bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years
Authors: Luo Man , Chapel Sunny , Sevinsky Heather , Savant Ishani , Cirincione Brenda , Bertz Richard , Roy Amit 
Published: April 2016

ABSTRACT

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (
n
= 168) and one study in healthy adults (
n
= 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (

V
C

), and absorption rate constant (

K
a

). The typical values of efavirenz apparent CL,

V
C

, oral peripheral volume of distribution (

V
P

), and

K
a

for a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h
−1
(0.375 to 0.453 h
−1
), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing <10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing ≥10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing ≥3.5 to <5 kg, 150 mg QD to children weighing ≥5 to <7.5 kg, and 200 mg QD to children weighing ≥7.5 to <10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.
Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease
Authors: Ferro Beatriz E. , Srivastava Shashikant , Deshpande Devyani , Pasipanodya Jotam G. , van Soolingen Dick , Mouton Johan W. , van Ingen Jakko , Gumbo Tawanda 
Published: April 2016

ABSTRACT

Current regimens used to treat pulmonary
Mycobacterium abscessus
disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which
M. abscessus
was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our
M. abscessus
strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (
k
el
) of 0.11 ± 0.05 h
−1
(mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (
E
max
) modeling revealed that the highest
E
max
was 3.15 ± 1.84 log
10
CFU/ml on day 3, and the exposure mediating 50% of
E
max
(EC
50
) was a 0- to 24-h area under the concentration time curve (AUC
0–24
)-to-MIC ratio of 41.99 ± 31.78 (
r
2
= 0.99). The EC
80
was an AUC
0–24
/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC
0–24
/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC
80
in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all
M. abscessus
clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against
M. abscessus
was poor, formal combination therapy studies with moxifloxacin are still recommended.
Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii
Authors: Tsuji Brian T. , Landersdorfer Cornelia B. , Lenhard Justin R. , Cheah Soon-Ee , Thamlikitkul Visanu , Rao Gauri G. , Holden Patricia N. , Forrest Alan , Bulitta Jürgen B. , Nation Roger L. , Li Jian 
Published: April 2016

ABSTRACT

Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (
Enterococcus faecium
,
Staphylococcus aureus
,
Klebsiella pneumoniae
,
Acinetobacter baumannii
,
Pseudomonas aeruginosa
, and
Enterobacter
species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of
Acinetobacter baumannii
in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (
t
1/2
= 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both
A. baumannii
isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log
10
CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an
f
AUC
0–24
(area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density
A. baumannii
infections.
Efficacy of Lantibiotic Treatment of Staphylococcus aureus-Induced Skin Infections, Monitored byIn VivoBioluminescent Imaging
Authors: van Staden Anton Du Preez , Heunis Tiaan , Smith Carine , Deane Shelly , Dicks Leon M. T. 
Published: April 2016

ABSTRACTStaphylococcus aureusis a bacterial pathogen responsible for the majority of skin and soft tissue infections. Antibiotics are losing their efficacy as treatment for skin and soft tissue infections as a result of increased resistance in a variety of pathogens, includingS. aureus. It is thus imperative to explore alternative antimicrobial treatments to ensure future treatment options for skin and soft tissue infections. A select few lantibiotics, a group of natural defense peptides produced by bacteria, inhibit the growth of numerous clinicalS. aureusisolates, including methicillin-resistant strains. In this study, the antimicrobial activities of nisin, clausin, and amyloliquecidin, separately administered, were compared to that of a mupirocin-based ointment, which is commonly used as treatment forS. aureus-induced skin infections. Full-thickness excisional wounds, generated on the dorsal surfaces of mice, were infected with a bioluminescent strain ofS. aureus(strain Xen 36). The infections were monitored in real time usingin vivobioluminescent imaging. Lantibiotic treatments significantly reduced the bioluminescence ofS. aureusXen 36 to a level similar to that recorded with mupirocin treatment. Wound closure, however, was more pronounced during lantibiotic treatment. Lantibiotics thus have the potential to be used as an alternative treatment option forS. aureus-induced skin infections.
Draft Genome Sequence of
Megasphaera
sp. Strain DJF_B143, an Isolate from Pig Hindgut Unable to Produce Skatole
Authors: Li Xiaoqiong , Marshall Ian P. G. , Schreiber Lars , Højberg Ole , Canibe Nuria , Jensen Bent Borg 
Published: April 2016

ABSTRACT

The butyrate-producing
Megasphaera
spp. predominate in the pig hindgut and may play important roles in gut health. Moreover, one
Megasphaera
isolate has been reported to produce the boar taint compound, skatole. Here, we provide a 2.58-Mbp draft genome of a pig hindgut isolate,
Megasphaera
sp. DJF_B143, unable to produce skatole.
Draft Genome Sequence of Olsenella scatoligenes SK9K4
T
, a Producer of 3-Methylindole (Skatole) and 4-Methylphenol (
p
-Cresol), Isolated from Pig Feces
Authors: Li Xiaoqiong , Højberg Ole , Noel Samantha Joan , Canibe Nuria , Jensen Bent Borg 
Published: April 2016

ABSTRACT

Olsenella scatoligenes
SK9K4
T
is a strictly anaerobic bacterium isolated from pig feces that produces the malodorous compounds 3-methylindole (skatole) and 4-methylphenol (
p
-cresol). Here, we report the 2.47 Mbp draft genome sequence of SK9K4
T
, exploring pathways for the synthesis of skatole and
p
-cresol from the amino acids tryptophan and tyrosine, respectively.
Draft Genome Sequence of the Broad-Spectrum Xenobiotic Degrader
Achromobacter xylosoxidans
ADAF13
Authors: Iyer Rupa , Damania Ashish 
Published: April 2016

ABSTRACT

Achromobacter xylosoxidans
ADAF13, isolated from farmland soil, possesses a large number of putative degradation genes and pathways that break down a wide variety of aromatic hydrocarbons, pesticides, endocrine disruptors, and other high-impact xenobiotics. These properties make this strain an excellent candidate for further development as a broad-spectrum bioremediation agent.
Complete Genome Sequence of
Salmonella enterica
Serovar Typhimurium Strain SO2 (Sequence Type 302) Isolated from an Asymptomatic Child in Mexico
Authors: Silva Claudia , Calva Edmundo , Puente José L. , Zaidi Mussaret B. , Vinuesa Pablo 
Published: April 2016

ABSTRACT

The complete genome sequence of
Salmonella enterica
serovar Typhimurium strain SO2, isolated from an asymptomatic child in Mexico, was determined using PacBio single-molecule real-time technology. Strain SO2 has six complete chromosomal prophages, namely, ST104, Gifsy-2, ST64B, Gifsy-1, ELPhiS, and FSL SP-004, and carries a
Salmonella
virulence plasmid.
Complete Genome Sequence of
Mycoplasma mycoides
subsp.
mycoides
T1/44, a Vaccine Strain against Contagious Bovine Pleuropneumonia
Authors: Gourgues Géraldine , Barré Aurélien , Beaudoing Emmanuel , Weber Johann , Magdelenat Ghislaine , Barbe Valérie , Schieck Elise , Jores Joerg , Vashee Sanjay , Blanchard Alain , Lartigue Carole , Sirand-Pugnet Pascal 
Published: April 2016

ABSTRACT

Mycoplasma mycoides
subsp.
mycoides
is the etiologic agent of contagious bovine pleuropneumonia. We report here the complete genome sequence of the strain T1/44, which is widely used as a live vaccine in Africa.
Genome Sequence of
Salegentibacter mishustinae
KCTC 12263, Containing a Complete Subtype I-B CRISPR-Cas System
Authors: Zhang Fei , Lin Wenxin , Zhang Rui , Zheng Qiang , Jiao Nianzhi 
Published: April 2016

ABSTRACT

Salegentibacter mishustinae
KCTC strain 12263 was isolated from the sea urchin
Strongylocentrotus intermedius
inhabiting the Sea of Japan. Here, we report the draft genome sequence of
Salegentibacter mishustinae
KCTC 12263. It comprises ~3.78 Mb in 38 contigs with a G+C content of 36.5%, and a total of 3,490 proteins-coding genes were obtained. One complete CRISPR-Cas gene cluster was identified in the genome, which shows the strategy against invasive genetic elements of the strain.
Draft Genome Sequence of
Pseudomonas stutzeri
ODKF13, Isolated from Farmland Soil in Alvin, Texas
Authors: Iyer Rupa , Damania Ashish 
Published: April 2016

ABSTRACT

Pseudomonas stutzeri
ODKF13 is a bacterial microorganism isolated from farmland soil in Alvin, Texas. This strain is notable for its naphthalene degradation and nitrogen fixation pathways and for its characterization as an organophosphate degrader of phosphotriester and phosphorothioate insecticides.
Draft Genome Sequence of Trueperella bernardiae LCDC 89-0504
T
, Isolated from a Human Blood Culture
Authors: Bernier Anne-Marie , Bernard Kathryn 
Published: April 2016

ABSTRACT

We report here the draft genome sequence of
Trueperella bernardiae
LCDC 89-0504
T
, an organism linked to mild to severe infections in humans and animals. The genome size is 2,028,874 bp, with a G+C content of 65.44%. Annotation of the genome revealed 5 rRNA sequences, 48 tRNA genes, and 1,762 coding sequences.
Hyaluronan Modulation Impacts Staphylococcus aureus Biofilm Infection
Authors: Ibberson Carolyn B. , Parlet Corey P. , Kwiecinski Jakub , Crosby Heidi A. , Meyerholz David K. , Horswill Alexander R. 
Published: April 2016

ABSTRACT

Staphylococcus aureus
is a leading cause of chronic biofilm infections. Hyaluronic acid (HA) is a large glycosaminoglycan abundant in mammalian tissues that has been shown to enhance biofilm formation in multiple Gram-positive pathogens. We observed that HA accumulated in an
S. aureus
biofilm infection using a murine implant-associated infection model and that HA levels increased in a mutant strain lacking hyaluronidase (HysA).
S. aureus
secretes HysA in order to cleave HA during infection. Through
in vitro
biofilm studies with HA, the
hysA
mutant was found to accumulate increased biofilm biomass compared to the wild type, and confocal microscopy showed that HA is incorporated into the biofilm matrix. Exogenous addition of purified HysA enzyme dispersed HA-containing biofilms, while catalytically inactive enzyme had no impact. Additionally, induction of
hysA
expression prevented biofilm formation and also dispersed an established biofilm in the presence of HA. These observations were corroborated in the implant model, where there was decreased dissemination from an
hysA
mutant biofilm infection compared to the
S. aureus
wild type. Histopathology demonstrated that infection with an
hysA
mutant caused significantly reduced distribution of tissue inflammation compared to wild-type infection. To extend these studies, the impact of HA and
S. aureus
HysA on biofilm-like aggregates found in joint infections was examined. We found that HA contributes to the formation of synovial fluid aggregates, and HysA can disrupt aggregate formation. Taken together, these studies demonstrate that HA is a relevant component of the
S. aureus
biofilm matrix and HysA is important for dissemination from a biofilm infection.
Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue
Authors: Hedges Jodi F. , Robison Amanda , Kimmel Emily , Christensen Kelly , Lucas Erin , Ramstead Andrew , Jutila Mark A. 
Published: April 2016

ABSTRACTCoxiella burnetiiis an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-γ) is critical for host protection from infection, but a role for type I IFN inC. burnetiiinfection has not been determined. Type I IFN supports host protection from a related pathogen,Legionella pneumophila, and we hypothesized that it would be similarly protective inC. burnetiiinfection. In contrast to our prediction, IFN-α receptor-deficient (IFNAR−/−) mice were protected fromC. burnetii-induced infection. Therefore, the role of type I IFN inC. burnetiiinfection was distinct from that inL. pneumophila. Mice treated with a double-stranded-RNA mimetic were protected fromC. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-α (rIFN-α). When rIFN-α was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-α by this route had dampened interleukin 1β (IL-1β) expression in bronchoalveolar lavage fluids. However, when rIFN-α was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction byC. burnetii, we assessed expression of IFN-β transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) fromC. burnetii. Understanding innate responses inC. burnetiiinfection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment.
Antibiofilm Peptides: Potential as Broad-Spectrum Agents
Authors: Pletzer Daniel , Hancock Robert E. W. 
Published: April 2016

ABSTRACT

The treatment of bacterial diseases is facing twin threats, with increasing bacterial antibiotic resistance and relatively few novel compounds or strategies under development or entering the clinic. Bacteria frequently grow on surfaces as biofilm communities encased in a polymeric matrix. The biofilm mode of growth is associated with 65 to 80% of all clinical infections. It causes broad adaptive changes; biofilm bacteria are especially (10- to 1,000-fold) resistant to conventional antibiotics and to date no antimicrobials have been developed specifically to treat biofilms. Small synthetic peptides with broad-spectrum antibiofilm activity represent a novel approach to treat biofilm-related infections. Recent developments have provided evidence that these peptides can inhibit even developed biofilms, kill multiple bacterial species in biofilms (including the ESKAPE [
Enterococcus faecium
,
Staphylococcus aureus
,
Klebsiella pneumoniae
,
Acinetobacter baumannii
,
Pseudomonas aeruginosa
, and
Enterobacter
species] pathogens), show strong synergy with several antibiotics, and act by targeting a universal stress response in bacteria. Thus, these peptides represent a promising alternative treatment to conventional antibiotics and work effectively in animal models of biofilm-associated infections.
Quorum Sensing Influences Burkholderia thailandensis Biofilm Development and Matrix Production
Authors: Tseng Boo Shan , Majerczyk Charlotte D. , Passos da Silva Daniel , Chandler Josephine R. , Greenberg E. Peter , Parsek Matthew R. 
Published: April 2016

ABSTRACT

Members of the genus
Burkholderia
are known to be adept at biofilm formation, which presumably assists in the survival of these organisms in the environment and the host. Biofilm formation has been linked to quorum sensing (QS) in several bacterial species. In this study, we characterized
Burkholderia thailandensis
biofilm development under flow conditions and sought to determine whether QS contributes to this process.
B. thailandensis
biofilm formation exhibited an unusual pattern: the cells formed small aggregates and then proceeded to produce mature biofilms characterized by “dome” structures filled with biofilm matrix material. We showed that this process was dependent on QS.
B. thailandensis
has three acyl-homoserine lactone (AHL) QS systems (QS-1, QS-2, and QS-3). An AHL-negative strain produced biofilms consisting of cell aggregates but lacking the matrix-filled dome structures. This phenotype was rescued via exogenous addition of the three AHL signals. Of the three
B. thailandensis
QS systems, we show that QS-1 is required for proper biofilm development, since a
btaR1
mutant, which is defective in QS-1 regulation, forms biofilms without these dome structures. Furthermore, our data show that the wild-type biofilm biomass, as well as the material inside the domes, stains with a fucose-binding lectin. The
btaR1
mutant biofilms, however, are negative for fucose staining. This suggests that the QS-1 system regulates the production of a fucose-containing exopolysaccharide in wild-type biofilms. Finally, we present data showing that QS ability during biofilm development produces a biofilm that is resistant to dispersion under stress conditions.

IMPORTANCE
The saprophyte
Burkholderia thailandensis
is a close relative of the pathogenic bacterium
Burkholderia pseudomallei
, the causative agent of melioidosis, which is contracted from its environmental reservoir. Since most bacteria in the environment reside in biofilms,
B. thailandensis
is an ideal model organism for investigating questions in
Burkholderia
physiology. In this study, we characterized
B. thailandensis
biofilm development and sought to determine if quorum sensing (QS) contributes to this process. Our work shows that
B. thailandensis
produces biofilms with unusual dome structures under flow conditions. Our findings suggest that these dome structures are filled with a QS-regulated, fucose-containing exopolysaccharide that may be involved in the resilience of
B. thailandensis
biofilms against changes in the nutritional environment.
Analysis of the Spore Membrane Proteome in Clostridium perfringens Implicates Cyanophycin in Spore Assembly
Authors: Liu Hualan , Ray W. Keith , Helm Richard F. , Popham David L. , Melville Stephen B. 
Published: April 2016

ABSTRACT

Heat-resistant endospore formation plays an important role in
Clostridium perfringens
-associated foodborne illnesses. The spores allow the bacterium to survive heating during normal cooking processes, followed by germination and outgrowth of the bacterium in contaminated foods. To identify proteins associated with germination and other spore functions, a comparative spore membrane proteome analysis of dormant and germinated spores of
C. perfringens
strain SM101 was performed by using gel-based protein separation and liquid chromatography coupled with matrix-assisted laser desorption ionization–tandem time of flight (MALDI-TOF/TOF) mass spectrometry. A total of 494 proteins were identified, and 117 of them were predicted to be integral membrane or membrane-associated proteins. Among these membrane proteins, 16 and 26 were detected only in dormant and germinated spores, respectively. One protein that was detected only in germinated spore membranes was the enzyme cyanophycinase, a protease that cleaves the polymer cyanophycin, which is composed of
l
-arginine-poly(
l
-aspartic acid), to β-Asp-Arg. Genes encoding cyanophycinase and cyanophycin synthetase have been observed in many species of
Clostridium
, but their role has not been defined. To determine the function of cyanophycin in
C. perfringens
, a mutation was introduced into the
cphA
gene, encoding cyanophycin synthetase. In comparison to parent strain SM101, the spores of the mutant strain retained wild-type levels of heat resistance, but fewer spores were made, and they were smaller, suggesting that cyanophycin synthesis plays a role in spore assembly. Although cyanophycin could not be extracted from sporulating
C. perfringens
cells, an
Escherichia coli
strain expressing the
cphA
gene made copious amounts of cyanophycin, confirming that
cphA
encodes a cyanophycin synthetase.

IMPORTANCE
Clostridium perfringens
is a common cause of food poisoning, and germination of spores after cooking is thought to play a significant role in the disease. How
C. perfringens
controls the germination process is still not completely understood. We characterized the proteome of the membranes from dormant and germinated spores and discovered that large-scale changes occur after germination is initiated. One of the proteins that was detected after germination was the enzyme cyanophycinase, which degrades the storage compound cyanophycin, which is found in cyanobacteria and other prokaryotes. A cyanophycin synthetase mutant was constructed and found to make spores with altered morphology but normal heat resistance, suggesting that cyanophycin plays a different role in
C. perfringens
than it does in cyanobacteria.