bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil
Authors: Srivastava Indresh K. , Vaidya Akhil B.
Published: October 2018

A combination of atovaquone and proguanil has been found to be quite effective in treating malaria, with little evidence of the emergence of resistance when atovaquone was used as a single agent. We have examined possible mechanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (ΔΨ

m

), it significantly enhanced the ability of atovaquone to collapse ΔΨ

m

when used in combination. This enhancement was observed at pharmacologically achievable doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrimethamine, also had no enhancing effect. Proguanil-mediated enhancement was specific for atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as myxothiazole and antimycin, were not altered by inclusion of proguanil. Surprisingly, proguanil did not enhance the ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites. These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses ΔΨ

m

in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner.
OXA-17, a Further Extended-Spectrum Variant of OXA-10 β-Lactamase, Isolated from
Pseudomonas aeruginosa
Authors: Danel Franck , Hall Lucinda M. C. , Duke Brigid , Gur Deniz , Livermore David M.
Published: October 2018

Pseudomonas aeruginosa
isolates 871 and 873 were isolated at Hacettepe University Hospital in Ankara and were highly resistant to ceftazidime (MIC, 128 μg/ml). Each produced three β-lactamases, with pIs of 5.3, 6.1, and 7.9. The β-lactamase with a pI of 5.3 was previously shown to be PER-1 enzyme. The antibiograms of the isolates were not entirely explained by production of PER-1 enzyme, insofar as ceftazidime resistance was incompletely reversed by clavulanate. The enzymes with pIs of 6.1 and 7.9 were therefore investigated. The enzyme with a pI of 6.1 proved to be a novel mutant of OXA-10, which we designated OXA-17, and had asparagine changed to serine at position 73 of the protein. When cloned into
Escherichia coli
XL1-blue, OXA-17 enzyme conferred greater resistance to cefotaxime, latamoxef, and cefepime than did OXA-10, but it had only a marginal (two- to fourfold) effect on the MIC of ceftazidime. This behavior contrasted with that of previous OXA-10 mutants, specifically OXA-11, -14, and -16, which predominately compromise ceftazidime. Extracted OXA-17 enzyme had relatively greater activity than OXA-10 against oxacillin, cloxacillin, and cefotaxime but, in terms of
k
cat
/

K
m

, it had lower catalytic efficiency against most β-lactams. The enzyme with a pI of 7.9 was shown by gene sequencing to be OXA-2.
Erythromycin-Resistant
Neisseria gonorrhoeae
and Oral Commensal
Neisseria
spp. Carry Known rRNA Methylase Genes
Authors: Roberts Marilyn C. , Chung Whasun O. , Roe Darcie , Xia Minsheng , Marquez Carolina , Borthagaray G. , Whittington William L. , Holmes King K.
Published: October 2018

Two
Neisseria gonorrhoeae
isolates from Seattle and two isolates from Uruguay were resistant to erythromycin (MIC, 4 to 16 μg/ml) and had reduced susceptibility to azithromycin (MIC, 1 to 4 μg/ml) due to the presence of the self-mobile rRNA methylase gene(s)
ermF
or
ermB
and
ermF
. The two Seattle isolates and one isolate from Uruguay were multiresistant, carrying either the 25.2-MDa
tetM
-containing plasmid (Seattle) or a β-lactamase plasmid (Uruguay). Sixteen commensal
Neisseria
isolates (10
Neisseria perflava
-
N. sicca
, 2
N. flava
, and 4
N. mucosa
) for which erythromycin MICs were 4 to 16 μg/ml were shown to carry one or more known rRNA methylase genes, including
ermB
,
ermC
, and/or
ermF
. Many of these isolates also were multiresistant and carried the
tetM
gene. This is the first time that a complete transposon or a complete conjugative transposon carrying an antibiotic resistance gene has been described for the genus
Neisseria
.
In Vivo Efficacies of Combinations of β-Lactams, β-Lactamase Inhibitors, and Rifampin against
Acinetobacter baumannii
in a Mouse Pneumonia Model
Authors: Wolff Michel , Joly-Guillou Marie-Laure , Farinotti Robert , Carbon Claude
Published: October 2018

The effects of various regimens containing combinations of β-lactams, β-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of
Acinetobacter baumannii
pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345–351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (≥3-log
10
reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of ≥65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (≥80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of β-lactams, β-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to
A. baumannii
.
In Vitro Activities of Designed Antimicrobial Peptides against Multidrug-Resistant Cystic Fibrosis Pathogens
Authors: Schwab Ute , Gilligan Peter , Jaynes Jesse , Henke David
Published: October 2018

The emergence of multidrug-resistant pathogens renders antibiotics ineffective in the treatment of lung infections in patients with cystic fibrosis (CF). Designed antimicrobial peptides (DAPs) are laboratory-synthesized peptide antibiotics that demonstrate a wide spectrum of antibacterial activity. Optimal conditions for susceptibility testing of these peptides have not yet been established. Medium composition is clearly a major factor influencing the results and reproducibilities of susceptibility tests. Using time-kill assays, we tested the effects of different media and buffers on the bactericidal activities of the peptides D2A21 and D4E1 on
Staphylococcus aureus
ATCC 29213 and
Pseudomonas aeruginosa
ATCC 27853. Each peptide at 1 and 5 μM was incubated with bacteria in the different media and buffers. Both peptides were most active in Tris-HCl buffer against
S. aureus
and
P. aeruginosa
. Among the more complex media tested, modified RPMI medium was the medium in which the peptides demonstrated the highest activity, while it supported the growth of the bacteria. The broth microdilution technique was used to test the activities of D2A21 and D4E1 in modified RPMI medium against multidrug-resistant pathogens from patients with CF. The MICs of DAPs for methicillin-resistant
S. aureus
ranged from 0.25 to 4 μg/ml, those for multidrug-resistant
P. aeruginosa
ranged from 0.125 to 4 μg/ml, those for
Stenotrophomonas maltophilia
ranged from 0.5 to 32 μg/ml, and those for
Burkholderia cepacia
ranged from 32 to ≥64 μg/ml. When the activity of peptide D2A21 was compared with that of the tracheal antimicrobial peptide (TAP), D2A21 had greater potency than TAP against
P. aeruginosa
. In addition, no difference in the MICs of D2A21 was seen when it was tested in nutrient broth supplemented with NaCl at different concentrations. Thus, DAPs are a class of salt-insensitive antibiotics potentially useful in the treatment of CF patients harboring multidrug-resistant
P. aeruginosa
.
Cloning and Nucleotide Sequence Determination of the Entire
mec
DNA of Pre-Methicillin-Resistant
Staphylococcus aureus
N315
Authors: Ito T. , Katayama Y. , Hiramatsu K.
Published: October 2018

In methicillin-resistant
Staphylococcus aureus
, the methicillin resistance gene
mecA
is localized within a large chromosomal region which is absent in the methicillin-susceptible
S. aureus
chromosome. The region, designated
mec
DNA, is speculated to have originated from the genome of another bacterial species and become integrated into the chromosome of the
S. aureus
cell in the past. We report here cloning and determination of the structure of the entire
mec
DNA sequence from a Japanese
S. aureus
strain, N315. The
mec
DNA was found to be 51,669 bp long, including terminal inverted repeats of 27 bp and a characteristic pair of direct repeat sequences of 15 bp each: one is situated in the right extremity of
mec
DNA, and the other is situated outside the
mec
DNA and abuts the left boundary of
mec
DNA. The integration site of
mec
DNA was found to be located in an open reading frame (ORF) of unknown function, designated
orfX
. Clusters of antibiotic resistance genes were noted in
mec
DNA carried by transposon Tn
554
and an integrated copy of plasmid pUB110. Both the transposon and plasmid were integrated in the proximity of the
mecA
gene, the latter being flanked by a pair of insertion sequence IS
431
elements. Many ORFs other than those encoding antibiotic resistance were considered nonfunctional because of the acquired mutations or partial deletions found in the ORFs. Two ORFs potentially encoding novel site-specific recombinases were found in
mec
DNA. However, there was no ORF that might encode
mec
DNA-specific transposase or integrase proteins, indicating that the
mec
DNA is not a transposon or a bacteriophage in nature.
Antimicrobial Susceptibility and Composition of Microcosm Dental Plaques Supplemented with Sucrose
Authors: Pratten J. , Wilson M.
Published: October 2018

The aims of this study were to evaluate the effects of repeated chlorhexidine gluconate (CHG) pulsing on the viability and bacterial composition of microcosm dental plaques derived from human saliva. The biofilms were grown on bovine enamel discs in a constant-depth film fermentor fed with an artificial saliva which was supplemented thrice daily with sucrose. The microcosm plaques had total viable anaerobic counts of 5 × 10
8
CFU per mm
2
and consisted of 12%
Actinomyces
spp., 85% streptococci, and 0.2%
Veillonella
spp. When pulsed twice daily with 0.2% CHG, there was an immediate 1.3-log
10
reduction in the total viable (anaerobic) count. However, as pulsing continued, the viable counts recovered, and after 4 days, the anaerobic count reached its pre-CHG-pulsing level, although the bacterial composition of the biofilms had changed. The results of this study show that twice-daily pulsing with 0.2% CHG over a 4-day period was ineffective at reducing the total anaerobic viable count of the biofilms but did alter their bacterial composition.
Multiple Resistant Phenotypes of
Candida albicans
Coexist during Episodes of Oropharyngeal Candidiasis in Human Immunodeficiency Virus-Infected Patients
Authors: Lopez-Ribot Jose L. , McAtee Robert K. , Perea Sofia , Kirkpatrick William R. , Rinaldi Michael G. , Patterson Thomas F.
Published: October 2018

Mechanisms of resistance to azoles in
Candida albicans
, the main etiologic agent of oropharyngeal candidiasis (OPC), include alterations in the target enzyme (lanosterol demethylase) and increased efflux of drug. Previous studies on mechanisms of resistance have been limited by the fact that only a single isolate from each OPC episode was available for study. Multiple isolates from each OPC episode were evaluated with oral samples plated in CHROMagar Candida with and without fluconazole to maximize detection of resistant yeasts. A total of 101 isolates from each of three serial episodes of OPC from four different patients were evaluated. Decreasing geometric means of fluconazole MICs with serial episodes of infection were detected in the four patients. However, 8-fold or larger (up to 32-fold) differences in fluconazole MICs were detected within isolates recovered at the same time point in 7 of 12 episodes. Strain identity was analyzed by DNA typing techniques and indicated that isolates from each patient represented mainly isogenic strains, but differed among patients. A Northern blot technique was used to monitor expression of
ERG11
(encoding lanosterol demethylase) and genes coding for efflux pumps. This analysis revealed that clinical isolates obtained from the same patient and episode were phenotypically heterogeneous in their patterns of expression of these genes involved in fluconazole resistance. These results demonstrate the complexity of the distribution of the molecular mechanisms of antifungal drug resistance and indicate that different subpopulations of yeasts may coexist at a given time in the same patient and may develop resistance through different mechanisms.
Combinations of Vancomycin and β-Lactams Are Synergistic against Staphylococci with Reduced Susceptibilities to Vancomycin
Authors: Climo Michael W. , Patron Roberto L. , Archer Gordon L.
Published: October 2018

Evidence of synergism between combinations of vancomycin and β-lactam antibiotics against 59 isolates of methicillin-resistant staphylococci (
Staphylococcus aureus
,
Staphylococcus epidermidis
, and
Staphylococcus haemolyticus
) for which vancomycin MICs ranged from 1 to 16 μg/ml were tested by broth microdilution checkerboard, disk diffusion, agar dilution, and time-kill antimicrobial susceptibility tests. The combination of vancomycin and oxacillin demonstrated synergy by all test methods against 30 of 59 isolates; no antagonism was seen. Synergy with vancomycin was also found by modified disk diffusion testing for ceftriaxone, ceftazidime, cefpodoxime, and amoxicillin-clavulanate but not for aztreonam. Evidence of synergy correlated directly with vancomycin MICs. The efficacy of vancomycin given alone and in combination with nafcillin was tested in the rabbit model of experimental endocarditis caused by three clinical isolates of glycopeptide-intermediate-susceptible
S. aureus
(GISA) (isolates HIP5827, HIP5836, and MU50). Two of the GISA isolates (isolates MU50 and HIP5836) were extremely virulent in this model, with 27 of 42 (64%) animals dying during the 3-day trial. Therapy with either vancomycin or nafcillin given as a single agent was ineffective for animals infected with HIP5827 or MU50. However, the combination of vancomycin and nafcillin resulted in a mean reduction of 4.52 log
10
CFU/g of aortic valvular vegetations per g compared to the reduction for controls for animals infected with HIP5827 and a reduction of 4.15 log
10
CFU/g for animals infected with MU50. Renal abscesses caused by HIP5827 were sterilized significantly better with the combination of vancomycin and nafcillin than by either treatment alone. We conclude that the combination of vancomycin and β-lactams with antistaphylococcal activity is an effective regimen for the treatment of infections with clinical strains of staphylococci which demonstrate reduced susceptibility to glycopeptides.
Heteroresistance to Fluconazole and Voriconazole in
Cryptococcus neoformans
Authors: Mondon P. , Petter R. , Amalfitano G. , Luzzati R. , Concia E. , Polacheck I. , Kwon-Chung K. J.
Published: October 2018

Cryptococcus neoformans
isolates that exhibited unusual patterns of resistance to fluconazole and voriconazole were isolated from seven isolates from two different geographical regions: one isolate from an Israeli non-AIDS patient and six serial isolates from an Italian AIDS patient who had suffered six recurrent episodes of cryptococcal meningitis. Each isolate produced cultures with heterogeneous compositions in which most of the cells were susceptible, but cells highly resistant to fluconazole (MICs, ≥64 μg/ml) were recovered at a variable frequency (7 × 10
−3
to 4.6 × 10
−2
). Evidence showed that this type of resistance is innate and is unrelated to drug exposure since the Israeli patient had never been treated with azoles or any other antimycotic agents. Analysis of clonal subpopulations of these two strains showed that they exhibited heterogeneous patterns of resistance. The number of subpopulations which grew on fluconazole or voriconazole agar declined progressively with increasing azole concentration without a sharp cutoff point. For the Italian serial isolates, the number of clonal populations resistant to fluconazole (64 μg/ml) and voriconazole (1 μg/ml) increased steadily, yielding the highest number for the isolate from the last episode. Attempts to purify a sensitive subpopulation failed, but clones highly resistant to fluconazole (100 μg/ml) and moderately resistant to voriconazole (1 μg/ml) always produced a homogeneous population of resistant cells. Upon maintenance on drug-free medium, however, the majority of the homogeneously resistant cells of these subclones lost their resistance and returned to the stable initial heteroresistant phenotype. The pattern of heteroresistance was not affected by the pH or osmolarity of the medium but was influenced by temperature. The resistance appeared to be suppressed at 35°C and was completely abolished at 40°C. Although heterogeneity in azole resistance among subpopulations of single isolates has been reported for
Candida
species, the transient changes in expression of resistance under different growth conditions reported here have not been observed in fungal pathogens.
Physiological Cost of Rifampin Resistance Induced In Vitro in
Mycobacterium tuberculosis
Authors: Billington O. J. , McHugh T. D. , Gillespie S. H.
Published: October 2018

Drug-resistant
Mycobacterium tuberculosis
is a major threat to public health. In clinical practice, a limited number of resistance mutations in a short sequence of the beta subunit of RNA polymerase (encoded by
rpoB
) have been described. Spontaneous resistance to rifampin was induced in vitro in
M. tuberculosis
H37Rv (ATCC 9360). Only three resistance patterns could be detected by PCR–single-strand conformation polymorphism analysis. Sequence analysis revealed that Ser
531
→Leu arose most frequently, followed by His
526
→Arg and then either His
526
→Tyr or His
526
→Asp. The relative Darwinian fitness of all but one of the mutant genotypes was less than that of the susceptible parent and, for these mutations, there was a significant correlation between fitness and clinical isolation rate (regression analysis
P
= 0.026). The fitness deficit in some mutants was small, suggesting that there is little likelihood of a spontaneous reversion to susceptibility.
Moderate-Level Resistance to Glycopeptide LY333328 Mediated by Genes of the
vanA
and
vanB
Clusters in Enterococci
Authors: Arthur Michel , Depardieu Florence , Reynolds Peter , Courvalin Patrice
Published: October 2018

Three of five natural plasmids carrying a wild-type
vanA
gene cluster did not confer LY333328 glycopeptide resistance on
Enterococcus faecalis
JH2-2 (MIC = 2 μg/ml). The two remaining plasmids conferred resistance to the drug (MIC, 8 μg/ml). The
vanB
gene cluster did not confer resistance to LY333328, since this antibiotic was not an inducer. Mutations in the

vanS
B

sensor gene that allowed induction by teicoplanin or constitutive expression of the
vanB
cluster led to LY333328 resistance (MIC, 8 to 16 μg/ml). Overproduction of the VanH, VanA, and VanX proteins for
d
-alanyl-
d
-lactate (
d
-Ala-
d
-Lac) synthesis and
d
-Ala-
d
-Ala hydrolysis was sufficient for resistance to LY333328 (MIC, 16 μg/ml). Mutations in the host
d
-Ala:
d
-Ala ligase contributed to LY333328 resistance in certain VanA- and VanB-type strains, but the MICs of the antibiotic did not exceed 16 μg/ml. Addition of
d
-2-hydroxybutyrate in the culture medium of mutants that did not produce the VanH
d
-lactate dehydrogenase led to incorporation of this
d
-2-hydroxy acid at the C-terminal ends of the peptidoglycan precursors and to LY333328 resistance (MIC, 64 μg/ml). The
vanZ
gene of the
vanA
cluster conferred resistance to LY333328 (MIC, 8 μg/ml) by an unknown mechanism. These data indicate that VanA- and VanB-type enterococci may acquire moderate-level resistance to LY333328 (MIC ≤ 16 μg/ml) in a single step by various mechanisms.
Susceptibilities of
Streptococcus pneumoniae
and
Haemophilus influenzae
to 10 Oral Antimicrobial Agents Based on Pharmacodynamic Parameters: 1997 U.S. Surveillance Study
Authors: Jacobs Michael R. , Bajaksouzian Saralee , Zilles Anne , Lin Gengrong , Pankuch Glenn A. , Appelbaum Peter C.
Published: October 2018

The susceptibilities of
Streptococcus pneumoniae
(1,476 strains) and untypeable
Haemophilus influenzae
(1,676 strains) to various oral β-lactam, macrolide-azalide, and fluoroquinolone antimicrobial agents were determined by broth microdilution. Organisms were isolated from specimens obtained from outpatients in six geographic regions of the United States. MIC data were interpreted according to pharmacodynamically derived breakpoints applicable to the oral agents tested. Among
H. influenzae
strains, 41.6% were β-lactamase positive. Virtually all
H. influenzae
strains were susceptible to amoxicillin-clavulanate (98%), cefixime (100%), and ciprofloxacin (100%), while 78% were susceptible to cefuroxime, 57% were susceptible to amoxicillin, 14% were susceptible to cefprozil, 9% were susceptible to loracarbef, 2% were susceptible to cefaclor, and 0% were susceptible to azithromycin and clarithromycin. Among
S. pneumoniae
isolates, 49.6% were penicillin susceptible, 17.9% were intermediate, and 32.5% were penicillin resistant, with penicillin MICs for 50 and 90% of the isolates tested of 0.12 and 4 μg/ml, respectively. Overall, 94% of
S. pneumoniae
isolates were susceptible to amoxicillin and amoxicillin-clavulanate, 69% were susceptible to azithromycin and clarithromycin, 63% were susceptible to cefprozil and cefuroxime, 52% were susceptible to cefixime, 22% were susceptible to cefaclor, and 11% were susceptible to loracarbef. Although ciprofloxacin has marginal activity against
S. pneumoniae
, no high-level fluoroquinolone-resistant strains were found. Significant cross-resistance was found between penicillin and macrolides-azalides among
S. pneumoniae
isolates, with 5% of the penicillin-susceptible strains being macrolide-azalide resistant, compared with 37% of the intermediate isolates and 66% of the resistant isolates. Resistance was highest in
S. pneumoniae
isolates from patients younger than 10 years of age, middle ear and paranasal sinus specimens, and the southern half of the United States. With the continuing rise in resistance, judicious use of oral antimicrobial agents is necessary in all age groups.
Comparison of Glycopeptide-Resistant
Enterococcus faecium
Isolates and Glycopeptide Resistance Genes of Human and Animal Origins
Authors: Descheemaeker Patrick R. M. , Chapelle Sabine , Devriese Luc A. , Butaye Patrick , Vandamme Peter , Goossens Herman
Published: October 2018

One hundred thirty-two glycopeptide-resistant
Enterococcus faecium
(GREF) isolates from different hospitals and pig and poultry farms in Belgium were compared on the basis of (i) their antibiotic susceptibilities, (ii) their
Sma
I pulsed-field gel electrophoresis (PFGE) patterns, and (iii) the organization of their Tn
1546
or related elements in order to detect possible phenotypic and genotypic relationships among both groups of isolates. Human and animal
vanA
-positive GREF isolates were found to have similar susceptibility patterns; they remained susceptible to gentamicin and were, in general, susceptible to ampicillin. PFGE demonstrated a very high degree of genomic heterogeneity in both groups of isolates. However, indistinguishable isolates were found within different farms or hospitals, and in two instances, epidemiologically unrelated pig and human isolates showed indistinguishable PFGE patterns. In total, eight different transposon types were identified, and all were related to the prototype transposon Tn
1546
. The two predominant types, Tn
1546
and type 2 transposons, which differed at three band positions, were present in both human and animal isolates. Type 2 transposons were significantly associated with pig isolates. The other types were seldom detected. These data suggest a possible exchange of glycopeptide resistance markers between animals and humans.
In Vitro Activities of Linezolid against Important Gram-Positive Bacterial Pathogens Including Vancomycin-Resistant Enterococci
Authors: Noskin Gary A. , Siddiqui Farida , Stosor Valentina , Hacek Donna , Peterson Lance R.
Published: October 2018

The emergence of resistance in gram-positive bacteria has necessitated a search for new antimicrobial agents. Linezolid is an oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to those of other antimicrobial agents against 3,945 clinical isolates. Linezolid demonstrated potent activity against all isolates tested. For all vancomycin-susceptible enterococci, staphylococci, and streptococci, the activity of linezolid was comparable to that of vancomycin. Against oxacillin-resistant staphylococci and vancomycin-resistant enterococci, linezolid was the most active agent tested. In summary, linezolid appears to be a promising new antimicrobial agent for the treatment of gram-positive infections.
The Structural Gene for Microcin H47 Encodes a Peptide Precursor with Antibiotic Activity
Authors: Rodríguez Eliana , Gaggero Carina , Laviña Magela
Published: October 2018

Microcin H47 is a bactericidal antibiotic produced by a naturally occurring
Escherichia coli
strain isolated in Uruguay. The microcin genetic system is located in the chromosome and extends over a 10-kb DNA segment containing the genes required for microcin synthesis, secretion, and immunity. The smallest microcin synthesis gene,
mchB
, was sequenced and shown to encode a highly hydrophobic peptide. An
mchB-phoA
gene fusion, which directed the synthesis of a hybrid bifunctional protein with both PhoA and microcin H47-like activities, was isolated. The results presented herein lead us to propose that microcin H47 is indeed a ribosomally synthesized peptide antibiotic and that its peptide precursor already has antibiotic activity of the same specificity as that of mature microcin.
Randomized, Double-Blind Trial of an Antibiotic-Lock Technique for Prevention of Gram-Positive Central Venous Catheter-Related Infection in Neutropenic Patients with Cancer
Authors: Carratalà Jordi , Niubó Jordi , Fernández-Sevilla Alberto , Juvé Eulalia , Castellsagué Xavier , Berlanga Juan , Liñares Josefina , Gudiol Francesc
Published: October 2018

The aim of the present study was to determine the efficacy of an antibiotic-lock technique in preventing endoluminal catheter-related infection with gram-positive bacteria in neutropenic patients with hematologic malignancies. Patients with nontunneled, multilumen central venous catheters were assigned in a randomized, double-blinded manner to receive either 10 U of heparin per ml (57 patients) or 10 U of heparin per ml and 25 μg of vancomycin per ml (60 patients), which were instilled in the catheter lumen and which were allowed to dwell in the catheter lumen for 1 h every 2 days. Insertion-site and hub swabs were taken twice weekly. The primary and secondary end points of the trial were significant colonization of the catheter hub and catheter-related bacteremia, respectively. Significant colonization of the catheter hub occurred in nine (15.8%) patients receiving heparin (seven patients were colonized with
Staphylococcus epidermidis
, one patient was colonized with
Staphylococcus capitis
, and one patient was colonized with
Corynebacterium
sp.), whereas the catheter hubs of none of the patients receiving heparin and vancomycin were colonized (
P
= 0.001). Catheter-related bacteremia developed in four (7%) patients receiving heparin (three patients had
S. epidermidis
bacteremia and one patient had
S. capitis
bacteremia), whereas none of the patients in the heparin and vancomycin group had catheter-related bacteremia (
P
= 0.05). The times to catheter hub colonization and to catheter-related bacteremia by the Kaplan-Meier method were longer in patients receiving heparin and vancomycin than in patients receiving heparin alone (
P
= 0.004 and
P
= 0.06, respectively). Our study shows that a solution containing heparin and vancomycin administered by using an antibiotic-lock technique effectively prevents catheter hub colonization with gram-positive bacteria and subsequent bacteremia during chemotherapy-induced neutropenia in patients with hematologic malignancy.
Oxfendazole Treatment of Sheep with Naturally Acquired Hydatid Disease
Authors: Dueger Erica L. , Moro Pedro L. , Gilman Robert H.
Published: October 2018

A blinded, randomized placebo-controlled trial assessed the efficacy and safety of oxfendazole for the treatment of ovine hydatid disease. Cyst fertility and parasite viability were measured following daily, weekly, and monthly treatment schedules with 30 mg of oxfendazole per kg of body weight. The 12-week trial was conducted in 215 adult sheep in the central Peruvian Andes and was masked for both treatment group and scheduling. In this trial oxfendazole significantly reduced protoscolex viability relative to controls in all treatment groups. In the daily, weekly, and monthly groups, 100, 97, and 78% of sheep, respectively, were either cured or improved following treatment, compared to 35% cured or improved animals in the control group. However, daily dosing at 30 mg of oxfendazole per kg proved highly toxic to sheep, resulting in a 24% death rate in the daily group as compared to a 4 to 6% mortality rate in all other groups. If found safe in humans, oxfendazole may prove to be a useful and inexpensive treatment for cestode infections in humans. This study suggests that a staggered dosing regimen of oxfendazole, and possibly other benzimidazoles, may be as efficacious as daily treatment regimens for hydatidosis while decreasing both the cost and adverse effects associated with daily dosing.
Pharmacokinetics and Safety of High-Dose and Extended-Interval Regimens of Levofloxacin in Human Immunodeficiency Virus-Infected Patients
Authors: Piscitelli Stephen C. , Spooner Katherine , Baird Barbara , Chow Andrew T. , Fowler Cynthia L. , Williams Rex R. , Natarajan Jaya , Masur Henry , Walker Robert E.
Published: October 2018

The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers.
Risk Factors for Detection, Survival, and Growth of Antibiotic-Resistant and Pathogenic Escherichia coli in Household Soils in Rural Bangladesh
Authors: Montealegre Maria Camila , Roy Subarna , Böni Franziska , Hossain Muhammed Iqbal , Navab-Daneshmand Tala , Caduff Lea , Faruque A. S. G. , Islam Mohammad Aminul , Julian Timothy R.
Published: October 2018

Soil may represent a direct source or act as an intermediary for the transmission of antibiotic-resistant and pathogenic
Escherichia coli
strains, particularly in low-income and rural settings. Thus, determining risk factors associated with detection, growth, and long-term survival of
E. coli
in soil environments is important for public health. Here, we demonstrate that household soils in rural Bangladesh are reservoirs for antibiotic-resistant and potentially pathogenic
E. coli
strains and can support
E. coli
growth and survival, and defined soil physicochemical characteristics are drivers of
E. coli
survival in this environment. In contrast, we found no evidence that household-level factors, including water, sanitation, and hygiene indicators, were associated with
E. coli
contamination of household soils.
Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1
Authors: Pryce Rhys , Ng Weng M. , Zeltina Antra , Watanabe Yasunori , El Omari Kamel , Wagner Armin , Bowden Thomas A.
Published: October 2018

The genetically and geographically diverse group of viruses within the family
Arenaviridae
includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface.
Curli-Containing Enteric Biofilms Inside and Out: Matrix Composition, Immune Recognition, and Disease Implications
Authors: Tursi Sarah A. , Tükel Çagla
Published: October 2018

Biofilms of enteric bacteria are highly complex, with multiple components that interact to fortify the biofilm matrix. Within biofilms of enteric bacteria such asEscherichia coliandSalmonellaspecies, the main component of the biofilm is amyloid curli. Other constituents include cellulose, extracellular DNA, O antigen, and various surface proteins, including BapA.
Sicker patients account for the weekend mortality effect among adult emergency admissions to a large hospital trust
Authors: Sun Jianxia , Girling Alan J , Aldridge Cassie , Evison Felicity , Beet Chris , Boyal Amunpreet , Rudge Gavin , Lilford Richard J , Bion Julian
Published: October 2018

Objective

To determine whether the higher weekend admission mortality risk is attributable to increased severity of illness.

Design

Retrospective analysis of 4 years weekend and weekday adult emergency admissions to a university teaching hospital in England.

Outcome measures

30-day postadmission weekend:weekday mortality ratios adjusted for severity of illness (baseline National Early Warning Score (NEWS)), routes of admission to hospital, transfer to the intensive care unit (ICU) and demographics.

Results

Despite similar emergency department daily attendance rates, fewer patients were admitted on weekends (mean admission rate 91/day vs 120/day) because of fewer general practitioner referrals. Weekend admissions were sicker than weekday (mean NEWS 1.8 vs 1.7, p=0.008), more likely to undergo transfer to ICU within 24 hours (4.2% vs 3.0%), spent longer in hospital (median 3 days vs 2 days) and less likely to experience same-day discharge (17.2% vs 21.9%) (all p values <0.001).

The crude 30-day postadmission mortality ratio for weekend admission (OR=1.13; 95% CI 1.08 to 1.19) was attenuated using standard adjustment (OR=1.11; 95% CI 1.05 to 1.17). In patients for whom NEWS values were available (90%), the crude OR (1.07; 95% CI 1.01 to 1.13) was not affected with standard adjustment. Adjustment using NEWS alone nullified the weekend effect (OR=1.02; 0.96–1.08).

NEWS completion rates were higher on weekends (91.7%) than weekdays (89.5%). Missing NEWS was associated with direct transfer to intensive care bypassing electronic data capture. Missing NEWS in non-ICU weekend patients was associated with a higher mortality and fewer same-day discharges than weekdays.

Conclusions

Patients admitted to hospital on weekends are sicker than those admitted on weekdays. The cause of the weekend effect may lie in community services.
Practical clinical approach to the evaluation of hepatobiliary disorders in inflammatory bowel disease
Authors: Yaccob Afif , Mari Amir
Published: October 2018

Hepatobiliary disorders are frequent extraintestinal manifestations in inflammatory bowel disease (IBD) and may appear at any time point during the natural course of the disease. Conceptually, these manifestations can be categorised as: (1) disorders that have an association with IBD; (2) diseases directly and structurally related to intestinal inflammation; (3) diseases related to the adverse effects of IBD treatment; and (4) disorders stemming from the metabolic derangements caused by IBD. The clinical presentations of these disorders range from a mild transient elevation of liver enzymes to liver failure and death. Given this wide differential diagnosis and spectrum of severity, it is understandable that the evaluation of patients with IBD with a hepatobiliary abnormality is often challenging. In this review, we present a concise summary of the common hepatic manifestations seen in patients with IBD and focus on the relevant practical issues encountered by gastroenterologists caring for patients with IBD. A practical clinical approach to the evaluation of liver enzyme abnormalities in patients with IBD is provided based on the predominant enzyme elevation pattern (hepatocellular vs cholestatic), before presenting a working scheme for the prevention of hepatitis B virus (HBV) reactivation in patients with IBD receiving immunosuppressive medications. Finally, we specify several laboratory alterations seen in patients with IBD that can potentially interfere with the interpretation of liver function tests, before defining the specific circumstances when a referral for a hepatological consultation is required for further assessment.
Large electrocaloric effect obtained in Ba(SnxTi1−x)O3 lead-free ceramics using direct and indirect measurements
Authors: Li Jiang , Li Dan-Dan , Lu Biao , Yao Ying-Bang , Tao Tao , Liang Bo , Lu Wen-Hui , Luo Ge-Li , Lu Sheng-Guo
Published: October 2018

The electrocaloric effect (ECE) in lead-free BaSnxTi[Formula: see text]O3 (BSnT, [Formula: see text], 0.10 and 0.15) ceramics were investigated using a direct ECE measurement. Results indicate that the maximum ECE occurs near the Curie temperature and it slightly shifts towards high temperatures. The directly measured ECE is larger than that calculated using the Maxwell relation and P-E loops. A maximum electrocaloric efficiency [Formula: see text][Formula: see text]KmV[Formula: see text] was procured for the composition with [Formula: see text] at [Formula: see text][Formula: see text]K. And it also shows a broad peak in the temperature range of 250–320[Formula: see text]K.
Forecasting Bond Risk Premia with Unspanned Macroeconomic Information
Authors: Liu Rui
Published: October 2018

I provide evidence on the existence of unspanned macro risk. I investigate the usefulness of unspanned macro information for forecasting bond risk premia in a macro-finance term structure model from the perspective of a bond investor. I account for model uncertainty by combining forecasts with and without unspanned output and inflation risks optimally from the forecaster’s objective. Incorporating macro information generates significant gains in forecasting bond risk premia relative to yield curve information at long forecast horizons, especially when allowing for time-varying combination weight. These gains in predictive accuracy significantly improve investor utility.
Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Authors: Gould Todd D. , Zarate Carlos A. , Thompson Scott M.
Published: October 2018

For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.
Leptin contributes to the beneficial effects of insulin treatment in streptozotocin-diabetic male mice
Authors: Neumann Ursula H. , Kwon Michelle M. , Baker Robert K. , Kieffer Timothy J.
Published: October 2018

It was long thought that the only hormone capable of reversing the catabolic consequences of diabetes was insulin. However, various studies have demonstrated that the adipocyte-derived hormone leptin can robustly lower blood glucose levels in rodent models of insulin-deficient diabetes. In addition, it has been suggested that some of the metabolic manifestations of insulin-deficient diabetes are due to hypoleptinemia as opposed to hypoinsulinemia. Because insulin therapy increases leptin levels, we sought to investigate the contribution of leptin to the beneficial effects of insulin therapy. To do this, we tested insulin therapy in streptozotocin (STZ) diabetic mice that were either on an ob/ ob background or that were given a leptin antagonist to determine if blocking leptin action would blunt the glucose-lowering effects of insulin therapy. We found that STZ diabetic ob/ ob mice have a diminished blood glucose-lowering effect in response to insulin therapy compared with STZ diabetic controls and exhibited more severe weight loss post-STZ injection. In addition, STZ diabetic mice administered a leptin antagonist through daily injection or plasmid expression respond less robustly to insulin therapy as assessed by both fasting blood glucose levels and blood glucose levels during an oral glucose tolerance test. However, leptin antagonism did not prevent the insulin-induced reduction in β-hydroxybutyrate and triglyceride levels. Therefore, we conclude that elevated leptin levels can contribute to the glucose-lowering effect of insulin therapy in insulin-deficient diabetes.
Angiotensin-(1–7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice
Authors: Loloi Justin , Miller Amanda J. , Bingaman Sarah S. , Silberman Yuval , Arnold Amy C.
Published: October 2018

Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1–7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1–7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1–7) mas receptor antagonist A779 (400 or 800 ng·kg−1·min−1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 ( n = 6–13/group). Captopril reduced body weight (28 ± 2 vs. 41 ± 2 g saline; P = 0.001), lowered systolic BP (109 ± 6 vs. 144 ± 7 mmHg saline; P = 0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31 ± 4 vs. 16 ± 2 mg·kg−1·min−1 saline; P = 0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23 ± 2 mg·kg−1·min−1; P = 0.042), with no effect on body weight (32 ± 2 g; P = 0.441) or BP (111 ± 7 mmHg; P = 0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1–7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.
Effect of Particle Size of Periclase on the Periclase Hydration and Expansion of Low‐Heat Portland Cement Pastes
Authors: Yan Man , Deng Min , Wang Chen , Chen Zhiyang
Published: October 2018

In this paper, low‐heat Portland cement (LHC) clinkers were prepared by calcining raw materials at 1350°C for 2.0 hours, 1400°C for 1.0 hour, 1400°C for 1.5 hours, 1400°C for 2.0 hours, 1450°C for 1.0 hour, and 1450°C for 2.0 hours. The clinkers were ground with gypsum to produce LHC. The particle size of periclase was analysed by BSEM. Expansion of LHC pastes due to hydration of periclase was measured. The hydration degree of periclase in LHC pastes was quantitatively determined by XRD internal standard method and BSEM. The results showed that the particle size of periclase was larger when clinkers were calcined at higher temperatures or for longer time. Smaller periclase (2.60 μm) in LHC pastes tended to hydrate faster. As a result, expansion of LHC pastes develops relatively faster. Smaller particle of periclase in clinker tends to result in higher hydration degree of periclase in pastes cured at 20°C for 240 days, and there is a small amount of brucite appearing around periclase. The hydration rate of 4.00 μm periclase particle in cement paste cured at 80°C is obviously faster than that in paste cured at 20°C and 40°C. When cement paste was cured at 80°C for 7 days, the periclase was hydrated for 32.56%. The smaller size periclase (1–3 μm) had fully hydrated when the curing age was 240 days, and a large amount of brucite was produced around the larger periclase particle.