bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penetration of Meropenem in Lung, Bronchial Mucosa, and Pleural Tissues
Authors: Byl Baudouin , Jacobs Frédérique , Roucloux Ingrid , de Franquen Philippe , Cappello Matteo , Thys Jean-Pierre 
Published: October 2018

ABSTRACT
Lung, bronchial mucosa, and pleural tissue samples were obtained from 14 patients undergoing lung surgery 1 to 5 h after administration of 1 g of meropenem. The mean (range) peak concentrations of meropenem were 3.9 (0.2 to 8.2), 6.6 (3.0 to 13.3), and 2.8 (0.6 to 7.8) mg/kg of tissue, respectively, exceeding the MICs at which 90% of isolates are inhibited for most respiratory pathogens.
Antibiotic Resistance Conferred by a Conjugative Plasmid and a Class I Integron in
Vibrio cholerae
O1 El Tor Strains Isolated in Albania and Italy
Authors: Falbo Vincenzo , Carattoli Alessandra , Tosini Fabio , Pezzella Cristina , Dionisi Anna Maria , Luzzi Ida 
Published: October 2018

ABSTRACT

Multidrug-resistant
Vibrio cholerae
O1 El Tor strains isolated during the 1994 outbreak of cholera in Albania and Italy were characterized for the molecular basis of antibiotic resistance. All strains were found to be resistant to tetracycline, streptomycin, spectinomycin, trimethoprim, sulfathiazole, and the vibriostatic compound O/129 (2,4-diamino-6,7-diisopropylteridine). Resistance genes were self-transferable by a conjugative plasmid of about 60 MDa, with the exception of spectinomycin resistance, which was conferred by the
aadA1
gene cassette located in the bacterial chromosome within a class 1 integron. The resistance to trimethoprim and O/129 was conferred by the
dfrA1
gene, which was present on the plasmid. Although the
dfrA1
gene is known to be borne on an integron cassette, class 1, 2, or 3
intI
genes were not detected as part of the plasmid DNA from the strains studied.
Emergence of Fosfomycin-Resistant Isolates of Shiga-Like Toxin-Producing
Escherichia coli
O26
Authors: Horii Toshinobu , Kimura Taku , Sato Kumiko , Shibayama Keigo , Ohta Michio 
Published: October 2018

ABSTRACT

We evaluated the susceptibilities of 129 Shiga-like toxin-producing
Escherichia coli
(STEC) isolates to various antibiotics. The numbers of isolates for which MICs were high (≧128 μg/ml) were as follows: 5 for fosfomycin, 14 for ampicillin, 1 for cefaclor, 6 for kanamycin, 22 for tetracycline, and 2 for doxycycline. For two isolates of STEC O26 MICs of fosfomycin were high (1,024 and 512 μg/ml, respectively). Conjugation experiments and glutathione
S
-transferase assays suggested that the fosfomycin resistance in these isolates was determined not by a plasmid but chromosomally. The amount of active intracellular fosfomycin in these STEC isolates was 100- to 200-fold less than that in
E. coli
C600 harboring pREFTT47B408 in the presence of either
l
-α-glycerophosphate or glucose-6-phosphate. Cloning, sequencing, and Northern blot analysis demonstrated that the transcriptional level of the
murA
gene encoding UDP-
N
-acetylglucosamine enolpyruvoyl transferase in these isolates was greater than that in
E. coli
C600. Our results suggest that the fosfomycin resistance in these STEC isolates is due to concurrent effects of alteration of the
glpT
and/or
uhp
transport systems and of the enhanced transcription of the
murA
gene.
High-Frequency, In Vitro Reversible Switching of
Candida lusitaniae
Clinical Isolates from Amphotericin B Susceptibility to Resistance
Authors: Yoon Stephanie A. , Vazquez Jose A. , Steffan Paul E. , Sobel Jack D. , Akins Robert A. 
Published: October 2018

ABSTRACT

Recent studies have revealed an increase in the incidence of serious infections caused by non-
albicans Candida
species.
Candida lusitaniae
is of special interest because of its sporadic resistance to amphotericin B (AmB). The present in vitro study demonstrated that, unlike other
Candida
species,
C. lusitaniae
isolates frequently generated AmB-resistant lineages form previously susceptible colonies. Cells switching from a resistant colony to a susceptible phenotype were also detected after treatment with either UV light, heat shock, or exposure to whole blood, all of which increased the frequency of switching. In some
C. lusitaniae
lineages, after a cell switched to a resistant phenotype, the resistant phenotype was stable; in other lineages, colonies were composed primarily of AmB-susceptible cells. Although resistant and susceptible lineages were identical in many aspects, their cellular morphologies were dramatically different. Switching mechanisms that involve exposure to antifungals may have an impact on antifungal therapeutic strategies as well as on standardized susceptibility testing of clinical yeast specimens.
Strength and Regulation of the Different Promoters for Chromosomal β-Lactamases of
Klebsiella oxytoca
Authors: Fournier Bénédicte , Gravel Annie , Hooper David C. , Roy Paul H. 
Published: October 2018

ABSTRACT

The two groups of chromosomal β-lactamases from
Klebsiella oxytoca
(OXY-1 and OXY-2) can be overproduced 73- to 223-fold, due to point mutations in the consensus sequences of their promoters. The different versions of promoters from
bla
OXY-1
and
bla
OXY-2
were cloned upstream of the chloramphenicol acetyltransferase (CAT) gene of pKK232-8, and their relative strengths were determined in
Escherichia coli
and in
K. oxytoca
. The three different mutations in the OXY β-lactamase promoters resulted in a 4- to 31-fold increase in CAT activity compared to that of the wild-type promoter. The G→T transversion in the first base of the −10 consensus sequence caused a greater increase in the promoter strength of the wild-type promoter than the two other principal mutations (a G-to-A transition of the fifth base of the −10 consensus sequence and a T-to-A transversion of the fourth base of the −35 sequence). The strength of the promoter carrying a double mutation (transition in the Pribnow box and the transversion in the −35 hexamer) was increased 15- to 61-fold in comparison to that of the wild-type promoter. A change from 17 to 16 bp between the −35 and −10 consensus sequences resulted in a ninefold decrease of the promoter strength. The expression of the
bla
OXY
promoter in
E. coli
differs from that in
K. oxytoca
, particularly for promoters carrying strong mutations. Furthermore, the
bla
OXY
promoter appears not to be controlled by DNA supercoiling or an upstream curved DNA, but it is dependent on the gene copy number.
Ampicillin-Sulbactam and Amoxicillin-Clavulanate Susceptibility Testing of
Escherichia coli
Isolates with Different β-Lactam Resistance Phenotypes
Authors: Oliver Antonio , Pérez-Vázquez María , Martínez-Ferrer Manuel , Baquero Fernando , de Rafael Luis , Cantón Rafael 
Published: October 2018

ABSTRACT

The activities of ampicillin-sulbactam and amoxicillin-clavulanate were studied with 100 selected clinical
Escherichia coli
isolates with different β-lactam susceptibility phenotypes by standard agar dilution and disk diffusion techniques and with a commercial microdilution system (PASCO). A fixed ratio (2:1) and a fixed concentration (clavulanate, 2 and 4 μg/ml; sulbactam, 8 μg/ml) were used in the agar dilution technique. The resistance frequencies for amoxicillin-clavulanate with different techniques were as follows: fixed ratio agar dilution, 12%; fixed concentration 4-μg/ml agar dilution, 17%; fixed ratio microdilution, 9%; and disk diffusion, 9%. Marked discrepancies were found when these results were compared with those obtained with ampicillin-sulbactam (26 to 52% resistance), showing that susceptibility to amoxicillin-clavulanic acid cannot be predicted by testing the isolate against ampicillin-sulbactam. Interestingly, the discrimination between susceptible and intermediate isolates was better achieved with 4 μg of clavulanate per ml than with the fixed ratio. In contrast, amoxicillin susceptibility was not sufficiently restored when 2 μg of clavulanate per ml was used, particularly in moderate (mean β-lactamase activity, 50.8 mU/mg of protein) and high-level (215 mU/mg) TEM-1 β-lactamase producer isolates. Four micrograms of clavulanate per milliliter could be a reasonable alternative to the 2:1 fixed ratio, because most high-level β-lactamase-hyperproducing isolates would be categorized as nonsusceptible, and low- and moderate-level β-lactamase-producing isolates would be categorized as nonresistant. This approach cannot be applied to sulbactam, either with the fixed 2:1 ratio or with the 8-μg/ml fixed concentration, because many low-level β-lactamase-producing isolates would be classified in the resistant category. These findings call for a review of breakpoints for β-lactam–β-lactamase inhibitor combinations.
Molecular Basis of AmpC Hyperproduction in Clinical Isolates of
Escherichia coli
Authors: Nelson E. C. , Elisha B. Gay 
Published: October 2018

ABSTRACT

DNA sequencing data showed that five clinical isolates of
Escherichia coli
with reduced susceptibility to ceftazidime, ceftriaxone, and cefotaxime contain an
ampC
gene that is preceded by a strong promoter. Transcription from the strong promoter was 8- to 18-fold higher than that from the promoter from a susceptible isolate. RNA studies showed that mRNA stability does not play a role in the control of AmpC synthesis.
In Vitro Activities of 13 Fluoroquinolones against
Staphylococcus aureus
Isolates with Characterized Mutations in
gyrA
,
gyrB
,
grlA
, and
norA
and against Wild-Type Isolates
Authors: Muñoz Bellido J. L. , Alonso Manzanares M. A. , Yagüe Guirao G. , Gutiérrez Zufiaurre M. N. , Toldos M. C. M. , Segovia Hernández M. , García-Rodríguez J. A. 
Published: October 2018

ABSTRACT

The in vitro activities of 13 fluoroquinolones (FQs) were tested against 90
Staphylococcus aureus
clinical isolates: 30 wild type for
gyrA
,
gyrB
,
grlA
and
norA
and 60 with mutations in these genes. Clinafloxacin (CI-960), sparfloxacin, and grepafloxacin were the most active FQs against wild-type isolates (MICs at which 90% of isolates were inhibited, 0.06 to 0.1 μg/ml). Mutations in
grlA
did not affect the MICs of newer FQs.
grlA-gyrA
double mutations led to higher MICs for all the FQs tested. Efflux mechanisms affected the newer FQs to a much lesser extent than the less recently developed FQs.
The Anti-Influenza Virus Drug Rimantadine Has Trypanocidal Activity
Authors: Kelly John M. , Miles Michael A. , Skinner Anita C. 
Published: October 2018

ABSTRACT

We report here that bloodstream forms of the African trypanosome,
Trypanosoma brucei
, are sensitive to the anti-influenza virus drug rimantadine (50% inhibitory concentration of 1.26 μg ml
−1
at pH 7.4). The activity is pH dependent and is consistent with a mechanism involving inhibition of the ability to regulate internal pH. Rimantadine is also toxic to the trypanosomatid parasites
Trypanosoma cruzi
and
Leishmania major.
Activities of Several Novel Oxazolidinones against
Mycobacterium tuberculosis
in a Murine Model
Authors: Cynamon M. H. , Klemens S. P. , Sharpe C. A. , Chase S. 
Published: October 2018

ABSTRACT

The activities of linezolid, eperezolid, and PNU-100480 were evaluated in a murine model of tuberculosis. Approximately 10
7
viable
Mycobacterium tuberculosis
ATCC 35801 organisms were given intravenously to 4-week-old outbred CD-1 mice. In the first study, treatment was started 1 day postinfection and was given by gavage for 4 weeks. Viable cell counts were determined from homogenates of spleens and lungs. PNU-100480 was as active as isoniazid. Linezolid was somewhat less active than PNU-100480 and isoniazid. Eperezolid had little activity in this model. In the next two studies, treatment was started 1 week postinfection. A dose-response study was performed with PNU-100480 and linezolid (both at 25, 50, and 100 mg/kg of body weight). PNU-100480 was more active than linezolid, and its efficacy increased with an escalation of the dose. Subsequently, the activity of PNU-100480 alone and in combination with rifampin or isoniazid was evaluated and was compared to that of isoniazid-rifampin. The activity of PNU-100480 was similar to that of isoniazid and/or rifampin in the various combinations tested. Further evaluation of these oxazolidinones in the murine test system would be useful prior to the development of clinical studies with humans.
In Vitro Activity of Syn-2869, a Novel Triazole Agent, against Emerging and Less Common Mold Pathogens
Authors: Johnson Elizabeth M. , Szekely Adrien , Warnock David W. 
Published: October 2018

ABSTRACT

The in vitro activity of Syn-2869 was compared with that of amphotericin B and itraconazole. MICs for 100 isolates of pathogenic molds belonging to 12 species were determined by a broth microdilution adaptation of the method recommended by the National Committee for Clinical Laboratory Standards. Syn-2869 and itraconazole showed comparable, good activity against the dematiaceous molds
Cladophialophora bantiana
,
Cladophialophora carrionii
,
Exophiala dermatitidis
,
Fonsecaea pedrosoi
,
Phialophora parasitica
, and
Ramichloridium mackenziei
. Neither of the azole agents was active against the hyaline molds
Fusarium solani
,
Scedosporium prolificans
, and
Scopulariopsis brevicaulis
, but both were more active than amphotericin B against
Scedosporium apiospermum
. The MICs of the three agents were comparable for the mucoraceous mold
Absidia corymbifera
, but Syn-2869 appeared to be the least active against the dimorphic mold
Sporothrix schenckii
. Our results suggest that Syn-2869 could be effective against a range of mold infections in humans.
Use of a Genetic Approach To Evaluate the Consequences of Inhibition of Efflux Pumps in
Pseudomonas aeruginosa
Authors: Lomovskaya Olga , Lee Angela , Hoshino Kazuki , Ishida Hiroko , Mistry Anita , Warren Mark S. , Boyer Eric , Chamberland Suzanne , Lee Ving J. 
Published: October 2018

ABSTRACT

Drug efflux pumps in
Pseudomonas aeruginosa
were evaluated as potential targets for antibacterial therapy. The potential effects of pump inhibition on susceptibility to fluoroquinolone antibiotics were studied with isogenic strains that overexpress or lack individual efflux pumps and that have various combinations of efflux- and target-mediated mutations. Deletions in three efflux pump operons were constructed. As expected, deletion of the MexAB-OprM efflux pump decreased resistance to fluoroquinolones in the wild-type
P. aeruginosa
(16-fold reduction for levofloxacin [LVX]) or in the strain that overexpressed
mexAB-oprM
operon (64-fold reduction for LVX). In addition to that, resistance to LVX was significantly reduced even for the strains carrying target mutations (64-fold for strains for which LVX MICs were >4 μg/ml). We also studied the frequencies of emergence of LVX-resistant variants from different deletion mutants and the wild-type strain. Deletion of individual pumps or pairs of the pumps did not significantly affect the frequency of emergence of resistant variants (at 4× the MIC for the wild-type strain) compared to that for the wild type (10
−6
to 10
−7
). In the case of the strain with a triple deletion, the frequency of spontaneous mutants was undetectable (<10
−11
). In summary, inhibition of drug efflux pumps would (i) significantly decrease the level of intrinsic resistance, (ii) reverse acquired resistance, and (iii) result in a decreased frequency of emergence of
P. aeruginosa
strains highly resistant to fluoroquinolones in clinical settings.
Characterization of Novel Antimicrobial Peptoids
Authors: Goodson Bob , Ehrhardt Anton , Ng Simon , Nuss John , Johnson Kirk , Giedlin Marty , Yamamoto Ralph , Moos Walter H. , Krebber Anke , Ladner Martha , Giacona Mary Beth , Vitt Charles , Winter Jill 
Published: October 2018

ABSTRACT

Peptoids differ from peptides in that peptoids are composed of N-substituted rather than alpha-carbon-substituted glycine units. In this paper we report the in vitro and in vivo antibacterial activities of several antibacterial peptoids discovered by screening combinatorial chemistry libraries for bacterial growth inhibition. In vitro, the peptoid CHIR29498 and some of its analogues were active in the range of 3 to 12 μg/ml against a panel of gram-positive and gram-negative bacteria which included isolates which were resistant to known antibiotics. Peptoid antimicrobial activity against
Staphylococcus aureus
was rapid, bactericidal, and independent of protein synthesis. β-Galactosidase and propidium iodide leakage assays indicated that the membrane is the most likely target of activity. Positional isomers of an active peptoid were also active, consistent with a mode of action, such as membrane disruption, that does not require a specific fit between the molecule and its target. In vivo, CHIR29498 protected
S. aureus
-infected mice in a simple infection model.
Piperacillin and Tazobactam Exhibit Linear Pharmacokinetics after Multiple Standard Clinical Doses
Authors: Auclair Barbara , Ducharme Murray P. 
Published: October 2018

ABSTRACTA population pharmacokinetic (PK) analysis was conducted to determine if piperacillin and tazobactam exhibited linear or nonlinear PKs and if incremental changes in the daily dosage of piperacillin affected tazobactam PKs. Four dosage groups were evaluated after multiple dosing regimens. Concentrations of drug in plasma and amounts in urine were best fitted by using a linear two-compartment PK model. No significant difference between dosing groups was seen for any piperacillin or tazobactam PK parameters. Both drugs exhibited linear PKs when given at usual clinical doses. Tazobactam PKs did not appear to be affected by the different dosing regimens of piperacillin.
Effect of HSR-903, a New Fluoroquinolone, on the Concentration of Theophylline in Serum
Authors: Niki Yoshihito , Watanabe Shinsuke , Tamada Sadao , Yoshida Koichiro , Miyashita Naoyuki , Nakajima Masamitu , Matsushima Toshiharu , Sekino Hisayuki , Matsuoka Osamu 
Published: October 2018

ABSTRACT
The effect of HSR-903, a new fluoroquinolone, on the concentration of theophylline in serum in healthy male volunteers was investigated. The concentration of theophylline in serum and the urinary excretion rates of theophylline on day 5 of concomitant dosing with HSR-903 tended to increase compared to those on day 4, when theophylline was given alone; however, the urinary excretion rates of 1-methyluric acid and 3-methylxanthine on day 5 of concomitant dosing with HSR-903 tended to decrease in comparison to those on day 4, when theophylline was given alone.
Pharmacokinetics and Pharmacodynamics of Amoxicillin-Sulbactam, a Novel Aminopenicillin–β-Lactamase Inhibitor Combination, against
Escherichia coli
Authors: Bantar Carlos , Nicola Federico , Arenoso Hector J. , Galas Marcelo , Soria Liliana , Dana Diego , Rossi Alicia , Bianchini Hebe , Jasovich Abel 
Published: October 2018

ABSTRACT

We evaluated the pharmacokinetics of amoxicillin-sulbactam (AMX-SUL), a novel drug combination, and its pharmacodynamics against
Escherichia coli
in 12 volunteers receiving a single oral dose (1,000 mg). Peak serum bactericidal and urine inhibitory activities in most volunteers were observed against
E. coli
strains for which AMX-SUL MICs were low (2- to 4-mg/liter) (2 strains) and high (≥16-mg/liter) (47 strains), respectively.
Cloning and Characterization of
bla
VIM
, a New Integron-Borne Metallo-β-Lactamase Gene from a
Pseudomonas aeruginosa
Clinical Isolate
Authors: Lauretti Laura , Riccio Maria Letizia , Mazzariol Annarita , Cornaglia Giuseppe , Amicosante Gianfranco , Fontana Roberta , Rossolini Gian Maria 
Published: October 2018

ABSTRACT

Production of a metallo-β-lactamase activity was detected in a carbapenem-resistant
Pseudomonas aeruginosa
clinical isolate (isolate VR-143/97) from an Italian inpatient at the Verona University Hospital (northern Italy). The metallo-β-lactamase determinant was isolated from a genomic library of VR-143/97, constructed in an
Escherichia coli
plasmid vector, by screening for clones with reduced susceptibility to imipenem. Sequencing of the cloned gene revealed that it encoded a new class B β-lactamase that was named VIM-1. At the sequence level VIM-1 was rather divergent from the other class B enzymes (16.4 to 38.7% identity), overall being more similar to members of subclass B1 including the β-lactamase II of
Bacillus cereus
(Bc-II), the
Bacteroides fragilis
CcrA, the
Chryseobacterium meningosepticum
BlaB, and the cassette-encoded IMP-1 enzymes. Among these, VIM-1 showed the highest degree of similarity to Bc-II. Similarly to
bla
IMP
,
bla
VIM
was also found to be carried on a gene cassette inserted into a class 1 integron. The
bla
VIM
-containing integron was located on the chromosome of
P. aeruginosa
VR-143/97, and the metallo-β-lactamase-encoding determinant was not transferable to
E. coli
by conjugation. Expression of the integron-borne
bla
VIM
gene in
E. coli
resulted in a significant decrease in susceptibility to a broad array of β-lactams (ampicillin, carbenicillin, piperacillin, mezlocillin, cefotaxime, cefoxitin, ceftazidime, cefoperazone, cefepime, and carbapenems), revealing a very broad substrate specificity of the VIM-1 enzyme.
β-Lactamase Production by Oral Anaerobic Gram-Negative Species in Infants in Relation to Previous Antimicrobial Therapy
Authors: Nyfors S. , Könönen E. , Takala A. , Jousimies-Somer H. 
Published: October 2018

ABSTRACT

The frequency of β-lactamase production in gram-negative bacteria has increased considerably during recent years. In this study, β-lactamase production by oral anaerobic gram-negative rods isolated from saliva was longitudinally examined for 44 Caucasian infants at the ages of 2, 6, and 12 months in relation to their documented exposure to antibiotics. Isolates showing decreased susceptibility to penicillin G (1 μg/ml) were examined for β-lactamase production by using a chromogenic cephalosporin disk test. β-Lactamase-positive, gram-negative anaerobic species were found in 11, 55, and 89% of each age group, respectively. β-Lactamase production was most frequent among organisms of the
Prevotella melaninogenica
group. At 12 months, 73% of the infants harbored β-lactamase-producing members of the
P. melaninogenica
group, 55% had nonpigmented
Prevotella
species, 25% had
Porphyromonas catoniae
, 23% had
Fusobacterium nucleatum
, and 5% had
Capnocytophaga
species. Several β-lactamase-producing species could be simultaneously found in the infants’ mouths. The presence of β-lactamase-producing species was significantly associated with the infants’ exposure to antibiotics through antimicrobial treatments given to the infants and/or their mothers.
Antifungal Properties and Target Evaluation of Three Putative Bacterial Histidine Kinase Inhibitors
Authors: Deschenes Robert J. , Lin Hong , Ault Addison D. , Fassler Jan S. 
Published: October 2018

ABSTRACT

Histidine protein kinases have been explored as potential antibacterial drug targets. The recent identification of two-component histidine kinases in fungi has led us to investigate the antifungal properties of three bacterial histidine kinase inhibitors (RWJ-49815, RWJ-49968, and RWJ-61907). All three compounds were found to inhibit growth of the
Saccharomyces cerevisiae
and
Candida albicans
strains, with MICs ranging from 1 to 20 μg/ml. However, deletion of
SLN1
, the only histidine kinase in
S. cerevisiae
, did not alter drug efficacy. In vitro kinase assays were performed by using the Sln1 histidine kinase purified from bacteria as a fusion protein to glutathione
S
-transferase. RWJ-49815 and RWJ-49968 inhibited kinase a 50% inhibitory concentration of 10 μM, whereas RWJ-61907 failed to inhibit at concentrations up to 100 μM. Based on these results, we conclude that these compounds have antifungal properties; however, their mode of action appears to be independent of histidine kinase inhibition.