bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of New Mutations in Pyrazinamide-Resistant Strains of
Mycobacterium tuberculosis
and Identification of Conserved Regions Important for the Catalytic Activity of the Pyrazinamidase PncA
Authors: Lemaitre Nadine , Sougakoff Wladimir , Truffot-Pernot Chantal , Jarlier Vincent 
Published: October 2018

ABSTRACT

A new set of mutations, including transposition of the insertion sequence IS
6110
, was identified in the
pncA
gene from 19 pyrazinamide-resistant
Mycobacterium tuberculosis
strains. Alignment of the PncA protein from
M. tuberculosis
with homologous proteins from different bacterial species revealed three highly conserved regions in PncA which may play an important role in the processing of pyrazinamide.
In Vitro Activity of HSR-903, a New Oral Quinolone, against Bacteria Causing Respiratory Infections
Authors: Watanabe Akira , Tokue Yutaka , Takahashi Hiroshi , Kikuchi Tohru , Kobayashi Takao , Gomi Kazunori , Fujimura Shigeru , Nukiwa Toshihiro 
Published: October 2018

ABSTRACT

The in vitro activity of HSR-903, an oral quinolone, against 196 recent clinical isolates of respiratory pathogens was evaluated. HSR-903 was 2 to 32 times more active than ofloxacin, ciprofloxacin, and sparfloxacin against
Staphylococcus aureus
, including methicillin-resistant strains, and
Streptococcus pneumoniae
and was at least as active as the other quinolones against gram-negative pathogens.
Construction and Characterization of Mutants of the TEM-1 β-Lactamase Containing Amino Acid Substitutions Associated with both Extended-Spectrum Resistance and Resistance to β-Lactamase Inhibitors
Authors: Stapleton Paul D. , Shannon Kevin P. , French Gary L. 
Published: October 2018

ABSTRACT

Extended-spectrum TEM β-lactamases (ESBLs) do not usually confer resistance to β-lactamase inhibitors such as clavulanate or tazobactam. To investigate the compatibility of the two phenotypes we used site-directed mutagenesis of the
bla
TEM-1
gene to introduce into the TEM-1 β-lactamase amino acid substitutions that confer the ESBL phenotype: TEM-12 (Arg164→Ser), TEM-26 (Arg164→Ser plus Glu104→Lys), TEM-19 (Gly238→Ser), and TEM-15 (Gly238→Ser plus Glu104→Lys). These were combined with three sets of substitutions that confer inhibitor resistance: TEM-31 (Arg244→Cys), TEM-33 (Met69→Leu), and TEM-35 (Met69→Leu and Asn276→Asp). Introduction of the Arg244→Cys substitution gave rise to inhibitor-resistant hybrid enzymes that either lost ESBL activity (TEM-12, TEM-15, and TEM-19) or had reduced activity (TEM-26) against ceftazidime. In contrast, the introduction of Met69→Leu or Met69→Leu plus Asn276→Asp substitutions did not significantly affect the abilities of the enzymes to confer resistance to ceftazidime, although increased susceptibility to cefotaxime was observed with
Escherichia coli
strains that expressed the TEM-19 and TEM-26 β-lactamases. With the exception of the TEM-12 β-lactamase, introduction of the Met69→Leu substitution did not give rise to enzymes with increased resistance to clavulanate compared to that of the TEM-1 β-lactamase. However, introduction of the double substitution Met69→Leu plus Asn276→Asp in the ESBLs did give rise to low-level (TEM-19, TEM-15, and TEM-26) or moderate-level (TEM-12) clavulanate resistance. None of the hybrid enzymes were as resistant to clavulanate as the corresponding inhibitor-resistant TEM β-lactamase mutant, suggesting that active-site configuration in the ESBLs limits the degree of clavulanate resistance conferred.
Safety and Tolerability of Fluconazole in Children
Authors: Novelli Vas , Holzel Helen 
Published: October 2018

ABSTRACTThe safety profile of fluconazole was assessed for 562 children (ages, 0 to 17 years) comprising 323 males and 239 females. The data are derived from 12 clinical studies of fluconazole as prophylaxis or treatment for a variety of fungal infections in predominantly immunocompromised patients. Most children received multiple doses of fluconazole in the range of 1 to 12 mg/kg of body weight; a few received single doses. Administration was mainly by oral suspension or intravenous injection. Overall, 58 (10.3%) children reported 80 treatment-related side effects. The most common side effects were associated with the gastrointestinal tract (7.7%) or skin (1.2%). Self-limiting, treatment-related side effects affecting the liver and biliary system were reported in three patients (0.5%). Overall, 18 patients (3.2%) discontinued treatment due to side effects, mainly gastrointestinal symptoms. Dose and age did not appear to influence the incidence and pattern of side effects. Treatment-related laboratory abnormalities were uncommon, the most frequent being transient elevated alanine aminotransferase (4.9%), aspartate aminotransferase (2.7%), and alkaline phosphatase (2.3%) levels. Although 98.6% of patients were taking concomitant medications, no clinical or laboratory interactions were observed. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies. Side effects were reported by more patients treated with fluconazole (45 of 382; 11.8%) than by those patients treated with comparable agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar for the two groups. In conclusion, fluconazole was well tolerated by the pediatric population, many of whom were suffering from severe underlying disease and were taking a variety of concurrent medications. The safety profile of fluconazole in children mirrors the excellent safety profile seen in adults.
A Family of Insertion Mutations between Codons 67 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Multinucleoside Analog Resistance
Authors: Larder B. A. , Bloor S. , Kemp S. D. , Hertogs Kurt , Desmet R. L. , Miller V. , Sturmer M. , Staszewski S. , Ren J. , Stammers D. K. , Stuart D. I. , Pauwels R. 
Published: October 2018

ABSTRACT
To investigate the occurrence of multinucleoside analog resistance during therapy failure, we surveyed the drug susceptibilities and genotypes of nearly 900 human immunodeficiency virus type 1 (HIV-1) samples. For 302 of these, the 50% inhibitory concentrations of at least four of the approved nucleoside analogs had fourfold-or-greater increases. Genotypic analysis of the reverse transcriptase (RT)-coding regions from these samples revealed complex mutational patterns, including the previously recognized codon 151 multidrug resistance cluster. Surprisingly, high-level multinucleoside resistance was associated with a diverse family of amino acid insertions in addition to “conventional” point mutations. These insertions were found between RT codons 67 and 70 and were commonly 69Ser-(Ser-Ser) or 69Ser-(Ser-Gly). Treatment history information showed that a common factor for the development of these variants was AZT (3′-azido-3′-deoxythymidine, zidovudine) therapy in combination with 2′,3′-dideoxyinosine or 2′,3′-dideoxycytidine, although treatment patterns varied considerably. Site-directed mutagenesis studies confirmed that 69Ser-(Ser-Ser) in an AZT resistance mutational background conferred simultaneous resistance to multiple nucleoside analogs. The insertions are located in the “fingers” domain of RT. Modelling the 69Ser-(Ser-Ser) insertion into the RT structure demonstrated the profound direct effect that this change is likely to have in the nucleoside triphosphate binding site of the enzyme. Our data highlight the increasing problem of HIV-1 multidrug resistance and underline the importance of continued resistance surveillance with appropriate, sufficiently versatile genotyping technology and phenotypic drug susceptibility analysis.
Inhibitors of DNA Polymerase III as Novel Antimicrobial Agents against Gram-Positive Eubacteria
Authors: Tarantino Paul M. , Zhi Chengxin , Wright George E. , Brown Neal C. 
Published: October 2018

ABSTRACT

6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme required for the replication of chromosomal DNA in gram-positive bacteria (N. C. Brown, L. W. Dudycz, and G. E. Wright, Drugs Exp. Clin. Res. 12:555–564, 1986). A new class of 6-anilinouracils based on N-3 alkyl substitution of the uracil ring was synthesized and analyzed for activity as inhibitors of the gram-positive bacterial DNA polymerase III and the growth of gram-positive bacterial pathogens. Favorable in vitro properties of N-3-alkyl derivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl and hydroxyalkyl groups. These hydroxyalkyl and methoxyalkyl derivatives displayed

K
i

values in the range from 0.4 to 2.8 μM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 μg/ml against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.
Activity of Telithromycin (HMR 3647) against Anaerobic Bacteria Compared to Those of Eight Other Agents by Time-Kill Methodology
Authors: Credito Kim L. , Ednie Lois M. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria. Time-kill studies were carried out with the addition of Oxyrase in order to prevent the introduction of CO
2
. Macrolide-azalide-ketolide MICs were 0.004 to 32.0 μg/ml. Of the latter group, telithromycin had the lowest MICs, especially against non-
Bacteroides fragilis
group strains, followed by azithromycin, clarithromycin, erythromycin A, and roxithromycin. Clindamycin was active (MIC ≤ 2.0 μg/ml) against all anaerobes except
Peptostreptococcus magnus
and
Bacteroides thetaiotaomicron
, while pristinamycin MICs were 0.06 to 4.0 μg/ml. Amoxicillin-clavulanate had MICs of ≤1.0 μg/ml, while metronidazole was active (MICs, 0.03 to 2.0 μg/ml) against all except
Propionibacterium acnes
. After 48 h at twice the MIC, telithromycin was bactericidal (≥99.9% killing) against 6 strains, with 99% killing of 9 strains and 90% killing of 10 strains. After 24 h at twice the MIC, 90, 99, and 99.9% killing of nine, six, and three strains, respectively, occurred. Lower rates of killing were seen at earlier times. Similar kill kinetics relative to the MIC were seen with other macrolides. After 48 h at the MIC, clindamycin was bactericidal against 8 strains, with 99 and 90% killing of 9 and 10 strains, respectively. After 24 h, 90% killing of 10 strains occurred at the MIC. The kinetics of clindamycin were similar to those of pristinamycin. After 48 h at the MIC, amoxicillin-clavulanate showed 99.9% killing of seven strains, with 99% killing of eight strains and 90% killing of nine strains. At four times the MIC, metronidazole was bactericidal against 8 of 10 strains tested after 48 h and against all 10 strains after 24 h; after 12 h, 99% killing of all 10 strains occurred.
TEM-24 Produced by Four Different Species of
Enterobacteriaceae
, Including
Providencia rettgeri
, in a Single Patient
Authors: Marchandin Helene , Carriere Christian , Sirot Danielle , Pierre Helene Jean- , Darbas Helene 
Published: October 2018

ABSTRACT

Four species of members of the family
Enterobacteriaceae
harboring extended-spectrum β-lactamase (ESBL) were recovered in a single patient hospitalized in an intensive care unit. Among these isolates, we describe for the first time an ESBL-producing
Providencia rettgeri
strain. Bacteria from the same species were shown to be genetically related by pulsed-field gel electrophoresis analysis. These strains produced the same TEM derivative ESBL, characterized as TEM-24. This enzyme had the peculiarity of being encoded by a large conjugative plasmid of 180 kb, never previously described for such an ESBL.
Stability of Antibiotics Used for Antibiotic-Lock Treatment of Infections of Implantable Venous Devices (Ports)
Authors: Anthony Thiele Umali , Rubin Lorry G. 
Published: October 2018

ABSTRACT
Antibiotic-lock is a treatment for catheter-related bloodstream infections in which a solution containing heparin and an antibiotic dwells in the lumen of the catheter or port. We tested the stability of vancomycin, cefazolin, ticarcillin-clavulanic acid, ceftazidime, or ciprofloxacin combined with heparin after incubation in vitro at 25 or 37°C for intervals of up to 10 days by bioassay. All the antibiotic solutions except ceftazidime retained ≥90% activity at both 25 and 37°C. Thus, studies of antibiotic-heparin lock solutions with dwell times of up to 10 days are feasible.
In Vitro Susceptibilities of Four
Bartonella bacilliformis
Strains to 30 Antibiotic Compounds
Authors: Sobraquès Mireille , Maurin Max , Birtles Richard J. , Raoult Didier 
Published: October 2018

ABSTRACT

We have evaluated for the first time in vitro antibiotic susceptibilities of four human strains of
Bartonella bacilliformis
, the agent of Carrion’s disease. Our results show that
B. bacilliformis
, like other
Bartonella
species, is highly susceptible to antibiotics, including most beta-lactams, aminoglycosides, chloramphenicol, rifampin, macrolides, tetracyclines, cotrimoxazole, and fluoroquinolones.
Cloning of a
Chryseobacterium
(
Flavobacterium
)
meningosepticum
Chromosomal Gene (
blaA
CME
) Encoding an Extended-Spectrum Class A β-Lactamase Related to the
Bacteroides
Cephalosporinases and the VEB-1 and PER β-Lactamases
Authors: Rossolini Gian Maria , Franceschini Nicola , Lauretti Laura , Caravelli Berardo , Riccio Maria Letizia , Galleni Moreno , Frère Jean-Marie , Amicosante Gianfranco 
Published: October 2018

ABSTRACT

In addition to the BlaB metallo-β-lactamase,
Chryseobacterium
(
Flavobacterium
)
meningosepticum
CCUG 4310 (NCTC 10585) constitutively produces a 31-kDa active-site serine β-lactamase, named CME-1, with an alkaline isoelectric pH. The
blaA
CME
gene that encodes the latter enzyme was isolated from a genomic library constructed in the
Escherichia coli
plasmid vector pACYC184 by screening for cefuroxime-resistant clones. Sequence analysis revealed that the CME-1 enzyme is a new class A β-lactamase structurally divergent from the other members of this class, being most closely related to the VEB-1 (also named CEF-1) and PER β-lactamases and the
Bacteroides
chromosomal cephalosporinases. The
blaA
CME
determinant is located on the chromosome and exhibits features typical of those of
C. meningosepticum
resident genes. The CME-1 protein was purified from an
E. coli
strain that overexpresses the cloned gene via a T7-based expression system by means of an anion-exchange chromatography step followed by a gel permeation chromatography step. Kinetic parameters for several substrates were determined. CME-1 is a clavulanic acid-susceptible extended-spectrum β-lactamase that hydrolyzes most cephalosporins, penicillins, and monobactams but that does not hydrolyze cephamycins and carbapenems. The enzyme exhibits strikingly different kinetic parameters for different classes of β-lactams, with both

K
m

and
k
cat
values much higher for cephalosporins than for penicillins and monobactams. However, the variability of both kinetic parameters resulted in overall similar acylation rates (
k
cat
/

K
m

ratios) for all types of β-lactam substrates.
Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives
Authors: Golenser Jacob , Frankenburg Shoshana , Ehrenfreund Tirtsa , Domb Abraham J. 
Published: October 2018

ABSTRACT

In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED
50
s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, for
Leishmania major
promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on
Leishmania infantum
-infected macrophages was more marked, with ED
50
s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with
L. major
were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.
Novel Expansions of the Gene Encoding Dihydropteroate Synthase in Trimethoprim-Sulfamethoxazole-Resistant
Streptococcus pneumoniae
Authors: Padayachee Thanugarani , Klugman Keith P. 
Published: October 2018

ABSTRACT

A study of eight sulfonamide-resistant clinical isolates of
Streptococcus pneumoniae
revealed chromosomal mutations within the gene encoding dihydropteroate synthase that play a role in conferring resistance to sulfamethoxazole. The presence of the
suld
mutation, found previously only in a laboratory mutant, was shown to occur in three of the wild-type clinical isolates. The duplication of Ser
61
, the other previously defined mutation in the dihydropteroate synthase gene of
S. pneumoniae
, was observed in only one of the isolates characterized. We report two previously unidentified amino acid alterations, namely, a duplication of Arg
58
and Pro
59
and an insertion of an arginine residue between Gly
60
and Ser
61
in trimethoprim-sulfamethoxazole-resistant strains. The significance of these mutations was confirmed by site-directed mutagenesis and by the transformation of a susceptible strain of
S. pneumoniae
to sulfamethoxazole resistance. Two resistant isolates did not contain any mutations within the gene encoding dihydropteroate synthase. The results presented suggest the independent generation of resistant mutations among South African clinical isolates. It is also proposed that the mechanism of sulfonamide resistance in
S. pneumoniae
involves the expansion of a specific region within dihydropteroate synthase, which probably forms part of the sulfonamide binding site.
Synergistic Effect of Clindamycin and Atovaquone in Acute Murine Toxoplasmosis
Authors: Djurković-Djaković Olgica , Nikolić Tatjana , Robert-Gangneux Florence , Bobić Branko , Nikolić Aleksandra 
Published: October 2018

ABSTRACT

The effect of clindamycin (CLI) combined with autovaquone (ATO) was examined in a murine model of acute toxoplasmosis. Swiss Webster mice intraperitoneally infected with 10
2
or 10
4
tachyzoites of the RH strain of
Toxoplasma gondii
were perorally treated with either drug alone (for ATO, 5, 25, 50, or 100 mg/kg of body weight/day; for CLI, 25, 50, or 400 mg/kg/day) or both combined (for ATO plus CLI, respectively, 5 plus 25, 25 plus 25, 25 plus 50, 50 plus 50, or 100 plus 400 mg/kg/day) starting with day 1 for 14 days. Survival was monitored during 7 weeks. Residual infection was assessed by a bioassay of representative 4-week survivors and by parasite DNA detection by PCR for representative 7-week survivors. An effect of treatment was shown in all treatment groups compared to untreated control mice (
P
= 0.0000). Among mice infected with 10
2
parasites, ATO and CLI at any dose combination protected significantly more animals than ATO alone (
P
= 0.0000), but compared to CLI alone, given its good effect, the combined drugs were no more effective (
P
> 0.05). For mice infected with 10
4
parasites, the drugs combined at the lowest and highest doses (5 plus 25 and 100 plus 400 mg/kg/day) were, similarly, more effective than ATO alone (
P
= 0.035 and 0.000, respectively) but not than CLI alone (
P
> 0.05). However, treatment with ATO plus CLI at 25 plus 25, 25 plus 50, and 50 plus 50 mg/kg/day protected 20, 33, and 78% of mice, respectively, compared to virtually no survivals among those treated with either drug alone (
P
< 0.0005), thus demonstrating a significant synergistic effect of ATO and CLI against
T. gondii
. Furthermore, the dose of ATO at a given dose of CLI was shown to be critical to the effect. Moreover, the absence of residual infection in some survivors shows the potential of this drug combination to eliminate the parasite.
Impact of decision aids used during clinical encounters on clinician outcomes and consultation length: a systematic review
Authors: Dobler Claudia Caroline , Sanchez Manuel , Gionfriddo Michael R , Alvarez-Villalobos Neri A , Singh Ospina Naykky , Spencer-Bonilla Gabriela , Thorsteinsdottir Bjorg , Benkhadra Raed , Erwin Patricia J , West Colin P , Brito Juan P , Murad Mohammad Hassan , Montori Victor M 
Published: October 2018

BackgroundClinicians’ satisfaction with encounter decision aids is an important component in facilitating implementation of these tools. We aimed to determine the impact of decision aids supporting shared decision making (SDM) during the clinical encounter on clinician outcomes.MethodsWe searched nine databases from inception to June 2017. Randomised clinical trials (RCTs) of decision aids used during clinical encounters with an unaided control group were eligible for inclusion. Due to heterogeneity among included studies, we used a narrative evidence synthesis approach.ResultsTwenty-five papers met inclusion criteria including 22 RCTs and 3 qualitative or mixed-methods studies nested in an RCT, together representing 23 unique trials. These trials evaluated healthcare decisions for cardiovascular prevention and treatment (n=8), treatment of diabetes mellitus (n=3), treatment of osteoporosis (n=2), treatment of depression (n=2), antibiotics to treat acute respiratory infections (n=3), cancer prevention and treatment (n=4) and prenatal diagnosis (n=1). Clinician outcomes were measured in only a minority of studies. Clinicians’ satisfaction with decision making was assessed in only 8 (and only 2 of them showed statistically significantly greater satisfaction with the decision aid); only three trials asked if clinicians would recommend the decision aid to colleagues and only five asked if clinicians would use decision aids in the future. Outpatient consultations were not prolonged when a decision aid was used in 9 out of 13 trials. The overall strength of the evidence was low, with the major risk of bias related to lack of blinding of participants and/or outcome assessors.ConclusionDecision aids can improve clinicians’ satisfaction with medical decision making and provide helpful information without affecting length of consultation time. Most SDM trials, however, omit outcomes related to clinicians’ perspective on the decision making process or the likelihood of using a decision aid in the future.