bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Pharmacokinetics and Pharmacodynamics of the Glycopeptide Antibiotic Oritavancin (LY333328) in a Model of J774 Mouse Macrophages
Authors: Van Bambeke Françoise , Carryn Stéphane , Seral Cristina , Chanteux Hugues , Tyteca Donatienne , Mingeot-Leclercq Marie-Paule , Tulkens Paul M. 
Published: July 2004

ABSTRACTThe intracellular pharmacokinetics and pharmacodynamics of oritavancin (LY333328) were studied in cultured cells. Oritavancin was avidly accumulated by J774 and THP-1 macrophages and rat fibroblasts and to a lesser extent by LLC-PK1 and Caco-2 cells. In J774 macrophages, the level of accumulation reached a plateau (at 370-fold the extracellular concentration) within 24 h and was partly defeated by a rise in serum protein levels. Efflux was incomplete (with a plateau at two-thirds of the original level at 6 h). In short-term kinetic studies, oritavancin uptake was linear for up to 4 h (as was the case for horseradish peroxidase and small latex beads, used as markers of the fluid phase and adsorptive endocytosis, respectively), which was in contrast to azithromycin and chloroquine uptake (which accumulate in cells by diffusion and segregation). The rates of clearance of oritavancin and latex beads were comparable (150 and 120 μl × mg of protein−1× h−1, respectively) and were approximately 200 times higher than that of horseradish peroxidase. Oritavancin accumulation was partially reduced by monensin but was unaffected by acidic pH (these conditions abolished chloroquine accumulation). Cell-associated oritavancin was found in lysosomal fractions after homogenization of J774 macrophages and fractionation by isopycnic centrifugation. Oritavancin was bactericidal against intracellularStaphylococcus aureus(phagolysosomal infection) but was unable to control the intracellular growth ofListeria monocytogenes(cytosolic infection), even though its cellular concentration largely exceeded the MIC (0.02 mg/liter) and minimal bactericidal concentration (2 mg/liter). We conclude that oritavancin enters cells by adsorptive endocytosis (favored by its lipophilic side chain and/or the presence of three protonatable amines), which drives it to lysosomes, where it exerts antibiotic activity.
Pilot Randomized Double-Blind Trial of Treatment ofMycobacterium ulceransDisease (Buruli Ulcer) with Topical Nitrogen Oxides
Authors: Phillips R. , Adjei O. , Lucas S. , Benjamin N. , Wansbrough-Jones M. 
Published: July 2004

ABSTRACTMycobacterium ulceransdisease (Buruli ulcer) is a serious ulcerating skin disease which is common in many tropical countries. Standard treatment, by extensive excision and skin grafting, is not available in rural communities where the disease is common. We evaluated the efficacy and safety of treatment with topical nitrogen oxides. Thirty-seven patients with a clinical diagnosis of Buruli ulcer caused byM. ulceransdisease were randomly assigned to one of two groups. In one group, two creams containing sodium nitrite (6%, wt/wt) or citric acid monohydrate (9%, wt/wt) were applied daily for 6 weeks, while the other group received a placebo. In the second 6 weeks, both groups received the nitrogen oxide-generating combination of creams. Treatment was continued for another 4 weeks for patients whose ulcers were not healed after 12 weeks. The ulcer surface area was monitored by weekly tracings made by assessors blinded to the treatment. In the first 6 weeks, patients on sodium nitrite and citric acid monohydrate (group I, active treatment) showed a rapid decrease in ulcer size from 28.6 ± 5.6 cm2(mean ± standard error) to 12.6 ± 3.2 cm2, a decrease significantly greater than that in group II (from 15.3 ± 3.1 to 11.7 ± 3.7 cm2;P= 0.03). Five ulcers in the placebo group enlarged during this period, compared with one in the active group. In the second 6 weeks (both groups on active treatment), the rates of healing were similar for the two groups and there was a significant reduction in ulcer size in group II (previously on placebo) compared to the first 6 weeks. Yellow pigmentation of the skin, which disappeared 3 days after treatment was stopped, was the only side effect to date. We conclude that creams releasing nitrogen oxides increase the healing rate of ulcers caused byM. ulceransinfection with minimal adverse events. This is the first controlled trial of any form of therapy which demonstrates efficacy in treating this disease.
Synergy of Daptomycin with Oxacillin and Other β-Lactams against Methicillin-Resistant
Staphylococcus aureus
Authors: Rand Kenneth H. , Houck Herbert J. 
Published: July 2004

ABSTRACT

We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of ≥128 μg/ml), we looked for synergy between daptomycin and other β-lactams against 18 strains of methicillin-resistant
Staphylococcus aureus
(MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca
2+
/liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of ≥256 μg/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 μg/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 μg/ml alone or in combination with oxacillin at a fixed concentration of 32 μg/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 μg of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other β-lactams. In this approach, daptomycin was incorporated into Ca
2+
-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Kirby-Bauer disks on agar with and without daptomycin. By this method, daptomycin with ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam showed synergy comparable to or greater than daptomycin with oxacillin. For seven of the eight strains tested, time-kill studies confirmed synergy between daptomycin and ampicillin-sulbactam with ampicillin in the range of 2 to 8 μg/ml. The combination of daptomycin and β-lactams may be useful for the treatment of MRSA infection, but further studies are needed to elucidate the mechanisms and to determine the in vivo efficacy of the combination.
Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide
Authors: Hwang Der-Ren , Tsai Yuan-Chin , Lee Jin-Ching , Huang Kuo-Kuei , Lin Ren-Kuo , Ho Chia-Hua , Chiou Jeng-Min , Lin Ying-Ting , Hsu John T. A. , Yeh Chau-Ting 
Published: July 2004

ABSTRACT

Hepatitis C virus (HCV) is a serious global problem, and present therapeutics are inadequate to cure HCV infection. In the present study, various antiviral assays show that As
2
O
3
at submicromolar concentrations is capable of inhibiting HCV replication. The 50% effective concentration (EC
50
) of As
2
O
3
required to inhibit HCV replication was 0.35 μM when it was determined by a reporter-based HCV replication assay, and the EC
50
was below 0.2 μM when it was determined by quantitative reverse transcription-PCR analysis. As
2
O
3
did not cause cellular toxicity at this concentration, as revealed by an MTS [3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay. A combination of As
2
O
3
and alpha interferon exerted synergistic effects against HCV, as revealed by a multiple linear logistic model and isobologram analysis. Furthermore, in an alternative HCV antiviral system that may recapitulate additional steps involved in HCV infection and replication, As
2
O
3
at 0.3 μM totally abolished the HCV signal, whereas alpha interferon at a high dose (5,000 IU/ml) only partially suppressed the HCV signal. The study highlights the indications for use of a novel class of anti-HCV agent. Further elucidation of the exact antiviral mechanism of As
2
O
3
may lead to the development of agents with potent activities against HCV or related viruses.
Effect of Amoxicillin Use on Oral Microbiota in Young Children
Authors: Ready D. , Lancaster H. , Qureshi F. , Bedi R. , Mullany P. , Wilson M. 
Published: July 2004

ABSTRACT

Dental plaque samples from 40 children were screened for the presence of bacteria resistant to amoxicillin. Fifteen children had used amoxicillin and 25 had not used any antibiotic in the 3 months prior to sample collection. All (100%) of the children harbored amoxicillin-resistant oral bacteria. The median percentage of the total cultivable oral microbiota resistant to amoxicillin was 2.4% (range, 0.1 to 14.3%) in children without amoxicillin use and 10.9% (range, 0.8 to 97.3%) in children with amoxicillin use, with the latter value being significantly higher (
P
< 0.01). A total of 224 amoxicillin-resistant bacteria were isolated and comprised three main genera:
Haemophilus
spp.,
Streptococcus
spp., and
Veillonella
spp. The biodiversity of the amoxicillin-resistant microbiota was similar among the isolates from children with and without previous antibiotic use. The amoxicillin MIC at which 90% of the isolates were inhibited for isolates from children who had used amoxicillin in the previous 3 months was higher (64 mg liter
−1
) than that obtained for the isolates from subjects who had not used antibiotics (16 mg liter
−1
). The majority of the amoxicillin-resistant isolates (65%) were also resistant to at least one of the three antibiotics tested (penicillin, erythromycin, and tetracycline), with resistance to penicillin (51% of isolates) being the most frequently encountered. However, significantly more (
P
< 0.05) of the amoxicillin-resistant isolates from subjects with previous amoxicillin use were also resistant to erythromycin. This study has demonstrated that a diverse collection of amoxicillin-resistant bacteria is present in the oral cavity and that the number, proportions, MICs, and resistance to erythromycin can significantly increase with amoxicillin use.
Ribosomal P0 Protein Domain Involved in Selectivity of Antifungal Sordarin Derivatives
Authors: Santos C. , Rodríguez-Gabriel M. A. , Remacha M. , Ballesta J. P. G. 
Published: July 2004

ABSTRACT

The ribosomal stalk protein P0 is involved in the susceptibility to the antifungal sordarin derivatives, as reported for a number of
Saccharomyces cerevisiae
resistant mutants. Mammals and some lower eukaryotes are naturally resistant to these compounds. It is shown here that expression in
S. cerevisiae
of the ribosomal protein P0 from
Homo sapiens
and from other sordarin-resistant organisms results in a decrease in the sensitivity of the cells to an agent of this class. To further characterize the P0 region responsible for inducing sordarin resistance, a series of protein chimeras containing complementary regions of the human and yeast P0 proteins were constructed and expressed in yeast. The chimeras complement the absence of the native yeast P0 except in chimeras containing the human P0 carboxyl-terminal domain. Resistance to sordarins was found to be associated with the presence of an HsP0 amino acid sequence comprising P118 to F138, which unexpectedly led to higher resistance than the presence of the complete human P0. A comparison of the corresponding region in P0 from yeast and sordarin-insensitive organisms, followed by site-directed mutagenesis, indicates that residues in positions 119, 124, and 126 have an important role in determining resistance to sordarins. Moreover, since sordarins block the eukaryotic elongation factor 2 (EF2) function, the P0 region affecting sordarin susceptibility must correspond to EF2-interacting domains of the ribosomal stalk protein, which affects the drug-binding site in the elongation factor.
Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis
Authors: Orenes Lorente Silvia , Rodrigues Juliany C. F. , Jiménez Jiménez Carmen , Joyce-Menekse Miranda , Rodrigues Carlos , Croft Simon L. , Yardley Vanessa , de Luca-Fradley Kate , Ruiz-Pérez Luis M. , Urbina Julio , de Souza Wanderley , González Pacanowska Dolores , Gilbert Ian H. 
Published: July 2004

ABSTRACT

This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. Azasterols are a known class of (
S
)-adenosyl-
l
-methionine: Δ
24
-sterol methyltransferase(24-SMT) inhibitors in fungi, plants, and some parasitic protozoa. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against
Leishmania
spp. and
Trypanosoma
spp. The enzymatic and sterol composition studies indicated that the most active compounds acted by inhibiting 24-SMT. The role of the free hydroxyl group at position 3 of the sterol nucleus was also probed. When an acetate was attached to the 3β-OH, the compounds did not inhibit the enzyme but had an effect on parasite growth and the levels of sterols in the parasite, suggesting that the acetate group was removed in the organism. Thus, an acetate group on the 3β-OH may have application as a prodrug. However, there may be an additional mode(s) of action for these acetate derivatives. These compounds were shown to have ultrastructural effects on
Leishmania amazonensis
promastigote membranes, including the plasma membrane, the mitochondrial membrane, and the endoplasmic reticulum. The compounds were also found to be active against the bloodstream form (trypomastigotes) of
Trypanosoma brucei rhodesiense
, a causative agent of African trypanosomiasis.
Modulation of Fibronectin Adhesins and Other Virulence Factors in a Teicoplanin-Resistant Derivative of Methicillin-Resistant
Staphylococcus aureus
Authors: Renzoni Adriana , Francois Patrice , Li Dongmei , Kelley William L. , Lew Daniel P. , Vaudaux Pierre , Schrenzel Jacques 
Published: July 2004

ABSTRACT

The impact of glycopeptide resistance on the molecular regulation of
Staphylococcus aureus
virulence and attachment to host tissues is poorly documented. We compared stable teicoplanin-resistant methicillin-resistant
S. aureus
(MRSA) strain 14-4 with its teicoplanin-susceptible MRSA parent, strain MRGR3, which exhibits a high degree of virulence in a rat model of chronic foreign body MRSA infection. The levels of fibronectin-mediated adhesion and surface display of fibronectin-binding proteins were higher in teicoplanin-resistant strain 14-4 than in its teicoplanin-susceptible parent or a teicoplanin-susceptible revertant (strain 14-4rev) that spontaneously emerged during tissue cage infection. Quantitative reverse transcription-PCR (qRT-PCR) showed four- and twofold higher steady-state levels of
fnbA
and
fnbB
transcripts, respectively, in strain 14-4 than in its teicoplanin-susceptible counterparts. Analysis of global regulatory activities by qRT-PCR revealed a strong reduction in the steady-state levels of RNAIII and RNAII in the teicoplanin-resistant strain compared to in its teicoplanin-susceptible counterparts. In contrast,
sarA
mRNA levels were more than fivefold higher in strain 14-4 than in MRGR3 and 14-4rev. Furthermore, the alternative transcription factor sigma B had a higher level of functional activity in the teicoplanin-resistant strain than in its teicoplanin-susceptible counterparts, as evidenced by significant increases in both the sigma B-dependent
asp23
mRNA levels and the
sarA
P3 promoter-derived transcript levels, as assayed by qRT-PCR and Northern blotting, respectively. These data provide further evidence that the emergence of glycopeptide resistance is linked by still poorly understood molecular pathways with significant pleiotropic changes in the expression and regulation of some major virulence genes. These molecular and phenotypic changes may have a profound impact on the bacterial adhesion and colonization properties of such multiresistant organisms.
Relationship between Triclosan and Susceptibilities of Bacteria Isolated from Hands in the Community
Authors: Aiello Allison E. , Marshall Bonnie , Levy Stuart B. , Della-Latta Phyllis , Larson Elaine 
Published: July 2004

ABSTRACT
The possible association between triclosan and bacterial susceptibility to antibiotic was examined among staphylococci and several species of gram-negative bacteria (GNB) isolated from the hands of individuals in a community setting. Hand cultures from individuals randomized to using either antibacterial cleaning and hygiene products (including a hand soap containing 0.2% triclosan) or nonantibacterial cleaning and hygiene products for a 1-year period were taken at baseline and at the end of the year. Although there was no statistically significant association between triclosan MICs and susceptibility to antibiotic, there was an increasing trend in the association the odds ratios (ORs) for all species were compared at baseline (OR = 0.65, 95% confidence interval [95%CI] = 0.33 to 1.27) versus at the end of the year (OR = 1.08, 95%CI = 0.62 to 1.97) and for GNB alone at baseline(OR = 0.66, 95%CI = 0.29 to 1.51) versus the end of year (OR = 2.69, 95%CI = 0.78 to 9.23) regardless of the hand-washing product used. Moreover, triclosan MICs were higher in some of the species compared to earlier reports on household, clinical, and industrial isolates, and some of these isolates had triclosan MICs in the range of concentrations used in consumer products. The absence of a statistically significant association between elevated triclosan MICs and reduced antibiotic susceptibility may indicate that such a correlation does not exist or that it is relatively small among the isolates that were studied. Still, a relationship may emerge after longer-term or higher-dose exposure of bacteria to triclosan in the community setting.
Nucleotide and Amino Acid Polymorphisms at Drug Resistance Sites in Non-B-Subtype Variants of Human Immunodeficiency Virus Type 1
Authors: Turner Dan , Brenner Bluma , Moisi Daniela , Detorio Mervi , Cesaire Raymond , Kurimura Takashi , Mori Haruyo , Essex Max , Maayan Shlomo , Wainberg Mark A. 
Published: July 2004

ABSTRACTWe have compared nucleotide substitutions and polymorphisms at codons known to confer drug resistance in subtype B strains of human immunodeficiency virus type 1 (HIV-1) with similar substitutions in viruses of other subtypes. Genotypic analysis was performed on viruses from untreated individuals. Nucleotide and amino acid diversity at resistance sites was compared with a consensus subtype B reference virus. Among patients with non-subtype B infections, polymorphisms relative to subtype B were observed at codon 10 in protease (PR). These included silent substitutions (CTC→CTT, CTA, TTA) and an amino acid mutation, L10I. Subtype A viruses possessed a V179I substitution in reverse transcriptase (RT). Subtype G viruses were identified by silent substitutions at codon 181 in RT (TAT→TAC). Similarly, subtype A/G viruses were identified by a substitution at position 67 in RT (GAC→GAT). Subtype C was distinguished by silent substitutions at codons 106 (GTA→GTG) and 219 (AAA→AAG) in RT and codon 48 (GGG→GGA) in PR. Variations relative to subtype B were seen at RT position 215 (ACC→ACT) for subtypes A and A/E. These substitutions and polymorphisms reflect different patterns of codon usage among viruses of different subtypes. However, the existence of different subtypes may only rarely affect patterns of drug resistance-associated mutations.
Possible Mechanism of Miltefosine-Mediated Death of
Leishmania donovani
Authors: Verma Navin K. , Dey Chinmoy S. 
Published: July 2004

ABSTRACT

Miltefosine causes leishmanial death, but the possible mechanism(s) of action is not known. The mode of action of miltefosine was investigated in vitro in
Leishmania donovani
promastigotes as well as in extra- and intracellular amastigotes. Here, we demonstrate that miltefosine induces apoptosis-like death in
L. donovani
based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against
Leishmania
parasites.
Emergence of
Streptococcus pneumoniae
with Very-High-Level Resistance to Penicillin
Authors: Schrag Stephanie J. , McGee Lesley , Whitney Cynthia G. , Beall Bernard , Craig Allen S. , Choate Miriam E. , Jorgensen James H. , Facklam Richard R. , Klugman Keith P. 
Published: July 2004

ABSTRACT

Penicillin resistance threatens the treatment of pneumococcal infections. We used sentinel hospital surveillance (1978 to 2001) and population-based surveillance (1995 to 2001) in seven states in the Active Bacterial Core surveillance of the Emerging Infections Program Network to document the emergence in the United States of invasive pneumococcal isolates with very-high-level penicillin resistance (MIC ≥ 8 μg/ml). Very-high-level penicillin resistance was first detected in 1995 in multiple pneumococcal serotypes in three regions of the United States. The prevalence increased from 0.56% (14 of 2,507) of isolates in 1995 to 0.87% in 2001 (
P
= 0.03), with peaks in 1996 and 2000 associated with epidemics in Georgia and Maryland. For a majority of the strains the MICs of amoxicillin (91%), cefuroxime (100%), and cefotaxime (68%), were ≥8 μg/ml and all were resistant to at least one other drug class. Pneumonia (50%) and bacteremia (36%) were the most common clinical presentations. Factors associated with very highly resistant infections included residence in Tennessee, age of <5 or ≥65 years, and resistance to at least three drug classes. Hospitalization and case fatality rates were not higher than those of other pneumococcal infection patients; length of hospital stay was longer, controlling for age. Among the strains from 2000 and 2001, 39% were related to Tennessee
23F
-4 and 35% were related to England
14-
9. After the introduction of the pneumococcal conjugate vaccine, the incidence of highly penicillin resistant infections decreased by 50% among children <5 years of age. The emergence, clonality, and association of very-high-level penicillin resistance with multiple drug resistance requires further monitoring and highlights the need for novel agents active against the pneumococcus.
Activities of Different Fluoroquinolones against
Bacillus anthracis
Mutants Selected In Vitro and Harboring Topoisomerase Mutations
Authors: Grohs Patrick , Podglajen Isabelle , Gutmann Laurent 
Published: July 2004

ABSTRACT

Three sets of mutants of
Bacillus anthracis
resistant to fluoroquinolones were selected on ciprofloxacin and moxifloxacin in a stepwise manner from a nalidixic acid-resistant but fluoroquinolone-susceptible plasmidless strain harboring a Ser85Leu GyrA mutation. A high level of resistance to fluoroquinolones could be obtained in four or five selection steps. In each case, ParC was the secondary target. However, in addition to the GyrA mutation, expression of high-level resistance required (i) in the first set of mutants, active drug efflux associated with a mutation in the QRDR of ParC; (ii) in the second set, two mutations in the QRDR of ParC associated with a mutation in GyrB; and (iii) in the third set, two QRDR mutations, one in ParC and one in GyrA. Interestingly, several selection steps occurred without obvious mutations in the QRDR of any topoisomerase, thereby implying the existence of other resistance mechanisms. Among the fluoroquinolones tested, garenoxacin showed the best activity.