bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visceral Leishmaniasis in the BALB/c Mouse: A Comparison of the Efficacy of a Nonionic Surfactant Formulation of Sodium Stibogluconate with Those of Three Proprietary Formulations of Amphotericin B
Authors: Mullen A. B. , Baillie A. J. , Carter K. C. 
Published: October 2018

ABSTRACT

In this study, treatment efficacies of a nonionic surfactant vesicle formulation of sodium stibogluconate (SSG-NIV) and of several formulations of amphotericin B were compared in a murine model of visceral leishmaniasis. Treatment with multiple doses of AmBisome, Abelcet, and Amphocil (total dose, 12.5 mg of amphotericin B/kg of body weight) resulted in a significant suppression of parasite burdens in liver (
P
< 0.0005) and spleen (
P
< 0.0005) compared with those of controls, with Abelcet having the lowest activity. Only AmBisome and Amphocil gave significant suppression of parasites in bone marrow (compared to control values,
P
< 0.005). In the acute-infection model, single-dose treatments of SSG-NIV (296 mg of Sb
V
/kg), SSG solution (296 mg of Sb
V
/kg), or AmBisome (8 mg of amphotericin B/kg) were equally effective against liver parasites (compared to control values,
P
< 0.0005). SSG-NIV and AmBisome treatment also significantly suppressed parasites in bone marrow and spleen (
P
< 0.005), with SSG-NIV treatment being more suppressive (>98% suppression in all three sites). Free-SSG treatment failed to suppress spleen or bone marrow parasites. Infection status influenced treatment outcome. In the chronic-infection model, the AmBisome single-dose treatment was less effective in all three infection sites and the SSG-NIV single-dose treatment was less effective in the spleen. The results of this study suggest that the antileishmanial efficacy of SSG-NIV compares favorably with those of the novel amphotericin B formulations.
Characterization of IS
18
, an Element Capable of Activating the Silent
aac(6′)-Ij
Gene of
Acinetobacter
sp. 13 Strain BM2716 by Transposition
Authors: Rudant Eric , Courvalin Patrice , Lambert Thierry 
Published: October 2018

ABSTRACT

Insertion sequence IS
18
was detected by analysis of the spontaneous aminoglycoside resistant mutant
Acinetobacter
sp. 13 strain BM2716-1. Insertion of the element upstream from the silent acetyltransferase gene
aac(6′)-Ij
created a hybrid promoter that putatively accounts for the expression of the aminoglycoside resistance gene. The 1,074-bp IS
18
element contained partially matched (20 out of 26 bases) terminal inverted repeats, one of which overlapped the 3′ end of a 935-bp open reading frame potentially encoding a protein related to the transposases of the IS
30
family. IS
18
was found in 6 out of 29 strains of
Acinetobacter
sp. 13 but not in 10 strains each of
A. baumannii
and
A. haemolyticus
.
Description of Two New Isolates of
Streptococcus pneumoniae
in Spain That Are Highly Resistant to Cefotaxime
Authors: Ruiz Joaquín , Sempere Marco , Simarro Encarnación , Fenoll Asunción 
Published: October 2018

ABSTRACT

Two strains of
Streptococcus pneumoniae
isolated from sputum and bronchoalveolar samples with high-level resistance to cefotaxime (MIC = 8 to 16 μg/ml) are described. One of them, belonging to serogroup 19, was also highly resistant to penicillin (MIC = 16 μg/ml), while the other, of serogroup 14, was intermediate in its resistance to penicillin (MIC = 0.25 μg/ml). To our knowledge, these are the first two strains to be isolated in Spain with such high levels of resistance to cefotaxime.
DNA Gyrase and Topoisomerase IV Are Dual Targets of Clinafloxacin Action in
Streptococcus pneumoniae
Authors: Pan Xiao-Su , Fisher L. Mark 
Published: October 2018

ABSTRACT

We examined the response of
Streptococcus pneumoniae
7785 to clinafloxacin, a novel C-8-substituted fluoroquinolone which is being developed as an antipneumococcal agent. Clinafloxacin was highly active against
S. pneumoniae
7785 (MIC, 0.125 μg/ml), and neither
gyrA
nor
parC
quinolone resistance mutations alone had much effect on this activity. A combination of both mutations was needed to register resistance, suggesting that both gyrase and topoisomerase IV are clinafloxacin targets in vivo. The sparfloxacin and ciprofloxacin MICs for the
parC-gyrA
mutants were 16 to 32 and 32 to 64 μg/ml, respectively, but the clinafloxacin MIC was 1 μg/ml, i.e., within clinafloxacin levels achievable in human serum.
S. pneumoniae
7785 mutants could be selected stepwise with clinafloxacin at a low frequency, yielding first-, second-, third-, and fourth-step mutants for which clinafloxacin MICs were 0.25, 1, 6, and 32 to 64 μg/ml, respectively. Thus, high-level resistance to clinafloxacin required four steps. Characterization of the quinolone resistance-determining regions of the
gyrA
,
parC
,
gyrB
, and
parE
genes by PCR,
Hin
fI restriction fragment length polymorphism, and DNA sequence analysis revealed an invariant resistance pathway involving sequential mutations in
gyrA
or
gyrB
, in
parC
, in
gyrA
, and finally in
parC
or
parE
. No evidence was found for other resistance mechanisms. The
gyrA
mutations in first- and third-step mutants altered GyrA hot spots Ser-83 to Phe or Tyr (
Escherichia coli
coordinates) and Glu-87 to Gln or Lys; second- and fourth-step
parC
mutations changed equivalent hot spots Ser-79 to Phe or Tyr and Asp-83 to Ala.
gyrB
and
parE
changes produced novel alterations of GyrB Glu-474 to Lys and of Pro-454 to Ser in the ParE PLRGK motif. Difficulty in selecting first-step gyrase mutants (isolated with 0.125 [but not 0.25] μg of clinafloxacin per ml at a frequency of 5.0 × 10
−10
to 8.5 × 10
−10
) accompanied by the small (twofold) MIC increase suggested only a modest drug preference for gyrase. Given the susceptibility of defined
gyrA
or
parC
mutants, the results suggested that clinafloxacin displays comparable if unequal targeting of gyrase and topoisomerase IV. Dual targeting and the intrinsic potency of clinafloxacin against
S. pneumoniae
and its first- and second-step mutants are desirable features in limiting the emergence of bacterial resistance.
Efficacy of Teicoplanin and Autoradiographic Diffusion Pattern of [
14
C]Teicoplanin in Experimental
Staphylococcus aureus
Infection of Joint Prostheses
Authors: Saleh Mghir Azzam , Claude Crémieux Anne , Bleton Rémy , Ismael Farid , Manteau Michel , Dautrey Sophie , Massias Laurent , Garry Louis , Sales Nicole , Mazière Bernard , Carbon Claude 
Published: October 2018

ABSTRACT

Prosthesis infections are difficult to cure. Infection with methicillin-resistant staphylococci is becoming more common in patients with orthopedic implants. Using a recently developed model of methicillin-resistant
Staphylococcus aureus
(MRSA) infection of a knee prosthesis, we compared the efficacies of teicoplanin and vancomycin. [
14
C]teicoplanin diffusion in this model was also studied by autoradiography. A partial knee replacement was performed with a silicone implant fitting into the intramedullary canal of the tibia, and 10
7
CFU of MRSA was injected into the knee. Treatment with teicoplanin or vancomycin (20 or 60 mg/kg of body weight, respectively, given intramuscularly twice daily) was started 7 days after inoculation and was continued for 7 days. The teicoplanin and vancomycin MICs for MRSA were 1 μg/ml. Mean peak and trough levels in serum were 39.1 and 23.5 μg/ml, respectively, for teicoplanin and 34.4 and 18.5 μg/ml, respectively, for vancomycin. Fifteen days after the end of therapy, the animals were killed and their tibias were removed, pulverized, and quantitatively cultured. Teicoplanin and vancomycin significantly reduced (
P
< 0.05) the bacterial density (2.7 ± 1.3 and 3.3 ± 1.6 log
10
CFU/g of bone, respectively) compared to those for the controls (5.04 ± 1.4 log
10
CFU/g of bone). The bacterial covents of teicoplanin- and vancomycin-treated rabbits were comparable. The [
14
C]teicoplanin autoradiographic diffusion patterns in rabbits with prostheses, two of which were uninfected and two of which were infected, were studied 15 days after inoculation. Sixty minutes after the end of an infusion of 250 μCi of [
14
C]teicoplanin, autoradiography showed that in the infected animals, the highest levels of radioactivity were located around the prosthesis and in the periosteum, bone marrow, and trabecular bone. Radioactivity was less intense in epiphyseal disk cartilage, femoral cartilage, articular ligaments, and muscles and was weak in compact bone. A similar distribution pattern was seen in uninfected rabbits. Thus, teicoplanin may represent an effective alternative therapy for the treatment of these infections.
Subinhibitory Concentrations of Antimicrobial Agents Reduce the Uptake of
Legionella pneumophila
into
Acanthamoeba castellanii
and U937 Cells by Altering the Expression of Virulence-Associated Antigens
Authors: Lück P. Christian , Schmitt Jürgen W. , Hengerer Arne , Helbig Jürgen H. 
Published: October 2018

ABSTRACT

We determined the MICs of ampicillin, ciprofloxacin, erythromycin, imipenem, and rifampin for two clinical isolates of
Legionella pneumophila
serogroup 1 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay and by quantitative culture. To test the influence of subinhibitory concentrations (sub-MICs) of antimicrobial agents on
Legionella
uptake into
Acanthamoeba castellanii
and U937 macrophage-like cells, both strains were pretreated with 0.25 MICs of the antibiotics for 24 h. In comparison to that for the untreated control, subinhibitory concentrations of antibiotics significantly reduced
Legionella
uptake into the host cells. Measurement of the binding of monoclonal antibodies against several
Legionella
antigens by enzyme-linked immunoassays indicated that sub-MIC antibiotic treatment reduced the expression of the macrophage infectivity potentiator protein (Mip), the Hsp 60 protein, the outer membrane protein (OmpM), an as-yet-uncharacterized protein of 55 kDa, and a few lipopolysaccharide (LPS) epitopes. In contrast, the expression of some LPS epitopes recognized by monoclonal antibodies 8/5 and 30/4 as well as a 45-kDa protein, a 58-kDa protein, and the major outer membrane protein (OmpS) remained unaffected.
Bacteriostatic and Bactericidal In Vitro Activities of Clarithromycin and Erythromycin against Periodontopathic
Actinobacillus actinomycetemcomitans
Authors: Piccolomini R. , Catamo G. , Di Bonaventura G. 
Published: October 2018

ABSTRACT

The susceptibilities of 87 periodontitis-associated strains of
Actinobacillus actinomycetemcomitans
to clarithromycin and erythromycin were determined by standard methodology recommended for
Haemophilus influenzae
. For clarithromycin the MIC at which 90% of the isolates were inhibited was ≤2.0 μg/ml and the minimal bactericidal concentration at which 90% of the strains were killed was ≤4.0 μg/ml, suggesting that it would be a candidate for therapeutic trials in patients with periodontitis.
Postantibiotic Effect and Postantibiotic Sub-MIC Effect of Quinupristin-Dalfopristin against Gram-Positive and -Negative Organisms
Authors: Pankuch Glenn A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

Quinupristin-dalfopristin produced postantibiotic effects (PAEs) and postantibiotic sub-MIC effects of >2 h against 18 gram-positive cocci. Mean pneumococcal and staphylococcal PAEs were 2.8 and 4.7 h, respectively, with shorter PAEs for constitutively than inducibly macrolide-resistant staphylococci. Mean PAEs for vancomycin-susceptible and -resistant
Enterococcus faecium
were 8.5 and 2.6 h, respectively.
High-Level Resistance to Trimethoprim in Clinical Isolates of
Campylobacter jejuni
by Acquisition of Foreign Genes (
dfr1
and
dfr9
) Expressing Drug-Insensitive Dihydrofolate Reductases
Authors: Gibreel Amera , Sköld Ola 
Published: October 2018

ABSTRACT

The pathogenic bacterium
Campylobacter jejuni
has been regarded as endogenously resistant to trimethoprim. The genetic basis of this resistance was characterized in two collections of clinical isolates of
C. jejuni
obtained from two different parts of Sweden. The majority of these isolates were found to carry foreign
dfr
genes coding for resistant variants of the dihydrofolate reductase enzyme, the target of trimethoprim. The resistance genes, found on the chromosome, were
dfr1
and
dfr9
. In about 10% of the strains, the
dfr1
and
dfr9
genes occurred simultaneously. About 10% of the examined isolates were found to be negative for these
dfr
genes and showed a markedly lower trimethoprim resistance level than the other isolates. The
dfr9
and
dfr1
genes were located in the context of remnants of a transposon and an integron, respectively. Two different surroundings for the
dfr9
gene were characterized. One was identical to the right-hand end of the transposon Tn
5393
, and in the other, the
dfr9
gene was flanked by only a few nucleotides of a Tn
5393
sequence. The insertion of the
dfr9
gene into the
C. jejuni
chromosome could have been mediated by Tn
5393
. The frequent occurrence of high-level trimethoprim resistance in clinical isolates of
C. jejuni
could be related to the heavy exposure of food animals to antibacterial drugs, which could lead to the acquisition of foreign resistance genes in naturally transformable strains of
C. jejuni.
Axenically Grown Amastigotes of
Leishmania infantum
Used as an In Vitro Model To Investigate the Pentavalent Antimony Mode of Action
Authors: Sereno D. , Cavaleyra M. , Zemzoumi K. , Maquaire S. , Ouaissi A. , Lemesre J. L. 
Published: October 2018

ABSTRACT

The mechanism(s) of activity of pentavalent antimony [Sb(V)] is poorly understood. In a recent study, we have shown that potassium antimonyl tartrate, a trivalent antimonial [Sb(III)], was substantially more potent than Sb(V) against both promastigotes and axenically grown amastigotes of three
Leishmania
species, supporting the idea of an in vivo metabolic conversion of Sb(V) into Sb(III). We report that amastigotes of
Leishmania infantum
cultured under axenic conditions were poorly susceptible to meglumine [Glucantime; an Sb(V)], unlike those growing inside THP-1 cells (50% inhibitory concentrations [IC
50
s], about 1.8 mg/ml and 22 μg/ml, respectively). In order to define more precisely the mode of action of Sb(V) agents in vivo, we first induced in vitro Sb(III) resistance by direct drug pressure on axenically grown amastigotes of
L. infantum
. Then we determined the susceptibilities of both extracellular and intracellular chemoresistant amastigotes to the Sb(V)-containing drugs meglumine and sodium stibogluconate plus
m
-chlorocresol (Pentostam). The chemoresistant amastigotes LdiR2, LdiR10, and LdiR20 were 14, 26, and 32 times more resistant to Sb(III), respectively, than the wild-type one (LdiWT). In accordance with the hypothesis described above, we found that intracellular chemoresistant amastigotes were resistant to meglumine [Sb(V)] in proportion to the initial level of Sb(III)-induced resistance. By contrast, Sb(III)-resistant cells were very susceptible to sodium stibogluconate. This lack of cross-resistance is probably due to the presence in this reagent of
m
-chlorocresol, which we found to be more toxic than Sb(III) to
L. infantum
amastigotes (IC
50
s, of 0.54 and 1.32 μg/ml, respectively). Collectively, these results were consistent with the hypothesis of an intramacrophagic metabolic conversion of Sb(V) into trivalent compounds, which in turn became readily toxic to the
Leishmania
amastigote stage.
OXA-16, a Further Extended-Spectrum Variant of OXA-10 β-Lactamase, from Two
Pseudomonas aeruginosa
Isolates
Authors: Danel Franck , Hall Lucinda M. C. , Gur Deniz , Livermore David M. 
Published: October 2018

ABSTRACT

Two extended-spectrum mutants of the class D β-lactamase OXA-10 (PSE-2) from
Pseudomonas aeruginosa
isolates obtained in Ankara, Turkey, were described previously and were designated OXA-11 and -14.
P. aeruginosa
906 and 961, isolated at the same hospital, were highly resistant to ceftazidime (MIC ≥ 128 μg/ml) and produced a β-lactamase with a pI of 6.2. The MICs of ceftriaxone, cefoperazone, cefsulodin, and cefepime were 4- to 16-fold above the typical values for
P. aeruginosa
, whereas the MICs of penicillins and cefotaxime were raised only marginally. Ceftazidime MICs were not significantly reduced by clavulanate or tazobactam at 4 μg/ml. Ceftazidime resistance did not transfer conjugatively but was mobilized to
P. aeruginosa
PU21 by plasmid pUZ8. Both isolates gave similar DNA restriction patterns, suggesting that they were replicates; moreover, they yielded identically sized
Bam
HI fragments that hybridized with a
bla
OXA-10
probe. DNA sequencing revealed that both isolates had the same new β-lactamase, designated OXA-16, which differed from OXA-10 in having threonine instead of alanine at position 124 and aspartate instead of glycine at position 157. The latter change is also present in OXA-11 and -14 and seems critical to ceftazidime resistance. Kinetic parameters showed that OXA-16 enzyme was very active against penicillins, cephaloridine, cefotaxime, and ceftriaxone, but hydrolysis of ceftazidime was not detected despite the ability of the enzyme to confer resistance.
Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071
Authors: Tai Chun Y. , Escarpe Paul A. , Sidwell Robert W. , Williams Matthew A. , Lew Willard , Wu Huiwei , Kim Choung U. , Mendel Dirk B. 
Published: October 2018

ABSTRACT

An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidase was isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-
d
- N -acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.
The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria
Authors: Swaney Steve M. , Aoki Hiroyuki , Ganoza M. Clelia , Shinabarger Dean L. 
Published: October 2018

ABSTRACT

The oxazolidinones represent a new class of antimicrobial agents which are active against multidrug-resistant staphylococci, streptococci, and enterococci. Previous studies have demonstrated that oxazolidinones inhibit bacterial translation in vitro at a step preceding elongation but after the charging of
N
-formylmethionine to the initiator tRNA molecule. The event that occurs between these two steps is termed initiation. Initiation of protein synthesis requires the simultaneous presence of
N
-formylmethionine-tRNA, the 30S ribosomal subunit, mRNA, GTP, and the initiation factors IF1, IF2, and IF3. An initiation complex assay measuring the binding of [
3
H]
N
-formylmethionyl-tRNA to ribosomes in response to mRNA binding was used in order to investigate the mechanism of oxazolidinone action. Linezolid inhibited initiation complex formation with either the 30S or the 70S ribosomal subunits from
Escherichia coli
. In addition, complex formation with
Staphylococcus aureus
70S tight-couple ribosomes was inhibited by linezolid. Linezolid did not inhibit the independent binding of either mRNA or
N
-formylmethionyl-tRNA to
E. coli
30S ribosomal subunits, nor did it prevent the formation of the IF2–
N
-formylmethionyl-tRNA binary complex. The results demonstrate that oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing formation of the
N
-formylmethionyl-tRNA–ribosome–mRNA ternary complex.
In Vitro Activity of the New Ketolide HMR3647 in Comparison with Those of Macrolides and Pristinamycins against
Enterococcus
spp
Authors: Torres C. , Zarazaga M. , Tenorio C. , Portillo A. , Saenz Y. , Ruiz F. , Baquero F. 
Published: October 2018

ABSTRACT

Ninety-four erythromycin-susceptible and 107 erythromycin-resistant enterococcal strains (MIC of ≥512 μg/ml) were inhibited by the ketolide HMR3647 at MICs of ≤0.007 to 0.06 and 0.03 to 8 μg/ml, respectively. Eighteen
vanA
-positive isolates and 29 high-level-penicillin-resistant isolates, all of them erythromycin resistant, were inhibited by HMR3647 at an MIC range of 0.015 to 4 μg/ml. The new ketolide has excellent activity against
Enterococcus
species.
Alteration in the GyrA Subunit of DNA Gyrase and the ParC Subunit of DNA Topoisomerase IV in Quinolone-Resistant Clinical Isolates of
Staphylococcus epidermidis
Authors: Li Zhiyu , Deguchi Takashi , Yasuda Mitsuru , Kawamura Takeshi , Kanematsu Emiko , Nishino Yoshinori , Ishihara Satoshi , Kawada Yukimichi 
Published: October 2018

ABSTRACT

We examined 22 clinical isolates of
Staphylococcus epidermidis
to analyze the association of alterations in GyrA and ParC with fluoroquinolone resistance. The simultaneous presence of GyrA and ParC alterations was associated with a high level of fluoroquinolone resistance in the clinical isolates of
S. epidermidis
.
Immunomodulating Effects of HMR 3004 on Pulmonary Inflammation Caused by Heat-Killed
Streptococcus pneumoniae
in Mice
Authors: Duong Michel , Simard Marie , Bergeron Yves , Ouellet Nathalie , Côté-Richer Mélanie , Bergeron Michel G. 
Published: October 2018

ABSTRACT

We investigated the influence of HMR 3004, a new ketolide antibiotic, on the pulmonary inflammation induced by heat-killed fluorescein isothiocyanate-labeled
Streptococcus pneumoniae
. HMR 3004 downregulated (
P
< 0.05) the pneumococcus-induced release of interleukin-6 (IL-6), IL-1β, and nitric oxide in bronchoalveolar lavage fluid. The drug limited (
P
< 0.05) neutrophil recruitment to lung tissues and alveoli but did not interfere with phagocytosis. HMR 3004 totally abrogated lung edema. By reducing inflammation in addition to possessing antimicrobial properties, HMR 3004 may participate in improving the outcome of bacterial pneumonia.
Comparative Efficacy of Trovafloxacin in Experimental Endocarditis Caused by Ciprofloxacin-Sensitive, Methicillin-Resistant
Staphylococcus aureus
Authors: Kim Young S. , Liu Quingxiang , Chow Lucien L. , Chambers Henry F. , Täuber Martin G. 
Published: October 2018

ABSTRACT

The new fluoroquinolone trovafloxacin was tested against a ciprofloxacin-sensitive, methicillin-resistant
Staphylococcus aureus
strain in the rabbit model of endocarditis. Trovafloxacin was more effective than vancomycin (CFU/g of vegetation, 2.65 ± 1.87 versus 4.54 ± 2.80 [mean ± standard deviation]; P < 0.05) or ampicillin-sulbactam plus rifampin (4.9 ± 1.1 CFU/g). The addition of ampicillin-sulbactam to trovafloxacin tended to reduce titers further.