bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Population Pharmacokinetic Analysis of the Penetration of the Prostate by Levofloxacin
Authors: Drusano G. L. , Preston S. L. , Van Guilder M. , North D. , Gombert M. , Oefelein M. , Boccumini L. , Weisinger B. , Corrado M. , Kahn J. 
Published: July 2002

ABSTRACT

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of the
Enterobacteriaceae
, particularly
Escherichia coli
, play a central role, while intracellular pathogens such as
Chlamydia
are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.
Effects of Fluconazole and Clarithromycin on Rifabutin and 25-
O
-Desacetylrifabutin Pharmacokinetics
Authors: Jordan M. Kelli , Polis Michael A. , Kelly Grace , Narang Prem K. , Masur Henry , Piscitelli Stephen C. 
Published: July 2002

ABSTRACT
Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the concentration-time curve of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together with rifabutin. Patients should be monitored for adverse effects of rifabutin administered concomitantly with clarithromycin and/or fluconazole.
Functional Analysis of the Active Site of a Metallo-β-Lactamase Proliferating in Japan
Authors: Haruta Shin , Yamaguchi Hitomi , Yamamoto Elise Tie , Eriguchi Yoshiro , Nukaga Michiyoshi , O'Hara Koji , Sawai Tetsuo 
Published: July 2002

ABSTRACT

An R-plasmid-mediated metallo-β-lactamase was found in
Klebsiella pneumoniae
DK4 isolated in Japan in 1991. The nucleotide sequence of its structural gene revealed that the β-lactamase termed DK4 was identical to the IMP-1 metallo-β-lactamase which was mediated by a chromosomal gene of
Serratia marcescens
TN9106 isolated in Japan in 1991 (E. Osano et al., Antimicrob. Agents Chemother. 38:71–78, 1994). The dose effect of DK4 β-lactamase production on the resistance levels indicated a significant contribution of the enzyme to bacterial resistance to all the β-lactams except monobactams. The enzymatic characteristics of the DK4 β-lactamase and its kinetic parameters for nine β-lactams were examined. The DK4 β-lactamase was confirmed to contain 2 mol of zinc per mol of enzyme protein. The apoenzyme that lacked the two zincs was structurally unstable, and the activities of only 30% of the apoenzyme molecules could be restored by the addition of 1 mM zinc sulfate. The substitution of five conserved histidines (His28, His86, His88, His149, His210) and a cysteine (Cys168) for an alanine indicated that His86, His88, and His149 served as ligands to one of the zincs and that Cys168 played a role as a ligand to the second zinc. Both zinc molecules contribute to the enzymatic process. Mutant enzymes that lack only one of these retained some activity. Additionally, a conserved aspartic acid at position 90 was replaced by asparagine. This mutant enzyme showed an approximately 1,000 times lower
k
cat
value for cephalothin than that of the wild-type enzyme but retained the two zincs even after dialysis against zinc-free buffer. The observed effect of pH on the activity suggested that Asp90 functions as a general base in the enzymatic process.
In Vitro Resistance Profile of the Human Immunodeficiency Virus Type 1 Protease Inhibitor BMS-232632
Authors: Gong Yi-Fei , Robinson Brett S. , Rose Ronald E. , Deminie Carol , Spicer Timothy P. , Stock David , Colonno Richard J. , Lin Pin-fang 
Published: July 2002

ABSTRACT

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC
50
], 2.6 to 5.3 nM; EC
90
, 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0.1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.
Effect of Dosing Schedule on Pharmacokinetics of Alpha Interferon and Anti-Alpha Interferon Neutralizing Antibody in Mice
Authors: Wang De-sheng , Ohdo Shigehiro , Koyanagi Satoru , Takane Hiroshi , Aramaki Hironori , Yukawa Eiji , Higuchi Shun 
Published: July 2002

ABSTRACTThe influences of dosing time and dosing schedule on the plasma alpha interferon (IFN-α) concentration and the production of anti-IFN-α neutralizing antibodies were investigated in ICR male mice adapted to cycles of 12 h of light and 12 h of dark. In mice pretreated with IFN-α for 21 days, the plasma IFN-α concentrations were significantly lower than those in control mice (P< 0.01). The clearance of IFN-α and its volume of distribution obtained at steady state were significantly higher in the animals with IFN-α pretreatment than in the mice without IFN-α pretreatment. The area under the concentration-time curve and the mean residence time of IFN-α were significantly smaller in IFN-α-pretreated animals than in control animals. The plasma IFN-α levels (measured 2 h after dosing) were significantly lower in mice treated daily with IFN-α, while the anti-IFN-α neutralizing antibody levels (measured 24 h after dosing) were significantly increased on days 15 and 21 of treatment. Plasma IFN-α levels were significantly decreased in association with the production of anti-IFN-α neutralizing antibodies in mice treated with IFN-α daily at either 0900 or 2100 h. By contrast, the plasma IFN-α levels (measured 2 h after dosing) remained stable in mice treated with IFN-α at 0900 h on alternate days, while they were significantly lower after 21 days of treatment in mice treated with IFN-α at 2100 h on alternate days. These changes were associated with a significant increase in the levels of anti-IFN-α neutralizing antibodies in the latter group. The present findings suggest that an appropriate dosing schedule and/or dosing time for IFN-α may reduce the level of production of anti-IFN-α neutralizing antibodies in experimental and clinical situations.
Genomic Rearrangement of the
mec
Regulator Region Mediated by Insertion of IS
431
in Methicillin-Resistant Staphylococci
Authors: Kobayashi Nobumichi , Alam Mohammed Mahbub , Urasawa Shozo 
Published: July 2002

ABSTRACT

Genomic diversification of the
mec
regulator region mediated by IS
431
was investigated for clinical isolates of methicillin-resistant staphylococci. A single rearranged form of the
mecR1
gene due to IS
431
insertion was detected in the three staphylococcal species, while another type of
mecR1
truncation with IS
431
and an IS
431
located downstream of
mecI
were found only in
Staphylococcus haemolyticus
. Genetic differentiation of IS
431
and staphylococcal isolates suggested transmission of
mec
DNA with IS
431
-mediated rearrangement among different staphylococcal species.
Prevalence and Mechanisms of Macrolide Resistance in
Streptococcus pyogenes
in Santiago, Chile
Authors: Palavecino E. L. , Riedel I. , Berrios X. , Bajaksouzian S. , Johnson D. , Kaplan E. , Jacobs M. R. 
Published: July 2002

ABSTRACT

Thirty-two macrolide-resistant
Streptococcus pyogenes
isolates were found among 594 clinical isolates collected from 1990 to 1998 in Santiago, Chile, for an overall prevalence of 7.2%. Among the 32 resistant isolates, 28 (87.5%) presented the M phenotype and 4 (12.5%) presented the MLS
B
phenotype. Serotyping and pulsed-field gel electrophoresis analysis showed genetic diversity among the resistant isolates.
Effects of AIDS and Gender on Steady-State Plasma and Intrapulmonary Ethambutol Concentrations
Authors: Conte John E. , Golden Jeffrey A. , Kipps Juliana , Lin Emil T. , Zurlinden Elisabeth 
Published: July 2002

ABSTRACTOur objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (±standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 ± 169) × 106cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean ± SD) at 2 and 4 h were 2.1 ± 1.2 and 2.1 ± 0.8 μg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 ± 1.1 μg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 ± 15.6 to 82.0 ± 39.4 μg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains ofMycobacterium tuberculosis. The AC ethambutol concentration (mean ± SD) in the smoking women (97.2 ± 32.1 μg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 ± 16.8 μg/ml) combined (P< 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.
Marked Potentiation of Activity of β-Lactams against Methicillin-Resistant
Staphylococcus aureus
by Corilagin
Authors: Shimizu Masato , Shiota Sumiko , Mizushima Tohru , Ito Hideyuki , Hatano Tsutomu , Yoshida Takashi , Tsuchiya Tomofusa 
Published: July 2002

ABSTRACT

We found that an extract of
Arctostaphylos uva-ursi
markedly reduced the MICs of β-lactam antibiotics, such as oxacillin and cefmetazole, against methicillin-resistant
Staphylococcus aureus
. We isolated the effective compound and identified it as corilagin. Corilagin reduced the MICs of various β-lactams by 100- to 2,000-fold but not the MICs of other antimicrobial agents tested. The effect of corilagin and oxacillin was synergistic. Corilagin showed a bactericidal action when added to the growth medium in combination with oxacillin.
Inhibitory Effects of Small-Molecule CCR5 Antagonists on Human Immunodeficiency Virus Type 1 Envelope-Mediated Membrane Fusion and Viral Replication
Authors: Takashima Katsunori , Miyake Hiroshi , Furuta Rika A. , Fujisawa Jun-Ichi , Iizawa Yuji , Kanzaki Naoyuki , Shiraishi Mitsuru , Okonogi Kenji , Baba Masanori 
Published: July 2002

ABSTRACT

We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed β-
d
-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC
50
s) for membrane fusion and viral replication were 0.87 ± 0.11 and 1.4 ± 0.1 nM, respectively. These values corresponded well to the IC
50
for
125
I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC
50
s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.
GeneyerP, Involved in Surfactin Self-Resistance inBacillus subtilis
Authors: Tsuge Kenji , Ohata Yuichiro , Shoda Makoto 
Published: July 2002

ABSTRACTSurfactin is a cyclic lipopeptide biosurfactant. Transposon mutagenesis was performed inBacillus subtilisstrain 168, and a surfactin-susceptible mutant, strain 801, was isolated. Analysis of the region of insertion revealed thatyerPwas the determinant of surfactin self-resistance. YerP had homology with the resistance, nodulation, and cell division (RND) family proton motive force-dependent efflux pumps only characterized in gram-negative strains. TheyerP-deficient strain 802, in which the internal region of theyerPgene ofB.subtilisstrain 168 was deleted, showed susceptibility to acriflavine and ethidium bromide. When strain 802 was converted to a surfactin producer by introducing a functionalsfpwhich encodes a 4′-phosphopantetheinyl transferase and is mutated inB.subtilisstrain 168, thisyerP-deficient strain produced surfactin, although surfactin production was significantly reduced. The expression ofyerPwas at its maximum at the end of the logarithmic growth phase and was not induced by surfactin.yerPis the first RND-like gene characterized in gram-positive strains and is supposed to be involved in the efflux of surfactin.
Characterization of a Chromosomally Encoded Extended-Spectrum Class A β-Lactamase from
Kluyvera cryocrescens
Authors: Decousser Jean W. , Poirel Laurent , Nordmann Patrice 
Published: July 2002

ABSTRACT

A chromosomally located β-lactamase gene, cloned and expressed in
Escherichia coli
from a reference strain of the enterobacterial species
Kluyvera cryocrescens
, encoded a clavulanic acid-inhibited Ambler class A enzyme, KLUC-1, with a pI value of 7.4. KLUC-1 shared 86% amino acid identity with a subgroup of plasmid-mediated CTX-M-type extended-spectrum β-lactamases (CTX-M-1, -3, -10, -11, and -12), the most closely related enzymes, and 77% amino acid identity with KLUA-1 from
Kluyvera ascorbata.
The substrate profile of KLUC-1 corresponded to that of CTX-M-type enzymes.
In Vitro Activities of Fluoroquinolones against the SpirocheteBorrelia burgdorferi
Authors: Kraiczy Peter , Weigand Judith , Wichelhaus Thomas A. , Heisig Peter , Backes Herbert , Schäfer Volker , Acker Georg , Brade Volker , Hunfeld Klaus-Peter 
Published: July 2002

ABSTRACTLittle is known to date about the in vitro activity of fluoroquinolones againstBorreliaspecies. Our study aimed at determining the in vitro activities of 15 quinolones against nine isolates of theBorrelia burgdorferisensu lato complex in addition to oneBorrelia valaisianaand oneBorrelia bissettiitick isolate. For the determination of MICs, a standardized colorimetric microdilution method was applied. Determination of minimal borreliacidal concentrations providing 100% killing of the final inoculum (MBCs) after 72 h and time-kill experiments were performed by conventional culture in Barbour-Stoenner-Kelly medium in combination with dark-field microscopy. The rank order of potency on a microgram-per-milliliter basis for the substances with in vitro activity againstB. burgdorferiwas gemifloxacin (MIC at which 90% of the isolates tested are inhibited [MIC90], 0.12 μg/ml) > sitafloxacin (MIC90, 0.5 μg/ml), grepafloxacin (MIC90, 0.5 μg/ml) > gatifloxacin (MIC90, 1 μg/ml), sparfloxacin (MIC90, 1 μg/ml), trovafloxacin (MIC90, 1 μg/ml) > moxifloxacin (MIC90, 2 μg/ml), ciprofloxacin (MIC90, 2 μg/ml) > levofloxacin (MIC90, 4 μg/ml) > ofloxacin (MIC90, 8 μg/ml), norfloxacin (MIC90, 8 μg/ml) > fleroxacin (MIC90, >16 μg/ml), and pefloxacin (MIC90, 32 μg/ml) > nalidixic acid (MIC90, 256 μg/ml). After 72 h of exposure, gemifloxacin was borreliacidal (100% killing) against the isolates investigated at a median MBC of 4 μg/ml. In the other compounds tested, median MBCs were higher (≥8 μg/ml). Results of electron microscopy and time-kill studies clearly support an in vitro activity of some fluoroquinolones against borreliae. Our study demonstrates for the first time the enhanced in vitro effectiveness of some of the recently introduced 4-quinolones againstB. burgdorferi.
Postneurosurgical Meningitis Due to
Proteus penneri
with Selection of a Ceftriaxone-Resistant Isolate: Analysis of Chromosomal Class A β-Lactamase HugA and its LysR-Type Regulatory Protein HugR
Authors: Liassine Nadia , Madec Stéphanie , Ninet Béatrice , Metral Catherine , Fouchereau-Peron Martine , Labia Roger , Auckenthaler Raymond 
Published: July 2002

ABSTRACT

We report on a case of a postneurosurgical meningitis due to ceftriaxone-susceptible
Proteus penneri
, with selection of a ceftriaxone-resistant isolate following treatment with ceftriaxone. The isolates presented identical patterns by pulsed-field gel electrophoresis and produced a single β-lactamase named HugA with an isoelectric point of 6.7. The ceftriaxone-resistant isolate hyperproduced the β-lactamase (increase in the level of production, about 90-fold). The sequences of the
hugA
β-lactamase gene and its regulator,
hugR
, were identical in both
P. penneri
strains and had 85.96% homology with those of
Proteus vulgaris
. The HugA β-lactamase belongs to molecular class A, and the transcriptional regulator HugR belongs to the LysR family.
Genetic Determinants of Tetracycline Resistance in
Vibrio harveyi
Authors: Teo Jeanette W. P. , Tan Theresa M. C. , Poh Chit Laa 
Published: July 2002

ABSTRACT

Isolates of
Vibrio harveyi
, a prawn pathogen, have demonstrated multiple antibiotic resistance to commonly used antimicrobial agents, such as oxytetracycline. In this paper, we describe the cloning and characterization of two tetracycline resistance determinants from
V. harveyi
strain M3.4L. The first resistance determinant, cloned as a 4,590-bp fragment, was identical to
tetA
and flanking sequences encoded on transposon Tn
10
from
Shigella flexneri.
The second determinant, cloned as a 3,358-bp fragment in pATJ1, contains two open reading frames, designated
tet35
and
txr
.
tet35
encodes a 369-amino-acid protein that was predicted to have nine transmembrane regions. It is a novel protein which has no homology to any other drug resistance protein but has low levels of homology (28%) to Na
+
/H
+
antiporters. Transposon mutagenesis showed that
tet35
and
txr
were required for tetracycline resistance in a heterologous
Escherichia coli
host. Tetracycline accumulation studies indicate that
E. coli
carrying
tet35
and
txr
can function as an energy-dependent tetracycline efflux pump but is less efficient than TetA.
Effect of Ciprofloxacin on Killing ofActinobacillus actinomycetemcomitansby Polymorphonuclear Leukocytes
Authors: Cacchillo David A. , Walters John D. 
Published: July 2002

ABSTRACTActinobacillus actinomycetemcomitans, a pathogen associated with aggressive periodontitis, resists phagocytic killing by polymorphonuclear leukocytes (PMNs). It is susceptible to ciprofloxacin, which PMNs actively accumulate. This study tested the hypothesis that ciprofloxacin-loaded PMNs are more effective at killingA. actinomycetemcomitansthan control PMNs. Isolated human PMNs were loaded by brief incubation with 0.5 μg of ciprofloxacin/ml. Opsonized bacteria (ATCC 43718) were incubated at 37°C with control and ciprofloxacin-loaded PMNs and in the presence and absence of 0.5 μg of ciprofloxacin/ml. When assayed at bacteria-to-PMN ratios of 30:1 and 90:1, ciprofloxacin-loaded PMNs killed significantly more bacteria and achieved significantly shorter half times for killing than control PMNs (P< 0.05; Tukey's test). At ratios of 3:1 and 10:1, these differences were not significant.
Incorporation of Protease K into Larval Insect Membrane Vesicles Does Not Result in Disruption of Integrity or Function of the Pore-Forming
Bacillus thuringiensis
δ-Endotoxin
Authors: Aronson Arthur 
Published: July 2002

ABSTRACT

Bacillus thuringiensis
δ-endotoxins insert into the brush border membranes of insect larval cells to form ion channels. A possible interaction of these toxins with a cytoplasmic component was examined by preloading vesicles from insect larval cells with protease K followed by incubation with toxin. There was no evidence for toxin antigens smaller than the intact toxin in extracts of solubilized vesicles, nor was there an effect of the inclusion of protease K on either of two functional properties, the formation of toxin aggregates or of ion pores. These toxins, physically and functionally, appear to be confined to the membrane.