bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic Interaction between Amprenavir and Rifabutin or Rifampin in Healthy Males
Authors: Polk Ronald E. , Brophy Donald F. , Israel Debra S. , Patron Roberto , Sadler Brian M. , Chittick Gregory E. , Symonds William T. , Lou Yu , Kristoff Debbie , Stein D. S. 
Published: July 2002

ABSTRACT

The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-
O
-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC
ss
) of rifabutin by 2.93-fold and the AUC
ss
of 25-
O
-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC
ss
of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-
O
-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.
Bioavailability and Preliminary Clinical Efficacy of Intrarectal Artesunate in Ghanaian Children with Moderate Malaria
Authors: Krishna Sanjeev , Planche Tim , Agbenyega Tsiri , Woodrow Charles , Agranoff Dan , Bedu-Addo George , Owusu-Ofori Alex K. , Appiah John Adabie , Ramanathan Surash , Mansor Sharif M. , Navaratnam Visweswaran 
Published: July 2002

ABSTRACT

We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%;
P
= 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [
P
= 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (
P
= 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (
P
= 0.001 and
P
= 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (
P
< 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.
Antibiotic Susceptibility Profiles of
Escherichia coli
Strains Lacking Multidrug Efflux Pump Genes
Authors: Sulavik Mark C. , Houseweart Chad , Cramer Christina , Jiwani Nilofer , Murgolo Nicholas , Greene Jonathan , DiDomenico Beth , Shaw Karen Joy , Miller George H. , Hare Roberta , Shimer George 
Published: July 2002

ABSTRACT

The contribution of seven known and nine predicted genes or operons associated with multidrug resistance to the susceptibility of
Escherichia coli
W3110 was assessed for 20 different classes of antimicrobial compounds that include antibiotics, antiseptics, detergents, and dyes. Strains were constructed with deletions for genes in the major facilitator superfamily, the resistance nodulation-cell division family, the small multidrug resistance family, the ATP-binding cassette family, and outer membrane factors. The agar dilution MICs of 35 compounds were determined for strains with deletions for multidrug resistance (MDR) pumps. Deletions in
acrAB
or
tolC
resulted in increased susceptibilities to the majority of compounds tested. The remaining MDR pump gene deletions resulted in increased susceptibilities to far fewer compounds. The results identify which MDR pumps contribute to intrinsic resistance under the conditions tested and supply practical information useful for designing sensitive assay strains for cell-based screening of antibacterial compounds.
Genetic Characterization of Highly Fluoroquinolone-Resistant Clinical
Escherichia coli
Strains from China: Role of
acrR
Mutations
Authors: Wang Hui , Dzink-Fox Joann L. , Chen Minjun , Levy Stuart B. 
Published: July 2002

ABSTRACT

The genetic basis for fluoroquinolone resistance was examined in 30 high-level fluoroquinolone-resistant
Escherichia coli
clinical isolates from Beijing, China. Each strain also demonstrated resistance to a variety of other antibiotics. PCR sequence analysis of the quinolone resistance-determining region of the topoisomerase genes (
gyrA/B, parC
) revealed three to five mutations known to be associated with fluoroquinolone resistance. Western blot analysis failed to demonstrate overexpression of MarA, and Northern blot analysis did not detect overexpression of
soxS
RNA in any of the clinical strains. The AcrA protein of the AcrAB multidrug efflux pump was overexpressed in 19 of 30 strains of
E. coli
tested, and all 19 strains were tolerant to organic solvents. PCR amplification of the complete
acrR
(regulator/repressor) gene of eight isolates revealed amino acid changes in four isolates, a 9-bp deletion in another, and a 22-bp duplication in a sixth strain. Complementation with a plasmid-borne wild-type
acrR
gene reduced the level of AcrA in the mutants and partially restored antibiotic susceptibility 1.5- to 6-fold. This study shows that mutations in
acrR
are an additional genetic basis for fluoroquinolone resistance.
Association of Amino Acid Substitutions in Penicillin-Binding Protein 3 with β-Lactam Resistance in β-Lactamase-Negative Ampicillin-Resistant
Haemophilus influenzae
Authors: Ubukata Kimiko , Shibasaki Yumi , Yamamoto Kentarou , Chiba Naoko , Hasegawa Keiko , Takeuchi Yasuo , Sunakawa Keisuke , Inoue Matsuhisa , Konno Masatoshi 
Published: July 2002

ABSTRACT

The affinity of [
3
H]benzylpenicillin for penicillin-binding protein (PBP) 3A was reduced in 25 clinical isolates of β-lactamase-negative ampicillin (AMP)-resistant (BLNAR)
Haemophilus influenzae
for which the AMP MIC was ≥1.0 μg/ml. The affinities of PBP 3B and PBP 4 were also reduced in some strains. The sequences of the
ftsI
gene encoding the transpeptidase domain of PBP 3A and/or PBP 3B and of the
dacB
gene encoding PBP 4 were determined for these strains and compared to those of AMP-susceptible Rd strains. The BLNAR strains were classified into three groups on the basis of deduced amino acid substitutions in the
ftsI
gene, which is thought to be involved in septal peptidoglycan synthesis. His-517, near the conserved Lys-Thr-Gly (KTG) motif, was substituted for Arg-517 in group I strains (
n
= 9), and Lys-526 was substituted for Asn-526 in group II strains (
n
= 12). In group III strains (
n
= 4), three residues (Met-377, Ser-385, and Leu-389), positioned near the conserved Ser-Ser-Asn (SSN) motif, were replaced with Ile, Thr, and Phe, respectively, in addition to the replacement with Lys-526. The MICs of cephem antibiotics with relatively high affinities for PBP 3A and PBP 3B were higher than those of AMP and meropenem for group III strains. The MICs of β-lactams for
H. influenzae
transformants into which the
ftsI
gene from BLNAR strains was introduced were as high as those for the donors, and PBP 3A and PBP 3B showed decreased affinities for β-lactams. There was no clear relationship between 7-bp deletions in the
dacB
gene and AMP susceptibility. Even though mutations in another gene(s) may be involved in β-lactam resistance, these data indicate that mutations in the
ftsI
gene are the most important for development of resistance to β-lactams in BLNAR strains.
Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against
Trichomonas vaginalis
Authors: Coombs Graham H. , Mottram Jeremy C. 
Published: July 2002

ABSTRACT

Methionine γ-lyase, the enzyme which catalyzes the single-step conversion of methionine to α-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasite
Trichomonas vaginalis
, to anaerobic bacteria containing methionine γ-lyase, and to
Escherichia coli
expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.
Pharmacokinetic and Pharmacodynamic Parameters for Antimicrobial Effects of Cefotaxime and Amoxicillin in an In Vitro Kinetic Model
Authors: Gustafsson I. , Löwdin E. , Odenholt I. , Cars O. 
Published: July 2002

ABSTRACT

An in vitro kinetic model was used to study the relation between pharmacokinetic and pharmacodynamic (PK-PD) parameters for antimicrobial effect, e.g., the time above MIC (T>MIC), maximum concentration in serum (
C
max
), and area under the concentration-time curve (AUC).
Streptococcus pyogenes
and
Escherichia coli
were exposed to cefotaxime, and the activity of amoxicillin against four strains of
Streptococcus pneumoniae
with different susceptibilities to penicillin was studied. The drug elimination rate varied so that the T>MIC ranged from 20 to 100% during 24 h, while the AUC and/or the initial concentration (
C
max
) were kept constant. For
S. pyogenes
and
E. coli
, the maximal antimicrobial effect (
E
max
) at 24 h occurred when the antimicrobial concentration exceeded the MIC for 50 and 80% of the strains tested, respectively. The penicillin-susceptible pneumococci (MIC, 0.03 mg/liter) and the penicillin-intermediate strain (MIC, 0.25 mg/liter) showed maximal killing by amoxicillin at a T>MIC of 50%. For a strain for which the MIC was 2 mg/liter,
C
max
needed to be increased to achieve the
E
max
. Under the condition that
C
max
was 10 times the MIC,
E
max
was obtained at a T>MIC of 60%, indicating that
C
max
, in addition to T>MIC, may be an important parameter for antimicrobial effect on moderately penicillin-resistant pneumococci. For the strain for which the MIC was 4 mg/liter, the reduction of bacteria varied from −0.4 to −3.6 log
10
CFU/ml at a T>MIC of 100%, despite an initial antimicrobial concentration of 10 times the MIC. Our studies have shown that the in vitro kinetic model is a useful complement to animal models for studying the PK-PD relationship for antimicrobial effect of antibiotics.
Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir
Authors: De Bony F. , Tod M. , Bidault R. , On N. T. , Posner J. , Rolan P. 
Published: July 2002

ABSTRACT

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (
C
max
) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir
C
max
by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.
Genetic and Biochemical Diversity among Isolates of
Paenibacillus alvei
Cultured from Australian Honeybee (
Apis mellifera
) Colonies
Authors: Djordjevic Steven P. , Forbes Wendy A. , Smith Lisa A. , Hornitzky Michael A. 
Published: July 2002

ABSTRACT

Twenty-five unique
Cfo
I-generated whole-cell DNA profiles were identified in a study of 30
Paenibacillus alvei
isolates cultured from honey and diseased larvae collected from honeybee (
Apis mellifera
) colonies in geographically diverse areas in Australia. The fingerprint patterns were highly variable and readily discernible from one another, which highlighted the potential of this method for tracing the movement of isolates in epidemiological studies. 16S rRNA gene fragments (length, 1,416 bp) for all 30 isolates were enzymatically amplified by PCR and subjected to restriction analysis with
Dra
I,
Hin
fI,
Cfo
I,
Alu
I,
Fok
I, and
Rsa
I. With each enzyme the restriction profiles of the 16S rRNA genes from all 30 isolates were identical (one restriction fragment length polymorphism [RFLP] was observed in the
Hin
fI profile of the 16S rRNA gene from isolate 17), which confirmed that the isolates belonged to the same species. The restriction profiles generated by using
Dra
I,
Fok
I, and
Hin
fI differentiated
P. alvei
from the phylogenetically closely related species
Paenibacillus macerans
and
Paenibacillus macquariensis
. Alveolysin gene fragments (length, 1,555 bp) were enzymatically amplified from some of the
P. alvei
isolates (19 of 30 isolates), and RFLP were detected by using the enzymes
Cfo
I,
Sau
3AI, and
Rsa
I. Extrachromosomal DNA ranging in size from 1 to 10 kb was detected in 17 of 30 (57%)
P. alvei
whole-cell DNA profiles. Extensive biochemical heterogeneity was observed among the 28
P. alvei
isolates examined with the API 50CHB system. All of these isolates were catalase, oxidase, and Voges-Proskauer positive and nitrate negative, and all produced acid when glycerol, esculin, and maltose were added. The isolates produced variable results for 16 of the 49 biochemical tests; negative reactions were recorded in the remaining 30 assays. The genetic and biochemical heterogeneity in
P. alvei
isolates may be a reflection of adaptation to the special habitats in which they originated.
Molecular Ecological Analysis of the Succession and Diversity of Sulfate-Reducing Bacteria in the Mouse Gastrointestinal Tract
Authors: Deplancke B. , Hristova K. R. , Oakley H. A. , McCracken V. J. , Aminov R. , Mackie R. I. , Gaskins H. R. 
Published: July 2002

ABSTRACT

Intestinal sulfate-reducing bacteria (SRB) growth and resultant hydrogen sulfide production may damage the gastrointestinal epithelium and thereby contribute to chronic intestinal disorders. However, the ecology and phylogenetic diversity of intestinal dissimilatory SRB populations are poorly understood, and endogenous or exogenous sources of available sulfate are not well defined. The succession of intestinal SRB was therefore compared in inbred C57BL/6J mice using a PCR-based metabolic molecular ecology (MME) approach that targets a conserved region of subunit A of the adenosine-5′-phosphosulfate (APS) reductase gene. The APS reductase-based MME strategy revealed intestinal SRB in the stomach and small intestine of 1-, 4-, and 7-day-old mice and throughout the gastrointestinal tract of 14-, 21-, 30-, 60-, and 90-day-old mice. Phylogenetic analysis of APS reductase amplicons obtained from the stomach, middle small intestine, and cecum of neonatal mice revealed that
Desulfotomaculum
spp. may be a predominant SRB group in the neonatal mouse intestine. Dot blot hybridizations with SRB-specific 16S ribosomal DNA (rDNA) probes demonstrated SRB colonization of the cecum and colon pre- and postweaning and colonization of the stomach and small intestine of mature mice only. The 16S rDNA hybridization data further demonstrated that SRB populations were most numerous in intestinal regions harboring sulfomucin-containing goblet cells, regardless of age. Reverse transcriptase PCR analysis demonstrated APS reductase mRNA expression in all intestinal segments of 30-day-old mice, including the stomach. These results demonstrate for the first time widespread colonization of the mouse intestine by dissimilatory SRB and evidence of spatial-specific SRB populations and sulfomucin patterns along the gastrointestinal tract.
Lack of Production of Electron-Shuttling Compounds or Solubilization of Fe(III) during Reduction of Insoluble Fe(III) Oxide by
Geobacter metallireducens
Authors: Nevin Kelly P. , Lovley Derek R. 
Published: July 2002

ABSTRACT

Studies with the dissimilatory Fe(III)-reducing microorganism
Geobacter metallireducens
demonstrated that the common technique of separating Fe(III)-reducing microorganisms and Fe(III) oxides with semipermeable membranes in order to determine whether the Fe(III) reducers release electron-shuttling compounds and/or Fe(III) chelators is invalid. This raised doubts about the mechanisms for Fe(III) oxide reduction by this organism. However, several experimental approaches indicated that
G. metallireducens
does not release electron-shuttling compounds and does not significantly solubilize Fe(III) during Fe(III) oxide reduction. These results suggest that
G. metallireducens
directly reduces insoluble Fe(III) oxide.
Surface of Lactic Acid Bacteria: Relationships between Chemical Composition and Physicochemical Properties
Authors: Boonaert Christophe J. P. , Rouxhet Paul G. 
Published: July 2002

ABSTRACT

The surface chemical composition and physicochemical properties (hydrophobicity and zeta potential) of two lactic acid bacteria,
Lactococcus lactis
subsp.
lactis
bv. diacetilactis and
Lactobacillus helveticus
, have been investigated using cells harvested in exponential or stationary growth phase. The surface composition determined by X-ray photoelectron spectroscopy (XPS) was converted into a molecular composition in terms of proteins, polysaccharides, and hydrocarbonlike compounds. The concentration of the last was always below 15% (wt/wt), which is related to the hydrophilic character revealed by water contact angles of less than 30°. The surfaces of
L. lactis
cells had a polysaccharide concentration about twice that of proteins. The S-layer of
L. helveticus
was either interrupted or crossed by polysaccharide-rich compounds; the concentration of the latter was higher in the stationary growth phase than in the exponential growth phase. Further progress was made in the interpretation of XPS data in terms of chemical functions by showing that the oxygen component at 531.2 eV contains a contribution of phosphate in addition to the main contribution of the peptide link. The isoelectric points were around 2 and 3, and the electrophoretic mobilities above pH 5 (ionic strength, 1 mM) were about −3.0 × 10
−8
and −0.6 × 10
−8
m
2
s
−1
V
−1
for
L. lactis
and
L. helveticus
, respectively. The electrokinetic properties of the latter reveal the influence of carboxyl groups, while the difference between the two strains is related to a difference between N/P surface concentration ratios, reflecting the relative exposure of proteins and phosphate groups at the surface.
Absence of a Putative Mannose-Specific Phosphotransferase System Enzyme IIAB Component in a Leucocin A-Resistant Strain of
Listeria monocytogenes
, as Shown by Two-Dimensional Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis
Authors: Ramnath M. , Beukes M. , Tamura K. , Hastings J. W. 
Published: July 2002

ABSTRACT

Leucocin A is a class IIa bacteriocin produced by
Leuconostoc
spp. that has previously been shown to inhibit the growth of
Listeria monocytogenes
. A spontaneous resistant mutant of
L. monocytogenes
was isolated and found to be resistant to leucocin A at levels in excess of 2 mg/ml. The mutant showed no significant cross-resistance to nontype IIa bacteriocins including nisaplin and ESF1-7GR. However, there were no inhibition zones found on a lawn of the mutant when challenged with an extract containing 51,200 AU of pediocin PA-2 per ml as determined by a simultaneous assay on the sensitive wild-type strain. DNA and protein analysis of the resistant and susceptible strains were carried out using silver-stained amplified fragment length polymorphism (ssAFLP) and one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), respectively. Two-dimensional SDS-PAGE clearly showed a 35-kDa protein which was present in the sensitive but absent from the resistant strain. The N-terminal end of the 35-kDa protein was sequenced and found to have an 83% homology to the mannose-specific phosphotransferase system enzyme IIAB of
Streptococcus salivarius
.
Identification of the Dimerization Domain of Dehalogenase IVa ofBurkholderia cepaciaMBA4
Authors: Tsang Jimmy S. H. , Pang Benjamin C. M. 
Published: July 2002

ABSTRACTHaloacid dehalogenases are enzymes that catalyze the hydrolytic removal of halogens from haloalkanoic acids. Dehalogenase IVa (DehIVa) fromBurkholderia cepaciaMBA4 and dehalogenase CI (DehCI) fromPseudomonassp. strain CBS3 exhibit 68% identity. Despite their similarity DehIVa is a dimeric enzyme while DehCI is a monomer. In this work, we describe the identification of the domain that confers the dimerization function of DehIVa. Recombinant DNA molecules were constructed by fusion of the respective dehalogenase geneshdlIVaanddehCI. When amino acids 73 to 89 of DehCI were replaced by amino acids 74 to 90 of DehIVa, the recombinant molecule migrated like that of DehIVa in a nondenaturing activity-stained gel. Similarly, when residues 73 to 89 of DehIVa were replaced by the corresponding residues of DehCI, the chimera migrated as a monomer. These 17 amino acid changes were able to determine the aggregation states of the molecules. The retention of the catalytic function in these chimeras indicated that the overall folding of these proteins was not affected. Site-directed mutagenesis onhdlIVahowever indicated that amino acids Phe58, Thr65, Leu78, and Phe92 of DehIVa are also important for the aggregation state of the protein. This indicates that the 17 residues are not sufficient for the dimerization of the protein.