bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Ethambutol under Fasting Conditions, with Food, and with Antacids
Authors: Peloquin Charles A. , Bulpitt Amy E. , Jaresko George S. , Jelliffe Roger W. , Childs James M. , Nix David E. 
Published: October 2018

ABSTRACT

Ethambutol (EMB) is the most frequent “fourth drug” used for the empiric treatment of
Mycobacterium tuberculosis
and a frequently used drug for infections caused by
Mycobacterium avium
complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (± standard deviation) EMB maximum concentration of drug in serum (
C
max
) of 4.5 ± 1.0 μg/ml, time to maximum concentration of drug in serum (
T
max
) of 2.5 ± 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC
0–∞
) of 28.9 ± 4.7 μg · h/ml. In the presence of antacids, subjects had a mean
C
max
of 3.3 ± 0.5 μg/ml,
T
max
of 2.9 ± 1.2 h, and AUC
0–∞
of 27.5 ± 5.9 μg · h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean
C
max
of 3.8 ± 0.8 μg/ml,
T
max
of 3.2 ± 1.3 h, and AUC
0–∞
of 29.6 ± 4.7 μg · h/ml. These reductions in
C
max
, delays in
T
max
, and modest reductions in AUC
0–∞
can be avoided by giving EMB on an empty stomach whenever possible.
Antimicrobial Activities of Synthetic Bismuth Compounds against
Clostridium difficile
Authors: Mahony D. E. , Lim-Morrison S. , Bryden L. , Faulkner G. , Hoffman P. S. , Agocs L. , Briand G. G. , Burford N. , Maguire H. 
Published: October 2018

ABSTRACT

Clostridium difficile
is a major nosocomial pathogen responsible for pseudomembranous colitis and many cases of antibiotic-associated diarrhea. Because of potential relapse of disease with current antimicrobial therapy protocols, there is a need for additional and/or alternative antimicrobial agents for the treatment of disease caused by
C. difficile
. We have synthesized a systematic series of 14 structurally simple bismuth compounds and assessed their biological activities against
C. difficile
and four other gastrointestinal species, including
Helicobacter pylori
. Here, we report on the activities of six compounds that exhibit antibacterial activities against
C. difficile
, and some of the compounds have MICs of less than 1 μg/ml. Also tested, for comparison, were the activities of bismuth subcitrate and ranitidine bismuth citrate obtained from commercial sources.
C. difficile
and
H. pylori
were more sensitive both to the synthetic bismuth compounds and to the commercial products than were
Escherichia coli
,
Pseudomonas aeruginosa
, and
Proteus mirabilis
, and the last three species were markedly resistant to the commercial bismuth salts. Testing with human foreskin fibroblast cells revealed that some of the synthetic compounds were more cytotoxic than others. Killing curves for
C. difficile
treated with the more active compounds revealed rapid death, and electron microscopy showed that the bismuth of these compounds was rapidly incorporated by
C. difficile
. Energy dispersive spectroscopy X-ray microanalysis of
C. difficile
cells containing electron-dense material confirmed the presence of internalized bismuth. Internalized bismuth was not observed in
C. difficile
treated with synthetic bismuth compounds that lacked antimicrobial activity, which suggests that the uptake of the metal is required for killing activity. The nature of the carrier would seem to determine whether bismuth is transported into susceptible bacteria like
C. difficile
.
Clindamycin Suppresses Endotoxin Released by Ceftazidime-Treated
Escherichia coli
O55:B5 and Subsequent Production of Tumor Necrosis Factor Alpha and Interleukin-1β
Authors: Kishi Kenji , Hirai Kazuhiro , Hiramatsu Kazufumi , Yamasaki Tohru , Nasu Masaru 
Published: October 2018

ABSTRACT

Treatment of septicemia caused by
Escherichia coli
with ceftazidime (CAZ) may be associated with the development of septic shock due to the release of bacterial lipopolysaccharide. We examined the suppressive effect of clindamycin (CLDM) on CAZ-induced release of endotoxin by cultured
E. coli
and the subsequent production of inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β]).
E. coli
ATCC 12014 was incubated in inactivated horse serum with or without CLDM for 1, 4, or 18 h, followed by the addition of CAZ and collection of the culture supernatant at 0, 1, and 2 h. The concentration of endotoxin in each sample was measured by a chromogenic
Limulus
test. Another portion of the culture supernatant was added to THP-1 cell culture and incubated for 4 h, and the concentrations of TNF-α and IL-1β in the supernatant were measured by an enzyme-linked immunosorbent assay. In the control group (no CLDM), CAZ administration resulted in significant increases in endotoxin, TNF-α, and IL-1β concentrations. Pretreatment of
E. coli
with CLDM for 4 or 18 h before the addition of CAZ significantly suppressed the concentrations of endotoxin, TNF-α, and IL-1β in a time-dependent manner. In addition, CAZ treatment transformed
E. coli
from rod-shaped bacteria to filament-like structures, as determined by electron microscopy, while pretreatment with CLDM prevented these morphological changes. Our in vitro studies showed that CAZ-induced release of large quantities of endotoxin by
E. coli
could be suppressed by prior administration of CLDM.
Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution in Children and Adolescents
Authors: Kearns Gregory L. , Abdel-Rahman Susan M. , James Laura P. , Blowey Douglas L. , Marshall James D. , Wells Thomas G. , Jacobs Richard F. ,   The Pediatric Pharmacology Research Unit Network
Published: October 2018

ABSTRACT

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 ± 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (
n
= 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/
Y
calc
) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means ± standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (
C
max
) was 1,272.5 ± 622.1 ng/ml. The time to
C
max
was 4.1 ± 1.5 h, and the lag time was 0.75 ± 0.56 h. The apparent absorption rate constant was 0.75 ± 0.48 1/h, and the elimination rate constant was 0.16 ± 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 ± 3,411.82 ng · h/ml. The apparent total plasma clearance was 0.81 ± 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 ± 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 ± 148.2 ng/ml) and 24 h (137.9 ± 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit >90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.
Genetic Evidence that InhA of
Mycobacterium smegmatis
Is a Target for Triclosan
Authors: McMurry Laura M. , McDermott Patrick F. , Levy Stuart B. 
Published: October 2018

ABSTRACT

Three
Mycobacterium smegmatis
mutants selected for resistance to triclosan each had a different mutation in InhA, an enoyl reductase involved in fatty acid synthesis. Two expressed some isoniazid resistance. A mutation originally selected on isoniazid also mediated triclosan resistance, as did the wild-type
inhA
gene on a multicopy plasmid. Replacement of the mutant chromosomal
inhA
genes with wild-type
inhA
eliminated resistance. These results suggest that
M. smegmatis
InhA, like its
Escherichia coli
homolog FabI, is a target for triclosan.
Lactic Acid Polymers as Biodegradable Carriers of Fluoroquinolones: An In Vitro Study
Authors: Kanellakopoulou Kyriaki , Kolia Maria , Anastassiadis Antonios , Korakis Themistoklis , Giamarellos-Bourboulis Evangelos J. , Andreopoulos Andreas , Dounis Eleftherios , Giamarellou Helen 
Published: October 2018

ABSTRACT

A biodegradable polymer of
dl
-dilactide that facilitates release of ciprofloxacin or pefloxacin at levels exceeding MICs for the causative microorganisms of chronic osteomyelitis is described. Duration and peak of release were found to depend on the molecular weight of the polymer. Its characteristics make it promising for treating chronic bone infections.
Exposure to Metronidazole In Vivo Readily Induces Resistance in
Helicobacter pylori
and Reduces the Efficacy of Eradication Therapy in Mice
Authors: Jenks Peter J. , Labigne Agnes , Ferrero Richard L. 
Published: October 2018

ABSTRACT

The
Helicobacter pylori
SS1 mouse model was used to characterize the development of resistance in
H. pylori
after treatment with metronidazole monotherapy and to examine the effect of prior exposure to metronidazole on the efficacy of a metronidazole-containing eradication regimen. Mice colonized with the metronidazole-sensitive
H. pylori
SS1 strain were treated for 7 days with either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole once a day or three times per day (TID). In a separate experiment,
H. pylori
-infected mice were administered either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole TID for 7 days, followed 1 month later by either peptone trypsin broth or the mouse equivalent of 20 mg of omeprazole, 250 mg of clarithromycin, and 400 mg of metronidazole twice a day for 7 days. At least 1 month after the completion of treatment, the mice were sacrificed and their stomachs were cultured for
H. pylori
. The susceptibilities of isolates to metronidazole were assessed by agar dilution determination of the MICs. Mixed populations of metronidazole-resistant and -sensitive strains were isolated from 70% of mice treated with 400 mg of metronidazole TID. The ratio of resistant to sensitive strains was 1:100, and the MICs for the resistant strains varied from 8 to 64 μg/ml. In the second experiment,
H. pylori
was eradicated from 70% of mice treated with eradication therapy alone, compared to 25% of mice pretreated with metronidazole (
P
< 0.01). Mice still infected after treatment with metronidazole and eradication therapy contained mixed populations of metronidazole-resistant and -sensitive isolates in a ratio of 1:25. These results demonstrate that
H. pylori
readily acquires resistance to metronidazole in vivo and that prior exposure of the organism to metronidazole is associated with failure of eradication therapy.
H. pylori
-infected mice provide a suitable model for the study of resistance mechanisms in
H. pylori
and will be useful in determining optimal regimens for the eradication of resistant strains.
Development of Resistance during Antimicrobial Therapy Caused by Insertion Sequence Interruption of Porin Genes
Authors: Hernández-Allés Santiago , Benedí Vicente J. , Martínez-Martínez Luis , Pascual Álvaro , Aguilar Alicia , Tomás Juan M. , Albertí Sebastián 
Published: October 2018

ABSTRACT

We have demonstrated by using an in vitro approach that interruption of the OmpK36 porin gene by insertion sequences (ISs) is a common type of mutation that causes loss of porin expression and increased resistance to cefoxitin in
Klebsiella pneumoniae
. This mechanism also operates in vivo: of 13 porin-deficient cefoxitin-resistant clinical isolates of
K. pneumoniae
, 4 presented ISs in their
ompK36
gene.
Mutations in the
gyrA
,
parC
, and
parE
Genes Associated with Fluoroquinolone Resistance in Clinical Isolates of
Mycoplasma hominis
Authors: Bebear Cécile M. , Renaudin Joel , Charron Alain , Renaudin Hélène , de Barbeyrac Bertille , Schaeverbeke Thierry , Bebear Christiane 
Published: October 2018

ABSTRACT

Five clinical isolates of
Mycoplasma hominis
from three different patients were examined for resistance to fluoroquinolones; some of these isolates were probably identical. All five isolates harbored amino acid substitutions in the quinolone resistance-determining regions of both DNA gyrase (GyrA) and topoisomerase IV (ParC or ParE). Furthermore, the novobiocin MIC for three isolates showed a significant increase. This is the first characterization of fluoroquinolone-resistant clinical mycoplasma isolates from humans.
Inhibition of the Emergence of Ciprofloxacin Resistance in
Streptococcus pneumoniae
by the Multidrug Efflux Inhibitor Reserpine
Authors: Markham Penelope N. 
Published: October 2018

ABSTRACT

Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in
Streptococcus pneumoniae
. In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants of
S. pneumoniae
, suggesting that the combination of a fluoroquinolone with an inhibitor of multidrug transport may help preserve the efficacy of this class of antibiotics.
Heterogeneity in the
vanB
Gene Cluster of Genomically Diverse Clinical Strains of Vancomycin-Resistant Enterococci
Authors: Dahl Kristin Hegstad , Simonsen Gunnar Skov , Olsvik Ørjan , Sundsfjord Arnfinn 
Published: October 2018

ABSTRACT

Molecular analysis of 17 genomically unrelated clinical VanB-type vancomycin-resistant enterococcus isolates from hospital patients in Germany, Norway, Sweden, the United Kingdom and the United States revealed three subtypes of the
vanB
gene cluster—
vanB1
,
vanB2
, and
vanB3
—which was in accordance with previous subtyping of the ligase gene sequence. There was no correlation between
vanB
subtype and levels of vancomycin resistance. All strains studied carried a structurally conserved
vanB
gene cluster as shown by long-range PCR (long PCR) covering 5,959 bp of the published sequence in
vanB1
strain V583. Restriction analysis of long PCR amplicons displayed one unique
vanB1
pattern and a second
vanB2
- and
vanB3
-specific pattern. The

vanS
B
-vanY
B

intergenic sequences with flanking coding regions were identical within each
vanB
subtype with one exception. A U.S.
vanB2
isolate had a 789-bp enlargement of this region containing a putative open reading frame (ORF) with substantial homology to an ORF in the
Clostridium perfringens
IS
1469
insertion element. The molecular heterogeneity within the
vanB
gene cluster has implications for the selection of PCR primers, as the primers must ensure detection of all
vanB
subtypes, and is of importance when considering reservoirs and dissemination of
vanB
resistance. The molecular identity within the
vanB1
and the
vanB2
subtype indicates horizontal transmission of both gene clusters between isolates in different geographical areas. Restriction analysis of long PCR
vanB
amplicons may reveal specific varieties that can be used as epidemiological markers for mobile determinants conferring VanB-type resistance. The finding of three distinct
vanB
gene clusters should encourage a search for different environmental reservoirs of
vanB
resistance determinants.
In Vitro Antibacterial Activities of Platelet Microbicidal Protein and Neutrophil Defensin against
Staphylococcus aureus
Are Influenced by Antibiotics Differing in Mechanism of Action
Authors: Xiong Yan-Qiong , Yeaman Michael R. , Bayer Arnold S. 
Published: October 2018

ABSTRACT

Thrombin-induced platelet microbicidal protein-1 (tPMP-1) and human neutrophil defensin-1 (HNP-1) are small, cationic antimicrobial peptides. These peptides exert potent in vitro microbicidal activity against a broad spectrum of human pathogens, including
Staphylococcus aureus
. Evidence suggests that tPMP-1 and HNP-1 target and disrupt the bacterial membrane. However, it is not yet clear whether membrane disruption itself is sufficient to kill the bacterium or whether subsequent, presumably intracellular, events are also involved in killing. We investigated the staphylocidal activities of tPMP-1 and HNP-1 in the presence or absence of pretreatment with antibiotics that differ in their mechanisms of action. The staphylocidal effects of tPMP-1 and HNP-1 on control cells (no antibiotic pretreatment) were rapid and concentration dependent. Pretreatment of
S. aureus
with either penicillin or vancomycin (bacterial cell wall synthesis inhibitors) significantly enhanced the anti-
S. aureus
effects of tPMP-1 compared with the effects against the respective control cells over the entire tPMP-1 concentration range tested (
P
< 0.05). Similarly,
S. aureus
cells pretreated with these antibiotics were more susceptible to HNP-1 than control cells, although the difference in the effects against cells that received penicillin pretreatment did not reach statistical significance (
P
< 0.05 for cells that received vancomycin pretreatment versus effects against control cells). Studies with isogenic pairs of strains with normal or deficient autolytic enzyme activities demonstrated that enhancement of
S. aureus
killing by cationic peptides and cell wall-active agents could not be ascribed to a predominant role of autolytic enzyme activation. Pretreatment of
S. aureus
cells with tetracycline, a 30S ribosomal subunit inhibitor, significantly decreased the staphylocidal effect of tPMP-1 over a wide peptide concentration range (0.16 to 1.25 μg/ml) (
P
< 0.05). Furthermore, pretreatment with novobiocin (an inhibitor of bacterial DNA gyrase subunit B) and with azithromycin, quinupristin, or dalfopristin (50S ribosomal subunit protein synthesis inhibitors) essentially blocked the
S. aureus
killing resulting from exposure to tPMP-1 or HNP-1 at most concentrations compared with the effects against the respective control cells (
P
< 0.05 for a tPMP-1 concentration range of 0.31 to 1.25 μg/ml and for an HNP-1 concentration range of 6.25 to 50 μg/ml). These findings suggest that tPMP-1 and HNP-1 exert anti-
S. aureus
activities through mechanisms involving both the cell membrane and intracellular targets.
Pharmacodynamics of Trovafloxacin, Ofloxacin, and Ciprofloxacin against
Streptococcus pneumoniae
in an In Vitro Pharmacokinetic Model
Authors: Lister Philip D. , Sanders Christine C. 
Published: October 2018

ABSTRACT

An in vitro pharmacokinetic model was used to simulate the pharmacokinetics of trovafloxacin, ofloxacin, and ciprofloxacin in human serum and to compare their pharmacodynamics against eight
Streptococcus pneumoniae
strains. The MICs of ofloxacin and ciprofloxacin ranged from 1 to 2 μg/ml. Trovafloxacin was 8- to 32-fold more potent, with MICs of 0.06 to 0.12 μg/ml. Logarithmic-phase cultures were exposed to peak concentrations of trovafloxacin, ofloxacin, or ciprofloxacin achieved in human serum after 200-, 400-, and 750-mg oral doses, respectively. Trovafloxacin was dosed at 0 and 24 h, and ofloxacin and ciprofloxacin were dosed at 0, 12, and 24 h. Human elimination pharmacokinetics were simulated, and viable bacterial counts were measured at 0, 2, 4, 6, 8, 12, 24, and 36 h. Trovafloxacin was rapidly and significantly bactericidal against all eight strains evaluated, with viable bacterial counts decreasing at least 5 logs to undetectable levels. Times to 99.9% killing were only 1 to 3 h. Although the rate of killing with ofloxacin was substantially slower than that with trovafloxacin, ofloxacin was also able to eradicate all eight strains from the model, despite a simulated area under the inhibitory curve/MIC ratio (AUC/MIC) of only 49. In contrast, ciprofloxacin eradicated only five strains (AUC/MIC = 44) from the model. Against the other three strains (AUC/MIC = 22), the antibacterial activity of ciprofloxacin was substantially diminished. These data corroborate clinical data and suggest that trovafloxacin has a pharmacodynamic advantage over ciprofloxacin and ofloxacin against
S. pneumoniae
in relation to its enhanced antipneumococcal activity.
BOCILLIN FL, a Sensitive and Commercially Available Reagent for Detection of Penicillin-Binding Proteins
Authors: Zhao Genshi , Meier Timothy I. , Kahl Steven D. , Gee Kyle R. , Blaszczak Larry C. 
Published: October 2018

ABSTRACT

We describe a new, sensitive, rapid, and nonradioactive method involving the use of the commercially available BOCILLIN FL, a fluorescent penicillin, as a labeling reagent for the detection and study of penicillin-binding proteins (PBPs). This method allowed rapid detection of 30 ng of a purified PBP protein under UV light and of 2 to 4 ng of the protein with the aid of a FluorImager. This method also allowed rapid determination of the PBP profiles of
Escherichia coli
,
Pseudomonas aeruginosa
, and
Streptococcus pneumoniae
. The PBP profiles obtained are virtually identical to those reported previously with
3
H-,
14
C-, or
125
I-labeled penicillin. Using this method enabled us to determine the 50% inhibitory concentrations of the penicillin-sensitive and -resistant PBP2x proteins of
S. pneumoniae
for penicillin G, thereby allowing a direct evaluation of their relative affinities for penicillin G. Finally, this method also allowed us to compare relative affinities of a PBP2x protein for different β-lactam antibiotics with the aid of fluorescence polarization technology and to monitor a PBP2x protein during purification.