bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Terbinafine on Theophylline Pharmacokinetics in Healthy Volunteers
Authors: Trépanier Eric F. , Nafziger Anne N. , Amsden Guy W. 
Published: October 2018

ABSTRACT

Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (
P
= 0.03), oral clearance decreased by 14% (
P
= 0.04), and half-life increased by 24% (
P
= 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.
Antimicrobial Resistance in Enterococci Isolated from Turkey Flocks Fed Virginiamycin
Authors: Welton L. A. , Thal L. A. , Perri M. B. , Donabedian S. , McMahon J. , Chow J. W. , Zervos M. J. 
Published: October 2018

ABSTRACT

From 125 separate cloacal cultures from three turkey flocks fed virginiamycin, 104
Enterococcus faecium
and 186
Enterococcus faecalis
isolates were obtained. As the turkeys aged, there was a higher percentage of quinupristin-dalfopristin-resistant
E. faecium
isolates, with isolates from the oldest flock being 100% resistant. There were no vancomycin-resistant enterococci. Results of pulsed-field gel electrophoresis (PFGE) indicated there were 11 PFGE types of
E. faecalis
and 7 PFGE types of
E. faecium
that were in more than one group of flock cultures.
Relationship between Didanosine Exposure and Surrogate Marker Response in Human Immunodeficiency Virus-Infected Outpatients
Authors: Adams John M. , Shelton Mark J. , Hewitt Ross G. , Grasela Thaddeus H. , DeRemer Mary , Morse Gene D. 
Published: October 2018

ABSTRACT

We used information available from routine clinic visits to characterize the pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected patients. A total of 271 blood samples were collected for the measurement of didanosine concentrations in plasma (mean ± standard deviation [SD], 3.30 ± 2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CL
oral
) were obtained for these patients by the POSTHOC option within the NONMEM software package. Population priors from a previous NONMEM analysis of didanosine pharmacokinetics were used. The mean ± SD CL
oral
was 132 ± 27.7 liters/h, which agrees reasonably well with estimates obtained from previous pharmacokinetic studies of didanosine. Estimates of individual didanosine exposure were then used to consider potential relationships between drug exposure and surrogate marker response over a 6-month period. No correlations were found between the didanosine area under the concentration-time curve from 0 to 6 months and the absolute CD4 cell count (
r
= 0.305; 0.1 <
P
< 0.2), weight response (
r
= 0.0857;
P
> 0.4), or percentage of CD4 lymphocytes (
r
= 0.0559;
P
> 0.4). Future efforts to characterize didanosine exposure in outpatients by random sampling methods should involve more directed efforts to limit residual variability in the data.
Cefotaxime-Resistant
Enterobacteriaceae
Isolates from a Hospital in Warsaw, Poland: Identification of a New CTX-M-3 Cefotaxime-Hydrolyzing β-Lactamase That Is Closely Related to the CTX-M-1/MEN-1 Enzyme
Authors: Gniadkowski Marek , Schneider Ines , Pałucha Andrzej , Jungwirth Renate , Mikiewicz Barbara , Bauernfeind Adolf 
Published: October 2018

ABSTRACT

A group of cefotaxime-resistant
Citrobacter freundii
and
Escherichia coli
isolates were collected by a clinical laboratory in a hospital in Warsaw, Poland, in July 1996. Detailed analysis has shown that all of these produced a β-lactamase (pI, 8.4) belonging to the CTX-M family, one of the minor extended-spectrum β-lactamase families with a strong cefotaxime-hydrolyzing activity. Sequencing has revealed that
C. freundii
isolates produced a new CTX-M-3 enzyme which is very closely related to the CTX-M-1/MEN-1 β-lactamase, sporadically identified in Europe over a period of 6 years. Amino acid sequences of these two β-lactamases differ at four positions: Val77Ala, Asp114Asn, Ser140Ala, and Asn288Asp (the first amino acid of each pair refers to CTX-M-1/MEN-1 and second refers to CTX-M-3). The partial sequence of the
E. coli
CTX-M gene was identical to the corresponding region of
bla
CTX-M-3
, but a transconjugant of the
E. coli
isolate expressed higher levels of resistance to β-lactams than did
C. freundii
transconjugants. These resistance differences correlated with differences in plasmid DNA restriction patterns. Our results suggest that CTX-M genes have been spread among different species of the family
Enterobacteriaceae
in the hospital and that the CTX-M-3-expressing
C. freundii
strain causing routine urinary tract infections has been maintained for a relatively long time in the hospital environment.
Unique Metabolism of a Novel Antiviral
l
-Nucleoside Analog, 2′-Fluoro-5-Methyl-β-
l
-Arabinofuranosyluracil: a Substrate for Both Thymidine Kinase and Deoxycytidine Kinase
Authors: Liu Shwu-Huey , Grove Kristie L. , Cheng Yung-Chi 
Published: October 2018

ABSTRACT

2′-Fluoro-5-methyl-β-
l
-arabinofuranosyluracil (
l
-FMAU) is the first
l
-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other
l
-nucleoside analogs examined.
l
-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion.
l
-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of
l
-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of
l
-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.
Cyclosporin Analogs Inhibit In Vitro Growth ofCryptosporidium parvum
Authors: Perkins Margaret E. , Wu Teresa W. , Le Blancq Sylvie M. 
Published: October 2018

ABSTRACTCyclosporine and nonimmunosuppressive cyclosporin (CS) analogs were demonstrated to be potent inhibitors of the growth of the intracellular parasiteCryptosporidium parvumin short-term (48-h) in vitro cultures. Fifty-percent inhibitory concentrations (IC50s) were 0.4 μM for SDZ 033-243, 1.0 μM for SDZ PSC-833, and 1.5 μM for cyclosporine. Two other analogs were less effective than cyclosporine: the IC50of SDZ 205-549 was 5 μM, and that of SDZ 209-313 was 7 μM. These were much lower than the IC50of 85 μM of paromomycin, a standard positive control for in vitro drug assays for this parasite. In addition, intracellular growth of excysted sporozoites that had been incubated for 1 h in cyclosporine was significantly reduced, suggesting that the drug can inhibit sporozoite invasion. The cellular activities of the CS analogs used have been characterized for mammalian cells and protozoa. The two analogs that were most active in inhibitingC. parvum, SDZ PSC-833 and SDZ 033-243, bind weakly to cyclophilin, a peptidyl proline isomerase which is the primary target of cyclosporine and CS analogs. However, they are potent modifiers of the activity of the P glycoproteins/multidrug resistance (MDR) transporters, members of the ATP-binding cassette (ABC) superfamily. Hence, both cyclophilin and some ABC transporters may be targets for this class of drugs, although drugs that preferentially interact with the latter are more potent. Cyclosporine (0.5 μM) had no significant chemosensitizing activity. That is, it did not significantly increase sensitivity to paromomycin, suggesting that an ABC transporter is not critical in the efflux of this drug. Cyclosporine at concentrations up to 50 μM was not toxic to host Caco-2 cells in the CellTiter 96 assay. The results of this study complement those of studies of the inhibitory effect of cyclosporine and CS analogs on other apicomplexan parasites,Plasmodium falciparum,Plasmodium vivax, andToxoplasma gondii.
Impact of Bacterial Biofilm Formation on In Vitro and In Vivo Activities of Antibiotics
Authors: Schwank Silvia , Rajacic Zarko , Zimmerli Werner , Blaser Jürg 
Published: October 2018

ABSTRACT

The impact of bacterial adherence on antibiotic activity was analyzed with two isogenic strains of
Staphylococcus epidermidis
that differ in the features of their in vitro biofilm formation. The eradication of bacteria adhering to glass beads by amikacin, levofloxacin, rifampin, or teicoplanin was studied in an animal model and in a pharmacokinetically matched in vitro model. The features of
S. epidermidis
RP62A that allowed it to grow on surfaces in multiple layers promoted phenotypic resistance to antibiotic treatment, whereas strain M7 failed to accumulate, despite initial adherence on surfaces and growth in suspension similar to those for RP62A. Biofilms of
S. epidermidis
M7 were better eradicated than those of strain RP62A in vitro (46 versus 31%;
P
< 0.05) as well as in the animal model (39 versus 9%;
P
< 0.01).
Fluconazole Pharmacokinetics in Burn Patients
Authors: Boucher Bradley A. , King Stephen R. , Wandschneider Heidi L. , Hickerson William L. , Hanes Scott D. , Herring Vanessa L. , Canada Todd W. , Hess Mary M. 
Published: October 2018

ABSTRACTThe pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P> 0.05). Combined parameter estimates (means ± standard deviations) for all nine patients for the two study periods were as follows:t1/2, 24.4 ± 5.8 h; CL, 0.36 ± 0.09 ml/min/kg; andV, 0.72 ± 0.12 liters/kg. These estimates oft1/2and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations.
Ribosomes from an Oxazolidinone-Resistant Mutant Confer Resistance to Eperezolid in a
Staphylococcus aureus
Cell-Free Transcription-Translation Assay
Authors: Murray Robert W. , Schaadt Ronda D. , Zurenko Gary E. , Marotti Keith R. 
Published: October 2018

ABSTRACT

Oxazolidinone-resistant mutants of
Staphylococcus aureus
, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 μg/ml) of eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50% inhibitory concentrations of 30 μM for the oxazolidinone-sensitive S30 extract and 75 μM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and -resistant
S. aureus
strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the
S. aureus
mutant.
Transferable, Plasmid-Mediated VanB-Type Glycopeptide Resistance in
Enterococcus faecium
Authors: Rice Louis B. , Carias Lenore L. , Donskey Curtis L. , Rudin Susan D. 
Published: October 2018

ABSTRACT

An approximately 60-kb transferable,
vanB
-carrying plasmid has been identified in a clinical
Enterococcus faecium
strain. A similar plasmid has been observed in an unrelated
E. faecium
strain, suggesting that plasmid transfer of
vanB
operons occurs in nature and plays a role in the dissemination of VanB-type resistance among strains of
E. faecium.
Alginate Lyase Promotes Diffusion of Aminoglycosides through the Extracellular Polysaccharide of MucoidPseudomonas aeruginosa
Authors: Hatch Richard A. , Schiller Neal L. 
Published: October 2018

ABSTRACTWe demonstrated that a 2% suspension ofPseudomonas aeruginosaalginate completely blocked the diffusion of gentamicin and tobramycin, but not that of carbenicillin, illustrating how alginate production can help protectP. aeruginosagrowing within alginate microcolonies in patients with cystic fibrosis (CF) from the effects of aminoglycosides. This aminoglycoside diffusion barrier was degraded with a semipurified preparation ofP. aeruginosaalginate lyase, suggesting that this enzyme deserves consideration as an adjunctive agent for CF patients colonized by mucoid strains ofP. aeruginosa.
Susceptibilities of Clinical and Laboratory Isolates of
Blastomyces dermatitidis
to Ketoconazole, Itraconazole, and Fluconazole
Authors: Chapman Stanley W. , Rogers P. David , Rinaldi Michael G. , Sullivan Donna C. 
Published: October 2018

ABSTRACT

Eighteen isolates of
Blastomyces dermatitidis
were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 μg/ml for ketoconazole, ≤0.018 to 0.07 μg/ml for itraconazole, and 2.5 to 4.0 μg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 μg/ml for ketoconazole, ≤0.018 to 0.07 μg/ml for itraconazole, and 10 to 40 μg/ml for fluconazole. Itraconazole was the most active agent against
B. dermatitidis
in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.
Fosfomycin Reduces CD15s-Related Antigen Expression ofStreptococcus pyogenes
Authors: Hirota Katsuhiko , Murakami Kinya , Nemoto Ken , Ono Tsuneko , Matsuo Takashi , Kumon Hiromi , Miyake Yoichiro 
Published: October 2018

ABSTRACTWe have previously shown the immunological mimicry of human sialyl-Lewisx(CD15s) by a surface antigen ofStreptococcus pyogenes. This mimicking surface antigen may act as a ligand to the selectin family and may induce antibody production against CD15s on host cells, suggesting a possible role in the pathogenesis ofS. pyogenes. In this study, the effects of antibiotics on the CD15s-related antigen expression ofS. pyogeneswere examined at a concentration below the MIC (sub-MIC). The amounts of CD15s on the surfaces ofS. pyogenescells and on the surfaces ofS. pyogenesbiofilms were determined by a whole-cell enzyme-linked immunosorbent assay and by laser scanning fluorescence microscopy, respectively, by using an anti-CD15s monoclonal antibody. At the sub-MICs, fosfomycin (1R,2S-1,2-epoxypropyl phosphonic acid), its enantiomer (1S,2R-1,2-epoxypropyl phosphonic acid), and benzylpenicillin significantly inhibited the CD15s expression of all strains studied. The effects of fosfomycin and its enantiomer on biofilms were also observed by scanning electron microscopy. Incubation ofS. pyogeneswith the sub-MIC of fosfomycin or its enantiomer, which has no antibacterial activity, reduced the amount of CD15s on the biofilm surface and made it smooth. These results suggest that fosfomycin or its enantiomer might be useful for preventingS. pyogenesadherence to human CD15s receptors and the resulting immunological pathogenicity.
Characterization of Vancomycin-Resistant
Enterococcus faecium
Isolates from the United States and Their Susceptibility In Vitro to Dalfopristin-Quinupristin
Authors: Eliopoulos G. M. , Wennersten C. B. , Gold H. S. , Schülin T. , Souli M. , Farris M. G. , Cerwinka S. , Nadler H. L. , Dowzicky M. , Talbot G. H. , Moellering R. C. 
Published: October 2018

ABSTRACT

In the course of clinical studies with the investigational streptogramin antimicrobial dalfopristin-quinupristin, isolates of vancomycin-resistant
Enterococcus faecium
were referred to our laboratory from across the United States. Seventy-two percent of the strains were of the VanA type, phenotypically and genotypically, while 28% were of the VanB type. High-level resistance to streptomycin or gentamicin was observed in 86 and 81%, respectively, of the VanA strains but in only 69 and 66%, respectively, of the VanB strains. These enterococci were resistant to ampicillin (MIC for 50% of the isolates tested [MIC
50
] and MIC
90
, 128 and 256 μg/ml, respectively) and to the other approved agents tested, with the exception of chloramphenicol (MIC
90
, 8 μg/ml) and novobiocin (MIC
90
, 1 μg/ml). Considering all of the isolates submitted, dalfopristin-quinupristin inhibited 86.4% of them at concentrations of ≤1 μg/ml and 95.1% of them at ≤2 μg/ml. However, for the data set comprised of only the first isolate submitted for each patient, 94.3% of the strains were inhibited at concentrations of ≤1 μg/ml and 98.9% were inhibited at concentrations of ≤2 μg/ml. Multiple drug resistance was very common among these isolates of vancomycin-resistant
E. faecium
, while dalfopristin-quinupristin inhibited the majority at concentrations that are likely to be clinically relevant.
Bactericidal Activity of a Single-Dose Combination of Ofloxacin plus Minocycline, with or without Rifampin, against
Mycobacterium leprae
in Mice and in Lepromatous Patients
Authors: Ji Baohong , Sow Samba , Perani Evelyne , Lienhardt Christian , Diderot Vimala , Grosset Jacques 
Published: October 2018

ABSTRACT

To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against
Mycobacterium leprae
was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10 patients but was less bactericidal than the RMP-OFLO-MINO combination. Both combinations were well tolerated. Because of these promising results, a test of the efficacy of multiple doses of ROM in a larger clinical trial appears justified.
Sorivudine versus Acyclovir for Treatment of Dermatomal Herpes Zoster in Human Immunodeficiency Virus-Infected Patients: Results from a Randomized, Controlled Clinical Trial
Authors: Gnann John W. , Crumpacker Clyde S. , Lalezari Jacob P. , Smith Jean A. , Tyring Stephen K. , Baum Kenneth F. , Borucki Michael J. , Joseph W. Patrick , Mertz Gregory J. , Steigbigel Roy T. , Cloud Gretchen A. , Soong Seng-jaw , Sherrill Lanette C. , DeHertogh Deborah A. , Whitley Richard J. ,   the Collaborative Antiviral Study Group (Casg)/aids Clinical Trials Group (Actg) Herpes Zoster Study Group
Published: October 2018

ABSTRACT

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-β-
d
-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36;
P
= 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04;
P
= 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days;
P
= 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days;
P
= 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.
Photoaffinity Analog of the Semisynthetic Echinocandin LY303366: Identification of Echinocandin Targets in
Candida albicans
Authors: Radding Jeffrey A. , Heidler Steven A. , Turner William W. 
Published: October 2018

ABSTRACT

The echinocandins are a family of cyclic lipopeptides with potent antifungal activity. These compounds inhibit the synthesis of β-1,3-glucan in fungi. The new semisynthetic echinocandin LY303366 was derivatized to produce a photoactivatable cross-linking echinocandin analog with antifungal activity. This analog was radioiodinated and used as a probe in microsomal membrane preparations of
Candida albicans
which contain glucan synthase activity. The photoaffinity probe identified two major proteins of 40 and 18 kDa in both membrane preparations. Labeling of these proteins was specific in that it required irradiation with UV light and was effectively competed against with unlabeled echinocandin analogs. In addition, the abilities of echinocandin analogs to compete with the photoaffinity probe correlated to their relative antifungal potencies and glucan synthase inhibition. The 40-kDa protein was isolated, and partial sequences were obtained from internal peptide fragments of the protein. Analysis of the sequences of these internal peptides of the 40-kDa protein revealed that it was a new protein not previously described as being involved in glucan synthesis or the mode of action of echinocandins.