bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activities of the Lipopeptides Palmitoyl (Pal)-Lys-Lys-NH
2
and Pal-Lys-Lys Alone and in Combination with Antimicrobial Agents against Multiresistant Gram-Positive Cocci
Authors: Kamysz Wojciech , Silvestri Carmela , Cirioni Oscar , Giacometti Andrea , Licci Alberto , Della Vittoria Agnese , Okroj Marcin , Scalise Giorgio 
Published: December 2006

ABSTRACT

The in vitro activities of the lipopeptides palmitoyl (Pal)-Lys-Lys-NH
2
and Pal-Lys-Lys against gram-positive cocci were investigated. Enterococci and streptococci demonstrated higher susceptibilities than staphylococci and
Rhodococcus equi
. A positive interaction was shown when the lipopeptides were combined with beta-lactams and vancomycin. These results suggest that lipopeptides are promising candidates for antimicrobial therapy for infections caused by gram-positive organisms.
Action of Disinfectant Quaternary Ammonium Compounds againstStaphylococcus aureus
Authors: Ioannou Christopher J. , Hanlon Geoff W. , Denyer Stephen P. 
Published: December 2006

ABSTRACTMode-of-action studies concluded that alkyldimethylbenzylammonium chloride (ADBAC) (a blend of C12, C14and C16alkyl homologues) and didecyldimethylammonium chloride (DDAC) are both membrane-active agents, possessing subtly different modes of action reflecting early cell interactions againstStaphylococcus aureus. ADBAC and DDAC exhibited similar MIC behaviors from 0.4 ppm to 1.8 ppm over an inoculum range of 1 × 105to 1 × 109CFU/ml at 35°C. For ADBAC and DDAC, an increased rapidity of killing againstS. aureus(final concentration, 2 × 109CFU/ml) was observed at 35°C compared to 25°C. Concentration exponents (η) for killing were <2.5 for both agents, and temperature influenced the η value. Examination of leakage and kill data suggested that a single leakage marker was not indicative of cell death. ADBAC and DDAC possessed Langmuir (L4) and high-affinity (H3/4) uptake isotherms, respectively. ADBAC molecules formed a single monolayer of coverage of cells at the end of primary uptake, and DDAC formed a double monolayer. Rapid cell leakage occurred at bactericidal concentrations, with total depletion of the intracellular potassium and 260-nm-absorbing pools released in this strict order. Autolysis was observed for ADBAC and DDAC at concentrations of 9 μg/ml (0.0278 mM and 0.0276 mM, respectively) and above, together with the depletion of approximately 30% of the internal potassium pool. Autolysis contributed to ADBAC and DDAC lethality, although high biocide concentrations may have inhibited autolytic enzyme activity.
Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy
Authors: Liu Ping , Foster Grover , LaBadie Robert , Somoza Eugene , Sharma Amarnath 
Published: December 2006

ABSTRACTThis trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n= 16) or matching placebo (n= 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (Cmax) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC0-24was increased by 103.4% (90% CI: 85.0%, 123.6%), and theCmaxwas increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.
Effect of Neutropenia and Treatment Delay on the Response to Antifungal Agents in Experimental Disseminated Candidiasis
Authors: Hope William W. , Drusano George L. , Moore Caroline B. , Sharp Andrew , Louie Arnold , Walsh Thomas J. , Denning David W. , Warn Peter A. 
Published: December 2006

ABSTRACTDisseminated candidiasis is associated with a high rate of morbidity and mortality. The presence of neutrophils and the timely administration of antifungal agents are likely to be critical factors for a favorable therapeutic outcome of this syndrome. The effect of neutropenia on the temporal profile of the burden ofCandida albicansin untreated mice and those treated with amphotericin B was determined using a pharmacodynamic model of disseminated candidiasis. A mathematical model was developed to describe the rate and extent of theC. albicanskilling attributable to neutrophils and to amphotericin B. The consequences of a delay in the administration of amphotericin B, flucytosine, or micafungin were studied by defining dose-response relationships. Neutrophils caused a logarithmic decline in fungal burden in treated and untreated mice. The combination of amphotericin B and neutrophils resulted in a high rate ofCandidakilling and a sustained anti-C. albicanseffect. In neutropenic mice, 5 mg/kg of body weight of amphotericin B was required to prevent progressive logarithmic growth. An increased delay in drug administration resulted in a reduction in the maximum effect to a point at which no drug effect could be observed. Neutrophils and the timely initiation of antifungal agents are critical determinants in the treatment of experimental disseminated candidiasis.
Semimechanistic Pharmacokinetic/Pharmacodynamic Model for Assessment of Activity of Antibacterial Agents from Time-Kill Curve Experiments
Authors: Nielsen Elisabet I. , Viberg Anders , Löwdin Elisabeth , Cars Otto , Karlsson Mats O. , Sandström Marie 
Published: December 2006

ABSTRACT

Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of
Streptococcus pyogenes
exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (
E
max
) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.
Quinolone Resistance in
Helicobacter pylori
Isolates in Germany
Authors: Glocker Erik , Stueger Hans-Peter , Kist Manfred 
Published: December 2006

ABSTRACT

We show that quinolone resistance in
Helicobacter pylori
has reached an alarming level in Germany. Our data suggest that the use of quinolones requires prior antimicrobial susceptibility testing, especially for isolates from patients who have already undergone previous unsuccessful eradication treatments, and also underline the further need for surveillance studies to monitor antibiotic resistance in
H. pylori
.
Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis
Authors: Scorpio Angelo , Chabot Donald J. , Day William A. , O'Brien David K. , Vietri Nicholas J. , Itoh Yoshifumi , Mohamadzadeh Mansour , Friedlander Arthur M. 
Published: December 2006

ABSTRACTThe poly-γ-d-glutamic acid capsule confers antiphagocytic properties onBacillus anthracisand is essential for virulence. In this study, we showed that CapD, a γ-polyglutamic acid depolymerase encoded on theB. anthraciscapsule plasmid, degraded purified capsule and removed the capsule from the surface of anthrax bacilli. Treatment with CapD induced macrophage phagocytosis of encapsulatedB. anthracisand enabled human neutrophils to kill encapsulated organisms. A second glutamylase, PghP, a γ-polyglutamic acid hydrolase encoded byBacillus subtilisbacteriophage ΦNIT1, had minimal activity in degradingB. anthraciscapsule, no effect on macrophage phagocytosis, and only minimal enhancement of neutrophil killing. Thus, the levels of both phagocytosis and killing corresponded to the degree of enzyme-mediated capsule degradation. The use of enzymes to degrade the capsule and enable phagocytic killing ofB. anthracisoffers a new approach to the therapy of anthrax.
Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines
Authors: Duewelhenke N. , Krut O. , Eysel P. 
Published: December 2006

ABSTRACT
Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 μg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 μg/ml for macrolides, clindamycin, and rifampin, 60 to 80 μg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 μg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
Synergistic Activities of Azithromycin and Amphotericin B against
Naegleria fowleri
In Vitro and in a Mouse Model of Primary Amebic Meningoencephalitis
Authors: Soltow Shannon M. , Brenner George M. 
Published: December 2006

ABSTRACT

Naegleria fowleri
is responsible for producing a rapidly fatal central nervous system infection known as primary amebic meningoencephalitis (PAM). To date, amphotericin B, an antifungal agent, is the only agent with established clinical efficacy in the treatment of PAM. However, amphotericin B is not always successful in treating PAM and is associated with severe adverse effects. We previously found azithromycin to be more effective than amphotericin B in a mouse model of PAM. We therefore investigated the combination of amphotericin B and azithromycin in vitro and in a mouse model of PAM. For the in vitro studies, 50% inhibitory concentrations were calculated for each drug alone and for the drugs in fixed combination ratios of 1:1, 3:1, and 1:3. We found amphotericin B and azithromycin to be synergistic at all three of the fixed combination ratios. In our mouse model of PAM, a combination of amphotericin B (2.5 mg/kg of body weight) and azithromycin (25 mg/kg) protected 100% of the mice, whereas amphotericin B alone (2.5 mg/kg) protected only 27% of mice and azithromycin alone (25 mg/kg) protected 40% of mice. This study indicates that amphotericin B and azithromycin are synergistic against the Lee strain of
N. fowleri
, suggesting that the combined use of these agents may be beneficial in treating PAM.
Aph(3′)-IIc, an Aminoglycoside Resistance Determinant from
Stenotrophomonas maltophilia
Authors: Okazaki Aki , Avison Matthew B. 
Published: December 2006

ABSTRACT

We report the characterization of an intrinsic, chromosomally carried
aph(3′)-IIc
gene from
Stenotrophomonas maltophilia
clinical isolate K279a, encoding an aminoglycoside phosphotransferase enzyme that significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in
Escherichia coli
. Disruption of
aph(3′)-IIc
in K279a results in decreased MICs of these drugs.
Association of QnrB Determinants and Production of Extended-Spectrum β-Lactamases or Plasmid-Mediated AmpC β-Lactamases in Clinical Isolates of
Klebsiella pneumoniae
Authors: Pai Hyunjoo , Seo Mi-Ran , Choi Tae Yeal 
Published: December 2006

ABSTRACT

Clinical isolates of
Escherichia coli
and
Klebsiella pneumoniae
producing extended-spectrum β-lactamases or plasmid-mediated AmpC β-lactamases were screened for
qnrA
and
qnrB
genes.
QnrB
was present in 54 of 54 DHA-1-producing
K. pneumoniae
isolates and 10 of 45 SHV-12-producing ones, suggesting that the distribution of plasmids conferring resistance to extended-spectrum cephalosporins and quinolones in clinical isolates of
K. pneumoniae
is widespread.
Comparative Pharmacokinetics of Azithromycin in Serum and White Blood Cells of Healthy Subjects Receiving a Single-Dose Extended-Release Regimen versus a 3-Day Immediate-Release Regimen
Authors: Liu Ping , Allaudeen Hameed , Chandra Richa , Phillips Kem , Jungnik Arvid , Breen Jeanne D. , Sharma Amarnath 
Published: December 2006

ABSTRACTThe pharmacokinetic profiles of azithromycin given as a single-dose regimen (2.0-g extended-release microspheres) were characterized in serum and white blood cells (WBC) and compared with those of a 3-day regimen (a 500-mg immediate-release tablet once daily; total dose, 1.5 g) in an open-label, randomized, parallel-group study of 24 healthy adult subjects. Serial blood samples were collected up to 5 days after the start of dosing for both regimens. Safety assessments were conducted throughout the study. A single 2.0-g dose of azithromycin microspheres achieved significantly higher exposures in serum and WBC during the first 24 h after the start of dosing than a 3-day regimen: an approximately threefold higher area under the curve from time zero to 24 h postdose (AUC0-24) and an approximately twofold higher mean peak concentration on day 1. The single-dose regimen provided total azithromycin exposures in serum and WBC similar to those of the 3-day regimen, as evidenced by the similar AUC0-120and trough azithromycin concentrations in serum and WBC (mononuclear leukocytes [MNL] and polymorphonuclear leukocytes [PMNL]). For both regimens, the average total azithromycin exposures in MNL and PMNL were approximately 300- and 600-fold higher than those in serum. Azithromycin concentrations in MNL and PMNL remained above 10 μg/ml for at least 5 days after the start of dosing for both regimens. This “front-loading” of the dose on day 1 is safely achieved by the extended-release microsphere formulation, which maximizes the drug exposure at the time when the bacterial burden is likely to be highest.
The Phytotoxin Albicidin is a Novel Inhibitor of DNA Gyrase
Authors: Hashimi Saeed M. , Wall Melisa K. , Smith Andrew B. , Maxwell Anthony , Birch Robert G. 
Published: December 2006

ABSTRACT

Xanthomonas albilineans
produces a family of polyketide-peptide compounds called albicidins which are highly potent antibiotics and phytotoxins as a result of their inhibition of prokaryotic DNA replication. Here we show that albicidin is a potent inhibitor of the supercoiling activity of bacterial and plant DNA gyrases, with 50% inhibitory concentrations (40 to 50 nM) less than those of most coumarins and quinolones. Albicidin blocks the religation of the cleaved DNA intermediate during the gyrase catalytic sequence and also inhibits the relaxation of supercoiled DNA by gyrase and topoisomerase IV. Unlike the coumarins, albicidin does not inhibit the ATPase activity of gyrase. In contrast to the quinolones, the albicidin concentration required to stabilize the gyrase cleavage complex increases 100-fold in the absence of ATP. The slow peptide poisons microcin B17 and CcdB also access ATP-dependent conformations of gyrase to block religation, but in contrast to albicidin, they do not inhibit supercoiling under routine assay conditions. Some mutations in
gyrA
, known to confer high-level resistance to quinolones or CcdB, confer low-level resistance or hypersensitivity to albicidin in
Escherichia coli
. Within the albicidin biosynthesis region in
X. albilineans
is a gene encoding a pentapeptide repeat protein designated AlbG that binds to
E. coli
DNA gyrase and that confers a sixfold increase in the level of resistance to albicidin in vitro and in vivo. These results demonstrate that DNA gyrase is the molecular target of albicidin and that
X. albilineans
encodes a gyrase-interacting protein for self-protection. The novel features of the gyrase-albicidin interaction indicate the potential for the development of new antibacterial drugs.
Mosaic Staphylococcal Cassette Chromosome
mec
Containing Two Recombinase Loci and a New
mec
Complex, B2
Authors: Heusser R. , Ender M. , Berger-Bächi B. , McCallum N. 
Published: December 2006

ABSTRACT

A novel staphylococcal cassette chromosome (SCC)
mec
from a clinical methicillin-resistant
Staphylococcus aureus
isolate (ST100/CC5) had a mosaic structure, composed of SCC DNA from several different backgrounds. It harbored two complete
ccr
loci and a new variant of
mec
complex B, with Δ
mecR1
interrupted by the aminoglycoside resistance transposon Tn
4001
.
Inhibition of Antiassociation Activity of Translation Initiation Factor 3 by Paromomycin
Authors: Hirokawa Go , Kaji Hideko , Kaji Akira 
Published: December 2006

ABSTRACT

The effect of paromomycin on the interaction of ribosomal subunits was studied. Paromomycin inhibited the antiassociation activity of initiation factor 3 (IF3). Furthermore, ribosomal subunits were associated to form 70S ribosomes by paromomycin even in the presence of 1 mM Mg
2+
. Paromomycin did not inhibit the binding of IF3 to the 30S ribosomal subunits. On the other hand, IF3 bound to the 30S subunits was expelled by paromomycin-induced subunit association (70S formation). These results indicate that the stabilization of 70S ribosomes by paromomycin may in part be responsible for its inhibitory effects on translocation and ribosome recycling.
Antibacterial Activity and Mechanism of Action of a Novel Anilinouracil-Fluoroquinolone Hybrid Compound
Authors: Butler Michelle M. , LaMarr William A. , Foster Kimberly A. , Barnes Marjorie H. , Skow Donna J. , Lyden Patrick T. , Kustigian Lauren M. , Zhi Chengxin , Brown Neal C. , Wright George E. , Bowlin Terry L. 
Published: December 2006

ABSTRACT

The anilinouracils (AUs) such as 6-(3-ethyl-4-methylanilino)uracil (EMAU) are a novel class of gram-positive, selective, bactericidal antibacterials which inhibit pol IIIC, the gram-positive-specific replicative DNA polymerase. We have linked various fluoroquinolones (FQs) to the N-3 position of EMAU to generate a variety of AU-FQ “hybrids” offering the potential for targeting two distinct steps in DNA replication. In this study, the properties of a hybrid, “251D,” were compared with those of representative AUs and FQs in a variety of in vitro assays, including pol IIIC and topoisomerase/gyrase enzyme assays, antibacterial, bactericidal, and mammalian cytotoxicity assays. Compound 251D potently inhibited pol IIIC and topoisomerase/gyrase, displayed gram-positive antibacterial potency at least 15 times that of the corresponding AU compound, and as expected, acted selectively on bacterial DNA synthesis. Compound 251D was active against a broad panel of antibiotic-resistant gram-positive pathogens as well as several gram-negative organisms and was also active against both AU- and FQ-resistant gram-positive organisms, demonstrating its capacity for attacking both of its potential targets in the bacterium. 251D also was bactericidal for gram-positive organisms and lacked toxicity in vitro. Although we obtained strains of
Staphylococcus aureus
resistant to the individual parent compounds, spontaneous resistance to 251D was not observed. We obtained 251D resistance in multiple-passage experiments, but resistance developed at a pace comparable to those for the parent compounds. This class of AU-FQ hybrids provides a promising new pharmacophore with an unusual dual mechanism of action and potent activity against antibiotic-sensitive and -resistant gram-positive pathogens.
Inhibition of Autoimmune Type 1 Diabetes by Gastrointestinal Helminth Infection
Authors: Saunders Karin A. , Raine Tim , Cooke Anne , Lawrence Catherine E. 
Published: December 2006

ABSTRACTGastrointestinal nematode infections are prevalent worldwide and are potent inducers of T helper 2 responses with the capacity to modulate the immune response to heterologous antigens. Parasitic helminth infection has even been shown to modulate the immune response associated with autoimmune diseases. Nonobese diabetic (NOD) mice provide a model for studying human autoimmune diabetes; as in humans, the development of diabetes in NOD mice has been linked to the loss of self-tolerance to beta cell autoantigens. Previous studies with the NOD mouse have shown that helminth and bacterial infection appears to inhibit type 1 diabetes by disrupting the pathways leading to the Th1-mediated destruction of insulin-producing beta cells. The aim of our study was to examine whether infection with the gastrointestinal helminthsTrichinella spiralisorHeligmosomoides polygyruscould inhibit the development of autoimmune diabetes in NOD mice and to analyze the mechanisms involved in protection and the role of Th2 responses. Protection from diabetes was afforded by helminth infection, appeared to inhibit autoimmune diabetes by disrupting pathways leading to the destruction of beta cells, and was mediated by seemingly independent mechanisms depending on the parasite but which may be to be related to the capacity of the host to mount a Th2 response.