bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function
Authors: Smith James P. , Weller Stephen , Johnson Benjamin , Nicotera Janet , Luther James M. , Haas David W. 
Published: December 2009

ABSTRACT

Valacyclovir, the
l
-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], ∼15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC
τ
) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.
Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in
Plasmodium falciparum
Isolates in India
Authors: Mixson-Hayden Tonya , Jain Vidhan , McCollum Andrea M. , Poe Amanda , Nagpal Avinash C. , Dash Aditya P. , Stiles Jonathan K. , Udhayakumar Venkatachalam , Singh Neeru 
Published: December 2009

ABSTRACT

Treatment of
Plasmodium falciparum
is complicated by the emergence and spread of parasite resistance to many of the first-line drugs used to treat malaria. Antimalarial drug resistance has been associated with specific point mutations in several genes, suggesting that these single nucleotide polymorphisms can be useful in tracking the emergence of drug resistance. In India,
P. falciparum
infection can manifest itself as asymptomatic, mild, or severe malaria, with or without cerebral involvement. We tested whether chloroquine- and antifolate drug-resistant genotypes would be more commonly associated with cases of cerebral malaria than with cases of mild malaria in the province of Jabalpur, India, by genotyping the
dhps
,
dhfr
,
pfmdr-1
, and
pfcrt
genes using pyrosequencing, direct sequencing, and real-time PCR. Further, we used microsatellites surrounding the genes to determine the origins and spread of the drug-resistant genotypes in this area. Resistance to chloroquine was essentially fixed, with 95% of the isolates harboring the
pfcrt
K76T mutation. Resistant genotypes of
dhfr
,
dhps
, and
pfmdr-1
were found in 94%, 17%, and 77% of the isolates, respectively. Drug-resistant genotypes were equally likely to be associated with cerebral malaria as with mild malaria. We found evidence of a selective sweep in
pfcrt
and, to a lesser degree, in
dhfr
, indicating high levels of resistance to chloroquine and evolving resistance to pyrimethamine. Microsatellites surrounding
pfcrt
indicate that the resistant genotypes (SVMNT) were most similar to those found in Papua New Guinea.
Detection of KPC in
Acinetobacter
spp. in Puerto Rico
Authors: Robledo Iraida E. , Aquino Edna E. , Santé María I. , Santana Jorge L. , Otero Diana M. , León Carlos F. , Vázquez Guillermo J. 
Published: December 2009

ABSTRACT

During an island-wide PCR-based surveillance study of beta-lactam resistance in multidrug-resistant (MDR)
Escherichia coli
,
Klebsiella pneumoniae
,
Pseudomonas aeruginosa
, and
Acinetobacter calcoaceticus-baumannii
complex isolates obtained from 17 different hospitals, 10 KPC-positive
Acinetobacter
isolates were identified. DNA sequencing of the
bla
KPC
gene identified KPC-2, -3, and -4 and a novel variant, KPC-10. This is the first report of a KPC-type beta-lactamase identified in
Acinetobacter
species.
Single Nucleotide Polymorphism Analysis of the Major Tripartite Multidrug Efflux Pump of
Escherichia coli
: Functional Conservation in Disparate Animal Reservoirs despite Exposure to Antimicrobial Chemotherapy
Authors: Elkins Christopher A. , Mullis Lisa B. , Lacher David W. , Jung Carina M. 
Published: December 2009

ABSTRACT

AcrAB-TolC imparts a strong intrinsic resistance phenotype to many clinically significant molecules in
Escherichia coli
. This complex is composed of a pump, AcrB, and a periplasmic protein, AcrA, that exports substrates through a common outer membrane porin, TolC. A sequence survey of the pump-specific components,
acrA
and
acrB
, was conducted on three discrete animal reservoirs: rodents, bovines, and catfish. Although two of the reservoirs (bovine and catfish) were agrarian, and antibiotic use (ceftiofur and oxytetracycline/Romet 30, respectively) was reported for them, the vast majority of structural polymorphisms were silent except for T104A (AcrA) and Q733R (AcrB), found in certain bovine-derived strains. Overall, the genes were well conserved, with high ratios of synonymous to nonsynonymous substitutions (

d
S

/

d
N

ratios), consistent with or, in the case of
acrB
, better than those of standard multilocus sequence typing (MLST) loci. Furthermore, predicted recombination points from single nucleotide polymorphism (SNP) patterns in
acrB
support a modular evolution of transporter proteins, consistent with an ancient origin. However, functional studies with clones representing the major silent SNPs and the nonsilent mutation in
acrB
failed to generate significant differences in resistance to a range of common efflux pump substrates. Interestingly, a comparison between log-phase
acrA
and
acrB
expression profiles yielded inconsistent trends, with
acrB
expression increasing modestly (<1.8-fold) in many strains from the antibiotic-enriched pools. Our results suggest that structural polymorphisms in this major efflux pump system may not contribute significantly to adaptive resistance by altering function or substrate specificity but may have a potential use in improving phylogenetic relationships and/or source tracking.
Acquisition of Flucytosine, Azole, and Caspofungin Resistance in
Candida glabrata
Bloodstream Isolates Serially Obtained from a Hematopoietic Stem Cell Transplant Recipient
Authors: Chapeland-Leclerc Florence , Hennequin Christophe , Papon Nicolas , Noël Thierry , Girard Aurélie , Socié Gérard , Ribaud Patricia , Lacroix Claire 
Published: December 2009

ABSTRACT

We describe the acquisition of flucytosine, azole, and caspofungin resistance in sequential
Candida glabrata
bloodstream isolates collected from a bone marrow transplant patient with clinical failure. Point mutations in
C. glabrata FUR1
(
CgFUR1
) and
CgFKS2
and overexpression of
CgCDR1
and
CgCDR2
were observed in resistant isolates.
Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals
Authors: Hurwitz Selwyn J. , Asif Ghazia , Fromentin Emilie , Tharnish Phillip M. , Schinazi Raymond F. 
Published: December 2009

ABSTRACTAmdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, β-d-dioxolane guanosine (DXG). DXG is synergistic with zidovudine (ZDV) in HIV-1-infected primary human lymphocytes. A recentin silicopharmacokinetic (PK)/enzyme kinetic study suggested that ZDV at 200 mg twice a day (b.i.d.) may reduce toxicity without compromising efficacy relative to the standard 300-mg b.i.d. dose. Therefore, an intense PK clinical study was conducted using AMDX/placebo, with or without ZDV, in 24 subjects randomized to receive oral AMDX at 500 mg b.i.d., AMDX at 500 mg plus ZDV at 200 or 300 mg b.i.d., or ZDV at 200 or 300 mg b.i.d. for 10 days. Full plasma PK profiles were collected on days 1 and 10, and complete urine sampling was performed on day 9. Plasma and urine concentrations of AMDX, DXG, ZDV, and ZDV-5′-O-glucuronide (GZDV) were measured using a validated liquid chromatography-tandem mass spectrometry method. Data were analyzed using noncompartmental methods, and multiple comparisons were performed on the log-transformed parameters, at steady state. Coadministration of AMDX with ZDV did not significantly change either of the plasma PK parameters or percent recovery in the urine of AMDX, DXG, or ZDV/GZDV. Larger studies with AMDX/ZDV, with a longer duration, are warranted.
Comparative Pharmacodynamics of Amphotericin B Lipid Complex and Liposomal Amphotericin B in a Murine Model of Pulmonary Mucormycosis
Authors: Lewis Russell E. , Albert Nathan D. , Liao Guangling , Hou Jingguo , Prince Randall A. , Kontoyiannis Dimitrios P. 
Published: December 2009

ABSTRACT

We compared the kinetics of amphotericin B (AMB) lung accumulation and fungal clearance by liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) in a neutropenic murine model of invasive pulmonary mucormycosis (IPM). Immunosuppressed BALB/c mice were inoculated with 1 × 10
6
Rhizopus oryzae
spores and administered L-AMB or ABLC at daily intravenous doses of 1, 5, or 10 mg/kg of body weight for 5 days starting 12 h after infection. At a dose of 10 mg/kg/day, both L-AMB and ABLC were effective at reducing the
R. oryzae
lung fungal burden and achieved lung tissue concentrations exceeding the isolate mean fungicidal concentration (MFC) of 8 μg/ml by 72 h. When ABLC was dosed at 5 mg/kg/day, the ABLC-treated animals had significantly higher AMB lung concentrations than the L-AMB treated animals at 24 h (6.64 and 1.44 μg/g, respectively;
P =
0.013) and 72 h (7.49 and 1.03 μg/g, respectively;
P
= 0.005), and these higher concentrations were associated with improved fungal clearance, as determined by quantitative real-time PCR (mean conidial equivalent of
R. oryzae
DNA per lung, 4.44 ± 0.44 and 6.57 ± 0.74 log
10
, respectively;
P
< 0.001). Analysis of the AMB tissue concentration-response relationships revealed that the suppression of
R. oryzae
growth in the lung required tissue concentrations that approached the MFC for the infecting isolate (50% effective concentration, 8.19 μg/g [95% confidence interval, 2.81 to 18.1 μg/g]). The rates of survival were similar in the animals treated with L-AMB and ABLC at 10 mg/kg/day. These data suggest that higher initial doses may be required during L-AMB treatment than during ABLC treatment of experimental IPM.
Early Curative Applications of the Aminoglycoside WR279396 on an ExperimentalLeishmania major-Loaded Cutaneous Site Do Not Impair the Acquisition of Immunity
Authors: Lecoeur Hervé , Buffet Pierre A. , Milon Geneviève , Lang Thierry 
Published: December 2009

ABSTRACTTopical therapy is an attractive approach for the treatment ofLeishmaniamajorcutaneous leishmaniasis (CL). WR279396, an expanded-spectrum aminoglycoside ointment, is now in phase 3 trials. Because the application of a cream is easier than the injection of pentavalent antimony, many patients with CL will likely be treated with WR279396 soon after the onset of a lesion. However, this new therapeutic approach may impair the acquisition of immunity. We evaluated the impact of early topical therapy on acquired immunity in an optimized mouse model ofL. major-induced CL. The efficacy of the WR279396 ointment in this model has been established previously. Acquired immunity was defined as the absence of lesions upon reinoculation of the same parasite isolate at a different skin site. Bioluminescence-based follow-up of luciferase-expressingL. majorloads was also performed. In this model, the control ofL. majorloads at the initial inoculation site and the acquisition of immunity are simultaneous (day 22 postinoculation). The clinical and parasitological efficacies of WR279396 applied as early as day 11 postinoculation, i.e., during theL. majormultiplication phase, did not impair the acquisition of immunity to a secondL. majorchallenge. This is reassuring from the perspective of the wide deployment of WR279396-based therapy in foci whereL. majoris endemic.
In Vitro
Activity of CEM-101, a New Fluoroketolide Antibiotic, against
Chlamydia trachomatis
and
Chlamydia
(
Chlamydophila
)
pneumoniae
Authors: Roblin Patricia M. , Kohlhoff Stephan A. , Parker Charles , Hammerschlag Margaret R. 
Published: December 2009

ABSTRACT

The
in vitro
activities of CEM-101, telithromycin, azithromycin, clarithromycin, and doxycycline against 10 isolates each of
Chlamydia trachomatis
and
Chlamydia
(
Chlamydophila
)
pneumoniae
were tested. The MIC at which 90% of the isolates of both
C. trachomatis
and
C. pneumoniae
were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed by CEM-101 were 0.25 μg/ml (ranges, 0.125 to 0.5 μg/ml for
C. trachomatis
and 0.25 to 1.0 μg/ml for
C. pneumoniae
).
Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture
Authors: Donahue Daniel A. , Sloan Richard D. , Kuhl Björn D. , Bar-Magen Tamara , Schader Susan M. , Wainberg Mark A. 
Published: December 2009

ABSTRACTRecent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data providein vitroevidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.
pilF
Polymorphism-Based PCR To Distinguish
Vibrio vulnificus
Strains Potentially Dangerous to Public Health
Authors: Roig Francisco J. , Sanjuán Eva , Llorens Amparo , Amaro Carmen 
Published: December 2009

ABSTRACT

Vibrio vulnificus
is a heterogeneous species that comprises strains virulent and avirulent for humans and fish, and it is grouped into three biotypes. In this report, we describe a PCR-based methodology that allows both the species identification and discrimination of those isolates that could be considered dangerous to public health. Discrimination is based on the amplification of a variable region located within the gene
pilF
, which seems to be associated with potential human pathogenicity, regardless of the biotype of the strain.
Genome-Wide Screening and Identification of Factors Affecting the Biosynthesis of Prodigiosin by
Hahella chejuensis
, Using
Escherichia coli
as a Surrogate Host
Authors: Kwon Soon-Kyeong , Park Yon-Kyoung , Kim Jihyun F. 
Published: December 2009

ABSTRACT

A marine bacterium,
Hahella chejuensis
, recently has attracted attention due to its lytic activity against a red-tide dinoflagellate. The algicidal function originates from its red pigment, prodigiosin, which also exhibits immunosuppressive or anticancer activity. Genome sequencing and functional analysis revealed a gene set contained in the
hap
gene cluster that is responsible for the biosynthesis of prodigiosin. To screen for the factors affecting the prodigiosin biosynthesis, we constructed a plasmid library of the
H. chejuensis
genomic DNA, introduced it into
Escherichia coli
strains harboring the
hap
cluster, and observed changes in production of the red pigment. Among the screened clones,
hapXY
genes whose products constitute a two-component signal transduction system were elucidated as positive regulators of the pigment production. In addition, an Hfq-dependent, noncoding region located at one end of the
hap
cluster was confirmed to play roles in regulation. Identification of factors involved in the regulation of prodigiosin biosynthesis should help in understanding how the prodigiosin-biosynthetic pathway is organized and controlled and also aid in modulating the overexpression of prodigiosin in a heterologous host, such as
E. coli
, or in the natural producer,
H. chejuensis
.
β-(1,3)-Glucan Exposure Assessment by Passive Airborne Dust Sampling and New Sensitive Immunoassays
Authors: Noss Ilka , Wouters Inge M. , Bezemer Gillina , Metwali Nervana , Sander Ingrid , Raulf-Heimsoth Monika , Heederik Dick J. J. , Thorne Peter S. , Doekes Gert 
Published: December 2009

ABSTRACT
Associations between house dust-associated β-(1,3)-glucan exposure and airway inflammatory reactions have been reported, while such exposures in early childhood have been suggested to protect against asthma and wheezing. Most epidemiological studies have used reservoir dust samples and an inhibition enzyme immunoassay (EIA) for β-(1,3)-glucan exposure assessment. The objective of this study was to develop inexpensive but highly sensitive enzyme immunoassays to measure airborne β-(1,3)-glucans in low-exposure environments, like homes. Specificities of available anti-β-(1,3)-glucan antibodies were defined by direct and inhibition experiments. Three suitable antibody combinations were selected for sandwich EIAs. β-(1,3)-Glucans in passive airborne dust collected with an electrostatic dust fall collector (EDC) and floor dust from seven homes were measured with the three EIAs. Floor dust samples were additionally analyzed in the inhibition EIA. The sandwich EIAs were sensitive enough for airborne glucan measurement and showed different specificities for commercial glucans, while the β-(1,3)-glucan levels in house dust samples correlated strongly. The feasibility of measuring glucans in airborne dust with the recently introduced EDC method was further investigated by selecting the most suitable of the three EIAs to measure and compare β-(1,3)-glucan levels in the EDC and in floor and actively collected airborne dust samples of the previously performed EDC validation study. The EDC β-(1,3)-glucan levels correlated moderately with β-(1,3)-glucans in actively collected airborne dust and floor dust samples, while the glucan levels in the airborne dust and floor dust samples did not correlate. The combination of the newly developed β-(1,3)-glucan sandwich EIA with EDC sampling now allows assessment in large-scale population studies of exposure to airborne β-(1,3)-glucans in homes or other low-exposure environments.
Selection of a
Bacillus pumilus
Strain Highly Active against
Ceratitis capitata
(Wiedemann) Larvae
Authors: Molina C. Alfonso , Caña-Roca Juan F. , Osuna Antonio , Vilchez Susana 
Published: December 2009

ABSTRACT

Ceratitis capitata
(Wiedemann) (Diptera: Tephritidae), the Mediterranean fruit fly (medfly), is one of the most important fruit pests worldwide. The medfly is a polyphagous species that causes losses in many crops, which leads to huge economic losses. Entomopathogenic bacteria belonging to the genus
Bacillus
have been proven to be safe, environmentally friendly, and cost-effective tools to control pest populations. As no control method for
C. capitata
based on these bacteria has been developed, isolation of novel strains is needed. Here, we report the isolation of 115 bacterial strains and the results of toxicity screening with adults and larvae of
C. capitata
. As a result of this analysis, we obtained a novel
Bacillus pumilus
strain, strain 15.1, that is highly toxic to
C. capitata
larvae. The toxicity of this strain for
C. capitata
was related to the sporulation process and was observed only when cultures were incubated at low temperatures before they were used in a bioassay. The mortality rate for
C. capitata
larvae ranged from 68 to 94% depending on the conditions under which the culture was kept before the bioassay. Toxicity was proven to be a special characteristic of the newly isolated strain, since other
B. pumilus
strains did not have a toxic effect on
C. capitata
larvae. The results of the present study suggest that
B. pumilus
15.1 could be considered a strong candidate for developing strategies for biological control of
C. capitata
.
Lyophilization Prior to Direct DNA Extraction from Bovine Feces Improves the Quantification of
Escherichia coli
O157:H7 and
Campylobacter jejuni
Authors: Rapp Delphine , Waller John , Brightwell Gale , Muirhead Richard W. 
Published: December 2009

ABSTRACT

Lyophilization was used to concentrate bovine feces prior to DNA extraction and analysis using real-time PCR. Lyophilization significantly improved the sensitivity of detection compared to that in fresh feces and was associated with reliable quantification of both
Escherichia coli
O157:H7 and
Campylobacter jejuni
bacteria present in feces at concentrations ranging between 2 log
10
and 6 log
10
CFU g
−
1
.
Evaluation of
Lactobacillus sobrius/L. amylovorus
as a New Microbial Marker of Pig Manure
Authors: Marti Romain , Dabert Patrick , Ziebal Christine , Pourcher Anne-Marie 
Published: December 2009

ABSTRACT

Based on a comparison of the dominant microbial populations in 17 pig manure samples and using a molecular typing method, we identified a species,
Lactobacillus sobrius
and
Lactobacillus amylovorus
(which now are considered a single species and are designated
L. sobrius
/
amylovorus
here), that was consistently found in manure. The aim of the present study was to confirm by real-time PCR the relevance of this species as a marker of pig fecal contamination. The specificity of
L. sobrius
/
amylovorus
was evaluated in human and animal DNA extracted from feces. The real-time PCR assay then was applied to water samples, including effluents from urban wastewater treatment plants, runoff water, and rivers.
L. sobrius
/
amylovorus
was consistently present in all samples of swine origin: 48 fecal samples, 18 from raw manure and 10 from biologically treated manure at mean concentrations of 7.2, 5.9, and 5.0 log
10
cells/g, respectively. The species was not detected in any of the other livestock feces (38 samples from cattle and 16 from sheep), in the 27 human fecal samples, or in the 13 effluent samples from urban wastewater treatment plants. Finally,
L. sobrius
/
amylovorus
was not detected in runoff water contaminated by cattle slurry, but it was quantified at concentrations ranging from 3.7 to 6.5 log
10
cells/100 ml in runoff water collected after pig manure was spread on soil. Among the stream water samples in which cultured
Escherichia coli
was detected, 23% tested positive for
L. sobrius
/
amylovorus
. The results of this study indicate that the quantification of
L. sobrius
/
amylovorus
using real-time PCR will be useful for identifying pig fecal contamination in surface waters.