bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamics of Moxifloxacin and Levofloxacin at Simulated Epithelial Lining Fluid Drug Concentrations against
Streptococcus pneumoniae
Authors: Florea Naomi R. , Tessier Pamela R. , Zhang Cuilian , Nightingale Charles H. , Nicolau David P. 
Published: March 2004

ABSTRACT

Recent clinical failures associated with levofloxacin treatment for
Streptococcus pneumoniae
infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of
S. pneumoniae
after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six
S. pneumoniae
containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The
S. pneumoniae
isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the
parC
or
parE
mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the
parC
and
gyrA
mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the
parC
,
gyrA
, and
parE
mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the
parC
or
parE
mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for
S. pneumoniae
was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.
Efficacy and Pharmacokinetics of Intravenous Nanocapsule Formulations of Halofantrine in
Plasmodium berghei
-Infected Mice
Authors: Mosqueira Vanessa C. F. , Loiseau Philippe M. , Bories Christian , Legrand Philippe , Devissaguet Jean-Philippe , Barratt Gillian 
Published: March 2004

ABSTRACT

The efficacy and pharmacokinetics of a new parenteral formulation of halofantrine were studied in mice infected with
Plasmodium berghei
. The formulation consisted of nanocapsules with an oily core, prepared from either poly(
d,l
-lactide) (PLA) homopolymer or PLA that was surface modified with grafted polyethylene glycol chains. They were compared with a previously described intravenous halofantrine preparation. No toxic effects were observed with halofantrine in form of nanocapsules after intravenous administration for doses of up to 100 mg/kg, whereas the solubilized form in polyethylene glycol-dimethylacetamide was toxic at this dose. The halofantrine-loaded nanocapsules showed activity that was similar to or better than that of the solution in the 4-day test and as a single dose in severely infected mice, with only minimal differences between the two nanocapsule formulations. Halofantrine pharmacokinetics were determined in parallel with parasite development in severely infected mice. Nanocapsules increased the area under the curve for halofantrine in plasma more than sixfold compared with the solution throughout the experimental period of 70 h. Furthermore, nanocapsules induced a significantly faster control of parasite development than the solution in the first 48 h posttreatment. While the parasitemia fell more rapidly with PLA nanocapsules, the effect was more sustained with the surface-modified ones. This is consistent with surface-modified nanocapsules remaining longer in the circulation. These results suggest that nanocapsule formulations could provide a more favorable halofantrine profile in the plasma and reduce the intravenous dose necessary and therefore the toxicity, thus suggesting the use of halofantrine by a parenteral route in severe malaria.
Involvement of Enterobactin Synthesis Pathway in Production of Microcin H47
Authors: Azpiroz María F. , Laviña Magela 
Published: March 2004

ABSTRACT

Microcin H47 (MccH47) is a gene-encoded peptide antibiotic produced by an
Escherichia coli
clinical isolate which is active on strains of gram-negative bacteria. Its uptake by
E. coli
K-12-susceptible cells depends on the presence of any of the outer membrane proteins Cir, Fiu, and FepA, the three catechol receptors of this organism. The nucleotide sequence of a portion of the MccH47 genetic system that had not yet been studied was elucidated. Five open reading frames were identified, three of which corresponded to genes encoding functions related to catechol-type siderophores:
mchA
and
mchS1
are
iroB
and
iroD
homologues, respectively, and
mchS4
was found to promote the production of the catecholate siderophore enterobactin. The possible relationship between enterobactin synthesis and MccH47 production was studied. Enterobactin-deficient strains failed to produce MccH47 when transformed with the antibiotic genetic determinants and upon introduction of the
ent
genetic cluster, the production of both the siderophore and MccH47 was restored. Further studies demonstrated that at least the enterobactin nonribosomal peptide synthase EntF is necessary for MccH47 synthesis. The relationship found between MccH47 and catecholate siderophore production is discussed, and a model outlining MccH47 synthesis is proposed.
Modulation of In Vitro Fungicidal Activity of Human Lactoferrin againstCandida albicansby Extracellular Cation Concentration and Target Cell Metabolic Activity
Authors: Viejo-Díaz Mónica , Andrés María T. , Fierro José F. 
Published: March 2004

ABSTRACTThe anti-Candidaactivity of the innate defense protein human lactoferrin was investigated. Lactoferrin displayed a clear fungicidal effect againstCandida albicansonly under low-strength conditions. This candidacidal activity was inversely correlated with the extracellular concentration of the monovalent cations and was prevented by Na+and K+(≥30 mM) and by divalent cations (Ca2+and Mg2+at ≥4 mM). A slight cellular release of K+, cytosolic acidification, and a change in the membrane potential were observed inC. albicanscells treated with lactoferrin, suggesting that this protein directly or indirectly interacts with the cytoplasmic membrane. Mitochondrial inhibitors (carbonyl cyanidem-chlorophenylhydrazone, 2,4-dinitrophenol, azide, and antimycin) as well as anaerobic conditions significantly reduced the killing effect of lactoferrin. These results suggest that low-strength conditions and the cellular metabolic state may modulate the candidacidal activity of human lactoferrin.
Mycobacterium tuberculosis
DNA Gyrase: Interaction with Quinolones and Correlation with Antimycobacterial Drug Activity
Authors: Aubry Alexandra , Pan Xiao-Su , Fisher L. Mark , Jarlier Vincent , Cambau Emmanuelle 
Published: March 2004

ABSTRACT

Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in
Mycobacterium tuberculosis
. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of
M. tuberculosis
have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the
M. tuberculosis
DNA gyrase GyrA and GyrB subunits as His-tagged proteins in
Escherichia coli
from pET plasmids carrying
gyrA
and
gyrB
genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC
50
) was measured for 22 different quinolones, and values ranged from 2 to 3 μg/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 μg/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against
M. tuberculosis
ranged from 0.12 μg/ml (for gatifloxacin) to 128 μg/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC
50
s (
R
2
= 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (
R
2
= 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against
M. tuberculosis
. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting
M. tuberculosis
gyrase.
Effect of
rpoB
Mutations Conferring Rifampin Resistance on Fitness of
Mycobacterium tuberculosis
Authors: Mariam Deneke H. , Mengistu Yohannes , Hoffner Sven E. , Andersson Dan I. 
Published: March 2004

ABSTRACT

Rifampin is a major drug used in the treatment of tuberculosis infections, and increasing rifampin resistance represents a worldwide clinical problem. Resistance to rifampin is caused by mutations in the
rpoB
gene, encoding the β-subunit of RNA polymerase. We examined the effect of three different
rpoB
mutations on the fitness of
Mycobacterium tuberculosis
. Rifampin-resistant mutants were isolated from a virulent clinical isolate of
M. tuberculosis
(strain Harlingen) in vitro at a mutation frequency of 2.3 × 10
−8
. Mutations in the
rpoB
gene were identified, and the growth rates of three defined mutants were measured by competition with the susceptible parent strain in laboratory medium and by single cultures in a macrophage cell line and in laboratory medium. All of the mutants showed a decreased growth rate in the three assays. The relative fitness of the mutants varied between 0.29 and 0.96 (that of the susceptible strain was set to 1.0) depending on the specific mutant and assay system. Unexpectedly, the relative fitness ranking of the mutants differed between the different assays. In conclusion, rifampin resistance is associated with a cost that is conditional.
Emerging Plasmid-Mediated Quinolone Resistance Associated with the
qnr
Gene in
Klebsiella pneumoniae
Clinical Isolates in the United States
Authors: Wang Minggui , Sahm Daniel F. , Jacoby George A. , Hooper David C. 
Published: March 2004

ABSTRACT

Although quinolone resistance commonly results from chromosomal mutation, recent studies indicate that such resistance can also be transferred on plasmids carrying the gene responsible,
qnr
. One hundred ten ciprofloxacin-resistant clinical isolates of
Klebsiella pneumoniae
and
Escherichia coli
from the United States were screened for the
qnr
gene by PCR and Southern hybridization of plasmid DNA. Conjugation experiments were done with azide-resistant
E. coli
J53 as the recipient and selection with azide and sulfonamide, a resistance frequently linked to
qnr
. EcoRI and BamHI digests of
qnr
-hybridizing plasmids were subjected to electrophoresis on agarose gels and probed with
qnr
by Southern hybridization.
qnr
was detected in 8 (11.1%) of 72
K. pneumoniae
strains. These eight positive strains were from six states in the United States.
qnr
was not found in any of the 38
E. coli
strains tested. Quinolone resistance was transferred from seven of the eight probe-positive strains. Transconjugants with
qnr
-hybridizing plasmids had 32-fold increases in ciprofloxacin MICs relative to
E. coli
J53. For all eight strains, the sequence of
qnr
was identical to that originally reported. By size and restriction digests, four plasmids were related to the first-reported plasmid, pMG252, and three were different. Five new
qnr
plasmids encoded FOX-5 β-lactamase, as did pMG252, but two others produced SHV-7 extended-spectrum β-lactamase. Transferable plasmid-mediated quinolone resistance associated with
qnr
is now widely distributed in quinolone-resistant clinical strains of
K. pneumoniae
in the United States. Plasmid-determined quinolone resistance contributes to the increasing quinolone resistance of
K. pneumoniae
isolates and to the linkage previously observed between resistance to quinolones and the latest β-lactam antibiotics.
Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase
Authors: Feng Joy Y. , Murakami Eisuke , Zorca Suzana M. , Johnson Allison A. , Johnson Kenneth A. , Schinazi Raymond F. , Furman Phillip A. , Anderson Karen S. 
Published: March 2004

ABSTRACTEmtricitabine [(−)FTC; (−)-β-l-2′-3′-dideoxy-5-fluoro-3′-thiacytidine] is an oxathiolane nucleoside analog recently approved by the Food and Drug Administration for the treatment of human immunodeficiency virus (HIV). Structurally, (−)FTC closely resembles lamivudine [(−)3TC] except that the former is 5-fluorinated on the cytosine ring. In HIV-1 reverse transcriptase (RT) enzymatic assays, the triphosphate of (−)FTC [(−)FTC-TP] was incorporated into both DNA-DNA and DNA-RNA primer-templates nearly 3- and 10-fold more efficiently than (−)3TC-TP. Animal studies and clinical trial studies have demonstrated a favorable safety profile for (−)FTC. However, a detailed study of the incorporation of (−)FTC-TP by human mitochondrial DNA polymerase γ, a host enzyme associated with nucleoside toxicity, is required for complete understanding of the molecular mechanisms of inhibition and toxicity. We studied the incorporation of (−)FTC-TP and its enantiomer (+)FTC-TP into a DNA-DNA primer-template by recombinant human mitochondrial DNA polymerase in a pre-steady-state kinetic analysis. (−)FTC-TP was incorporated 2.9 × 105-, 1.1 × 105-, 1.6 × 103-, 7.9 × 103-, and 100-fold less efficiently than dCTP, ddCTP, (+)3TC-TP, (+)FTC-TP, and (−)3TC-TP, respectively. The rate of removal of (−)FTC-MP from the corresponding chain-terminated 24-mer DNA by polymerase γ's 3′→5′ exonuclease activity was equal to the removal of (+)FTC-MP, 2-fold slower than the removal of (−)3TC-MP and (+)3TC-MP, and 4.6-fold slower than the excision of dCMP. These results demonstrate that there are clear differences between HIV-1 RT and polymerase γ in terms of preferences for substrate structure.
Enhancement of the
mexAB
-
oprM
Efflux Pump Expression by a Quorum-Sensing Autoinducer and Its Cancellation by a Regulator, MexT, of the
mexEF
-
oprN
Efflux Pump Operon in
Pseudomonas aeruginosa
Authors: Maseda Hideaki , Sawada Isao , Saito Kohjiro , Uchiyama Hiroo , Nakae Taiji , Nomura Nobuhiko 
Published: March 2004

ABSTRACT

nfxC
-type cells of
Pseudomonas aeruginosa
that produce the MexEF-OprN efflux pump exhibit resistance to fluoroquinolones and chloramphenicol and hypersusceptibility to most classical β-lactam antibiotics. We investigated the molecular mechanism of how the
nfxC
mutation causes β-lactam hypersusceptibility. The MexAB-OprM extrusion pump transports and confers resistance to β-lactam antibiotics. Interestingly, expression of the
mexAB-oprM
operon reached the highest level during the mid-stationary growth phase in both wild-type and
nfxC
-type mutant strains, suggesting that expression of the
mexAB-oprM
operon may be controlled by cell density-dependent regulation such as quorum sensing. This assumption was verified by demonstrating that exogenous addition of the quorum-sensing autoinducer
N
-butyryl-
l
-homoserine lactone (C4-HSL) enhanced the expression of MexAB-OprM, whereas
N
-(3-oxododecanoyl)-
l
-homoserine lactone had only a slight effect. Furthermore, this C4-HSL-mediated enhancement of
mexAB-oprM
expression was repressed by MexT, a positive regulator of the
mexEF-oprN
operon. It was concluded that β-lactam hypersusceptibility in
nfxC
-type mutant cells is caused by MexT-mediated cancellation of C4-HSL-mediated enhancement of MexAB-OprM expression.
Activities of Artesunate and Primaquine againstAsexual- and Sexual-Stage Parasites in FalciparumMalaria
Authors: Pukrittayakamee Sasithon , Chotivanich Kesinee , Chantra Arun , Clemens Ralf , Looareesuwan Sornchai , White Nicholas J. 
Published: March 2004

ABSTRACT

The
activities of primaquine in combination with quinine or artesunate
against asexual- and sexual-stage parasites were assessed in 176 adult
Thai patients with uncomplicated
Plasmodium falciparum
malaria. Patients were randomized to one of the six following 7-day
oral treatment regimens: (i) quinine alone, (ii) quinine with
tetracycline, (iii) quinine with primaquine at 15 mg/day, (iv) quinine
with primaquine at 30 mg/day, (v) artesunate alone, or (vi) artesunate
with primaquine. Clinical recovery occurred in all patients. There were
no significant differences in fever clearance times, rates of
P.
falciparum
reappearance, or recurrent vivax malaria between the
six treatment groups. Patients treated with artesunate alone or in
combination with primaquine had significantly shorter parasite
clearance times (mean ± standard deviation = 65±
18 versus 79 ± 21 h) and lower gametocyte
carriage rates (40 versus 62.7%) than those treated with quinine
(
P
≤ 0.007). Primaquine did not affect the therapeutic
response (
P
> 0.2). Gametocytemia was detected in 98
patients (56% [22% before treatment and 34%
after treatment]). Artesunate reduced the appearance of
gametocytemia (relative risk [95% confidence
interval] = 0.34 [0.17 to 0.70]), whereas
combinations containing primaquine resulted in shorter gametocyte
clearance times (medians of 66 versus 271 h for quinine
groups and 73 versus 137 h for artesunate groups;
P
≤
0.038). These results suggest that artesunate predominantly
inhibits gametocyte development whereas primaquine accelerates
gametocyte clearance in
P. falciparum
malaria.
Potent Synergistic In Vitro Interaction between Nonantimicrobial Membrane-Active Compounds and Itraconazole against Clinical Isolates of
Aspergillus fumigatus
Resistant to Itraconazole
Authors: Afeltra Javier , Vitale Roxana G. , Mouton Johan W. , Verweij Paul E. 
Published: March 2004

ABSTRACT

To develop new approaches for the treatment of invasive infections caused by
Aspergillus fumigatus
, the in vitro interactions between itraconazole (ITZ) and seven different nonantimicrobial membrane-active compounds—amiodarone (AMD), amiloride, lidocaine, lansoprazole (LAN), nifedipine (NIF), verapamil, and fluphenazine—against seven ITZ-susceptible and seven ITZ-resistant (ITZ-R) strains were evaluated by the checkerboard microdilution method based on National Committee for Clinical Laboratory Standards M-38A guidelines. The nature and the intensity of the interactions were assessed by a nonparametric approach (fractional inhibitory concentration [FIC] index model), a fully parametric response surface approach (Greco model) of the Loewe additivity no-interaction theory, and the nonparametric (Prichard model) and semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory. Statistically significant synergy was found for the combination of ITZ and AMD and the combination of LAN and NIF, although with different intensities against ITZ-R strains. The FIC index values ranged from 1 to 0.02 for ITZ-AMD, 0.53 to 0.04 for ITZ-LAN, and 0.28 to 0.06 for ITZ-NIF. By use of the BI-based model, the strongest synergy was found for the combination of ITZ with AMD, followed by the combination of ITZ and NIF. The parametric models could not be fit adequately because most of the drugs alone did not show any effect and, thus, no sigmoid dose-response. In general, the combination of ITZ with calcium pump blockers displayed in vitro synergistic activity, primarily against ITZ-R strains, and warrants further investigation.
Mutations in a 23S rRNA Gene of
Chlamydia trachomatis
Associated with Resistance to Macrolides
Authors: Misyurina O. Y. , Chipitsyna E. V. , Finashutina Y. P. , Lazarev V. N. , Akopian T. A. , Savicheva A. M. , Govorun V. M. 
Published: March 2004

ABSTRACT

For six clinical isolates of
Chlamydia trachomatis
, in vitro susceptibility to erythromycin, azithromycin, and josamycin has been determined. Four isolates were resistant to all the antibiotics and had the mutations A2058C and T2611C (
Escherichia coli
numbering) in the 23S rRNA gene. All the isolates had mixed populations of bacteria that did and did not carry 23S rRNA gene mutations.
Dissemination ofblaCMY-2amongEscherichia coliIsolates from Food Animals, Retail Ground Meats, and Humans in Southern Taiwan
Authors: Yan Jing-Jou , Hong Ching-Yi , Ko Wen-Chien , Chen Yuan-Jui , Tsai Shu-Huei , Chuang Chin-Luan , Wu Jiunn-Jong 
Published: March 2004

ABSTRACTTwenty-sixEscherichia coliisolates recovered from food animal feces and retail ground meats and 14 urinaryE. coliisolates from outpatients were shown to carryblaCMY-2. Similar CMY-2-encoding plasmids were found among seven human and three ground-pork isolates. These data indicate the community spread ofblaCMY-2in southern Taiwan.
6,7-Dihydroxyflavone Dramatically Intensifies the Susceptibility of Methicillin-Resistant or -Sensitive
Staphylococcus aureus
to β-Lactams
Authors: Sato Youichi , Shibata Hirofumi , Arakaki Naokatu , Higuti Tomihiko 
Published: March 2004

ABSTRACT

We have demonstrated that 6,7-dihydroxyflavone by itself has only a weak antibacterial effect on methicillin-resistant
Staphylococcus aureus
(MRSA) but that at concentrations less than MIC it synergistically elevates the susceptibility of clinically isolated MRSA and methicillin-sensitive
S. aureus
strains to β-lactam antibiotics from 8- to 32,800-fold.
Increasing Prevalence of Methicillin-Resistant
Staphylococcus aureus
Causing Nosocomial Infections at a University Hospital in Taiwan from 1986 to 2001
Authors: Hsueh Po-Ren , Teng Lee-Jene , Chen Wen-Hwei , Pan Huei-Ju , Chen Mei-Lin , Chang Shan-Chwen , Luh Kwen-Tay , Lin Fang-Yue 
Published: March 2004

ABSTRACT

A rapid emergence of nosocomial methicillin-resistant
Staphylococcus aureus
(MRSA) infection (from 26.3% in 1986 to 77% in 2001) was found. The susceptibility of 200 nonduplicate blood isolates of MRSA and 100 MRSA isolates causing refractory bacteremia to 22 antimicrobial agents disclosed that glycopeptides, quinupristin-dalfopristin, and linezolid remained the most active agents.
Clonal Relatedness of Erythromycin-Resistant
Streptococcus pyogenes
Isolates in Germany
Authors: Reinert Ralf R. , Lütticken Rudolf , Sutcliffe Joyce A. , Tait-Kamradt Amelia , Cil Murat Y. , Schorn Holger M. , Bryskier André , Al-Lahham Adnan 
Published: March 2004

ABSTRACT

In a nationwide study in Germany, a total of 381
Streptococcus pyogenes
were collected. Erythromycin A-resistant strains were characterized for the underlying resistance genotype, showing 55.6% had the efflux type
mef
(A), 31.5% had
erm
(A), and 13.0% had
erm
(B). A total of 23 different multilocus sequence types were observed.
Reduction in Glycopeptide Resistance in Vancomycin-Resistant Enterococci as a Result of
vanA
Cluster Rearrangements
Authors: Lee Wee Gyo , Huh Ji Young , Cho Sung Ran , Lim Young Ae 
Published: March 2004

ABSTRACT

The molecular characterization of five clinical isolates of
vanA
-containing vancomycin-resistant enterococci with altered resistance to glycopeptides was examined. One strain represented an IS
1216V
insertion accompanied by partial deletion of the reading frame of
vanX
following a transposition event. The other four strains represented IS
1216V
within the
vanX
-
vanY
intergenic region associated with deletion of
vanY
or
vanZ
.