bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Dapsone Administered Daily and Weekly in Human Immunodeficiency Virus-Infected Children
Authors: Mirochnick Mark , Cooper Ellen , McIntosh Ken , Xu Jing , Lindsey Jane , Jacobus David , Mofenson Lynne , Sullivan John L. , Dankner Wayne , Frenkel Lisa M. , Nachman Sharon , Wara Diane W. , Johnson Daniel , Bonagura Vincent R. , Rathore Mobeen H. , Cunningham Coleen K. , McNamara James 
Published: October 2018

ABSTRACTAlthough dapsone is a commonly used alternative agent for prophylaxis againstPneumocystis cariniipneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0.3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h;P= 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.
Accumulation of 3-Ketosteroids Induced by Itraconazole in Azole-Resistant ClinicalCandida albicansIsolates
Authors: Marichal Patrick , Gorrens Jos , Laurijssens Leen , Vermuyten Karen , Van Hove Carl , Le Jeune Ludo , Verhasselt Peter , Sanglard Dominique , Borgers Marcel , Ramaekers Frans C. S. , Odds Frank , Vanden Bossche Hugo 
Published: October 2018

ABSTRACTThe effects of itraconazole on ergosterol biosynthesis were investigated in a series of 16 matched clinicalCandida albicansisolates which had been previously analyzed for mechanisms of resistance to azoles (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother., 39:2378–2386, 1995). Under control conditions, all isolates contained ergosterol as the predominant sterol, except two strains (C48 and C56). In isolates C48 and C56, both less susceptible to azoles than their parent, C43, substantial concentrations (20 to 30%) of 14α-methyl-ergosta-8,24(28)-diene-3β,6α-diol (3,6-diol) were found. Itraconazole treatment of C43 resulted in a dose-dependent inhibition of ergosterol biosynthesis (50% inhibitory concentration, 2 nM) and accumulation of 3,6-diol (up to 60% of the total sterols) together with eburicol, lanosterol, obtusifoliol, 14α-methyl-ergosta-5,7,22,24(28)-tetraene-3βol, and 14α-methyl-fecosterol. In strains C48 and C56, no further increase of 3,6-diol was observed after exposure to itraconazole. Ergosterol synthesis was less sensitive to itraconazole inhibition, as was expected for these azole-resistant isolates which overexpress ATP-binding cassette transporter genesCDR1andCDR2. In addition to 3,6-diol, substantial amounts of obtusifolione were found after exposure to itraconazole. This toxic 3-ketosteroid was demonstrated previously to accumulate after itraconazole treatment inCryptococcus neoformansandHistoplasma capsulatumbut has not been reported inCandidaisolates. Accumulation of obtusifolione correlated with nearly complete growth inhibition in these azole-resistant strains compared to that found in the susceptible parent strain, although the onset of growth inhibition only occurred at higher concentrations of itraconazole.ERG25andERG26are the only genes assigned to the 4-demethylation process, of which the 3-ketoreductase is part. To verify whether mutations in theseERG25genes contributed to obtusifolione accumulation, their nucleotide sequences were determined in all three related isolates. No mutations inERG25alleles of isolates C48 and C56 were found, suggesting that this gene is not involved in obtusifolione accumulation. The molecular basis for the accumulation of this sterol in these two strains remains to be established.
Genetic Analysis of Azole Resistance by Transposon Mutagenesis in
Saccharomyces cerevisiae
Authors: Kontoyiannis D. P. 
Published: October 2018

ABSTRACT

The increasing resistance of
Candida
species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in
Saccharomyces cerevisiae
, a genetically tractable yeast that is closely related to
Candida albicans
. This technique, which permits the generation and analysis of multiple random Tn
3
::
LEU2
::
lacZ
fusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087–1105, 1994). By using the Tn
3
::
LEU2
::
lacZ
library as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g.,
PDR5
and
CPR1
, and in genes previously found to be involved in azole sensitivity, e.g.,
ERG3
. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes,
ADA3
and
SPT7
, are general transcriptional regulators; the third,
YMR034c
, is a putative sterol transporter. Finally, by screening the Tn
3
::
LEU2
::
lacZ
library for
lacZ
fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of
S. cerevisiae
to antifungal drugs.
Pharmacokinetics of [
14
C]Abacavir, a Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitor, Administered in a Single Oral Dose to HIV-1-Infected Adults: a Mass Balance Study
Authors: McDowell James A. , Chittick Gregory E. , Ravitch Joshua R. , Polk Ronald E. , Kerkering Thomas M. , Stein Daniel S. 
Published: October 2018

ABSTRACT

Abacavir (1592U89) {(−)-(1
S
, 4
R
)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol} is a 2′-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 μCi of [
14
C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5′-carboxylate (2269W93) and a 5′-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 μg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 μg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5′-carboxylate and the 5′-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.
Incidence and Characterization of Integrons, Genetic Elements Mediating Multiple-Drug Resistance, in Avian
Escherichia coli
Authors: Bass Lydia , Liebert Cynthia A. , Lee Margie D. , Summers Anne O. , White David G. , Thayer Stephan G. , Maurer John J. 
Published: October 2018

ABSTRACT

Antibiotic resistance among avian bacterial isolates is common and is of great concern to the poultry industry. Approximately 36% (
n
= 100) of avian, pathogenic
Escherichia coli
isolates obtained from diseased poultry exhibited multiple-antibiotic resistance to tetracycline, oxytetracycline, streptomycin, sulfonamides, and gentamicin. Clinical avian
E. coli
isolates were further screened for the presence of markers for class 1 integrons, the integron recombinase
intI1
and the quaternary ammonium resistance gene
qacEΔ1
, in order to determine the contribution of integrons to the observed multiple-antibiotic resistance phenotypes. Sixty-three percent of the clinical isolates were positive for the class 1 integron markers
intI1
and
qacEΔ1
. PCR analysis with the conserved class 1 integron primers yielded amplicons of approximately 1 kb from
E. coli
isolates positive for
intI1
and
qacEΔ1
. These PCR amplicons contained the spectinomycin-streptomycin resistance gene
aadA1
. Further characterization of the identified integrons revealed that many were part of the transposon Tn
21
, a genetic element that encodes both antibiotic resistance and heavy-metal resistance to mercuric compounds. Fifty percent of the clinical isolates positive for the integron marker gene
intI1
as well as for the
qacEΔ1
and
aadA1
cassettes also contained the mercury reductase gene
merA
. The correlation between the presence of the
merA
gene with that of the integrase and antibiotic resistance genes suggests that these integrons are located in Tn
21
. The presence of these elements among avian
E. coli
isolates of diverse genetic makeup as well as in
Salmonella
suggests the mobility of Tn
21
among pathogens in humans as well as poultry.
A New Method for Assessing Metronidazole Susceptibility of
Giardia lamblia
Trophozoites
Authors: Sousa M. Céu , Poiares-da-Silva J. 
Published: October 2018

ABSTRACT

A quantitative, simple, and rapid assay has been developed to assess
Giardia lamblia
trophozoite sensitivity to metronidazole [1-(2-hydroxyetyl)-2-methyl-5-nitroimidazole] (MTZ). This new assay utilizes the ability of live (surviving) trophozoites to take up oxygen after have been exposed to MTZ. The effect of MTZ on oxygen uptake was compared with its effect on viability as evaluated by a culture method and morphological assays. Oxygen uptake rates decreased in trophozoites treated with MTZ, and this effect was drug concentration dependent: O
2
uptake rates went from 3.04 μM O
2
min
−1
per 10
6
cells to 0.72 μM O
2
min
−1
per 10
6
cells with increasing drug concentration (0.15 to 0.6 mM) in the preincubation. Concentrations of the drug which inhibited oxygen uptake by 28 to 76% in trophozoites killed from 39 to 82% of trophozoites, as evaluated by the culture method, and altered the morphology of 21 to 86% of the trophozoites. Thus, the trophozoites killed by MTZ are nonmotile cells and do not take up oxygen. A good correlation was found between the inhibitory effects of MTZ, as evaluated by oxygen uptake, and cellular viability. Similar 50% inhibitory concentrations were obtained: 0.33 mM by oxygen uptake, 0.26 mM by the culture method, and 0.35 mM by morphological criteria. Oxygen uptake appears to be a good indicator of parasite viability. Therefore, this new method can provide a convenient means to assess MTZ susceptibility in
G. lamblia
and can be applied for screening potential antigiardial agents.
In Vitro Activities of SCH27899 Alone and in Combination with 17 Other Antimicrobial Agents
Authors: Fuchs Peter C. , Barry Arthur L. , Brown Steven D. 
Published: October 2018

ABSTRACT

SCH27899, an everninomicin antibiotic, was tested for its in vitro activity against 718 bacterial isolates representing 27 species. The
Enterobacteriaceae
and nonenteric gram-negative bacilli were resistant to ≥8.0 μg/ml, but all others were inhibited by ≤1.0 μg/ml. When tested in combination with 17 other antimicrobial agents against 110 strains, SCH27899 demonstrated no significant antagonism or synergy. Consequently, combination therapy is not contraindicated.
Exposure to Antibiotics Induces Expression of the
Mycobacterium tuberculosis sigF
Gene: Implications for Chemotherapy against Mycobacterial Persistors
Authors: Michele Theresa M. , Ko Chiew , Bishai William R. 
Published: October 2018

ABSTRACT

The
sigF
gene encodes an alternate sigma factor found in
Mycobacterium tuberculosis
and related pathogenic mycobacteria. Determination of conditions of
sigF
expression is an important step in understanding the conditional gene regulation which may govern such processes as virulence and dormancy in mycobacteria. We constructed an in-frame translational
lacZ-kan
fusion within the
sigF
gene to determine the conditions of
sigF
expression. This reporter construct was expressed from a multicopy plasmid in a strain of BCG harboring an integrated luciferase reporter gene under the control of the mycobacteriophage L5 gp71 promoter. Antibiotic exposure, in particular, ethambutol, rifampin, streptomycin, and cycloserine treatment, increased the level of SigF reporter specific expression in a dose-dependent fashion. The level of SigF reporter specific expression increased over 100-fold in late-stationary-phase growth compared to that in exponential growth. During the exponential phase, SigF specific expression could be induced by a number of other stresses. Anaerobic metabolism induced SigF by greater than 150-fold, particularly in the presence of metronidazole. Cold shock increased the level of SigF specific expression, while heat shock decreased it. Oxidative stress was also an important inducer of SigF specific expression; a greater induction was seen with cumene hydroperoxide than with hydrogen peroxide. Comparisons of bacterial viability as determined by the luciferase assay or by plating serial dilutions revealed that luciferase gp71-dependent activity was an unreliable predictor of the numbers of CFU during stationary-phase growth and anaerobic metabolism. The induction of
sigF
following antibiotic exposure suggests that this bacterial transcription factor may control genes which are important for mycobacterial persistence in the host during chemotherapy.
Expression in
Escherichia coli
of a New Multidrug Efflux Pump, MexXY, from
Pseudomonas aeruginosa
Authors: Mine Tomoyuki , Morita Yuji , Kataoka Atsuko , Mizushima Tohru , Tsuchiya Tomofusa 
Published: October 2018

ABSTRACT

Two new genes (
mexXY
) similar to
mexAB
,
mexCD
, and
mexEF
and mediating multidrug resistance were cloned from the chromosome of
Pseudomonas aeruginosa
. Elevated ethidium extrusion was observed with
Escherichia coli
cells harboring the plasmid carrying
mexXY
. This MexXY system confers higher resistance to fluoroquinolones than the MexAB and MexCD systems, and
E. coli
TolC or
P. aeruginosa
OprM is necessary for the function of the MexXY system.
Comparative Activities of Clinafloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Ofloxacin, Sparfloxacin, and Trovafloxacin and Nonquinolones Linozelid, Quinupristin-Dalfopristin, Gentamicin, and Vancomycin against Clinical Isolates of Ciprofloxacin-Resistant and -Susceptible
Staphylococcus aureus
Strains
Authors: Jones Mark E. , Visser Maarten R. , Klootwijk Miriam , Heisig Peter , Verhoef Jan , Schmitz Franz-Josef 
Published: October 2018

ABSTRACT

The activities of eight fluoroquinolones and linezolid, quinupristin-dalfopristin (Synercid), gentamicin, and vancomycin were tested against 96 ciprofloxacin-susceptible and 205 ciprofloxacin-resistant
Staphylococcus aureus
strains. Overall, clinafloxacin, followed by moxifloxacin and trovafloxacin, was the most active quinolone tested. For all isolates, linezolid and quinupristin-dalfopristin showed activities that were at least comparable to vancomycin, with no cross-resistance to any other test compound.
Metabolic Characterization of a Tripeptide Human Immunodeficiency Virus Type 1 Protease Inhibitor, KNI-272, in Rat Liver Microsomes
Authors: Kiriyama Akiko , Nishiura Tomoyuki , Yamaji Hirokazu , Takada Kanji 
Published: October 2018

ABSTRACT

KNI-272 is a tripeptide protease inhibitor for treating human immunodeficiency virus type 1 (HIV-1). In in vitro stability studies using rat tissue homogenates, KNI-272 concentrations in the liver, kidney, and brain decreased significantly with time. Moreover, in tissue distribution studies, KNI-272 distributed highly to the liver, kidney, and small intestine in vivo. From these results and reported physiological parameters such as the tissue volume and tissue blood flow rate, we considered the liver to be the main organ which takes part in the metabolic elimination of KNI-272. Then the hepatic metabolism of KNI-272 was more thoroughly investigated by using rat liver microsomes. KNI-272 was metabolized in the rat liver microsomes, and five metabolites were found. The initial metabolic rate constant (
k
metabolism
) tended to decrease when the KNI-272 concentration in microsomal suspensions increased. The calculated Michaelis-Menten constant

(K
m
)

and the maximum velocity of KNI-272 metabolism (
V
max
), after correction for the unbound drug concentration, were 1.12 ± 0.09 μg/ml (1.68 ± 0.13 μM) and 0.372 ± 0.008 μg/mg of protein/min (0.558 ± 0.012 nmol/mg of protein per min), respectively. The metabolic clearance (CL
int,metabo
), calculated as
V
max
/

K
m

, was 0.332 ml/mg of protein per min. Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform. In addition, ketoconazole, a representative CYP3A inhibitor, inhibited KNI-272 metabolism competitively, and the inhibition constant

(K
i
)

was 4.32 μM.
Efficacy of Ampicillin plus Ceftriaxone in Treatment of Experimental Endocarditis Due to
Enterococcus faecalis
Strains Highly Resistant to Aminoglycosides
Authors: Gavaldà Joan , Torres Carmen , Tenorio Carmen , López Pedro , Zaragoza Myriam , Capdevila Josep A. , Almirante Benito , Ruiz Fernanda , Borrell Nuria , Gomis Xavier , Pigrau Carles , Baquero Fernando , Pahissa Albert 
Published: October 2018

ABSTRACT

The purpose of this work was to evaluate the in vitro possibilities of ampicillin-ceftriaxone combinations for 10
Enterococcus faecalis
strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg
E. faecalis
. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained when ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 μg/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 μg of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 μg of ceftriaxone per ml showed a ≥2 log
10
reduction in CFU per milliliter with respect to ampicillin alone and to the initial inoculum for all 10
E. faecalis
strains studied. This effect was obtained for seven strains with the combination of 2 μg of ampicillin per ml plus 10 μg of ceftriaxone per ml and for six strains with 5 μg of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 10
8
CFU of
E. faecalis
V48 or 10
5
CFU of
E. faecalis
V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by
E. faecalis
V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of ampicillin plus ceftriaxone than in those treated with ampicillin alone (
P
< 0.001). The combination of ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAg
E. faecalis
.
Fluoroquinolone Action against Clinical Isolates of
Mycobacterium tuberculosis
: Effects of a C-8 Methoxyl Group on Survival in Liquid Media and in Human Macrophages
Authors: Zhao Ben Yang , Pine Richard , Domagala John , Drlica Karl 
Published: October 2018

ABSTRACT

When the lethal action of a C-8 methoxyl fluoroquinolone against clinical isolates of
Mycobacterium tuberculosis
in liquid medium was measured, the compound was found to be three to four times more effective (as determined by measuring the 90% lethal dose) than a C-8-H control fluoroquinolone or ciprofloxacin against cells having a wild-type
gyrA
(gyrase) gene. Against ciprofloxacin-resistant strains, the C-8 methoxyl group enhanced lethality when alanine was replaced by valine at position 90 of the GyrA protein or when aspartic acid 94 was replaced by glycine, histidine, or tyrosine. During infection of a human macrophage model by wild-type
Mycobacterium bovis
BCG, the C-8 methoxyl group lowered survival 20- to 100-fold compared with the same concentration of a C-8-H fluoroquinolone. The C-8 methoxyl fluoroquinolone was also more effective than ciprofloxacin against a
gyrA
Asn94 mutant of
M. bovis
BCG. In an
M. tuberculosis
-macrophage system the C-8 methoxyl group improved fluoroquinolone action against both quinolone-susceptible and quinolone-resistant clinical isolates. Thus, a C-8 methoxyl group enhances the bactericidal activity of quinolones with N1-cyclopropyl substitutions; these data encourage further refinement of fluoroquinolones as antituberculosis agents.
Comparison of Efficacies of Oral Levofloxacin and Oral Ciprofloxacin in a Rabbit Model of a Staphylococcal Abscess
Authors: Fernandez Jeffrey , Barrett John F. , Licata Lisa , Amaratunga Dhammika , Frosco Marybeth 
Published: October 2018

ABSTRACT

Oral levofloxacin was compared to oral ciprofloxacin in a
Staphylococcus aureus
subcutaneous abscess model in rabbits. Rabbits were surgically prepared with subcutaneous wiffle balls (43 mm in diameter) and allowed to recover for 4 to 6 weeks. Rabbits were infected by direct injection into the capsule with
S. aureus
ATCC 29213 (5 × 10
5
CFU) and were allowed to remain infected for 8 days before the initiation of anti-infective treatment. Efficacy was determined by assessing the bacterial load within the capsule over a 10-day treatment period. In single-dose pharmacokinetic studies in infected rabbits, similar area under the concentration-time curve/MIC ratios were obtained in the plasma and abscess fluid for levofloxacin at 45 mg/kg of body weight and ciprofloxacin at 200 mg/kg of body weight. Similar efficacies were seen with levofloxacin at 45 mg/kg/day and ciprofloxacin 400 mg/kg/day by day 10. In this model, levofloxacin was significantly more efficacious than ciprofloxacin (
P
< 0.01).