bluuebunny/crossref_metadata_2025_split huggingface dataset:
Active Efflux of Norfloxacin by
Bacteroides fragilis
Authors: Miyamae Shin , Nikaido Hiroshi , Tanaka Yoshinobu , Yoshimura Fuminobu 
Published: October 2018

ABSTRACT

Norfloxacin was actively pumped out by
Bacteroides fragilis
, which is intrinsically resistant to most fluoroquinolones. Reserpine moderately inhibited the efflux. A one-step spontaneous mutant had increased resistance to norfloxacin, ethidium bromide, and puromycin, a result suggesting that the efflux is catalyzed by a multidrug pump with specificity similar to that of NorA/Bmr.
Molecular Characterization of a TEM-21 β-Lactamase in a Clinical Isolate of
Morganella morganii
Authors: Tessier F. , Arpin C. , Allery A. , Quentin C. 
Published: October 2018

ABSTRACT

A clinical isolate of
Morganella morganii
, with reduced susceptibility to expanded-spectrum cephalosporins and aztreonam, was found to produce an extended-spectrum β-lactamase with a pI of 6.4. The nucleotide sequence of the encoding gene was that of the gene encoding TEM-21. This is the first molecular characterization of an extended-spectrum β-lactamase in
M. morganii.
Inhibitor-Resistant OXY-2-Derived β-Lactamase Produced by
Klebsiella oxytoca
Authors: Sirot D. , Labia R. , Pouedras P. , Chanal-Claris C. , Cerceau C. , Sirot J. 
Published: October 2018

ABSTRACT

Klebsiella oxytoca
strains are generally moderately resistant to amoxicillin and ticarcillin due to the activities of the chromosomally encoded OXY-1 and OXY-2 class A β-lactamase families. These enzymes have the ability to hydrolyze not only penicillins but also cephalosporins, including cefuroxime, ceftriaxone, and aztreonam, and are inhibited by clavulanic acid. A
Klebsiella oxytoca
strain was isolated from a culture of blood from a patient who had been treated with amoxicillin-clavulanate (3 g/day) for 10 days 1 month earlier. This strain harbored an unusual phenotype characterized by resistance to amoxicillin-clavulanate. It produced an OXY-2-type β-lactamase (pI 6.3), as confirmed by PCR amplification with primers specific for the OXY-2-encoding gene. Gene sequencing revealed a point mutation (A→G) corresponding to the amino acid substitution Ser→Gly at position 130. This mutant enzyme was poorly inhibited by inhibitors, and its kinetic constants compared to those of the parent enzyme were characterized by an increased

K
m

value for ticarcillin, with a drastically reduced activity against cephalosporins, as is observed with inhibitor-resistant TEM enzymes. The substitution Ser→Gly-130 was previously described in the inhibitor-resistant β-lactamase SHV-10 derived from an SHV-5 variant, but this is the first report of such a mutant in OXY enzymes from
K. oxytoca
.
Synergy of Nitric Oxide and Azoles against
Candida
Species In Vitro
Authors: McElhaney-Feser Gail E. , Raulli Robert E. , Cihlar Ronald L. 
Published: October 2018

ABSTRACT

The candidacidal activity of nitric oxide (NO) as delivered by a class of compounds termed diazeniumdiolates has been investigated. Diazeniumdiolates are stable agents capable of releasing NO in a biologically usable form at a predicted rate, and three such compounds were examined for activity. One compound, (
Z
)-1-[
N
-(2-aminoethyl)-
N
-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), proved to be most suitable for examining NO activity due to its relatively long half-life (20 h) and because of limited candidacidal activity of the uncomplexed DETA nucleophile. DETA-NO was active against six species of
Candida
for which the MICs necessary to inhibit 50% growth (MIC
50
s) ranged from 0.25 to 1.0 mg/ml.
C. parapsilosis
and
C. krusei
were the most susceptible to the compound. In addition to a determination of NO effects alone, the complex was utilized to investigate the synergistic potential of released NO in combination with ketoconazole, fluconazole, and miconazole. Activity was investigated in vitro against representative strains of
Candida albicans
,
C. krusei
,
C. parapsilosis
,
C. tropicalis
,
C. glabrata
, and
C. dubliniensis
. Determination of MIC
50
, MIC
80
and MICs indicated that DETA-NO inhibits all strains tested, with strains of
C. parapsilosis
and
C. krusei
being consistently the most sensitive. The combination of DETA-NO with each azole was synergistic against all strains tested as measured by fractional inhibitory concentration indices that ranged from 0.1222 to 0.4583. The data suggest that DETA-NO or compounds with similar properties may be useful in the development of new therapeutic strategies for treatment of
Candida
infections.
In Vivo Activities of Amoxicillin and Amoxicillin-Clavulanate against
Streptococcus pneumoniae
: Application to Breakpoint Determinations
Authors: Andes D. , Craig W. A. 
Published: October 2018

ABSTRACT

The in vivo activities of amoxicillin and amoxicillin-clavulanate against 17 strains of
Streptococcus pneumoniae
with penicillin MICs of 0.12–8.0 mg/liter were assessed in a cyclophosphamide-induced neutropenic murine thigh infection model. Renal impairment was produced by administration of uranyl nitrate to prolong the amoxicillin half-life in the mice from 21 to 65 min, simulating human pharmacokinetics. Two hours after thigh infection with 10
5
to 10
6
CFU, groups of mice were treated with 7 mg of amoxicillin per kg of body weight alone or combined with clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log
10
CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log
10
CFU/thigh at 24 h by amoxicillin and amoxicillin-clavulanate, respectively. The four strains for which MICs were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2.3 logs at 24 h despite therapy with amoxicillin and amoxicillin-clavulanate, respectively. Infection was uniformly fatal by 72 h in untreated mice. Amoxicillin therapy resulted in no mortality with organisms for which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms for which MICs were 2 mg/liter, and 80 to 100% mortality with organisms for which MICs were 4.0–5.6 mg/liter. Lower and higher doses (0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log
10
or greater in CFU/thigh at 24 h is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of
S. pneumoniae
.
Dynamics of Clarithromycin and Azithromycin Efficacies against ExperimentalHaemophilus influenzaePulmonary Infection
Authors: Alder J. D. , Ewing P. J. , Nilius A. M. , Mitten M. , Tovcimak A. , Oleksijew A. , Jarvis K. , Paige L. , Tanaka S. K. T. 
Published: October 2018

ABSTRACTThe dynamics of clarithromycin and azithromycin efficacy against pulmonaryHaemophilus influenzaeinfection in rats were evaluated. Efficacy was measured by reduction in pulmonaryH. influenzaeburden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains ofH. influenzaetested, including four strains for which MICs were above the susceptible breakpoint (8 μg/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats,H. influenzaewas found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs forH. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy.
Pharmacokinetics of Pentoxifylline and Its Metabolites in Healthy Mice and in Mice Infected with
Candida albicans
Authors: Miller Kenneth , Louie Arnold , Baltch Aldona L. , Smith Raymond P. , Davis Patrick J. , Gordon Morris A. 
Published: October 2018

ABSTRACT

Pentoxifylline has immunomodulatory properties and has been shown to decrease organ damage and improve survival in animals with gram-negative sepsis or endotoxemia. This effect is mediated by a reduction in endotoxin-induced production of tumor necrosis factor alpha (TNF-α) by the host. In earlier studies, we observed an unexpected increase in mortality in mice infected with
Candida albicans
that were given pentoxifylline even though concentrations of TNF-α in serum were not affected. The current study was designed to determine whether the pharmacokinetics of pentoxifylline and its metabolites were altered in
C. albicans
-infected mice and, if so, whether these changes could have contributed to the increased mortality. Noninfected mice and mice infected with
C. albicans
were treated with pentoxifylline (60 mg/kg of body weight) intraperitoneally every 8 h. Serum was collected from animals after one (day 0), four (day 1), or seven (day 2) injections of pentoxifylline or saline (controls). The first dose was administered 6 h after
C. albicans
infection. Serum was pooled. Concentrations of pentoxifylline and metabolites I, IV, and V were determined by capillary gas chromatography. Renal function and hepatic profiles were assessed. Pharmacokinetic parameters (maximum concentration of pentoxifylline in serum, half-life, and area under the concentration-time curve from 0 h to infinity [AUC
0–∞
]) for all noninfected mice were similar and did not differ from those for day 0-infected mice. For day 1-infected mice, values of these three pharmacokinetic parameters for pentoxifylline and metabolite I were increased two- to fourfold over values for noninfected and day 0-infected mice. For metabolites IV and V, the AUC
0–∞
was increased approximately eightfold over control values. In addition, day 1-infected mice demonstrated evidence of renal and hepatic dysfunction. In summary,
C. albicans
infection produced marked changes in the pharmacokinetics of pentoxifylline and its metabolites in the mice. The high concentrations of pentoxifylline and its metabolites in serum attained in infected mice may have contributed to the increased mortality of mice with systemic candidiasis.
Single-Dose Pharmacokinetics of Meropenem during Continuous Venovenous Hemofiltration
Authors: Thalhammer Florian , Schenk Peter , Burgmann Heinz , El Menyawi Ibrahim , Hollenstein Ursula M. , Rosenkranz Alexander R. , Sunder-Plassmann Gere , Breyer Stefan , Ratheiser Klaus 
Published: October 2018

ABSTRACT
The pharmacokinetic properties of meropenem were investigated in nine critically ill patients treated by continuous venovenous hemofiltration (CVVH). All patients received one dose of 1 g of meropenem intravenously. High-flux polysulfone membranes were used as dialyzers. Meropenem levels were measured in plasma and ultrafiltrate by high-performance liquid chromatography. The total body clearance and elimination half-life were 143.7 ± 18.6 ml/min and 2.46 ± 0.41 h, respectively. The post- to prehemofiltration ratio of meropenem was 0.24 ± 0.06. Peak plasma drug concentrations measured 60 min postinfusion were 28.1 ± 2.7 μg/ml, and trough levels after 6 h of CVVH were 6.6 ± 1.5 μg/ml. The calculated total daily meropenem requirement in these patients with acute renal failure and undergoing CVVH was 2,482 ± 321 mg. Based on these data, we conclude that patients with severe infections who are undergoing CVVH can be treated effectively with 1 g of meropenem every 8 h.
Susceptibilities of
Candida
Species Isolated from the Lower Gastrointestinal Tracts of High-Risk Patients to the New Semisynthetic Echinocandin LY303366 and Other Antifungal Agents
Authors: Zhanel George G. , Karlowsky James A. , Zelenitsky Sheryl A. , Turik Michael A. , Hoban Daryl J. 
Published: October 2018

ABSTRACT

Fifty-two percent of stool specimens collected from 1,200 high-risk patients were colonized with yeasts, primarily
Candida albicans
(53.6%) and
Candida glabrata
(35.7%). Susceptibilities to all antifungal agents tested, including LY303366, were similar to those reported previously for
Candida
species isolated from blood.
Synergism between Poly-(1-6)-β-
d
-Glucopyranosyl-(1-3)-β
d
-Glucopyranose Glucan and Cefazolin in Prophylaxis of Staphylococcal Wound Infection in a Guinea Pig Model
Authors: Kaiser Allen B. , Kernodle Douglas S. 
Published: October 2018

ABSTRACT

To determine whether the infection-preventing capability of the neutrophil-activating agent poly-(1-6)-β-
d
-glucopyranosyl-(1-3)-β-
d
-glucopyranose glucan (PGG-glucan) can be enhanced with antibiotic prophylaxis, we administered PGG-glucan and cefazolin, alone and in combination, to guinea pigs inoculated with isolates of staphylococci. Guinea pigs receiving both PGG-glucan and cefazolin had 50% infective doses that were 8- to 20-fold higher than those obtained with cefazolin alone and 100- to 200-fold higher than those obtained with PGG-glucan alone. PGG-glucan and cefazolin are synergistic in their ability to prevent staphylococcal wound infection.
Antimalarial Activities of Polyhydroxyphenyl and Hydroxamic Acid Derivatives
Authors: Holland Kevin P. , Elford Howard L. , Bracchi Valerie , Annis Charles G. , Schuster Sheldon M. , Chakrabarti Debopam 
Published: October 2018

ABSTRACT

Several known mammalian ribonucleotide reductase inhibitors featuring a polyhydroxyphenyl and/or hydroxamate moiety as the active group were screened for potency in inhibiting growth of the malaria parasite
Plasmodium falciparum
. Compounds containing a 2,3- or 3,4-dihydroxyphenyl group as well as benzohydroxamate appear to be the most effective inhibitors of the malaria parasite.
Penetration of Oral Fluconazole into Gynecological Tissues
Authors: Mikamo Hiroshige , Kawazoe Kyoko , Sato Yasumasa , Izumi Koji , Ito Toshiya , Ito Kunihiko , Tamaya Teruhiko 
Published: October 2018

ABSTRACT
Penetration of fluconazole into female genital tissues was examined. Fluconazole was administered orally at a dose of 150 mg to patients undergoing total abdominal hysterectomy 1 to 151 h prior to surgery. During surgery, blood, uterus, ovary, and oviduct were sampled. Fluconazole concentrations in each tissue were determined by high-performance liquid chromatography. The peak concentrations in serum reached approximately 6.1 μg/ml 1.0 h after a drip infusion was begun. At each time after the infusion, the concentrations in portio vaginalis, cervix uteri, myometrium, endometrium, ovary, and oviduct were higher than those in the serum: the peaks in the tissues ranged from 6.4 to 9.5 μg/g around 1.0 h after the drip infusion was begun. Thus, the levels of penentration of fluconazole into gynecological tissues appeared to be similar to or slightly above those in serum samples. Fluconazole can rapidly penetrate from plasma into the female genital organs, supporting high efficacy of fluconazole against fungal infections in the field of gynecology.
Targeting the Shikimate Pathway in the Malaria Parasite
Plasmodium falciparum
Authors: McConkey Glenn A. 
Published: October 2018

ABSTRACT

The shikimate pathway presents an attractive target for malaria chemotherapy. Three shikimic acid analogs exhibited different effects on
Plasmodium falciparum
growth. (6
R
)-6-Fluoro-shikimate and (6
S
)-6-fluoro-shikimate inhibited growth (50% inhibitory concentrations, 1.5 × 10
−5
and 2.7 × 10
−4
M, respectively), whereas 2-fluoro-shikimate had no effect.
para
-Aminobenzoic acid abrogated the inhibition, demonstrating that the shikimate pathway was specifically targeted.
Development of Rifapentine Susceptibility Tests for
Mycobacterium tuberculosis
Authors: Heifets L. , Sanchez T. , Vanderkolk J. , Pham V. 
Published: October 2018

ABSTRACT

Two methods for testing the susceptibility of
Mycobacterium tuberculosis
to rifapentine have been developed: the agar proportion method and the radiometric BACTEC technique. A critical concentration of 0.5 μg of rifapentine per ml is proposed for both methods since it provides a reliable means of distinguishing between susceptible and resistant
M. tuberculosis
isolates. It is recommended that two quality control
M. tuberculosis
strains be used at the introduction of these tests in a clinical laboratory: one that is pansusceptible (H37Rv) and one that is resistant to rifapentine. The resistant strain can be obtained from the American Type Culture Collection, where it is deposited under the number ATCC 700457.
Characterization of Mutations in the
rpoB
Gene in Naturally Rifampin-Resistant
Rickettsia
Species
Authors: Drancourt Michel , Raoult Didier 
Published: October 2018

ABSTRACT

Rickettsiae are gram-negative, obligately intracellular bacteria responsible for arthropod-borne spotted fevers and typhus. Experimental studies have delineated a cluster of naturally rifampin-resistant spotted fever group species. We sequenced the 4,122- to 4,125-bp RNA polymerase β-subunit-encoding gene (
rpoB
) from typhus and spotted fever group representatives and obtained partial sequences for all naturally rifampin-resistant species. A single point mutation resulting in a phenylalanine-to-leucine change at position 973 of the
Rickettsia conorii rpoB
sequence and present in all the rifampin-resistant species was absent in all the rifampin-susceptible species.
rpoB
-based phylogenetic relationships among these rickettsial species yielded topologies which were in accordance with previously published phylogenies.
Phenotypic and Genetic Characterization of Thymidine Kinase from Clinical Strains of Varicella-Zoster Virus Resistant to Acyclovir
Authors: Morfin Florence , Thouvenot Danielle , De Turenne-Tessier Mireille , Lina Bruno , Aymard Michèle , Ooka Tadamasa 
Published: October 2018

ABSTRACT

Varicella-zoster virus (VZV) is a common herpesvirus responsible for disseminated or chronic infections in immunocompromised patients. Effective drugs such as acyclovir (ACV), famciclovir (prodrug of penciclovir), and foscarnet are available to treat these infections. Here we report the phenotypic and genetic characterization of four ACV-resistant VZV strains isolated from AIDS patients and transplant recipients. Sensitivity to six antiviral drugs was determined by an enzyme-linked immunosorbent assay, viral thymidine kinase (TK) activity was measured by comparing [
3
H]thymidine and 1-β-
d
-arabinofuranosyl-[
3
H]thymine as substrates, and the TK gene open reading frame was sequenced. Three strains were found to be TK deficient, and the fourth was a mixed population composed of TK-positive and TK-deficient viruses. Each strain presented a unique TK gene mutation that could account for ACV resistance. In one strain, the deletion of two nucleotides at codon 215 induced a premature stop signal at codon 217. In another strain, a single nucleotide addition at codon 167 resulted in a premature stop signal at codon 206. In both other strains, we identified amino acid substitutions already described in other ACV-resistant VZV strains: either Glu→Gly at residue 48 or Arg→Gly at residue 143. According to our work and data previously reported on resistant VZV strains, there are three areas in the TK gene where 71% of the mutations described to date are located. These areas are putative candidates for a genotypic diagnosis of ACV resistance.
Propagation of TEM- and PSE-Type β-Lactamases among Amoxicillin-Resistant
Salmonella
spp. Isolated in France
Authors: Llanes Catherine , Kirchgesner Veronique , Plesiat Patrick 
Published: October 2018

ABSTRACT

A survey conducted between 1987 and 1994 at the University Hospital of Besançon, France, demonstrated a dramatic increase (from 0 to 42.5%) in the prevalence of amoxicillin resistance among
Salmonella
spp. Of the 96 resistant isolates collected during this period (including 77 Typhimurium), 54 were found to produce TEM-1 β-lactamase, 40 produced PSE-1 (equivalent to CARB-2), one produced PSE-1 plus TEM-2, and one produced OXA-1 in isoelectric focusing and DNA hybridization experiments. Plasmids coding for these β-lactamases were further characterized by (i) profile analysis, (ii) restriction fragmentation pattern analysis, (iii) hybridization with an
spvCD-orfE
virulence probe, and (iv) replicon typing. In addition, isolates of
S. typhimurium
were genotypically compared by pulsed-field gel electrophoresis of
Xba
I-macrorestricted chromosomal DNA. Altogether, these methods showed that 40 of the 41 PSE-1 producers were actually the progeny of a single epidemic
S. typhimurium
strain lysotype DT104. Isolates of that strain were found to harbor RepFIC virulence plasmids with somewhat different restriction profiles, but which all carried the
bla
PSE-1
gene. Of these virulence/resistance plasmids, 15 were transmissible to
Escherichia coli
. TEM-1-producing
S. typhimurium
displayed much greater genotypic and plasmidic diversities, suggesting the acquisition of the
bla
TEM-1
gene from multiple bacterial sources by individual strains. In agreement with this, 32 of the 35
S. typhimurium
plasmids encoding TEM-1 were found to be conjugative. These data show that development of amoxicillin resistance among
Salmonella
, especially in serovar Typhimurium, results from both gene transfers and strain dissemination.
Metabolism and Selective Toxicity of 6-Nitrobenzylthioinosine in
Toxoplasma gondii
Authors: el Kouni Mahmoud H. , Guarcello Vincenzo , Al Safarjalani Omar N. , Naguib Fardos N. M. 
Published: October 2018

ABSTRACT

The purine nucleoside analogue NBMPR {nitrobenzylthioinosine or 6-[(4-nitrobenzyl)thio]-9-β-
d
-ribofuranosylpurine} was selectively phosphorylated to its nucleoside 5′-monophosphate by
Toxoplasma gondii
but not mammalian adenosine kinase (EC
2.7.1.20
). NBMPR was also cleaved in toxoplasma to its nucleobase, nitrobenzylmercaptopurine. However, nitrobenzylmercaptopurine was not a substrate for either adenosine kinase or hypoxanthine-guanine-xanthine phosphoribosyltransferase (EC
2.4.2.8
). Because of this unique and previously unknown metabolism of NBMPR by the parasite, the effect of NBMPR as an antitoxoplasmic agent was tested. NBMPR killed
T. gondii
grown in human fibroblasts in a dose-dependent manner, with a 50% inhibitory concentration of approximately 10 μM and without apparent toxicity to host cells. Doses of up to 100 μM had no significant toxic effect on uninfected host cells. The promising antitoxoplasmic effect of NBMPR led to the testing of other 6-substituted 9-β-
d
-ribofuranosylpurines, which were shown to be good ligands of the parasite adenosine kinase (M. H. Iltzsch, S. S. Uber, K. O. Tankersley, and M. H. el Kouni, Biochem. Pharmacol. 49:1501–1512, 1995), as antitoxoplasmic agents. Among the analogues tested, 6-benzylthioinosine,
p
-nitrobenzyl-6-selenopurine riboside,
N
6
-(
p
-azidobenzyl)adenosine, and
N
6
-(
p
-nitrobenzyl)adenosine, like NBMPR, were selectively toxic to parasite-infected cells. Thus, it appears that the unique characteristics of purine metabolism in
T. gondii
render certain 6-substituted 9-β-
d
-ribofuranosylpurines promising antitoxoplasmic drugs.