 
Published: November 2013

ABSTRACT

During the dormant phase of tuberculosis,
Mycobacterium tuberculosis
persists in lung granulomas by residing in foamy macrophages (FM) that contain abundant lipid bodies (LB) in their cytoplasm, allowing bacilli to accumulate lipids as intracytoplasmic lipid inclusions (ILI). An experimental model of FM is presented where bone marrow-derived mouse macrophages are infected with
M. avium
and exposed to very-low-density lipoprotein (VLDL) as a lipid source. Quantitative analysis of detailed electron microscope observations showed the following results. (i) Macrophages became foamy, and mycobacteria formed ILI, for which host triacylglycerides, rather than cholesterol, was essential. (ii) Lipid transfer occurred via mycobacterium-induced fusion between LB and phagosomes. (iii) Mycobacteria showed a thinned cell wall and became elongated but did not divide. (iv) Upon removal of VLDL, LB and ILI declined within hours, and simultaneous resumption of mycobacterial division restored the number of mycobacteria to the same level as that found in untreated control macrophages. This showed that the presence of ILI resulted in a reversible block of division without causing a change in the mycobacterial replication rate. Fluctuation between ILI either partially or fully extending throughout the mycobacterial cytoplasm was suggestive of bacterial cell cycle events. We propose that VLDL-driven FM constitute a well-defined cellular system in which to study changed metabolic states of intracellular mycobacteria that may relate to persistence and reactivation of tuberculosis.
Toxoplasma gondii Inhibits Gamma Interferon (IFN-γ)- and IFN-β-Induced Host Cell STAT1 Transcriptional Activity by Increasing the Association of STAT1 with DNA
Authors: Rosowski Emily E. , Nguyen Quynh P. , Camejo Ana , Spooner Eric , Saeij Jeroen P. J. 
Published: November 2013

ABSTRACTThe gamma interferon (IFN-γ) response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogenToxoplasma gondii, but prior infection withToxoplasmacan inhibit this response. Recently, it was reported that theToxoplasmatype II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma-related gene 1 (BRG-1) to promoters of IFN-γ-induced secondary response genes such asCiitaand major histocompatibility complex class II genes in murine macrophages, thereby inhibiting their expression. We report here that a type I strain ofToxoplasmainhibits the expression of primary IFN-γ response genes such asIRF1through a distinct mechanism not dependent on the activity of histone deacetylases. Instead, infection with a type I, II, or III strain ofToxoplasmainhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-γ-induced binding of STAT1 at theIRF1promoter in host cells and increased global IFN-γ-induced association of STAT1 with chromatin.Toxoplasmatype I infection also inhibits IFN-β-induced interferon-stimulated gene factor 3-mediated gene expression, and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain ofToxoplasmawithout complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries.