bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Linezolid in Subjects with Renal Dysfunction
Authors: Brier Michael E. , Stalker Dennis J. , Aronoff George R. , Batts Donald H. , Ryan Kristi K. , O'Grady Margaret , Hopkins Nancy K. , Jungbluth Gail L. 
Published: August 2003

ABSTRACT
Linezolid is a member of a new, unique class of synthetic antibacterial agents called oxazolidinones that are effective against gram-positive bacteria, including vancomycin-resistant organisms. We tested the hypothesis that the linezolid clearance would not be altered in subjects with renal dysfunction. Twenty-four subjects with renal function that ranged from normal to severe chronic impairment were enrolled, including patients with end-stage renal disease who were maintained on hemodialysis. Hemodialysis subjects were studied while they were both on and off dialysis. Linezolid was administered as a single oral 600-mg dose, and plasma and urine samples were assayed for linezolid and metabolites for 48 h for all subjects and for up to 96 h for those subjects with impaired renal function not on dialysis. The total apparent oral clearance of linezolid did not change with renal function and ranged from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increased from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. Approximately one-third of the dose was removed by dialysis. However, those subjects with severe renal insufficiency (creatinine clearance, <40 ml/min) and those with end-stage renal disease maintained on hemodialysis had higher concentrations of both metabolites. We conclude that no adjustment of the linezolid dosage is needed in subjects with renal dysfunction or subjects on hemodialysis.
Pharmacokinetics, Toxicities, and Efficacies of Sodium Stibogluconate Formulations after Intravenous Administration in Animals
Authors: Nieto J. , Alvar J. , Mullen A. B. , Carter K. C. , Rodríguez C. , San Andrés M. I. , San Andrés M. D. , Baillie A. J. , González F. 
Published: August 2003

ABSTRACTThe pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P= 0.01), and the volume of distribution at steady state (VSS) was also increased (VSSfor SSG, 0.21 liters/kg;VSSfor SSG-NIV-dextran, 0.34 liters/kg [P= 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P< 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.
Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults
Authors: Courtney Rachel , Pai Sudhakar , Laughlin Mark , Lim Josephine , Batra Vijay 
Published: August 2003

ABSTRACTThe pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.
Association of the Endotoxin Antagonist E5564 with High-Density Lipoproteins In Vitro: Dependence on Low-Density and Triglyceride-Rich Lipoprotein Concentrations
Authors: Wasan Kishor M. , Sivak Olena , Cote Richard A. , MacInnes Aaron I. , Boulanger Kathy D. , Lynn Melvyn , Christ William J. , Hawkins Lynn D. , Rossignol Daniel P. 
Published: August 2003

ABSTRACTThe objective of this study was to determine the distribution profile of the novel endotoxin antagonist E5564 in plasma obtained from fasted human subjects with various lipid concentrations. Radiolabeled E5564 at 1 μM was incubated in fasted plasma from seven human subjects with various total cholesterol (TC) and triglyceride (TG) concentrations for 0.5 to 6 h at 37°C. Following these incubations, plasma samples were separated into their lipoprotein and lipoprotein-deficient fractions by ultracentrifugation and were assayed for E5564 radioactivity. TC, TG, and protein concentrations in each fraction were determined by enzymatic assays. Lipoprotein surface charge within control and phosphatidylinositol-treated plasma and E5564’s influence on cholesteryl ester transfer protein (CETP) transfer activity were also determined. We observed that the majority of E5564 was recovered in the high-density lipoprotein (HDL) fraction. We further observed that incubation in plasma with increased levels of TG-rich lipoprotein (TRL) lipid (TC and TG) concentrations resulted in a significant increase in the percentage of E5564 recovered in the TRL fraction. In further experiments, E5564 was preincubated in human TRL. Then, these mixtures were incubated in hypolipidemic human plasma for 0.5 and 6 h at 37°C. Preincubation of E5564 in purified TRL prior to incubation in human plasma resulted in a significant decrease in the percentage of drug recovered in the HDL fraction and an increase in the percentage of drug recovered in the TRL and low-density lipoprotein fractions. These findings suggest that the majority of the drug binds to HDLs. Preincubation of E5564 in TRL prior to incubation in normolipidemic plasma significantly decreased the percentage of drug recovered in the HDL fraction. Modifications to the lipoprotein negative charge did not alter the E5564 concentration in the HDL fraction. In addition, E5564 does not influence CETP-mediated transfer activity. Information from these studies could be used to help identify the possible components of lipoproteins which influence the interaction of E5564 with specific lipoprotein particles.
Antimicrobial Characterization of Human β-Defensin 3 Derivatives
Authors: Hoover David M. , Wu Zhibin , Tucker Kenneth , Lu Wuyuan , Lubkowski Jacek 
Published: August 2003

ABSTRACTHuman β-defensin 3 (hBD3) is a highly basic 45-amino-acid protein that acts both as an antimicrobial agent and as a chemoattractant molecule. Although the nature of its antimicrobial activity is largely electrostatic, the importance of the molecular structure on this activity is poorly understood. Two isoforms of hBD3 were synthesized: the first with native disulfide linkages and the second with nonnative linkages. In a third synthetic peptide, all cysteine residues were replaced with α-aminobutyric acid, creating a completely linear peptide. A series of six small, linear peptides corresponding to regions of hBD3 with net charges ranging from +4 to +8 (at pH 7) and lengths ranging from 9 to 20 amino acids were also synthesized. The linear full-length peptide showed the highest microbicidal activity againstEscherichia coliandStaphylococcus aureus, while all three full-length forms showed equal activity againstCandida albicans. The linear peptide also showed high activity againstEnterococcus faeciumandPseudomonas aeruginosa.Peptides corresponding to the C terminus showed higher activities when tested againstE. coli, with the most active peptides being the most basic. However, only the peptide corresponding to the N terminus of hBD3 showed any activity againstS. aureusandC. albicans. Further, N-terminal deletion mutants of native hBD3 showed diminished activities againstS. aureus. Thus, the antimicrobial properties of hBD3 derivatives are determined by both charge and structure.
Shikonin, a Component of Chinese Herbal Medicine, Inhibits Chemokine Receptor Function and Suppresses Human Immunodeficiency Virus Type 1
Authors: Chen Xin , Yang Lu , Zhang Ning , Turpin Jim A. , Buckheit Robert W. , Osterling Clay , Oppenheim Joost J. , Howard O. M. Zack 
Published: August 2003

ABSTRACT

Shikonin is a major component of zicao (purple gromwell, the dried root of
Lithospermum erythrorhizon
), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1α], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1α]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC
50
s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC
50
of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.
In Vitro Hypersusceptibility of Human Immunodeficiency Virus Type 1 Subtype C Protease to Lopinavir
Authors: Gonzalez Luis M. F. , Brindeiro Rodrigo M. , Tarin Michelle , Calazans Alexandre , Soares Marcelo A. , Cassol Sharon , Tanuri Amilcar 
Published: August 2003

ABSTRACT

In order to characterize the impact of genetic polymorphisms on the susceptibility of subtype C strains of human immunodeficiency virus type 1 to protease inhibitors (PIs), a subtype B protease that originated from an infectious clone was modified through site-directed mutagenesis to include the amino acid residue signatures of subtype C viruses (I15V, M36I, R41K, H69K, L89 M) with (clone C6) or without (clone C5) an I93L polymorphism present as a molecular signature of the worldwide subtype C protease. Their susceptibilities to commercially available PIs were measured by a recombinant virus phenotyping assay. We could not detect any differences in the 50% inhibitory concentration (IC
50
s) of amprenavir, indinavir, ritonavir, saquinavir, and nelfinavir for the clones analyzed. However, we did observe hypersusceptibility to lopinavir solely in clone C6, which includes the I93L substitution (a 2.6-fold decrease in the IC
50
compared to that for the subtype B reference strain). The same phenotypic behavior was observed for 11 Brazilian and South African clinical isolates tested, in which only subtype C isolates carrying the I93L mutation presented significant hypersusceptibility to lopinavir.
Deciphering Tuberactinomycin Biosynthesis: Isolation, Sequencing, and Annotation of the Viomycin Biosynthetic Gene Cluster
Authors: Thomas Michael G. , Chan Yolande A. , Ozanick Sarah G. 
Published: August 2003

ABSTRACT

The tuberactinomycin antibiotics are essential components in the drug arsenal against
Mycobacterium tuberculosis
infections and are specifically used for the treatment of multidrug-resistant tuberculosis. These antibiotics are also being investigated for their targeting of the catalytic RNAs involved in viral replication and for the treatment of bacterial infections caused by methicillin-resistant
Staphylococcus aureus
strains and vancomycin-resistant enterococci. We report on the isolation, sequencing, and annotation of the biosynthetic gene cluster for one member of this antibiotic family, viomycin, from
Streptomyces
sp. strain ATCC 11861. This is the first gene cluster for a member of the tuberactinomycin family of antibiotics sequenced, and the information gained can be extrapolated to all members of this family. The gene cluster covers 36.3 kb of DNA and encodes 20 open reading frames that we propose are involved in the biosynthesis, regulation, export, and activation of viomycin, in addition to self-resistance to the antibiotic. These results enable us to predict the metabolic logic of tuberactinomycin production and begin steps toward the combinatorial biosynthesis of these antibiotics to complement existing chemical modification techniques to produce novel tuberactinomycin derivatives.
Role of AcrR and RamA in Fluoroquinolone Resistance in Clinical
Klebsiella pneumoniae
Isolates from Singapore
Authors: Schneiders T. , Amyes S. G. B. , Levy S. B. 
Published: August 2003

ABSTRACT

The MICs of ciprofloxacin for 33 clinical isolates of
K. pneumoniae
resistant to extended-spectrum cephalosporins from three hospitals in Singapore ranged from 0.25 to >128 μg/ml. Nineteen of the isolates were fluoroquinolone resistant according to the NCCLS guidelines. Strains for which the ciprofloxacin MIC was ≥0.5 μg/ml harbored a mutation in DNA gyrase A (Ser83→Tyr, Leu, or IIe), and some had a secondary Asp87→Asn mutation. Isolates for which the MIC was 16 μg/ml possessed an additional alteration in ParC (Ser80→IIe, Trp, or Arg). Tolerance of the organic solvent cyclohexane was observed in 10 of the 19 fluoroquinolone-resistant strains; 3 of these were also pentane tolerant. Five of the 10 organic solvent-tolerant isolates overexpressed AcrA and also showed deletions within the
acrR
gene. Complementation of the mutated
acrR
gene with the wild-type gene decreased AcrA levels and produced a two- to fourfold reduction in the fluoroquinolone MICs. None of the organic solvent-tolerant clinical isolates overexpressed another efflux-related gene,
acrE.
While
marA
and
soxS
were not overexpressed, another
marA
homologue,
ramA
, was overexpressed in 3 of 10 organic solvent-tolerant isolates. These findings indicate that multiple target and nontarget gene changes contribute to fluoroquinolone resistance in
K. pneumoniae.
Besides AcrR mutations,
ramA
overexpression (but not
marA
or
soxS
overexpression) was related to increased AcrAB efflux pump expression in this collection of isolates.
Molecular Characterization of a New Class 3 Integron in
Klebsiella pneumoniae
Authors: Correia Mário , Boavida Filipa , Grosso Filipa , Salgado M. J. , Lito L. M. , Cristino J. Melo , Mendo Sónia , Duarte Aida 
Published: August 2003

ABSTRACT

Klebsiella pneumoniae
FFUL 22K was isolated in April 1999 from the urine of an intensive care unit patient in Portugal. The strain showed an extended-spectrum cephalosporin resistance profile. A typical synergistic effect between cefotaxime or cefepime and clavulanic acid was observed. An
Escherichia coli
transformant displayed a similar resistance phenotype and harbored a ca. 9.4-kb plasmid (p22K9). Cloning experiments revealed that the extended-spectrum β-lactamase was encoded by
bla
GES-1
, previously described in class 1 integrons from
K. pneumoniae
ORI-1 and
Pseudomonas aeruginosa
Pa695. Further sequence analysis demonstrated that the
bla
GES-1
gene cassette was located on a new class 3 integron. The integron was 2,863 bp long and consisted of an
intI3
integrase gene, an
attI3
recombination site, two promoter regions, and two gene cassettes. The IntI3 integrase was 98.8% identical to that of
Serratia marcescens
AK9373. The
bla
GES-1
gene cassette was inserted at the
attI3
site. The second gene cassette was the result of a fusion event between
bla
OXA-10
-type and
aac(6′)-Ib
gene cassettes and conferred resistance to kanamycin. This is the second class 3 integron reported and the first time that the
bla
GES-1
gene cassette has been found on an integron belonging to this class, highlighting the considerable heterogeneity of their genetic environment and the spread of gene cassettes among different classes of integrons.
Presence of the
tet
(O) Gene in Erythromycin- and Tetracycline-Resistant Strains of
Streptococcus pyogenes
and Linkage with either the
mef
(A) or the
erm
(A) Gene
Authors: Giovanetti Eleonora , Brenciani Andrea , Lupidi Remo , Roberts Marilyn C. , Varaldo Pietro E. 
Published: August 2003

ABSTRACT

Sixty-three recent Italian clinical isolates of
Streptococcus pyogenes
resistant to both erythromycin (MICs ≥ 1 μg/ml) and tetracycline (MICs ≥ 8 μg/ml) were genotyped for macrolide and tetracycline resistance genes. We found 19 isolates carrying the
mef
(A) and the
tet
(O) genes; 25 isolates carrying the
erm
(A) and
tet
(O) genes; and 2 isolates carrying the
erm
(A),
tet
(M), and
tet
(O) genes. The resistance of all
erm
(A)-containing isolates was inducible, but the isolates could be divided into two groups on the basis of erythromycin MICs of either >128 or 1 to 4 μg/ml. The remaining 17 isolates included 15 isolates carrying the
erm
(B) gene and 2 isolates carrying both the
erm
(B) and the
mef
(A) genes, with all 17 carrying the
tet
(M) gene. Of these, 12 carried Tn
916
-Tn
1545
-like conjugative transposons. Conjugal transfer experiments demonstrated that the
tet
(O) gene moved with and without the
erm
(A) gene and with the
mef
(A) gene. These studies, together with the results of pulsed-field gel electrophoresis experiments and hybridization assays with DNA probes specific for the
tet
(O),
erm
(A), and
mef
(A) genes, suggested a linkage of
tet
(O) with either
erm
(A) or
mef
(A) in erythromycin- and tetracycline-resistant
S. pyogenes
isolates. By amplification and sequencing experiments, we detected the
tet
(O) gene ca. 5.5 kb upstream from the
mef
(A) gene. This is the first report demonstrating the presence of the
tet
(O) gene in
S. pyogenes
and showing that it may be linked with another gene and can be moved by conjugation from one chromosome to another.
Biological Costs and Mechanisms of Fosfomycin Resistance in
Escherichia coli
Authors: Nilsson Annika I. , Berg Otto G. , Aspevall Olle , Kahlmeter Gunnar , Andersson Dan I. 
Published: August 2003

ABSTRACT

Fosfomycin is a cell wall inhibitor used mainly for the treatment of uncomplicated lower urinary tract infections. As shown here, resistance to fosfomycin develops rapidly in
Escherichia coli
under experimental conditions, but in spite of the relatively high mutation rate in vitro, resistance in clinical isolates is rare. To examine this apparent contradiction, we mathematically modeled the probability of resistance development in the bladder during treatment. The modeling showed that during a typical episode of urinary tract infection, the probability of resistance development was high (>10
−2
). However, if resistance was associated with a reduction in growth rate, the probability of resistance development rapidly decreased. To examine if fosfomycin resistance causes a reduced growth rate, we isolated in vitro and in vivo a set of resistant strains. We determined their resistance mechanisms and examined the effect of the different resistance mutations on bacterial growth in the absence and presence of fosfomycin. The types of mutations found in vitro and in vivo were partly different. Resistance in the mutants isolated in vitro was caused by
ptsI
,
cyaA
,
glpT
,
uhpA/T
, and unknown mutations, whereas no
cyaA
or
ptsI
mutants could be found in vivo. All mutations caused a decreased growth rate both in laboratory medium and in urine, irrespective of the absence or presence of fosfomycin. According to the mathematical model, the reduced growth rate of the resistant strains will prevent them from establishing in the bladder, which could explain why fosfomycin resistance remains rare in clinical isolates.
Molecular and Biochemical Characterization of OXA-45, an Extended-Spectrum Class 2d′ β-Lactamase inPseudomonas aeruginosa
Authors: Toleman Mark A. , Rolston Kenneth , Jones Ronald N. , Walsh Timothy R. 
Published: August 2003

ABSTRACTAs part of the CANCER Antimicrobial Surveillance Program in North America, a clinical strain ofPseudomonas aeruginosa, strain 07-406, isolated in Texas was found to be resistant to all antimicrobials except polymyxin B. Genetic analysis of this isolate identified two unique extended-spectrum β-lactamase genes. One,blaVIM-7, encoded a metallo-β-lactamase (unpublished data), and the other,blaOXA-45, described here, encoded a class D extended-spectrum β-lactamase.blaOXA-45was isolated on aSau3A1 genomic fragment of 1.8 kb and encodes a protein of 264 amino acids with the highest identities to OXA-18 (65.9%), OXA-9 (42.8%), OXA-22 (40.2%), OXA-12 (38.6%), and OXA-29 (35.2%) but weak identities with other class D β-lactamases.blaOXA-45was found to be harbored on a 24-kb plasmid in a region that displays high identities with a section of the 43-kb genomic island ofSalmonella entericaserovar Typhimurium DT104. Biochemically OXA-45 is most similar to OXA-18 in its substrate profile and inhibition by clavulanic acid and is a member of the 2d′ class of β-lactamases.