bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae
Authors: Bulman Zackery P. , Satlin Michael J. , Chen Liang , Kreiswirth Barry N. , Shin Beom Soo , Walsh Thomas J. , Holden Patricia N. , Forrest Alan , Nation Roger L. , Li Jian , Tsuji Brian T. 
Published: February 2017

ABSTRACT

Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined against
Klebsiella pneumoniae
carbapenemase-producing
Klebsiella pneumoniae
(KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log
10
CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log
10
CFU/ml at 78 h and the time required for regrowth was more than doubled versus the 2-drug combinations. Remarkably, combinations with a high single-dose polymyxin B burst plus rifampin preserved KPC-Kp polymyxin susceptibility (MIC
240 h
= 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC
240 h
= 32 mg/liter).
Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?
Authors: Marshall Steven , Hujer Andrea M. , Rojas Laura J. , Papp-Wallace Krisztina M. , Humphries Romney M. , Spellberg Brad , Hujer Kristine M. , Marshall Emma K. , Rudin Susan D. , Perez Federico , Wilson Brigid M. , Wasserman Ronald B. , Chikowski Linda , Paterson David L. , Vila Alejandro J. , van Duin David , Kreiswirth Barry N. , Chambers Henry F. , Fowler Vance G. , Jacobs Michael R. , Pulse Mark E. , Weiss William J. , Bonomo Robert A. 
Published: February 2017

ABSTRACT

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the
in vitro
efficacy of a unique combination of CAZ-AVI and ATM against 21 representative
Enterobacteriaceae
isolates with a complex molecular background that included
bla
IMP
,
bla
NDM
,
bla
OXA-48
,
bla
CTX-M
,
bla
AmpC
, and combinations thereof. Time-kill assays were conducted, and the
in vivo
efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The
in vitro
activity of CAZ-AVI in combination with ATM against diverse
Enterobacteriaceae
possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log
10
-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log
10
-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing
Enterobacteriaceae
.
Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model
Authors: da Costa-Silva Thais Alves , Galisteo Andrés Jimenez , Lindoso José Angelo Lauletta , Barbosa Leandro R. S. , Tempone Andre Gustavo 
Published: February 2017

ABSTRACTVisceral leishmaniasis is a fatal parasitic neglected disease affecting 1.5 million people worldwide. Based on a drug repositioning approach, the aim of this work was to investigate thein vitroimmunomodulatory potential of buparvaquone (BPQ) and to establish a safe regimen to evaluate thein vivoefficacy of BPQ entrapped by negatively charged nanoliposomes (BPQ-LP) inLeishmania infantum-infected hamsters. Small-angle X-ray scattering, dynamic light scattering, and the ζ-potential were applied in order to study the influence of BPQ on the liposome structure. Our data revealed that BPQ was located in the polar-apolar interface, snorkeling the polar region, and protected against aggregation inside the lipophilic region. The presence of BPQ also decreased the Z-average hydrodynamic diameter and increased the surface charge. Compared to intravenous and intramuscular administration, a subcutaneous route was a more effective route for BPQ-LP; at 0.4 mg/kg, BPQ-LP reduced infection in the spleen and liver by 98 and 96%, respectively. Treatment for 5 days resulted in limited efficacy, but 10 days of treatment resulted in an efficacy similar to that of a 15-day regimen. The nanoliposomal drug was highly effective, with a mean 50% effective dose of 0.25 mg/kg, reducing the parasite load in bone marrow by 80%, as detected using quantitative PCR analysis. In addition, flow cytometry studies showed that BPQ upregulated cytokines as tumor necrosis factor, monocyte chemoattractant protein 1, interleukin-10 (IL-10), and IL-6 inLeishmania-infected macrophages, eliminating the parasites via a nitric oxide-independent mechanism. This new formulation proved to be a safe and effective treatment for murine leishmaniasis that could be a useful candidate against visceral leishmaniasis.
Nephrotoxicity in Patients with or without Cystic Fibrosis Treated with Polymyxin B Compared to Colistin
Authors: Crass Ryan L. , Rutter W. Cliff , Burgess Donna R. , Martin Craig A. , Burgess David S. 
Published: February 2017

ABSTRACT

Nephrotoxicity is the primary adverse effect of the polymyxins. The relative rates of toxicity of polymyxin B and colistin have not been fully elucidated, especially in patients with cystic fibrosis (CF). A retrospective cohort study of adults treated with polymyxin B or colistin for at least 48 h was conducted. The primary endpoint was the incidence of kidney injury assessed by RIFLE (i.e.,
r
isk,
i
njury,
f
ailure,
l
oss,
e
nd-stage renal disease) criteria. Risk factors for kidney injury were evaluated using multivariate Cox regression. A total of 414 patients were evaluated, 220 of whom had CF. In patients without CF, there was no difference in kidney injury with polymyxin B and colistin (42.9% versus 50.3%,
P
= 0.46). Loop diuretic exposure was a risk factor for kidney injury (adjusted hazard ratio [aHR], 1.82; 95% confidence interval [CI], 1.16 to 2.83) in this population. In patients with CF, polymyxin B and colistin were associated with similar rates of kidney injury (34.5% versus 29.8%,
P
= 0.77). Diabetes (aHR, 2.68; 95% CI, 1.01 to 7.11), loop diuretics (aHR, 3.02; 95% CI, 1.36 to 6.73), and progressive care unit admission (aHR, 8.21; 95% CI, 2.55 to 26.46) were risk factors for kidney injury, while higher baseline serum creatinine levels (per 1 mg/dl) were protective (aHR, 0.08; 95% CI, 0.01 to 0.48). Total unadjusted kidney injury in polymyxin-treated patients was less frequent in those who had CF (30.5% versus 48.5%,
P
< 0.001). Polymyxin B and colistin are associated with a high incidence of kidney injury; cystic fibrosis may be protective against polymyxin nephrotoxicity, but further investigation is needed to confirm this conjecture.
Intracellular Targeting Mechanisms by Antimicrobial Peptides
Authors: Le Cheng-Foh , Fang Chee-Mun , Sekaran Shamala Devi 
Published: February 2017

ABSTRACT
Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.
Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States
Authors: Satlin Michael J. , Chen Liang , Patel Gopi , Gomez-Simmonds Angela , Weston Gregory , Kim Angela C. , Seo Susan K. , Rosenthal Marnie E. , Sperber Steven J. , Jenkins Stephen G. , Hamula Camille L. , Uhlemann Anne-Catrin , Levi Michael H. , Fries Bettina C. , Tang Yi-Wei , Juretschko Stefan , Rojtman Albert D. , Hong Tao , Mathema Barun , Jacobs Michael R. , Walsh Thomas J. , Bonomo Robert A. , Kreiswirth Barry N. 
Published: February 2017

ABSTRACT

Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant
Enterobacteriaceae
(CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among
Enterobacteriaceae
bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (
cps
), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or had undergone transplantation. The prevalences of carbapenem resistance among
Klebsiella pneumoniae
,
Enterobacter
spp., and
Escherichia coli
bacteremias were 9.7%, 2.2%, and 0.1%, respectively. Ninety percent of CRE were
K. pneumoniae
and 92% produced
K. pneumoniae
carbapenemase (KPC-3, 48%; KPC-2, 44%). Two CRE produced NDM-1 and OXA-48 carbapenemases. Sequence type 258 (ST258) predominated among KPC-producing
K. pneumoniae
(KPC-
Kp
). The
wzi154
allele, corresponding to
cps-2
, was present in 93% of KPC-3-
Kp
, whereas KPC-2-
Kp
had greater
cps
diversity. Ninety-nine percent of CRE were ceftazidime-avibactam (CAZ-AVI)-susceptible, although 42% of KPC-3-
Kp
had an CAZ-AVI MIC of ≥4/4 μg/ml. There was a median of 47 h from bacteremia onset until active antimicrobial therapy, 38% of patients had septic shock, and 49% died within 30 days. KPC-3-
Kp
bacteremia (adjusted odds ratio [aOR], 2.58;
P
= 0.045), cancer (aOR, 3.61,
P
= 0.01), and bacteremia onset in the intensive care unit (aOR, 3.79;
P
= 0.03) were independently associated with mortality. Active empirical therapy and combination therapy were not associated with survival. Despite a decade of experience with CRE, patients with CRE bacteremia have protracted delays in appropriate therapies and high mortality rates, highlighting the need for rapid diagnostics and evaluation of new therapeutics.
Phenotypic and Molecular Antimicrobial Susceptibility of Helicobacter pylori
Authors: Chen Derrick , Cunningham Scott A. , Cole Nicolynn C. , Kohner Peggy C. , Mandrekar Jayawant N. , Patel Robin 
Published: February 2017

ABSTRACT

Failure to eradicate
Helicobacter pylori
infection is often a result of antimicrobial resistance, which for clarithromycin is typically mediated by specific point mutations in the 23S rRNA gene. The purpose of this study was to define current patterns of antimicrobial susceptibility in
H. pylori
isolates derived primarily from the United States and to survey them for the presence of point mutations in the 23S rRNA gene and assess the ability of these mutations to predict phenotypic clarithromycin susceptibility. Antimicrobial susceptibility testing was performed using agar dilution on 413
H. pylori
isolates submitted to Mayo Medical Laboratories for susceptibility testing. For a subset of these isolates, a 150-bp segment of the 23S rRNA gene was sequenced. A total of 1,970 MICs were reported over the 4-year study period. The rate of clarithromycin resistance was high (70.4%), and elevated MICs were frequently observed for metronidazole (82.4% of isolates had an MIC of >8 μg/ml) and ciprofloxacin (53.5% of isolates had an MIC of >1 μg/ml). A total of 111 archived
H. pylori
isolates underwent 23S rRNA gene sequencing; we found 95% concordance between genotypes and phenotypes (
P
= 0.9802). Resistance to clarithromycin was most commonly due to an A2143G mutation (82%), followed by A2142G (14%) and A2142C (4%) mutations. Clinical
H. pylori
isolates derived primarily from the United States demonstrated a high rate of clarithromycin resistance and elevated metronidazole and ciprofloxacin MICs. The relative distribution of point mutations at positions 2143 and 2142 in the 23S rRNA gene in clarithromycin-resistant
H. pylori
was similar to that reported from other parts of the world; these mutations predict phenotypic resistance to clarithromycin.
Global Molecular Epidemiology of IMP-Producing Enterobacteriaceae
Authors: Matsumura Yasufumi , Peirano Gisele , Motyl Mary R. , Adams Mark D. , Chen Liang , Kreiswirth Barry , DeVinney Rebekah , Pitout Johann D. D. 
Published: February 2017

ABSTRACT

International data on the molecular epidemiology of
Enterobacteriaceae
with IMP carbapenemases are lacking. We performed short-read (Illumina) whole-genome sequencing on a global collection of 38 IMP-producing clinical
Enterobacteriaceae
(2008 to 2014). IMP-producing
Enterobacteriaceae
(7 varieties within 11 class 1 integrons) were mainly present in the South Pacific and Asia. Specific
bla
IMP
-containing integrons (In809 with
bla
IMP-4
, In722 with
bla
IMP-6
, and In687 with
bla
IMP-14
) were circulating among different bacteria in countries such as Australia, Japan, and Thailand. In1312 with
bla
IMP-1
was present in
Klebsiella pneumoniae
from Japan and
Citrobacter freundii
from Brazil.
Klebsiella pneumoniae
(
n
= 22) was the most common species; clonal complex 14 (CC14) from Philippines and Japan was the most common clone and contained In1310 with
bla
IMP-26
and In1321 with
bla
IMP-6
. The
Enterobacter cloacae
complex (
n
= 9) consisted of
Enterobacter hormaechei
and
E. cloacae
cluster III. CC78 (from Taiwan) containing In73 with
bla
IMP-8
was the most common clone among the
E. cloacae
complex. This study highlights the importance of surveillance programs using the latest molecular techniques for providing insight into the characteristics and global distribution of
Enterobacteriaceae
with
bla
IMP
genes.
Pleiotropic Regulation of Virulence Genes in Streptococcus mutans by the Conserved Small Protein SprV
Authors: Shankar Manoharan , Hossain Mohammad S. , Biswas Indranil 
Published: February 2017

ABSTRACT

Streptococcus mutans
, an oral pathogen associated with dental caries, colonizes tooth surfaces as polymicrobial biofilms known as dental plaque.
S. mutans
expresses several virulence factors that allow the organism to tolerate environmental fluctuations and compete with other microorganisms. We recently identified a small hypothetical protein (90 amino acids) essential for the normal growth of the bacterium. Inactivation of the gene, SMU.2137, encoding this protein caused a significant growth defect and loss of various virulence-associated functions. An
S. mutans
strain lacking this gene was more sensitive to acid, temperature, osmotic, oxidative, and DNA damage-inducing stresses. In addition, we observed an altered protein profile and defects in biofilm formation, bacteriocin production, and natural competence development, possibly due to the fitness defect associated with SMU.2137 deletion. Transcriptome sequencing revealed that nearly 20% of the
S. mutans
genes were differentially expressed upon SMU.2137 deletion, thereby suggesting a pleiotropic effect. Therefore, we have renamed this hitherto uncharacterized gene as
sprV
(
s
treptococcal
p
leiotropic
r
egulator of
v
irulence). The transcript levels of several relevant genes in the
sprV
mutant corroborated the phenotypes observed upon
sprV
deletion. Owing to its highly conserved nature, inactivation of the
sprV
ortholog in
Streptococcus gordonii
also resulted in poor growth and defective UV tolerance and competence development as in the case of
S. mutans
. Our experiments suggest that SprV is functionally distinct from its homologs identified by structure and sequence homology. Nonetheless, our current work is aimed at understanding the importance of SprV in the
S. mutans
biology.

IMPORTANCE
Streptococcus mutans
employs several virulence factors and stress resistance mechanisms to colonize tooth surfaces and cause dental caries. Bacterial pathogenesis is generally controlled by regulators of fitness that are critical for successful disease establishment. Sometimes these regulators, which are potential targets for antimicrobials, are lost in the genomic context due to the lack of annotated homologs. This work outlines the regulatory impact of a small, highly conserved hypothetical protein, SprV, encoded by
S. mutans
. We show that SprV affects the transcript levels of various virulence factors required for normal growth, biofilm formation, stress tolerance, genetic competence, and bacteriocin production.
Vibrio Phage KVP40 Encodes a Functional NAD
+
Salvage Pathway
Authors: Lee Jae Yun , Li Zhiqun , Miller Eric S. 
Published: February 2017

ABSTRACT

The genome of T4-type
Vibrio
bacteriophage KVP40 has five genes predicted to encode proteins of pyridine nucleotide metabolism, of which two,
nadV
and
natV
, would suffice for an NAD
+
salvage pathway. NadV is an apparent nicotinamide phosphoribosyltransferase (NAmPRTase), and NatV is an apparent bifunctional nicotinamide mononucleotide adenylyltransferase (NMNATase) and nicotinamide-adenine dinucleotide pyrophosphatase (Nudix hydrolase). Genes encoding the predicted salvage pathway were cloned and expressed in
Escherichia coli
, the proteins were purified, and their enzymatic properties were examined. KVP40 NadV NAmPRTase is active
in vitro
, and a clone complements a
Salmonella
mutant defective in both the bacterial
de novo
and salvage pathways. Similar to other NAmPRTases, the KVP40 enzyme displayed ATPase activity indicative of energy coupling in the reaction mechanism. The NatV NMNATase activity was measured in a coupled reaction system demonstrating NAD
+
biosynthesis from nicotinamide, phosphoribosyl pyrophosphate, and ATP. The NatV Nudix hydrolase domain was also shown to be active, with preferred substrates of ADP-ribose, NAD
+
, and NADH. Expression analysis using reverse transcription-quantitative PCR (qRT-PCR) and enzyme assays of infected
Vibrio parahaemolyticus
cells demonstrated
nadV
and
natV
transcription during the early and delayed-early periods of infection when other KVP40 genes of nucleotide precursor metabolism are expressed. The distribution and phylogeny of NadV and NatV proteins among several large double-stranded DNA (dsDNA) myophages, and also those from some very large siphophages, suggest broad relevance of pyridine nucleotide scavenging in virus-infected cells. NAD
+
biosynthesis presents another important metabolic resource control point by large, rapidly replicating dsDNA bacteriophages.

IMPORTANCE
T4-type bacteriophages enhance DNA precursor synthesis through reductive reactions that use NADH/NADPH as the electron donor and NAD
+
for ADP-ribosylation of proteins involved in transcribing and translating the phage genome. We show here that phage KVP40 encodes a functional pyridine nucleotide scavenging pathway that is expressed during the metabolic period of the infection cycle. The pathway is conserved in other large, dsDNA phages in which the two genes,
nadV
and
natV
, share an evolutionary history in their respective phage-host group.
A Cross-Sectional Survey of Pain Catastrophising and Acupuncture Use among Breast Cancer Survivors
Authors: Lee Iris , Garland Sheila N , DeMichele Angela , Farrar John T , Im Eun-Ok , Mao Jun J 
Published: February 2017

Introduction Treatment-related joint pain affects almost half of all women with breast cancer using aromatase inhibitors and is a major reason for terminating treatment. Although acupuncture is becoming an increasingly popular, evidence-based option for treating pain, little is known about the potential influence of psychological factors on acupuncture use. Objective We aimed to evaluate the association between pain catastrophising and use of acupuncture in breast cancer survivors experiencing arthralgia. Methods We conducted a cross-sectional survey of arthralgic breast cancer patients. Patients were asked if they had used acupuncture since their cancer diagnosis. The Pain Catastrophising Scale (PCS) was used to measure negative coping styles related to the experience of pain. We performed multiple logistic regression analysis to evaluate the relationship between pain catastrophising and acupuncture use, adjusting for covariates. Results Of the 424 participants, 69 (16%) reported use of acupuncture since their breast cancer diagnosis. In multivariate analyses, compared to those in the lowest PCS score tertile, patients with the highest PCS scores were more likely to have used acupuncture (p=0.03). In particular, patients with high levels of rumination (p=0.005) and magnification (p=0.008) were more likely to have used acupuncture. Helplessness was not associated with acupuncture use (p=0.23). Conclusions High levels of pain catastrophising, and specifically the processes of rumination and magnification, were associated with greater acupuncture use. We believe this could have important implications for understanding which population is more likely to seek acupuncture treatment and how this alternative therapy could be better targeted to these patients.
Randomised controlled trial examining the effect of an outpatient exercise training programme on haemodynamics and cardiac MR parameters of right ventricular function in patients with pulmonary arterial hypertension: the ExPAH study protocol
Authors: Chia Karen S W , Faux Steven G , Wong Peter K K , Holloway Cameron , Assareh Hassan , McLachlan Craig S , Kotlyar Eugene 
Published: February 2017

IntroductionPulmonary hypertension (PH) is a potentially life-threatening condition characterised by elevated pulmonary artery pressure. Early stage PH patients are often asymptomatic. Disease progression is associated with impairment of right ventricular function and progressive dyspnoea. Current guidelines recommend exercise training (grade IIa, level B). However, many questions remain regarding the mechanisms of improvement, intensity of supervision and optimal frequency, duration and intensity of exercise. This study will assess the effect of an outpatient rehabilitation programme on haemodynamics and cardiac right ventricular function in patients with pulmonary arterial hypertension (PAH), a subgroup of PH.Methods and analysisThis randomised controlled trial involves both a major urban tertiary and smaller regional hospital in New South Wales, Australia. The intervention will compare an outpatient rehabilitation programme with a control group (home exercise programme). Participants will be stable on oral PAH-specific therapy. The primary outcome measure will be right ventricular ejection fraction measured by cardiac MRI. Secondary outcomes will include haemodynamics measured by right heart catheterisation, endurance, functional capacity, health-related quality of life questionnaires and biomarkers of cardiac function and inflammation.Ethics approval and disseminationEthical approval has been granted by St Vincent's Hospital, Sydney (HREC/14/SVH/341). Results of this study will be disseminated through presentation at scientific conferences and in scientific journals.Trial registration numberACTRN12615001041549; pre-results.