bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1
Authors: Strizki Julie M. , Tremblay Cecile , Xu Serena , Wojcik Lisa , Wagner Nicole , Gonsiorek Waldemar , Hipkin R. William , Chou Chuan-Chu , Pugliese-Sivo Catherine , Xiao Yushi , Tagat Jayaram R. , Cox Kathleen , Priestley Tony , Sorota Steve , Huang Wei , Hirsch Martin , Reyes Gregory R. , Baroudy Bahige M. 
Published: November 2005

ABSTRACT

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[
35
S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.
Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus
Authors: Zhu Weimin , Burnette Angela , Dorjsuren Dorjbal , Roberts Paula E. , Huleihel Mahmoud , Shoemaker Robert H. , Marquez Victor E. , Agbaria Riad , Sei Shizuko 
Published: November 2005

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS). Blocking lytic KSHV replication may hinder KS tumorigenesis. Here, we report potent in vitro anti-KSHV activity of 2′-
exo
-methanocarbathymidine [North-methanocarbathymidine (N-MCT)], a thymidine analog with a pseudosugar ring locked in the northern conformation, which has previously been shown to block the replication of herpes simplex virus types 1 and 2. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC
50
) than those of cidofovir (CDV) and ganciclovir (GCV) (IC
50
, mean ± standard deviation: 0.08 ± 0.03, 0.42 ± 0.07, and 0.96 ± 0.49 μM for N-MCT, CDV, and GCV, respectively). The reduction in KSHV virion production was accompanied by a corresponding decrease in KSHV DNA levels in the N-MCT-treated BCBL-1 cells, indicating that the compound blocked lytic KSHV DNA replication. A time- and dose-dependent accumulation of N-MCT-triphosphate (TP) was demonstrated in lytically induced BCBL-1 cells, while uninfected cells showed virtually no accumulation. The levels of N-MCT-TP were significantly decreased in the presence of 5′-ethynylthymidine, a potent inhibitor of herpesvirus thymidine kinase, resulting in the abrogation of anti-KSHV activity of N-MCT. N-MCT-TP more effectively blocked in vitro DNA synthesis by KSHV DNA polymerase with an IC
50
of 6.24 ± 0.08 μM (mean ± standard deviation) compared to CDV-diphosphate (14.70 ±2.47 μM) or GCV-TP (24.59 ± 5.60 μM). Taken together, N-MCT is a highly potent and target-specific anti-KSHV agent which inhibits lytic KSHV DNA synthesis through its triphosphate metabolite produced in KSHV-infected cells expressing a virally encoded thymidine kinase.
Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis
Authors: Marchand Sandrine , Dahyot Claire , Lamarche Isabelle , Plan Elodie , Mimoz Olivier , Couet William 
Published: November 2005

ABSTRACTThe aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg−1over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n= 8) and control (n= 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P< 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.
Antibiotic Susceptibility Testing of
Mycoplasma genitalium
by TaqMan 5′ Nuclease Real-Time PCR
Authors: Hamasuna Ryoichi , Osada Yukio , Jensen Jørgen Skov 
Published: November 2005

ABSTRACT

Mycoplasma genitalium
is an important pathogen in male nongonococcal urethritis (NGU). Isolation of
M. genitalium
from clinical specimens by axenic culture is very difficult and time-consuming, and very few strains are available for antibiotic susceptibility testing. Primary isolation of
M. genitalium
by coculture with Vero cells improves the isolation rate significantly. However, some strains cannot be adapted to axenic culture. In this study, we determined the antibiotic susceptibility of
M. genitalium
strains grown in Vero cell culture with dilutions of antibiotics. Growth of
M. genitalium
was monitored by a quantitative PCR assay detecting a single-copy region of the
mgpB
adhesin gene. Growth inhibition in the presence of antibiotics was expressed as a percentage of the DNA load of controls grown in the absence of antibiotics. Eighteen strains were examined, including 6 new strains isolated from urethral swab specimens and 4 new strains isolated from urine specimens collected from Japanese men. Eight strains adapted to axenic culture were also tested by the conventional broth dilution method. The two methods had an acceptable correlation. Azithromycin was the most active drug against
M. genitalium
. Among the fluoroquinolones, moxifloxacin had the highest activity, with MICs ranging from 0.03 to 0.5 mg/liter, whereas ciprofloxacin and levofloxacin were considerably less active, with MICs ranging from 0.5 to 16 mg/liter and 0.25 to 4 mg/liter, respectively. MICs for tetracycline ranged from 0.125 to 4 mg/liter. This new method could increase the number of
M. genitalium
strains available for antibiotic susceptibility testing and significantly shorten the time from sampling to MIC results.
Absolute Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Patients with Cystic Fibrosis
Authors: Beringer Paul , Huynh Kitty My Tu , Kriengkauykiat Jane , Bi Luke , Hoem Nils , Louie Stan , Han Emily , Nguyen Thao , Hsu Donald , Rao Purush A. , Shapiro Bertrand , Gill Mark 
Published: November 2005

ABSTRACT

Chronic pulmonary infections with
Pseudomonas aeruginosa
are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg;
P
< 0.01) and body mass index (19.7 versus 23.2;
P
< 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h;
P
= 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%;
P
= 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h
−1
;
P
= 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h
−1
;
P
< 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 ± 6.0 mg/liter) far exceeded the maximum serum drug concentration (∼50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.
In Vitro Activity of Linezolid against Key Gram-Positive Organisms Isolated in the United States: Results of the LEADER 2004 Surveillance Program
Authors: Draghi Deborah C. , Sheehan Daniel J. , Hogan Patricia , Sahm Daniel F. 
Published: November 2005

ABSTRACT

Since the approval of linezolid in 2000, sporadic reports of resistance have been given and a greater understanding of the underlying mechanisms of resistance has been gained. However, since these developments, an updated status of the in vitro activity of linezolid against gram-positive organisms from the United States has not been reported. The LEADER 2004 surveillance initiative was undertaken to obtain current and representative data on the activity of linezolid against key species, including isolates with significant resistance phenotypes. Organisms were isolated during 2004 and included 2,872
Staphylococcus aureus
, 496 coagulase-negative staphylococcus (CNS), 428
Enterococcus faecalis
, 196
Enterococcus faecium
, and 422
Streptococcus pneumoniae
isolates. All
S. aureus
isolates (54.2% oxacillin resistant) were susceptible to linezolid (MIC
90
= 2 μg/ml); MIC distributions were consistent, regardless of oxacillin or multidrug resistance status. For CNS, one nonsusceptible isolate was encountered (
Staphylococcus epidermidis
; MIC = 32 μg/ml), but overall, the MIC
90
(1 μg/ml) was lower than that obtained with
S. aureus
. For
E. faecalis
and
E. faecium
, 99.5% and 96.4% of isolates, respectively, were linezolid susceptible. Both species had an MIC
90
of 2 μg/ml, and MIC distributions did not vary with the vancomycin susceptibility status of the populations analyzed. Linezolid nonsusceptibility was not encountered among the
S. pneumoniae
isolates. These findings indicate that linezolid nonsusceptibility has remained rare among staphylococci and uncommon and sporadic among enterococci. Nonetheless, careful and ongoing monitoring of the in vitro effectiveness of linezolid will be needed so that any changes to the current status may be detected as soon as possible.
Vancomycin-Resistant
Enterococcus faecium
: Catheter Colonization,
esp
Gene, and Decreased Susceptibility to Antibiotics in Biofilm
Authors: Raad Issam I. , Hanna Hend A. , Boktour Maha , Chaiban Gassan , Hachem Ray Y. , Dvorak Tanya , Lewis Russell , Murray Barbara E. 
Published: November 2005

ABSTRACT

To evaluate the molecular characteristics and antibiotic susceptibility in biofilm of vancomycin-resistant
Enterococcus faecium
(VREF) organisms that had caused catheter-related VREF bacteremia (VREF-CRB), we compared 22 isolates causing bacteremia obtained from patients with VREF-CRB with 30 isolates from control patients with gastrointestinal colonization by VREF. Using pulsed-field gel electrophoresis, we identified 17 unique strains among the 22 VREF-CRB isolates and 23 strains among the gastrointestinal isolates. The
esp
gene was detected in 53% (9 of 17) of the VREF-CRB and 61% (14 of 23) of the control strains (
P
= 0.6). VREF-CRB produced heavier biofilm colonization of silicone disks than did control organisms (
P
< 0.001). Daptomycin, minocycline, and quinupristin-dalfopristin were each independently more active than linezolid in reducing biofilm colonization by VREF-CRB (
P
< 0.01), with daptomycin being the most active, followed by minocycline. In conclusion, the
esp
gene in VREF is not associated with heavy biofilm colonization or catheter-related bacteremia. In biofilm, daptomycin and minocycline were the most active antibiotics against VREF, and linezolid was the least active.
Erythromycin Resistance and Genetic Elements Carrying Macrolide Efflux Genes in
Streptococcus agalactiae
Authors: Marimón José María , Valiente Adoración , Ercibengoa María , García-Arenzana José M. , Pérez-Trallero Emilio 
Published: November 2005

ABSTRACT

The macrolide resistance determinants and genetic elements carrying the
mef
(A) and
mef
(E) subclasses of the
mef
gene were studied with
Streptococcus agalactiae
isolated in 2003 and 2004 from 7,084 vaginorectal cultures performed to detect carrier pregnant women. The prevalence of carriage was 18% (1,276 isolates), and that of erythromycin resistance 11.0% (129 of the 1,171 isolates studied).
erm
(B),
erm
(A) subclass
erm
(TR), and the
mef
gene, either subclass
mef
(A) or
mef
(E), were found in 72 (55.8%), 41 (31.8%), and 12 (9.3%) erythromycin-resistant isolates, while 4 isolates had more than 1 erythromycin resistance gene. Of the 13 M-phenotype
mef
-containing erythromycin-resistant
S. agalactiae
isolates, 11 had the
mef
(E) subclass gene alone, one had both the
mef
(E) and the
erm
(TR) subclass genes, and one had the
mef
(A) subclass gene.
mef
(E) subclass genes were associated with the carrying element mega in 10 of the 12
mef
(E)-containing strains, while the single
mef
(A) subclass gene found was associated with the genetic element Tn
1207.3
. The nonconjugative nature of the mega element and the clonal diversity of
mef
(E)-containing strains determined by pulsed-field gel electrophoresis suggest that transformation is the main mechanism through which this resistance gene is acquired.
In Vivo Measurement of Levofloxacin Penetration into Lung Tissue after Cardiac Surgery
Authors: Hutschala Doris , Skhirtladze Keso , Zuckermann Andreas , Wisser Wilfried , Jaksch Peter , Mayer-Helm Bernhard Xaver , Burgmann Heinz , Wolner Ernst , Müller Markus , Tschernko Edda M. 
Published: November 2005

ABSTRACT

Nosocomial pneumonia is a severe complication after cardiac surgery (CS). Levofloxacin, a fluoroquinolone, qualifies for the therapy of postoperative pneumonia. However, penetration properties of levofloxacin into the lung tissue could be substantially affected by CS: atelectasis, low cardiac output after CS, high volume loads, and inflammatory capillary leak potentially influence drug distribution. The aim of our study was to gain information on interstitial antibiotic concentrations in lung tissue in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Therefore, six patients undergoing elective CS participated in this prospective study. A dose of 500 mg of levofloxacin was administered intravenously in addition to standard antibiotic prophylaxis immediately after the end of surgery. Time versus concentration profiles of levofloxacin in the interstitial lung tissue and plasma were determined. A microdialysis technique was used for lung interstitial concentration measurements. The microdialysis procedure was well tolerated in all patients and no adverse events were observed. The median area under the concentration curve (AUC) of levofloxacin in interstitial lung fluid was 18.6 μg · h/ml (range, 10.1 to 33.6). The median AUC for tissue (AUC
tissue
) of unbound levofloxacin/AUC
total
in plasma was 0.6 (range, 0.4 to 0.9). The median unbound AUC
tissue
/MIC was 2.4 (range, 1.3 to 4.2) for
Pseudomonas aeruginosa
. Our study demonstrated the feasibility and safety of microdialysis in human lung tissue in vivo after CS. The unbound AUC/MIC ratio revealed that levofloxacin used in the described manner was borderline sufficient for the treatment of nosocomial pneumonia caused by
Klebsiella pneumoniae
and insufficient for the treatment of pneumonia caused by
Pseudomonas aeruginosa
, because the breakpoint of 30 to 40 for AUC/MIC could not be reached by the conventionally used dosage schema in our post-CS setting. Penetration was lower than in previous reports.
Moxifloxacin and Azithromycin but not Amoxicillin Protect Human Respiratory Epithelial Cells against
Streptococcus pneumoniae
In Vitro when Administered up to 6 Hours after Challenge
Authors: Ulrich Martina , Albers Cordula , Möller Jan-Georg , Dalhoff Axel , Korfmann Gisela , Künkele Frank , Döring Gerd 
Published: November 2005

ABSTRACT

We determined the protective effect of moxifloxacin, azithromycin, and amoxicillin against
Streptococcus pneumoniae
infection of respiratory cells. Moxifloxacin and azithromycin effectively killed intracellular
S. pneumoniae
strains and protected respiratory epithelial cells significantly even when given 6 h after
S. pneumoniae
challenge. Amoxicillin was less effective.
Efficacy of Caspofungin against
Aspergillus terreus
Authors: Barchiesi Francesco , Spreghini Elisabetta , Santinelli Alfredo , Fothergill Annette W. , Fallani Stefania , Manso Esther , Pisa Eleonora , Giannini Daniele , Novelli Andrea , Cassetta Maria I. , Mazzei Teresita , Rinaldi Michael G. , Scalise Giorgio 
Published: November 2005

ABSTRACT

We investigated the in vitro and in vivo activities of caspofungin against
Aspergillus terreus
. The drug increased survival and reduced tissue fungal burden in neutropenic mice. Therefore, our data support the role of caspofungin in treating systemic infections due to this emerging pathogen.
Horizontal Transfer of Erythromycin Resistance from
Clostridium difficile
to
Butyrivibrio fibrisolvens
Authors: Spigaglia Patrizia , Barbanti Fabrizio , Mastrantonio Paola 
Published: November 2005

ABSTRACT

This study demonstrates for the first time the in vitro transfer of the erythromycin resistance gene
erm
(B) between two obligate anaerobes, the human spore-forming pathogen
Clostridium difficile
and the rumen commensal
Butyrivibrio fibrisolvens
, suggesting that this event might occur also in the natural environment.
Variants of the
Klebsiella pneumoniae
OKP Chromosomal Beta-Lactamase Are Divided into Two Main Groups, OKP-A and OKP-B
Authors: Fevre Cindy , Passet Virginie , Weill François-Xavier , Grimont Patrick A. D. , Brisse Sylvain 
Published: November 2005

ABSTRACT

Two
bla
OKP
subgroups were found, diverging by 4.2%. Subgroups
bla
OKP-A
(10 enzyme variants, pIs from 7.1 to 8.3) and
bla
OKP-B
(11 variants, pI 7.1) showed similar antibiotic susceptibilities. Sequencing of
rpoB
,
gyrA
, and
mdh
demonstrated a concordant subdivision of
Klebsiella pneumoniae
phylogenetic group KpII into two subgroups, KpII-A and KpII-B.
In Vitro Synergy of Daptomycin plus Rifampin against
Enterococcus faecium
Resistant to both Linezolid andVancomycin
Authors: Pankey George , Ashcraft Deborah , Patel Nalini 
Published: November 2005

ABSTRACT

In
vitro synergy testing of daptomycin plus rifampin was performed against
24 unique isolates of
Enterococcus faecium
resistant to both
linezolid and vancomycin. Synergy testing showed that 21/24 (88%) were
synergistic and 3/24 (12%) were indifferent by the Etest method.
Time-kill assays revealed synergy for 18/24 (75%) and indifference for
6/24
(25%).
Interaction of Monobenzamidine-Linked Trypanocides with the
Trypanosoma brucei
P2 Aminopurine Transporter
Authors: Stewart Mhairi L. , Boussard Cyrille , Brun Reto , Gilbert Ian H. , Barrett Michael P. 
Published: November 2005

ABSTRACT

Single benzamidine group-carrying compounds were shown to interact with the
Trypanosoma brucei
P2 aminopurine transporter. Replacement of the amidine with a guanidine group decreased affinity. Trypanocidal activity was evident, but compounds were equally toxic against trypanosomes lacking the P2 transporter, which indicates additional uptake routes for monobenzamidine-derived compounds.
Novel Rearrangement of a Class 2 Integron in Two Non-Epidemiologically Related Isolates of
Acinetobacter baumannii
Authors: Ramírez María Soledad , Quiroga Cecilia , Centrón Daniela 
Published: November 2005

ABSTRACT

Tn
7
::In2-8 contains
sat2
-
aadB
-
catB2
(
ΔattC
)-
dfrA1
-
sat2
-
aadA1
-
orfX
in the variable region of a class 2 integron embedded in the Tn
7
-like transposon. This novel transposon was inserted in its preferred site downstream of the
glms
gene in
Acinetobacter baumannii
. Acquisition of the pseudocassette
catB2
could have arisen by a secondary-site integrase-mediated intermolecular recombination event.
Antipneumococcal Activity of Dalbavancin Compared to Other Agents
Authors: Lin Gengrong , Smith Kathy , Ednie Lois M. , Appelbaum Peter C. 
Published: November 2005

ABSTRACT
Against 307 pneumococci of various resistotypes, dalbavancin MICs were 0.008 to 0.125 μg/ml. All strains were susceptible to vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin. Dalbavancin at 2× MIC was bactericidal against all 10 pneumococci tested after 24 h. Vancomycin and teicoplanin killed 10 and 8 strains, respectively, at 2× MIC after 24 h.
Human Immunodeficiency Virus Type 1 Latency Model for High-Throughput Screening
Authors: Micheva-Viteva Sofiya , Pacchia Annmarie L. , Ron Yacov , Peltz Stuart W. , Dougherty Joseph P. 
Published: November 2005

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) is not eliminated from patients even after years of antiretroviral therapy, apparently due to the presence of latently infected cells. Here we describe the development of a cell-based system of latency that can be used for high-throughput screening aimed at novel drug discovery to eradicate HIV-1 infection.