bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity
Authors: Hikida Muneo , Itahashi Kouju , Igarashi Atsumi , Shiba Toshiharu , Kitamura Masataka 
Published: October 2018

ABSTRACT

LJC 11,036 is the active metabolite of L-084, a novel oral carbapenem that exhibits potent broad-spectrum activity. Antibacterial activities of LJC 11,036 against clinical isolates from respiratory infections, such as
Streptococcus pneumoniae
(
n
= 52),
Streptococcus pyogenes
(
n
= 19),
Haemophilus influenzae
(
n
= 50),
Klebsiella pneumoniae
(
n
= 53), and
Moraxella catarrhalis
(
n
= 53), and from urinary-tract infections, such as
Escherichia coli
(
n
= 53) (MICs at which 90% of the isolates were inhibited [MIC
90
s], 0.1, ≤0.006, 0.39, 0.05, 0.05, and 0.05 μg/ml, respectively), were 2- to 64-fold higher than those of imipenem, cefdinir, and faropenem. Moreover, against these bacterial species, except for
H. influenzae
, the MIC
90
s of LJC 11,036 were 4- to 512-fold lower than those of levofloxacin. LJC 11,036 showed bactericidal activity equal or superior to that of imipenem. Bactericidal activity against penicillin-resistant
S. pneumoniae
(PRSP) did not vary with the phase of growth. LJC 11,036 had potent activity against various β-lactamase-producing strains, excluding carbapenemase producers. Against renal dehydropeptidase-I, LJC 11,036 was more stable than imipenem. Furthermore, LJC 11,036 produced in vitro postantibiotic sub-MIC effects against PRSP HSC-3 (6.0 h at one-fourth the MIC) and
H. influenzae
LJ5 (9.2 h at one-half the MIC). LJC 11,036 showed high binding affinities for PBP1A, -1B, -2A/2X, -2B, and -3 of PRSP and for PBP1B, -2, -3A, and -3B of
H. influenzae
.
Comparative In Vitro Activities of Ciprofloxacin, Clinafloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin, and Trovafloxacin against
Klebsiella pneumoniae
,
Klebsiella oxytoca
,
Enterobacter cloacae
, and
Enterobacter aerogenes
Clinical Isolates with Alterations in GyrA and ParC Proteins
Authors: Brisse Sylvain , Milatovic Dana , Fluit Ad C. , Verhoef Jan , Martin Nele , Scheuring Sybille , Köhrer Karl , Schmitz Franz-Josef 
Published: October 2018

ABSTRACT

The in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin were tested against 72 ciprofloxacin-resistant and 28 ciprofloxacin-susceptible isolates of
Klebsiella pneumoniae
,
Klebsiella oxytoca
,
Enterobacter cloacae
, and
Enterobacter aerogenes
. Irrespective of the alterations in GyrA and ParC proteins, clinafloxacin exhibited greater activity than all other fluoroquinolones tested against
K. pneumoniae
and
E. aerogenes
.
Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis
Authors: Miyazaki Eishi , Chaisson Richard E. , Bishai William R. 
Published: October 2018

ABSTRACT

Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with
Mycobacterium tuberculosis
and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.
Comparative Studies of Mutations in Animal Isolates and Experimental In Vitro- and In Vivo-Selected Mutants of
Salmonella
spp. Suggest a Counterselection of Highly Fluoroquinolone-Resistant Strains in the Field
Authors: Giraud Etienne , Brisabois Anne , Martel Jean-Louis , Chaslus-Dancla Elisabeth 
Published: October 2018

ABSTRACT

The occurrence of mutations in the genes coding for gyrase (
gyrA
and
gyrB
) and topoisomerase IV (
parE
and
parC
) of
Salmonella typhimurium
experimental mutants selected in vitro and in vivo and of 138 nalidixic acid-resistant
Salmonella
field isolates was investigated. The sequencing of the quinolone resistance-determining region of these genes in highly fluoroquinolone-resistant mutants (MICs of 4 to 16 μg/ml) revealed the presence of
gyrA
mutations at codons corresponding to Gly-81 or Ser-83, some of which were associated with a mutation at Asp-87. No mutations were found in the
gyrB
,
parC
, and
parE
genes. An assay combining allele-specific PCR and restriction fragment length polymorphism was developed to rapidly screen mutations at codons 81, 83, and 87 of
gyrA
. The MICs of ciprofloxacin for the field isolates reached only 2 μg/ml, versus 16 μg/ml for some in vitro-selected mutants. The field isolates, like the mutants selected in vivo, had only a single
gyrA
mutation at codon 83 or 87. Single
gyrA
mutations were also found in highly resistant in vitro-selected mutants (MIC of ciprofloxacin, 8 μg/ml), which indicates that mechanisms other than the unique modification of the intracellular targets could participate in fluoroquinolone resistance in
Salmonella
spp. A comparison of experimental mutants selected in vitro, field strains, and mutants selected in vivo suggests that highly fluoroquinolone-resistant strains are counterselected in field conditions in the absence of selective pressure.
Antifungal Activity of LY303366, a Novel Echinocandin B, in Experimental Disseminated Candidiasis in Rabbits
Authors: Petraitiene Ruta , Petraitis Vidmantas , Groll Andreas H. , Candelario Myrna , Sein Tin , Bell Aaron , Lyman Caron A. , McMillian Carl L. , Bacher John , Walsh Thomas J. 
Published: October 2018

ABSTRACT

The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 10
3
Candida albicans
blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of
C. albicans
from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of
C. albicans
from tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of
C. albicans
only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of
C. albicans
. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.
VanE, a New Type of Acquired Glycopeptide Resistance in
Enterococcus faecalis
BM4405
Authors: Fines Marguerite , Perichon Bruno , Reynolds Peter , Sahm Daniel F. , Courvalin Patrice 
Published: October 2018

ABSTRACT

Enterococcus faecalis
BM4405 was resistant to low levels of vancomycin (MIC, 16 μg/ml) and was susceptible to teicoplanin (MIC, 0.5 μg/ml). No PCR product was obtained when the total DNA of this clinical isolate was used as a template with primers specific for glycopeptide resistance genes
vanA
,
vanB
,
vanC
, and
vanD
. However, a 604-bp PCR fragment was obtained when V1 and V2 degenerate primers were used and total DNA was digested with
Hin
dIII as a template. The product was cloned and sequenced. The deduced amino acid sequence had greater identity (55%) with VanC than with VanA (45%), VanB (43%), or VanD (44%). This was consistent with the fact that BM4405 synthesized peptidoglycan precursors that terminated in
d
-serine residues. After induction with vancomycin, weak
d
,
d
-dipeptidase and penicillin-insensitive
d
,
d
-carboxypeptidase activities were detected in cytoplasmic extracts of BM4405, whereas a serine racemase activity was found in the membrane preparation. This new type of acquired glycopeptide resistance was named VanE.
A New Azole Derivative of 1,4-Benzothiazine Increases the Antifungal Mechanisms of Natural Effector Cells
Authors: Pitzurra Lucia , Fringuelli Renata , Perito Stefano , Schiaffella Fausto , Barluzzi Roberta , Bistoni Francesco , Vecchiarelli Anna 
Published: October 2018

ABSTRACTThe most widely used drug for treatment of candidiasis is fluconazole (FCZ). Recently, a new derivative of 1,4-benzothiazine, compound FS5, was developed. FS5 had an appreciable protective effect against murine candidiasis. The present study was designed to dissect the antifungal mechanisms triggered by FS5 and to establish whether this compound could enhance the antimicrobial abilities of natural effector cells. The results show that intraperitoneal injection of FS5 in mice (i) induced an increase in circulating neutrophil levels comparable to that observed in FCZ-treated mice; (ii) enhanced phagocytosis and the killing activities of macrophages (Mφs) isolated from the spleen or peritoneal cavity, with the latter effect correlating with induction of nitric oxide synthesis and production by Mφs; and (iii) increased the levels of expression and synthesis of tumor necrosis factor alpha. These results suggest that the compound-induced synthesis of antimicrobial and proinflammatory molecules by heterogeneous Mφ populations is part of the beneficial effect of FS5 exerted against murine candidiasis.
Low-Dose Treatment with Sulfadoxine-Pyrimethamine Combinations Selects for Drug-Resistant
Plasmodium falciparum
Strains
Authors: Kun Jürgen F. J. , Lehman Leopold G. , Lell Bertrand , Schmidt-Ott Ruprecht , Kremsner Peter G. 
Published: October 2018

ABSTRACT

A total of 252 children were enrolled in a drug trial to assess the effect of minimal doses of sulfadoxine (Sdx) and pyrimethamine (Pyr). Parasite samples isolated from these patients were analyzed before and after treatment to investigate the level of drug-resistant strains. The parasite genes encoding dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) were assayed for point mutations that are associated with resistance against drugs. Before treatment, Pyr
r
genotypes of the DHFR gene were found in 42% of all samples, 8% of the patients harbored a mixed parasite population and 50% had a sensitive DHFR genotype. In terms of the DHPS gene, we found mutations in 45% of the parasites. Twenty-four percent had a Ser
436
mutation, and 26% had a Gly
437
mutation. Recrudescent parasites were highly enriched for both Pyr
r
and Sdx
r
strains after treatment (
P
< 0.001 and
P
= 0.029, respectively).
Enterococci with Glycopeptide Resistance in Turkeys, Turkey Farmers, Turkey Slaughterers, and (Sub)Urban Residents in the South of The Netherlands: Evidence for Transmission of Vancomycin Resistance from Animals to Humans?
Authors: Stobberingh Ellen , van den Bogaard Anthony , London Nancy , Driessen Christel , Top Janetta , Willems Rob 
Published: October 2018

ABSTRACT

The number of vancomycin-resistant enterococci (VRE) relative to the total number of enterococci was determined in fecal samples from turkeys and three human populations in 1996, each with a different level of contact with turkeys, i.e., turkey farmers, turkey slaughterers, and (sub)urban residents. The percentage of VRE relative to the total enterococcal population (i.e., the degree of resistance) was low (2 to 4%) in all groups (except in six samples). No difference was observed between farmers who used avoparcin and those who did not. The pulsed-field gel electrophoresis (PFGE) patterns of the VRE isolates from the different populations were quite heterogeneous, but isolates with the same PFGE pattern were found among animal and human isolates, in addition to the isolates which were described previously (A. E. van den Bogaard, L. B. Jensen, and E. E. Stobberingh, N. Engl. J. Med. 337:1558–1559, 1997). Detailed molecular characterization of
vanA
-containing transposons from different isolates showed, that in addition to a previously reported strain, similar transposons were present in VRE isolates from turkeys and turkey farmers. Moreover, similar VanA elements were found not only in isolates with the same PFGE pattern but also in other strains from both humans and animals.
In Vitro Activity of Gemifloxacin (SB 265805) against Anaerobes
Authors: Goldstein Ellie J. C. , Citron Diane M. , Warren Yumi , Tyrrell Kerin , Merriam C. Vreni 
Published: October 2018

ABSTRACT

Gemifloxacin mesylate (SB 265805), a new fluoronaphthyridone, was tested against 359 recent clinical anaerobic isolates by the National Committee for Clinical Laboratory Standards reference agar dilution method with supplemented brucella blood agar and an inoculum of 10
5
CFU/spot. Comparative antimicrobials tested included trovafloxacin, levofloxacin, grepafloxacin, sparfloxacin, sitafloxacin (DU-6859a), penicillin G, amoxicillin clavulanate, imipenem, cefoxitin, clindamycin, and metronidazole. The MIC
50
and MIC
90
(MICs at which 50 and 90% of the isolates were inhibited) of gemifloxacin against various organisms (with the number of strains tested in parentheses) were as follows (in micrograms per milliliter): for
Bacteroides fragilis
(28), 0.5 and 2; for
Bacteroides thetaiotaomicron
(24), 1 and 16; for
Bacteroides caccae
(12), 1 and 16; for
Bacteroides distasonis
(12), 8 and >16; for
Bacteroides ovatus
(12), 4 and >16; for
Bacteroides stercoris
(12), 0.5 and 0.5; for
Bacteroides uniformis
(12), 1 and 4; for
Bacteroides vulgatus
(11), 4 and 4; for
Clostridium clostridioforme
(15), 0.5 and 0.5; for
Clostridium difficile
(15), 1 and >16; for
Clostridium innocuum
(13), 0.125 and 2; for
Clostridium perfringens
(13), 0.06 and 0.06; for
Clostridium ramosum
(14), 0.25 and 8; for
Fusobacterium nucleatum
(12), 0.125 and 0.25; for
Fusobacterium necrophorum
(11), 0.25 and 0.5; for
Fusobacterium varium
(13), 0.5 and 1; for
Fusobacterium
spp. (12), 1 and 2; for
Peptostreptococcus anaerobius
(13), 0.06 and 0.06; for
Peptostreptococcus asaccharolyticus
(13), 0.125 and 0.125; for
Peptostreptococcus magnus
(14), 0.03 and 0.03; for
Peptostreptococcus micros
(12), 0.06 and 0.06; for
Peptostreptococcus prevotii
(14), 0.06 and 0.25; for
Porphyromonas asaccharolytica
(11), 0.125 and 0.125; for
Prevotella bivia
(10), 8 and 16; for
Prevotella buccae
(10), 2 and 2; for
Prevotella intermedia
(10), 0.5 and 0.5; and for
Prevotella melaninogenica
(11), 1 and 1. Gemifloxacin mesylate (SB 265805) was 1 to 4 dilutions more active than trovafloxacin against fusobacteria and peptostreptococci, and the two drugs were equivalent against clostridia and
P. asaccharolytica
. Gemifloxacin was equivalent to sitafloxacin (DU 6859a) against peptostreptococci,
C. perfringens
, and
C. ramosum
, and sitafloxacin was 2 to 3 dilutions more active against fusobacteria. Sparfloxacin, grepafloxacin, and levofloxacin were generally less active than gemifloxacin against all anaerobes.
In Vitro Activities of BMS-207147 against Over 600 Contemporary Clinical Bloodstream Isolates of
Candida
Species from the SENTRY Antimicrobial Surveillance Program in North America and Latin America
Authors: Diekema D. J. , Pfaller M. A. , Messer S. A. , Houston A. , Hollis R. J. , Doern G. V. , Jones R. N. ,   The SENTRY PARTICIPANTS GROUP
Published: October 2018

ABSTRACT

We compared the in vitro activity of BMS-207147, an investigational triazole, with those of itraconazole and fluconazole against 613 clinical bloodstream isolates of
Candida
spp. collected from SENTRY participating hospitals during 1997 and 1998. Overall, BMS-207147 was the most active azole against all
Candida
spp. While both BMS-207147 and itraconazole displayed a stepwise decrease in activity against isolates for which the fluconazole MICs were elevated, BMS-207147 had two- to fourfold greater activity than itraconazole both against
Candida
spp. that were dose-dependently fluconazole susceptible and against those that were fluconazole resistant.
Quantitation of Intracellular Triphosphate of Emtricitabine in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Patients
Authors: Darque Albert , Valette Gilles , Rousseau Frank , Wang Laurene H. , Sommadossi Jean-Pierre , Zhou Xiao-Jian 
Published: October 2018

ABSTRACT

An analytical methodology combining solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) was developed to quantitate the intracellular active 5′-triphosphate (TP) of β-
l
-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (emtricitabine) (FTC) in human peripheral blood mononuclear cells (PBMCs). The FTC nucleotides, including 5′-mono-, di-, and triphosphates, were successively resolved on an anion-exchange SPE cartridge by applying a gradient of potassium chloride. The FTC-TP was subsequently digested to release the parent nucleoside that was finally analyzed by HPLC with UV detection (HPLC-UV). Validation of the methodology was performed by using PBMCs from healthy donors exposed to an isotopic solution of [
3
H]FTC with known specific activity, leading to the formation of intracellular FTC-TP that was quantitated by an anion-exchange HPLC method with radioactive detection. These levels of FTC-TP served as reference values and were used to validate the data obtained by HPLC-UV. The assay had a limit of quantitation of 4.0 pmol of FTC-TP (amount on column from approximately 10
7
cells). Intra-assay precision (coefficient of variation percentage of repeated measurement) and accuracy (percentage deviation of the nominal reference value), estimated by using quality control samples at 16.2, 60.7, and 121.5 pmol, ranged from 1.3 to 3.3% and −1.0 to 4.8%, respectively. Interassay precision and accuracy varied from 3.0 to 10.2% and from 2.5 to 6.7%, respectively. This methodology was successfully applied to the determination of FTC-TP in PBMCs of patients infected with human immunodeficiency virus after oral administration of various dosing regimens of FTC monotherapy.
In Vitro Activities of Azithromycin and Ofloxacin againstChlamydia pneumoniaein a Continuous-Infection Model
Authors: Kutlin Andrei , Roblin Patricia M. , Hammerschlag Margaret R. 
Published: October 2018

ABSTRACTChlamydia pneumoniaeis a well-established cause of community-acquired pneumonia and bronchitis in adults and children. Chronic infections withC. pneumoniaehave been implicated in the development of atherosclerosis and other diseases in humans. Methods currently used for the culture and propagation ofC. pneumoniaeare not analogous to the infection as it occurs in vivo. We have established a model of continuousC. pneumoniaeinfection in vitro. HEp-2 cells inoculated with CM-1 and TW-183 strains have been persistently infected for periods of over 1.5 and 2 years, respectively. The cultures were maintained without centrifugation or the addition of cycloheximide, fresh host cells, or chlamydia. We observed cycles of host cell lysis, detachment, and regrowth with both strains ofC. pneumoniae. ContinuousC. pneumoniaeinfections may more closely resemble the actual events as they occur in vivo and, therefore, may be a better model for the in vitro study ofC. pneumoniaeinfection. When we used continuously infected cells to determine the effects of azithromycin and ofloxacin onC. pneumoniaepropagation in vitro, we found that both drugs reduced but did not completely eliminate the organism. This may be an important observation, as the failure of antibiotic therapy againstC. pneumoniaeinfection in humans has been described.
Incidence of Quinolone Resistance Over the Period 1986 to 1998 in Veterinary
Salmonella
Isolates from Germany
Authors: Malorny Burkhard , Schroeter Andreas , Helmuth Reiner 
Published: October 2018

ABSTRACT

A total of 24,591 nonhuman salmonella strains isolated in Germany between 1986 and 1998 were examined for their resistance to nalidixic acid by an agar diffusion method. The rate of resistance (inhibition zone, ≤13 mm) ranged from 0.2% in 1986 to a peak of 14.8% in 1990. Between 1991 and 1998 the MICs for nalidixic acid-resistant strains ranged from more than 256 μg/ml for nalidixic acid to between 0.25 and 128 μg/ml for enrofloxacin. In the early 1990s a particularly high incidence of fluoroquinolone resistance (49.5%) was seen among isolates of
Salmonella enterica
serotype Typhimurium (
Salmonella
Typhimurium) definitive phage type 204c that mainly originated from cattle. Among isolates from poultry an increase in the incidence of nalidixic acid resistance to a peak of 14.4% was observed in 1994. This peak was due to the presence of specific resistant serotypes, mainly serotypes Hadar, Saintpaul, Paratyphi B (
d
-tartrate positive; formerly serotype Java) and Newport. Such strains exhibited a decreased susceptibility to enrofloxacin (MIC, 1 μg/ml). Among isolates from pigs the peak incidence of resistance was reached in 1993, with 7.5% of isolates resistant to nalidixic acid and enrofloxacin. The study demonstrates an increase in the incidence of strains that are resistant to nalidixic acid and that have decreased susceptibility to enrofloxacin after the licensing of enrofloxacin. In addition, the number of other serotypes that exhibited nalidixic acid resistance or reduced enrofloxacin susceptibility increased among the total number of isolates investigated between 1992 and 1998.