bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Activity andIn VitroMutation Development Pathways of MK-6186, a Novel Nonnucleoside Reverse Transcriptase Inhibitor
Authors: Lu Meiqing , Felock Peter J. , Munshi Vandna , Hrin Renee C. , Wang Ying-Jie , Yan Youwei , Munshi Sanjeev , McGaughey Georgia B. , Gomez Robert , Anthony Neville J. , Williams Theresa M. , Grobler Jay A. , Hazuda Daria J. , McKenna Philip M. , Miller Michael D. , Lai Ming-Tain 
Published: March 2012

ABSTRACTMK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations,in vitroresistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).
Functional Characterization of a Cassette-Specific Promoter in the Class 1 Integron-Associated
qnrVC1
Gene
Authors: da Fonseca Érica Lourenço , Vicente Ana Carolina Paulo 
Published: March 2012

ABSTRACT

Integrons are natural expression vectors due to the presence of an intrinsic promoter (P
c
). Although rare, gene cassettes can harbor their own promoter. This study determined the functionality of an internal promoter in the
qnrVC1
cassette whose presence was suggested by a level of transcription similar to that of the preceding cassette (
aadA2
) and confirmed by
in silico
analysis. Its functionality was determined by 5′ rapid amplification of cDNA ends (RACE) and cloning into promoter-probe vectors. P
qnrVC
was found in the
qnrVC
cassette family, stressing its role in contributing to resistance manifestation.
Assessment of the Pharmacokinetic Interaction between Eltrombopag and Lopinavir-Ritonavir in Healthy Adult Subjects
Authors: Wire Mary B. , McLean Heidi B. , Pendry Carolyn , Theodore Dickens , Park Jung W. , Peng Bin 
Published: March 2012

ABSTRACTEltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.
The Composition of the Culture Medium Influences the β-1,3-Glucan Metabolism of Aspergillus fumigatus and the Antifungal Activity of Inhibitors of β-1,3-Glucan Synthesis
Authors: Clavaud Cécile , Beauvais Anne , Barbin Lise , Munier-Lehmann Hélène , Latgé Jean-Paul 
Published: March 2012

ABSTRACT

In vitro
testing of
Aspergillus fumigatus
susceptibility to echinocandins has always been a challenge. Using a simple and quick colorimetric method to analyze the activity of inhibitors of β-1,3-glucan synthesis, we found that the composition of the culture medium significantly influences glucan synthesis and consequently the antifungal properties of inhibitors of β-1,3-glucan synthesis when they are tested alone or in combination with chitin synthase inhibitors.
Bactericidal Activity of Multiple Combinations of Tigecycline and Colistin against NDM-1-Producing Enterobacteriaceae
Authors: Albur Mahableshwar , Noel Alan , Bowker Karen , MacGowan Alasdair 
Published: March 2012

ABSTRACT

The interaction between colistin and tigecycline against eight well-characterized NDM-1-producing
Enterobacteriaceae
strains was studied. Time-kill methodology was employed using a 4-by-4 exposure matrix with pharmacokinetically achievable free drug peak, trough, and average 24-h serum concentrations. Colistin sulfate and methanesulfonate alone showed good early bactericidal activity, often with subsequent regrowth. Tigecycline alone had poor activity. Addition of tigecycline to colistin does not produce increased bacterial killing; instead, it may cause antagonism at lower concentrations.
Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring
Authors: Dolton Michael J. , Ray John E. , Marriott Deborah , McLachlan Andrew J. 
Published: March 2012

ABSTRACT
Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.
Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance
Authors: Diacon A. H. , Donald P. R. , Pym A. , Grobusch M. , Patientia R. F. , Mahanyele R. , Bantubani N. , Narasimooloo R. , De Marez T. , van Heeswijk R. , Lounis N. , Meyvisch P. , Andries K. , McNeeley D. F. 
Published: March 2012

ABSTRACT

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71;
P
= 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%;
P
= 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.
Empirical Use of Ciprofloxacin for Acute Uncomplicated Pyelonephritis Caused by Escherichia coli in Communities Where the Prevalence of Fluoroquinolone Resistance Is High
Authors: Jeon Jae Hyun , Kim Kyuseok , Han Woong Dae , Song Sang Hoon , Park Kyoung Un , Rhee Joong Eui , Song Kyoung-Ho , Park Wan Beom , Kim Eu Suk , Park Sang Won , Kim Nam Joong , Oh Myoung-don , Kim Hong Bin 
Published: March 2012

ABSTRACT

There is little information about the effectiveness of ciprofloxacin in regions where ciprofloxacin-resistant
Escherichia coli
is prevalent. This study was conducted to evaluate whether ciprofloxacin is effective as the initial empirical antibiotic for treatment of uncomplicated acute pyelonephritis (APN) due to ciprofloxacin-resistant
E. coli
. A total of 255 women with clinical diagnoses of uncomplicated APN due to
E. coli
were enrolled in the emergency department between March 2005 and December 2008. All enrolled patients were initially treated with ciprofloxacin. Patients were followed up 4 to 7 days after the start of therapy and 14 to 21 days after its completion. At the first follow-up visit, ciprofloxacin was changed to the appropriate antibiotic when necessary, depending on the antibiotic susceptibility results. Not only improvement of symptoms and signs but also microbiologic eradication was assessed at each visit. Fifteen percent (39/255) of the
E. coli
isolates were resistant to ciprofloxacin. There was no statistically significant difference between the clinical cure rates of the ciprofloxacin-susceptible group and the ciprofloxacin-resistant group at the first follow-up (87.0% versus 76.9%,
P
= 0.135) or the second follow-up (98.6% versus 94.9%,
P
= 0.177). However, there was a lower microbiologic cure rate in the ciprofloxacin-resistant group than in the ciprofloxacin-susceptible group (92.4% versus 41.7%,
P
= 0.000) at the first follow-up visit. No complications occurred in the ciprofloxacin-resistant group during the follow-up period. Our findings indicate that ciprofloxacin is an appropriate choice for empirical therapy of uncomplicated APN and has no serious adverse outcomes, if it is tailored appropriately, even for women infected with ciprofloxacin-resistant
E. coli
.
Activity of a Novel Cyclic Lipopeptide, CB-183,315, against Resistant Clostridium difficile and Other Gram-Positive Aerobic and Anaerobic Intestinal Pathogens
Authors: Snydman D. R. , Jacobus N. V. , McDermott L. A. 
Published: March 2012

ABSTRACT

We evaluated the activity of CB-183,315 against
Clostridium difficile
, including strains that are resistant to fluoroquinolones and metronidazole and with elevated MICs to vancomycin as well as other Gram-positive intestinal pathogens. The MICs of CB-183,315 against all
C. difficile
isolates were ≤1 μg/ml. CB-183,315 had greater activity than vancomycin and metronidazole against
C. difficile
isolates and was more active than the comparators against vancomycin-resistant enterococcus (VRE). CB-183,315 also had excellent activity against methicillin-resistant
Staphylococcus aureus
(MRSA), other
Clostridium
spp., and
Peptostreptococcus
spp.
Effects of Dimerization on the Structure and Biological Activity of Antimicrobial Peptide Ctx-Ha
Authors: Lorenzón E. N. , Cespedes G. F. , Vicente E. F. , Nogueira L. G. , Bauab T. M. , Castro M. S. , Cilli E. M. 
Published: March 2012

ABSTRACT

It is well known that cationic antimicrobial peptides (cAMPs) are potential microbicidal agents for the increasing problem of antimicrobial resistance. However, the physicochemical properties of each peptide need to be optimized for clinical use. To evaluate the effects of dimerization on the structure and biological activity of the antimicrobial peptide Ctx-Ha, we have synthesized the monomeric and three dimeric (Lys-branched) forms of the Ctx-Ha peptide by solid-phase peptide synthesis using a combination of 9-fluorenylmethyloxycarbonyl (Fmoc) and
t
-butoxycarbonyl (Boc) chemical approaches. The antimicrobial activity assay showed that dimerization decreases the ability of the peptide to inhibit growth of bacteria or fungi; however, the dimeric analogs displayed a higher level of bactericidal activity. In addition, a dramatic increase (50 times) in hemolytic activity was achieved with these analogs. Permeabilization studies showed that the rate of carboxyfluorescein release was higher for the dimeric peptides than for the monomeric peptide, especially in vesicles that contained sphingomyelin. Despite different biological activities, the secondary structure and pore diameter were not significantly altered by dimerization. In contrast to the case for other dimeric cAMPs, we have shown that dimerization selectively decreases the antimicrobial activity of this peptide and increases the hemolytic activity. The results also show that the interaction between dimeric peptides and the cell wall could be responsible for the decrease of the antimicrobial activity of these peptides.
Effects of Antibiotics on Shiga Toxin 2 Production and Bacteriophage Induction by Epidemic Escherichia coli O104:H4 Strain
Authors: Bielaszewska Martina , Idelevich Evgeny A. , Zhang Wenlan , Bauwens Andreas , Schaumburg Frieder , Mellmann Alexander , Peters Georg , Karch Helge 
Published: March 2012

ABSTRACT

The role of antibiotics in treatment of enterohemorrhagic
Escherichia coli
(EHEC) infections is controversial because of concerns about triggering hemolytic-uremic syndrome (HUS) by increasing Shiga toxin (Stx) production. During the recent large EHEC O104:H4 outbreak, antibiotic therapy was indicated for some patients. We tested a diverse panel of antibiotics to which the outbreak strain is susceptible to interrogate the effects of subinhibitory antibiotic concentrations on induction of
stx
2
-harboring bacteriophages,
stx
2
transcription, and Stx2 production in this emerging pathogen. Ciprofloxacin significantly increased
stx
2
-harboring phage induction and Stx2 production in outbreak isolates (
P
values of <0.001 to <0.05), while fosfomycin, gentamicin, and kanamycin insignificantly influenced them (
P
> 0.1) and chloramphenicol, meropenem, azithromycin, rifaximin, and tigecycline significantly decreased them (
P
≤ 0.05). Ciprofloxacin and chloramphenicol significantly upregulated and downregulated
stx
2
transcription, respectively (
P
< 0.01); the other antibiotics had insignificant effects (
P
> 0.1). Meropenem, azithromycin, and rifaximin, which were used for necessary therapeutic or prophylactic interventions during the EHEC O104:H4 outbreak, as well as tigecycline, neither induced
stx
2
-harboring phages nor increased
stx
2
transcription or Stx2 production in the outbreak strain. These antibiotics might represent therapeutic options for patients with EHEC O104:H4 infection if antibiotic treatment is inevitable. We await further analysis of the epidemic to determine if usage of these agents was associated with an altered risk of developing HUS.
Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine
Authors: Rower Joseph E. , Meditz Amie , Gardner Edward M. , Lichtenstein Kenneth , Predhomme Julie , Bushman Lane R. , Klein Brandon , Zheng Jia-Hua , MaWhinney Samantha , Anderson Peter L. 
Published: March 2012

ABSTRACT

The cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC)
in vivo
is not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (
C
ss
) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higher
C
ss
estimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (
P
> 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [−19%, 38%];
P
= 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [−9%, 20%] and −5% [−26%, 12%] for HIV serostatus and race, respectively;
P
> 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacology
in vivo
and provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.
The Vibrio parahaemolyticus ToxRS Regulator Is Required for Stress Tolerance and Colonization in a Novel Orogastric Streptomycin-Induced Adult Murine Model
Authors: Whitaker W. Brian , Parent Michelle A. , Boyd Aoife , Richards Gary P. , Boyd E. Fidelma 
Published: March 2012

ABSTRACT

Vibrio parahaemolyticus
, a marine bacterium, is the causative agent of gastroenteritis associated with the consumption of seafood. It contains a homologue of the
toxRS
operon that in
V. cholerae
is the key regulator of virulence gene expression. We examined a nonpolar mutation in
toxRS
to determine the role of these genes in
V. parahaemolyticus
RIMD2210633, an O3:K6 isolate, and showed that compared to the wild type, Δ
toxRS
was significantly more sensitive to acid, bile salts, and sodium dodecyl sulfate stresses. We demonstrated that ToxRS is a positive regulator of
ompU
expression, and that the complementation of Δ
toxRS
with
ompU
restores stress tolerance. Furthermore, we showed that ToxRS also regulates type III secretion system genes in chromosome I via the regulation of the
leuO
homologue VP0350. We examined the effect of Δ
toxRS in vivo
using a new orogastric adult murine model of colonization. We demonstrated that streptomycin-treated adult C57BL/6 mice experienced prolonged intestinal colonization along the entire intestinal tract by the streptomycin-resistant
V. parahaemolyticus
. In contrast, no colonization occurred in non-streptomycin-treated mice. A competition assay between the Δ
toxRS
and wild-type
V. parahaemolyticus
strains marked with the β-galactosidase gene
lacZ
demonstrated that the Δ
toxRS
strain was defective in colonization compared to the wild-type strain. This defect was rescued by ectopically expressing
ompU
. Thus, the defect in stress tolerance and colonization in Δ
toxRS
is solely due to OmpU. To our knowledge, the orogastric adult murine model reported here is the first showing sustained intestinal colonization by
V. parahaemolyticus
.
Density-dependent regulation of year-class strength in age-0 juvenile striped bass (Morone saxatilis)
Authors: Martino E.J. , Houde E.D. 
Published: March 2012

Abundance of age-0 striped bass ( Morone saxatilis ) exhibits 50-fold variability in Chesapeake Bay. Processes that act to reduce and thus regulate this variability were investigated. The potential for density-dependent regulation of growth and mortality in the early juvenile stage and its causes were investigated. Data from multiple seine and trawl surveys in upper Chesapeake Bay and tributaries were analyzed to construct growth and mortality indices having a high degree of spatial and temporal resolution. Age-0 mean lengths in September were inversely related to density, ranging from 67.8 mm in 1994, when mean density was 0.036·m–2, to 104.5 mm in 1992, when mean density was 0.003·m–2. Except for the Potomac River, evidence for density-dependent growth was consistent across subpopulations. Bioenergetics modeling indicated that prey consumption was limiting except in low-abundance years. Mortality increased with respect to abundance and also was density-dependent. The significant interaction between age-0 juvenile length in September and subsequent winter temperature on mortality indicated that density-dependent growth leads to size-selective overwinter mortality. A statistical model including age-0 abundances, age-0 lengths, and winter temperature explained a substantial fraction of variability and the mechanisms for regulation of striped bass recruitment.