bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the Toxicity of Amphotericin B in 5% Dextrose with That of Amphotericin B in Fat Emulsion in a Randomized Trial with Cancer Patients
Authors: Nucci Marcio , Loureiro Monique , Silveira Fernanda , Casali Anna Raquel , Bouzas Luis Fernando , Velasco Eduardo , Spector Nelson , Pulcheri Wolmar 
Published: October 2018

ABSTRACT

A multicentric randomized trial was undertaken to compare the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in a fat emulsion (Intralipid) in cancer patients. Group 1 (
n
= 33) received amphotericin B diluted in 5% dextrose with premedication consisting of promethazine plus an antipyretic. Group 2 (
n
= 28) received amphotericin B diluted in 20% Intralipid without premedication. Amphotericin B was infused daily at a dose of 1 mg/kg of body weight over a 1-h period to members of both groups for empirical antifungal therapy (in neutropenic patients) or for the treatment of documented fungal infections. The majority of patients (80%) received empirical amphotericin B treatment. The two groups were comparable with regard to age, gender, underlying disease, and the following baseline characteristics: use of other nephrotoxic drugs and serum levels of potassium and creatinine. The median cumulative doses of amphotericin B were 240 mg in group 1 and 245 mg in group 2 (
P
= 0.73). Acute adverse events occurred in 88% of patients in group 1 and in 71% of those in group 2 (
P
= 0.11). Forty percent of the infusions in group 1 were associated with fever, compared to 23% in group 2 (
P
< 0.0001). In addition, patients in group 2 required less meperidine for the control of acute adverse events (
P
= 0.008), and fewer members of this group presented with hypokalemia (
P
= 0.004) or rigors (
P
< 0.0001). There was no difference in the proportions of patients with nephrotoxicity (
P
= 0.44). The success rates of empirical antifungal treatment were similar in the two groups (
P
= 0.9). Amphotericin B diluted in a lipid emulsion seems to be associated with a smaller number of acute adverse events and fewer cases of hypokalemia than amphotericin B diluted in 5% dextrose.
Molecular Characterization of Multidrug Resistance in
Streptococcus mitis
Authors: Poutanen Susan M. , de Azavedo Joyce , Willey Barbara M. , Low Donald E. , MacDonald Kelly S. 
Published: October 2018

ABSTRACT

Antimicrobial resistance was characterized for 14 strains of
Streptococcus mitis
.
Hin
fI restriction fragment length mapping of
gyrA
PCR amplicons from three ciprofloxacin-resistant isolates correlated with mutations associated with such resistance in other organisms. By using PCR, seven erythromycin-resistant strains were found to possess either the
mef
or
ermB
gene. Hybridization revealed
tet
(M) in seven tetracycline-resistant isolates.
Biochemical-Genetic Analysis and Distribution of FAR-1, a Class A β-Lactamase from
Nocardia farcinica
Authors: Laurent Frederic , Poirel Laurent , Naas Thierry , Chaibi El Bachir , Labia Roger , Boiron Patrick , Nordmann Patrice 
Published: October 2018

ABSTRACT

From genomic DNA of the clinical isolate
Nocardia farcinica
VIC, a 1.6-kb
Sau
3AI fragment was cloned and expressed in
Escherichia coli
JM109. The recombinant strain expressed a β-lactamase (pI, 4.6), FAR-1, which conferred high levels of resistance to amoxicillin, piperacillin, ticarcillin, and cephalothin. The hydrolysis constants (

k
cat

,

K
m

,

K
i

, and 50% inhibitory concentration) confirmed the MIC results and showed that FAR-1 activity is inhibited by clavulanic acid and at a low level by tazobactam and sulbactam. Moreover, FAR-1 β-lactamase hydrolyzes aztreonam (at a low level) without significant activity against ceftazidime, cefotaxime and imipenem. FAR-1 mature protein of molecular mass ca 32 kDa, has less than 60% amino acid identity with any other class A β-lactamases, being most closely related to PEN-A from
Burkholderia cepacia
(52%). A
bla
FAR-1
-like gene was found in all studied
N. farcinica
strains, underlining the constitutive origin of this gene.
In Vitro Antifungal Activity and Cytotoxicity of a Novel Membrane-Active Peptide
Authors: Hong Sung Yu , Oh Jong Eun , Lee Keun Hyeung 
Published: October 2018

ABSTRACT

In the present study, we investigated the antifungal activity and cytotoxicity of a novel membrane-active peptide, KKVVFKVKFKK (MP). MP inhibited the growth of various pathogenic fungi isolated from patients and of fluconazole-resistant fungi at concentrations of 2 to 32 μg/ml. MP had potent fungicidal activity; the minimal fungicidal concentrations of the peptide were no more than fourfold greater than the MICs. Time course experiments of MP-induced killing of
Candida albicans
ATCC 36232 showed that the rate of killing was rapid and depended on the concentration of MP. MP had a strong synergism with other antifungal drugs; the fractional inhibitory concentration index values of MP with amphotericin B and fluconazole for
C. albicans
were 0.16 and 0.02, respectively. The 50% inhibitory concentrations of MP for NIH 3T3 and Jurkat cells were approximately 100 times higher than the MIC for
C. albicans
ATCC 36232, indicating that MP had high selectivity between the fungal and mammalian cells. These results suggest that MP has great advantages in the development of antifungal agents.
Efficacy of Gatifloxacin in Experimental
Escherichia coli
Meningitis
Authors: Lutsar Irja , Friedland Ian R. , Jafri Hasan S. , Wubbel Loretta , Ng Winston , Ghaffar Faryal , McCracken George H. 
Published: October 2018

ABSTRACT

The effectiveness of gatifloxacin therapy (15 mg/kg every 5 h [q5h]) was compared with that of meropenem (75 mg/kg q5h) and cefotaxime (75 mg/kg q5h) therapy in experimental meningitis caused by a β-lactamase-producing strain of
Escherichia coli
. Gatifloxacin therapy was more rapidly bactericidal than cefotaxime but similar to meropenem therapy (bacterial killing rates at 5 h, 0.83 ± 0.26, 0.46 ± 0.3, and 0.73 ± 0.17 CFU/ml/h, respectively;
P
= 0.03 for gatifloxacin versus cefotaxime). At 10 h, seven of eight animals treated with gatifloxacin had <10 CFU/ml in their cerebrospinal fluid, compared with one of seven treated with cefotaxime therapy (
P
= 0.01). Gatifloxacin was at least as effective as currently available antibiotics in this model of
E. coli
meningitis.
In Vitro Susceptibilities of
Chlamydia pneumoniae
Isolates from German Patients and Synergistic Activity of Antibiotic Combinations
Authors: Freidank Heike M. , Losch Philipp , Vögele Heike , Wiedmann-Al-Ahmad Margit 
Published: October 2018

ABSTRACT

The susceptibilities of six
Chlamydia pneumoniae
type strains and of six German patient isolates to erythromycin, azithromycin, roxithromycin, clarithromycin, doxycycline, ofloxacin, and rifampin were investigated. MICs and minimal chlamydicidal concentrations were all within the ranges reported previously. Combinations of azithromycin with either ofloxacin, doxycycline, or rifampin, as well as combinations of three antibiotics (rifampin, azithromycin, and ofloxacin or doxycycline), showed synergistic activity against
C. pneumoniae
.
Analysis of Vancomycin Population Susceptibility Profiles, Killing Activity, and Postantibiotic Effect against Vancomycin-Intermediate
Staphylococcus aureus
Authors: Aeschlimann Jeffrey R. , Hershberger Ellie , Rybak Michael J. 
Published: October 2018

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
strains with decreased vancomycin susceptibility have been isolated from patients in the United States and Japan. The impact of decreased vancomycin susceptibility on the drug’s pharmacodynamic parameters has not been addressed. We studied the activity of vancomycin against three clinical strains of vancomycin intermediate-susceptible
Staphylococcus aureus
(VISA) under high- and low-inoculum conditions, with stationary- and logarithmic-growth-phase kill curves, and in postantibiotic effect (PAE) experiments. We also investigated the stability of the decreased vancomycin susceptibility by using population susceptibility profiles. The respective vancomycin microdilution MICs and MBCs for VISA strains HIP5836, 14379, and Mu50 were 8 and 8, 8 and 8, and 8 and 16 μg/ml. HIP5836 had the most homogeneous elevation of vancomycin MICs, because the MIC for nearly all bacteria in the inoculum was 8 μg/ml. The population MICs (defined as the lowest vancomycin concentration inhibiting 99.9% of growth) for the first serial passages of HIP5836, Mu50, and 14379 were 8, 4, and 2 μg/ml, respectively. After 10 passages, they decreased to 4, 2, and 1 μg/ml, respectively. The Mu50 population MIC increased to 12 μg/ml after five serial passages on vancomycin agar. In the low- and high-inoculum kill curves, time to 99.9% killing was significantly (
P
< 0.05) longer for both Mu50 and HIP5836 than that for 14379 and a control strain. However, colony counts at 24 h were similar to those of the vancomycin-sensitive strain for all VISA strains. The PAE (at 4× MIC) ranged from 1.3 h for 14379 to 2.0 h for HIP5836 and was similar to or greater than the PAE against the vancomycin-sensitive strain. In conclusion, we found that the decreased vancomycin susceptibility increased during persistent exposures to the drug and decreased upon removal of the selective pressure. The decreased vancomycin susceptibility decreased the rate of vancomycin killing, but did not affect the extent of killing or the PAE.
Phenotypes and Genotypes of Erythromycin-Resistant
Streptococcus pyogenes
Strains in Italy and Heterogeneity of Inducibly Resistant Strains
Authors: Giovanetti Eleonora , Montanari Maria Pia , Mingoia Marina , Varaldo Pietro Emanuele 
Published: October 2018

ABSTRACT

A total of 387 clinical strains of erythromycin-resistant (MIC, ≥1 μg/ml)
Streptococcus pyogenes
, all isolated in Italian laboratories from 1995 to 1998, were examined. By the erythromycin-clindamycin double-disk test, 203 (52.5%) strains were assigned to the recently described M phenotype, 120 (31.0%) were assigned to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLS) phenotype, and 64 (16.5%) were assigned to the constitutive MLS resistance (cMLS) phenotype. The inducible character of the resistance of the iMLS strains was confirmed by comparing the clindamycin MICs determined under normal testing conditions and those determined after induction by pregrowth in 0.05 μg of erythromycin per ml. The MICs of erythromycin, clarithromycin, azithromycin, josamycin, spiramycin, and the ketolide HMR3004 were then determined and compared. Homogeneous susceptibility patterns were observed for the isolates of the cMLS phenotype (for all but one of the strains, HMR3004 MICs were 0.5 to 8 μg/ml and the MICs of the other drugs were >128 μg/ml) and those of the M phenotype (resistance only to the 14- and 15-membered macrolides was recorded, with MICs of 2 to 32 μg/ml). Conversely, heterogeneous susceptibility patterns were observed in the isolates of the iMLS phenotype, which were subdivided into three distinct subtypes designated iMLS-A, iMLS-B, and iMLS-C. The iMLS-A strains (
n
= 84) were highly resistant to the 14-, 15-, and 16-membered macrolides and demonstrated reduced susceptibility to low-level resistance to HMR3004. The iMLS-B strains (
n
= 12) were highly resistant to the 14- and 15-membered macrolides, susceptible to the 16-membered macrolides (but highly resistant to josamycin after induction), and susceptible to HMR3004 (but intermediate or resistant after induction). The iMLS-C strains (
n
= 24) had lower levels of resistance to the 14- and 15-membered macrolides (with erythromycin MICs increasing two to four times after induction), were susceptible to the 16-membered macrolides (but resistant to josamycin after induction), and remained susceptible to HMR3004, also after induction. The erythromycin resistance genes in 100 isolates of the different groups were investigated by PCR. All cMLS and iMLS-A isolates tested had the
ermAM
(
ermB
) gene, whereas all iMLS-B and iMLS-C isolates had the
ermTR
gene (neither methylase gene was found in isolates of other groups). The M isolates had only the macrolide efflux (
mefA
) gene, which was also found in variable proportions of cMLS, iMLS-A, iMLS-B, and iMLS-C isolates. The three iMLS subtypes were easily differentiated by a triple-disk test set up by adding a josamycin disk to the erythromycin and clindamycin disks of the conventional double-disk test. Tetracycline resistance was not detected in any isolate of the iMLS-A subtype, whereas it was observed in over 90% of both iMLS-B and iMLS-C isolates.
A Novel Injectable Water-Soluble Amphotericin B-Arabinogalactan Conjugate
Authors: Falk Rama , Domb Abraham J. , Polacheck Itzhack 
Published: October 2018

ABSTRACTNew, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs forCandida albicansandCryptococcus neoformans(MICs, 0.1 to 0.2 μg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.
Contribution of Topoisomerase IV and DNA Gyrase Mutations in
Streptococcus pneumoniae
to Resistance to Novel Fluoroquinolones
Authors: Pestova Ekaterina , Beyer Rebecca , Cianciotto Nicholas P. , Noskin Gary A. , Peterson Lance R. 
Published: October 2018

ABSTRACT

In this study, we assessed the activity of ciprofloxacin, levofloxacin, sparfloxacin, and trovafloxacin against clinical isolates of
Streptococcus pneumoniae
that were resistant to the less-recently developed fluoroquinolones by using defined amino acid substitutions in DNA gyrase and topoisomerase IV. The molecular basis for resistance was assessed by using mutants selected with trovafloxacin, ciprofloxacin, and levofloxacin in vitro. This demonstrated that the primary target of trovafloxacin in
S. pneumoniae
is the ParC subunit of DNA topoisomerase IV, similar to most other fluoroquinolones. However, first-step mutants bearing the Ser79→Phe/Tyr substitution in topoisomerase IV subunit ParC were susceptible to trovafloxacin with a minimum inhibitory concentration of 0.25 μg/ml, and mutations in the structural genes for both topoisomerase IV subunit ParC (
parC
) and the DNA gyrase subunit (
gyrA
) were required to achieve levels of resistance above the breakpoint. The data also suggest that enhanced activity of trovafloxacin against pneumococci is due to a combination of factors that may include reduced efflux of this agent and an enhanced activity against both DNA gyrase and topoisomerase IV.
Effects of the Human Immunodeficiency Virus (HIV) Proteinase Inhibitors Saquinavir and Indinavir on In Vitro Activities of Secreted Aspartyl Proteinases of
Candida albicans
Isolates from HIV-Infected Patients
Authors: Korting Hans C. , Schaller Martin , Eder Gabriele , Hamm Gerald , Böhmer Ursula , Hube Bernhard 
Published: October 2018

ABSTRACT

The effects of therapeutically relevant concentrations of the human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on the in vitro proteinase activity of
Candida albicans
were investigated with isolates from HIV-infected and uninfected patients with oral candidiasis. After exposure to the HIV proteinase inhibitors, proteinase activity was significantly reduced in a dose-dependent manner. These inhibitory effects, which were similar to that of pepstatin A, and the reduced virulence phenotype in experimental candidiasis after application of saquinavir indicate the usefulness of these HIV proteinase inhibitors as potential anticandidal agents.
Histatin 3-Mediated Killing of
Candida albicans
: Effect of Extracellular Salt Concentration on Binding and Internalization
Authors: Xu Yanying , Ambudkar Indu , Yamagishi Hisako , Swaim William , Walsh Thomas J. , O’Connell Brian C. 
Published: October 2018

ABSTRACT

Human saliva contains histidine-rich proteins, histatins, which have antifungal activity in vitro. The mechanism by which histatins are able to kill
Candida albicans
may have clinical significance but is currently unknown. Using radiolabeled histatin 3, we show that the protein binds to
C. albicans
spheroplasts in a manner that is dependent on time and concentration. Binding to the spheroplasts was saturable and could be competed with unlabeled histatin 3. A single histatin 3 binding site with a

K
d

= 5.1 μM was detected. Histatin 3 binding resulted in potassium and magnesium efflux, predominantly within the first 30 min of incubation. Studies with fluorescent histatin 3 demonstrate that the protein is internalized by
C. albicans
and that translocation of histatin inside the cell is closely associated with cell death. Histatin binding, internalization, and cell death are accelerated in low-ionic-strength conditions. Indeed, a low extracellular salt concentration was essential for cell death to occur, even when histatin 3 was already bound to the cell. The interaction of histatin 3 with
C. albicans
, and subsequent cell death, is inhibited at low temperature. These results demonstrate that the candidacidal activity of histatin 3 is not due exclusively to binding at the cell surface but also involves subsequent interactions with the cell.
Bactericidal/Permeability-Increasing Protein Inhibits Growth of a Strain of
Acholeplasma laidlawii
and L Forms of the Gram-Positive Bacteria
Staphylococcus aureus
and
Streptococcus pyogenes
Authors: Horwitz Arnold H. , Williams Robert E. , Liu Pei-Syan , Nadell Rossana 
Published: October 2018

ABSTRACT

Bactericidal/permeability-increasing protein (BPI) inhibited growth of cell wall-deficient
Acholeplasma laidlawii
and L forms of certain strains of
Staphylococcus aureus
and
Streptococcus pyogenes
. However, the same strains of
S. aureus
and
S. pyogenes
with intact cell walls were not susceptible to the growth-inhibitory effects of BPI.
In Vitro Activities of
Strychnos
Alkaloids and Extracts against
Plasmodium falciparum
Authors: Frederich Michel , Hayette Marie-Pierre , Tits Monique , De Mol Patrick , Angenot Luc 
Published: October 2018

ABSTRACT

The in vitro antimalarial activities of 46 alkaloids and extracts from
Strychnos
species were evaluated. Two types of quasidimeric alkaloids exhibit high and selective activities against
Plasmodium
. Strychnopentamine and isostrychnopentamine were active against chloroquine-sensitive and -resistant strains (50% inhibitory concentration [IC
50
] ≈ 0.15 μM), while dihydrousambarensine exhibited a 30-fold higher activity against the chloroquine-resistant strain (IC
50
= 0.03 μM) than it did against the chloroquine-sensitive strain.
Improving quality of care during childbirth in primary health centres: a stepped-wedge cluster-randomised trial in India
Authors: Agarwal Ramesh , Chawla Deepak , Sharma Minakshi , Nagaranjan Shyama , Dalpath Suresh K , Gupta Rakesh , Kumar Saket , Chaudhuri Saumyadripta , Mohanty Premananda , Sankar Mari Jeeva , Agarwal Krishna , Rani Shikha , Thukral Anu , Jain Suksham , Yadav Chandra Prakash , Gathwala Geeta , Kumar Praveen , Sarin Jyoti , Sreenivas Vishnubhatla , Aggarwal Kailash C , Kumar Yogesh , Kharya Pradip , Bisht Surender Singh , Shridhar Gopal , Arora Raksha , Joshi Kapil , Bhalla Kapil , Soni Aarti , Singh Sube , Devakirubai Prischillal , Samuel Ritu , Yadav Reena , Bahl Rajiv , Kumar Vijay , Paul Vinod Kumar 
Published: October 2018

BackgroundLow/middle-income countries need a large-scale improvement in the quality of care (QoC) around the time of childbirth in order to reduce high maternal, fetal and neonatal mortality. However, there is a paucity of scalable models.MethodsWe conducted a stepped-wedge cluster-randomised trial in 15 primary health centres (PHC) of the state of Haryana in India to test the effectiveness of a multipronged quality management strategy comprising capacity building of providers, periodic assessments of the PHCs to identify quality gaps and undertaking improvement activities for closure of the gaps. The 21-month duration of the study was divided into seven periods (steps) of 3  months each. Starting from the second period, a set of randomly selected three PHCs (cluster) crossed over to the intervention arm for rest of the period of the study. The primary outcomes included the number of women approaching the PHCs for childbirth and 12 directly observed essential practices related to the childbirth. Outcomes were adjusted with random effect for cluster (PHC) and fixed effect for ‘months of intervention’.ResultsThe intervention strategy led to increase in the number of women approaching PHCs for childbirth (26 vs 21 women per PHC-month, adjusted incidence rate ratio: 1.22; 95% CI 1.17 to 1.28). Of the 12 practices, 6 improved modestly, 2 remained near universal during both intervention and control periods, 3 did not change and 1 worsened. There was no evidence of change in mortality with a majority of deaths occurring either during referral transport or at the referral facilities.ConclusionA multipronged quality management strategy enhanced utilisation of services and modestly improved key practices around the time of childbirth in PHCs in India.Trial registration numberCTRI/2016/05/006963.