bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Intravenous Anthrax Immune Globulin for Treatment of Inhalation Anthrax
Authors: Mytle Nutan , Hopkins Robert J. , Malkevich Nina V. , Basu Subhendu , Meister Gabriel T. , Sanford Daniel C. , Comer Jason E. , Van Zandt Kristopher E. , Al-Ibrahim Mohamed , Kramer William G. , Howard Cris , Daczkowski Nancy , Chakrabarti Ajoy C. , Ionin Boris , Nabors Gary S. , Skiadopoulos Mario H. 
Published: August 2013

ABSTRACT

Bacillus anthracis
toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized
B. anthracis
spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at
ClinicalTrials.gov
under registration no. NCT00845650.)
Transdermal Glyceryl Trinitrate as an Effective Adjunctive Treatment with Artemether for Late-Stage Experimental Cerebral Malaria
Authors: Orjuela-Sánchez Pamela , Ong Peng Kai , Zanini Graziela M. , Melchior Benoît , Martins Yuri C. , Meays Diana , Frangos John A. , Carvalho Leonardo J. M. 
Published: August 2013

ABSTRACT

Cerebral malaria (CM) is associated with low nitric oxide (NO) bioavailability, cerebrovascular constriction, occlusion, and hypoperfusion. Administration of exogenous NO partially prevents the neurological syndrome and associated vascular pathology in an experimental CM (ECM) mouse model. In this study, we evaluated the effects of transdermal glyceryl trinitrate in preventing ECM and, in combination with artemether, rescuing late-stage ECM mice from mortality. The glyceryl trinitrate and/or artemether effect on survival and clinical recovery was evaluated in C57BL/6 mice infected with
P. berghei
ANKA. NO synthase (NOS) expression in mouse brain was determined by Western blots. Mean arterial pressure (MAP) and pial arteriolar diameter were monitored using a tail-cuff blood pressure system and a cranial window preparation, respectively. Preventative administration of glyceryl trinitrate at 0.025 mg/h decreased ECM mortality from 67 to 11% and downregulated inducible NOS expression in the brain. When administered as adjunctive rescue therapy with artemether, glyceryl trinitrate increased survival from 47 to 79%. The adjunctive therapy caused a sustained reversal of pial arteriolar vasoconstriction in ECM mice, an effect not observed with artemether alone. Glyceryl trinitrate induced a 13% decrease in MAP in uninfected mice but did not further affect MAP in hypotensive ECM mice. Glyceryl trinitrate, when combined with artemether, was an effective adjunctive rescue treatment for ECM. This treatment ameliorated pial arteriolar vasospasm and did not significantly affect MAP. These results indicate that transdermal glyceryl trinitrate has potential to be considered as a candidate for adjunctive therapy for CM.
Bioengineered Lysozyme Reduces Bacterial Burden and Inflammation in a Murine Model of Mucoid Pseudomonas aeruginosa Lung Infection
Authors: Teneback Charlotte C. , Scanlon Thomas C. , Wargo Matthew J. , Bement Jenna L. , Griswold Karl E. , Leclair Laurie W. 
Published: August 2013

ABSTRACT

The spread of drug-resistant bacterial pathogens is a growing global concern and has prompted an effort to explore potential adjuvant and alternative therapies derived from nature's repertoire of bactericidal proteins and peptides. In humans, the airway surface liquid layer is a rich source of antibiotics, and lysozyme represents one of the most abundant and effective antimicrobial components of airway secretions. Human lysozyme is active against both Gram-positive and Gram-negative bacteria, acting through several mechanisms, including catalytic degradation of cell wall peptidoglycan and subsequent bacterial lysis. In the infected lung, however, lysozyme's dense cationic character can result in sequestration and inhibition by polyanions associated with airway inflammation. As a result, the efficacy of the native enzyme may be compromised in the infected and inflamed lung. To address this limitation, we previously constructed a charge-engineered variant of human lysozyme that was less prone to electrostatic-mediated inhibition
in vitro
. Here, we employ a murine model to show that this engineered enzyme is superior to wild-type human lysozyme as a treatment for mucoid
Pseudomonas aeruginosa
lung infections. The engineered enzyme effectively decreases the bacterial burden and reduces markers of inflammation and lung injury. Importantly, we found no evidence of acute toxicity or allergic hypersensitivity upon repeated administration of the engineered biotherapeutic. Thus, the charge-engineered lysozyme represents an interesting therapeutic candidate for
P. aeruginosa
lung infections.
Effect of a High-Calorie, High-Fat Meal on the Bioavailability and Pharmacokinetics of PA-824 in Healthy Adult Subjects
Authors: Winter Helen , Ginsberg Ann , Egizi Erica , Erondu Ngozi , Whitney Karl , Pauli Elliott , Everitt Daniel 
Published: August 2013

ABSTRACT

PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of
C
max
and AUC
0–∞
revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median
T
max
in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median
T
max
was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered at
ClinicalTrials.gov
under registration numbers NCT01828827 and NCT01830439.)
Human Herpesvirus 6 U69 Kinase Phosphorylates the Methylenecyclopropane Nucleosides Cyclopropavir, MBX 2168, and MBX 1616 to Their Monophosphates
Authors: Komazin-Meredith Gloria , Cardinale Steven C. , Williams John D. , Peet Norton P. , Prichard Mark N. , Bowlin Terry L. 
Published: August 2013

ABSTRACT
Dihydroxymethyl and monohydroxymethyl methylenecyclopropane nucleosides are effective inhibitors of both variants of human herpesvirus 6 (HHV-6). We investigated involvement of HHV-6 U69 protein kinase in their mechanism of action. Phosphorylation of the dihydroxymethyl analogue cyclopropavir and monohydroxymethyl nucleosides with either a 6-ether moiety (MBX 2168) or a 6-thioether moiety (MBX 1616) with purified U69 was examined. All three compounds were substrates of this viral kinase and had similar Michaelis-Menten kinetic parameters.
In VitroCross-Resistance Profile of Nucleoside Reverse Transcriptase Inhibitor (NRTI) BMS-986001 against Known NRTI Resistance Mutations
Authors: Li Zhufang , Terry Brian , Olds William , Protack Tricia , Deminie Carol , Minassian Beatrice , Nowicka-Sans Beata , Sun Yongnian , Dicker Ira , Hwang Carey , Lataillade Max , Hanna George J. , Krystal Mark 
Published: August 2013

ABSTRACTBMS-986001 is a novel HIV nucleoside reverse transcriptase inhibitor (NRTI). To date, little is known about its resistance profile. In order to examine the cross-resistance profile of BMS-986001 to NRTI mutations, a replicating virus system was used to examine specific amino acid mutations known to confer resistance to various NRTIs. In addition, reverse transcriptases from 19 clinical isolates with various NRTI mutations were examined in the Monogram PhenoSense HIV assay. In the site-directed mutagenesis studies, a virus containing a K65R substitution exhibited a 0.4-fold change in 50% effective concentration (EC50) versus the wild type, while the majority of viruses with the Q151M constellation (without M184V) exhibited changes in EC50versus wild type of 0.23- to 0.48-fold. Susceptibility to BMS-986001 was also maintained in an L74V-containing virus (0.7-fold change), while an M184V-only-containing virus induced a 2- to 3-fold decrease in susceptibility. Increasing numbers of thymidine analog mutation pattern 1 (TAM-1) pathway mutations correlated with decreases in susceptibility to BMS-986001, while viruses with TAM-2 pathway mutations exhibited a 5- to 8-fold decrease in susceptibility, regardless of the number of TAMs. A 22-fold decrease in susceptibility to BMS-986001 was observed in a site-directed mutant containing the T69 insertion complex. Common non-NRTI (NNRTI) mutations had little impact on susceptibility to BMS-986001. The results from the site-directed mutants correlated well with the more complicated genotypes found in NRTI-resistant clinical isolates. Data from clinical studies are needed to determine the clinically relevant resistance cutoff values for BMS-986001.
High-Level Pacidamycin Resistance in Pseudomonas aeruginosa Is Mediated by an Opp Oligopeptide Permease Encoded by the
opp-fabI
Operon
Authors: Mistry Anita , Warren Mark S. , Cusick John K. , Karkhoff-Schweizer RoxAnn R. , Lomovskaya Olga , Schweizer Herbert P. 
Published: August 2013

ABSTRACT

Pacidamycins (or uridyl peptide antibiotics) possess selective
in vivo
activity against
Pseudomonas aeruginosa
. An important limitation for the therapeutic use of pacidamycins with
P. aeruginosa
is the high frequency (10
−6
to 10
−7
) at which resistant mutants emerge. To elucidate the mechanism(s) of this resistance, pacidamycin-resistant
P. aeruginosa
mutants were isolated. Two types of mutants were obtained. Type 1, or high-level resistance mutants with a pacidamycin MIC of 512 μg/ml, were more abundant, with a frequency of ∼2 × 10
−6
, and did not show cross-resistance with other antibiotics. Type 2, low-level resistance mutants, were isolated with a frequency of ∼10
−8
and had a pacidamycin MIC of 64 μg/ml (the MIC for the wild-type strain was 4 to 16 μg/ml). These mutants were cross-resistant to levofloxacin, tetracycline, and erythromycin and were shown to overexpress either the MexAB-OprM or MexCD-OprJ multidrug resistance efflux pumps. High-level resistant mutants were isolated by transposon mutagenesis and one insertion was localized to
oppB
, one of two periplasmic binding protein components of an oligopeptide transport system which is encoded by the
opp-fabI
operon. The Opp system is required for uptake of pacidamycin across the inner membrane, since various
opp
, but not
fabI
, mutants were resistant to high levels of pacidamycin. Both of the two putative Opp periplasmic binding proteins, OppA and OppB, were required for pacidamycin uptake. Although both impaired uptake into and efflux from the cell can cause pacidamycin resistance in
P. aeruginosa
, our data suggest that impaired uptake is the primary reason for the high-frequency and high-level pacidamycin resistance.
Biological Markers of Pseudomonas aeruginosa Epidemic High-Risk Clones
Authors: Mulet Xavier , Cabot Gabriel , Ocampo-Sosa Alain A. , Domínguez M. Angeles , Zamorano Laura , Juan Carlos , Tubau Fe , Rodríguez Cristina , Moyà Bartolomé , Peña Carmen , Martínez-Martínez Luis , Oliver Antonio 
Published: August 2013

ABSTRACT

A limited number of
Pseudomonas aeruginosa
genotypes (mainly ST-111, ST-175, and ST-235), known as high-risk clones, are responsible for epidemics of nosocomial infections by multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains worldwide. We explored the potential biological parameters that may explain the success of these clones. A total of 20 isolates from each of 4 resistance groups (XDR, MDR, ModR [resistant to 1 or 2 classes], and MultiS [susceptible to all antipseudomonals]), recovered from a multicenter study of
P. aeruginosa
bloodstream infections performed in 10 Spanish hospitals, were analyzed. A further set of 20 XDR isolates belonging to epidemic high-risk clones (ST-175 [
n
= 6], ST-111 [
n
= 7], and ST-235 [
n
= 7]) recovered from different geographical locations was also studied. When unknown, genotypes were documented through multilocus sequence typing. The biological parameters evaluated included twitching, swimming, and swarming motility, biofilm formation, production of pyoverdine and pyocyanin, spontaneous mutant frequencies, and the
in vitro
competition index (CI) obtained with a flow cytometry assay. All 20 (100%) XDR, 8 (40%) MDR, and 1 (5%) ModR bloodstream isolate from the multicenter study belonged to high-risk clones. No significant differences were observed between clonally diverse ModR and MultiS isolates for any of the parameters. In contrast, MDR/XDR high-risk clones showed significantly increased biofilm formation and mutant frequencies but significantly reduced motility (twitching, swimming, and swarming), production of pyoverdine and pyocyanin, and fitness. The defined biological markers of high-risk clones, which resemble those resulting from adaptation to chronic infections, could be useful for the design of specific treatment and infection control strategies.
In Vitro
Activity of Ceftaroline-Avibactam against Gram-Negative and Gram-Positive Pathogens Isolated from Patients in Canadian Hospitals from 2010 to 2012: Results from the CANWARD Surveillance Study
Authors: Karlowsky James A. , Adam Heather J. , Baxter Melanie R. , Lagacé-Wiens Philippe R. S. , Walkty Andrew J. , Hoban Daryl J. , Zhanel George G. 
Published: August 2013

ABSTRACT

The
in vitro
activities of ceftaroline-avibactam, ceftaroline, and comparative agents were determined for a collection of bacterial pathogens frequently isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9,758 isolates were tested by using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (document M07-A9, 2012), with MICs interpreted by using CLSI breakpoints (document M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC
90
, ≤0.5 μg/ml) against
Escherichia coli
,
Klebsiella pneumoniae
,
Klebsiella oxytoca
,
Proteus mirabilis
,
Enterobacter cloacae
,
Enterobacter aerogenes
,
Serratia marcescens
,
Morganella morganii
,
Citrobacter freundii
, and
Haemophilus influenzae
; >99% of isolates of
E. coli
,
K. pneumoniae
,
K. oxytoca
,
P. mirabilis
,
M. morganii
,
C. freundii
, and
H. influenzae
were susceptible to ceftaroline-avibactam according to CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species of
Enterobacteriaceae
tested, with rates of susceptibility ranging from 93.9% (
P. mirabilis
) to 54.0% (
S. marcescens
). All isolates of methicillin-susceptible
Staphylococcus aureus
(MIC
90
, 0.25 μg/ml) and 99.6% of methicillin-resistant
S. aureus
isolates (MIC
90
, 1 μg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates of
Streptococcus pneumoniae
(MIC
90
, 0.03 μg/ml),
Streptococcus pyogenes
(MIC
90
, ≤0.03 μg/ml), and
Streptococcus agalactiae
(MIC
90
, 0.015 μg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates of
Enterobacteriaceae
resistant to third-generation cephalosporins, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing
E. coli
and ESBL-producing
K. pneumoniae
, while maintaining potent activity against staphylococci and streptococci.
Azole Resistance in Cryptococcus gattii from the Pacific Northwest: Investigation of the Role of
ERG11
Authors: Gast Charles E. , Basso Luiz R. , Bruzual Igor , Wong Brian 
Published: August 2013

ABSTRACT

Cryptococcus gattii
is responsible for an expanding epidemic of serious infections in Western Canada and the Northwestern United States (Pacific Northwest). Some patients with these infections respond poorly to azole antifungals, and high azole MICs have been reported in Pacific Northwest
C. gattii
. In this study, multiple azoles (but not amphotericin B) had higher MICs for 25 Pacific Northwest
C. gattii
than for 34 non-Pacific Northwest
C. gattii
or 20
Cryptococcus neoformans
strains. We therefore examined the roles in azole resistance of overexpression of or mutations in the gene (
ERG11
) encoding the azole target enzyme.
ERG11
/
ACT1
mRNA ratios were higher in
C. gattii
than in
C. neoformans
, but these ratios did not differ in Pacific Northwest and non-Pacific Northwest
C. gattii
strains, nor did they correlate with fluconazole MICs within any group. Three Pacific Northwest
C. gattii
strains with low azole MICs and 2 with high azole MICs had deduced Erg11p sequences that differed at one or more positions from that of the fully sequenced Pacific Northwest
C. gattii
strain R265. However, the azole MICs for conditional
Saccharomyces cerevisiae
erg11
mutants expressing the 5 variant
ERG11
s were within 2-fold of the azole MICs for
S. cerevisiae
expressing the
ERG11
gene from
C. gattii
R265, non-Pacific Northwest
C. gattii
strain WM276, or
C. neoformans
strains H99 or JEC21. We conclude that neither
ERG11
overexpression nor variations in
ERG11
coding sequences was responsible for the high azole MICs observed for the Pacific Northwest
C. gattii
strains we studied.
In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites
Authors: Barna Fabienne , Debache Karim , Vock Carsten A. , Küster Tatiana , Hemphill Andrew 
Published: August 2013

ABSTRACTUpon the screening of 16 antiproliferative compounds againstToxoplasma gondiiandNeospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.
The RNA Chaperone Hfq Is Required for Virulence of Bordetella pertussis
Authors: Bibova Ilona , Skopova Karolina , Masin Jiri , Cerny Ondrej , Hot David , Sebo Peter , Vecerek Branislav 
Published: August 2013

ABSTRACTBordetella pertussisis a Gram-negative pathogen causing the human respiratory disease called pertussis or whooping cough. Here we examined the role of the RNA chaperone Hfq inB. pertussisvirulence. Hfq mediates interactions between small regulatory RNAs and their mRNA targets and thus plays an important role in posttranscriptional regulation of many cellular processes in bacteria, including production of virulence factors. We characterized anhfqdeletion mutant (Δhfq) ofB. pertussis18323 and show that the Δhfqstrain produces decreased amounts of the adenylate cyclase toxin that plays a central role inB. pertussisvirulence. Production of pertussis toxin and filamentous hemagglutinin was affected to a lesser extent.In vitro, the ability of the Δhfqstrain to survive within macrophages was significantly reduced compared to that of the wild-type (wt) strain. The virulence of the Δhfqstrain in the mouse respiratory model of infection was attenuated, with its capacity to colonize mouse lungs being strongly reduced and its 50% lethal dose value being increased by one order of magnitude over that of the wt strain. In mixed-infection experiments, the Δhfqstrain was then clearly outcompeted by the wt strain. This requirement for Hfq suggests involvement of small noncoding RNA regulation inB. pertussisvirulence.
Transcriptional Profiling of Neisseria meningitidis Interacting with Human Epithelial Cells in a Long-Term
In Vitro
Colonization Model
Authors: Hey Ariann , Li Ming-Shi , Hudson Michael J. , Langford Paul R. , Kroll J. Simon 
Published: August 2013

ABSTRACT

Neisseria meningitidis
is a commensal of humans that can colonize the nasopharyngeal epithelium for weeks to months and occasionally invades to cause life-threatening septicemia and meningitis. Comparatively little is known about meningococcal gene expression during colonization beyond those first few hours. In this study, the transcriptome of adherent serogroup B
N. meningitidis
strain MC58 was determined at intervals during prolonged cocultivation with confluent monolayers of the human respiratory epithelial cell line 16HBE14. At different time points up to 21 days, 7 to 14% of the meningococcal genome was found to be differentially regulated. The transcriptome of adherent meningococci obtained after 4 h of coculture was markedly different from that obtained after prolonged cocultivation (24 h, 96 h, and 21 days). Genes persistently upregulated during prolonged cocultivation included three genes (
hfq
,
misR
/
phoP
, and
lrp
) encoding global regulatory proteins. Many genes encoding known adhesins involved in epithelial adherence were upregulated, including those of a novel locus (spanning
NMB0342
to
NMB0348
[
NMB0342-NMB0348
]) encoding epithelial cell-adhesive function. Sixteen genes (including
porA
,
porB
,
rmpM
, and
fbpA
) encoding proteins previously identified by their immunoreactivity to sera from individuals colonized long term with serogroup B meningococci were also upregulated during prolonged cocultivation, indicating that our system models growth conditions
in vivo
during the commensal state. Surface-expressed proteins downregulated in the nasopharynx (and thus less subject to selection pressure) but upregulated in the bloodstream (and thus vulnerable to antibody-mediated bactericidal activity) should be interesting candidate vaccine antigens, and in this study, three new proteins fulfilling these criteria have been identified: NMB0497, NMB0866, and NMB1882.