bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Amodiaquine and Desethylamodiaquine in Pregnant and Postpartum Women with Plasmodium vivax Malaria
Authors: Rijken Marcus J. , McGready Rose , Jullien Vincent , Tarning Joel , Lindegardh Niklas , Phyo Aung Pyae , Win Aye Kyi , Hsi Poe , Cammas Mireille , Singhasivanon Pratap , White Nicholas J. , Nosten François 
Published: June 2011

ABSTRACT

In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with
Plasmodium vivax
malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (
n
= 24) and postpartum (
n
= 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of
P. vivax
infections during pregnancy.
Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates
Authors: Tayman C. , El-Attug M. N. , Adams E. , Van Schepdael A. , Debeer A. , Allegaert K. , Smits A. 
Published: June 2011

ABSTRACTAmikacin efficacy is based on peak concentrations and the possibility of reaching therapeutic levels at the infection site. This study aimed to describe amikacin concentrations in the epithelial lining fluid (ELF) through bronchoalveolar lavage (BAL) in newborns. BAL fluid was collected in ventilated neonates treated with intravenous (i.v.) amikacin. Clinical characteristics, amikacin therapeutic drug monitoring serum concentrations, and the concentrations of urea in plasma were extracted from the individual patient files. Amikacin and urea BAL fluid concentrations were determined using liquid chromatography with pulsed electrochemical detection (LC-PED) and capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D), respectively. ELF amikacin concentrations were converted from BAL fluid concentrations through quantification of dilution (urea in plasma/urea in BAL fluid) during the BAL procedure. Twenty-two observations in 17 neonates (postmenstrual age, 31.9 [range, 25.1 to 41] weeks; postnatal age, 3.5 [range, 2 to 37] days) were collected. Median trough and peak amikacin serum concentrations were 2.1 (range, 1 to 7.1) mg/liter and 39.1 (range, 24.1 to 73.2) mg/liter; the median urea plasma concentration was 30 (8 to 90) mg/dl. The median amikacin concentration in ELF was 6.5 mg/liter, the minimum measured concentration was 1.5 mg/liter, and the maximum (peak) was 23 mg/liter. The highest measured ELF concentration was reached between 6 and 14.5 h after i.v. amikacin administration, and an estimated terminal elimination half-life was 8 to 10 h. The median and highest (peak) ELF amikacin concentrations observed in our study population were, respectively, 6.5 and 23 mg/liter. Despite the frequent use of amikacin in neonatal (pulmonary) infections, this is the first report of amikacin quantification in ELF in newborns.
Activity of Ceftaroline and Epidemiologic Trends in Staphylococcus aureus Isolates Collected from 43 Medical Centers in the United States in 2009
Authors: Richter Sandra S. , Heilmann Kristopher P. , Dohrn Cassie L. , Riahi Fathollah , Costello Andrew J. , Kroeger Jennifer S. , Biek Donald , Critchley Ian A. , Diekema Daniel J. , Doern Gary V. 
Published: June 2011

ABSTRACT

A
Staphylococcus aureus
surveillance program was initiated in the United States to examine the
in vitro
activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened for
mecA
by PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistant
S. aureus
(MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosome
mec
(SCC
mec
) type. All isolates had ceftaroline MICs of ≤2 μg/ml with an MIC
50
of 0.5 and an MIC
90
of 1 μg/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC ≥ 4 μg/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. The
mecA
PCR was positive for 53.4% of the isolates. The ceftaroline MIC
90
s were 0.25 μg/ml for methicillin-susceptible
S. aureus
and 1 μg/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCC
mec
type IV) and 17% were USA100 (93.4% SCC
mec
type II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC ≥ 4 μg/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potent
in vitro
activity against recent
S. aureus
clinical isolates, including MRSA, daptomycin-nonsusceptible, and linezolid-resistant strains.
Recombinant Phenotyping of Cytomegalovirus UL54 Mutations That Emerged during Cell Passages in the Presence of either Ganciclovir or Foscarnet
Authors: Gilbert Christian , Azzi Arezki , Goyette Nathalie , Lin Sheng-Xiang , Boivin Guy 
Published: June 2011

ABSTRACTSelection of human cytomegalovirus variants in the presence of ganciclovir or foscarnet led to 18 DNA polymerase mutations, 14 of which had not been previously studied. Using bacterial artificial chromosome technology, each of these mutations was individually transferred into the genome of a reference strain. Following reconstitution of infectious viral stocks, each mutant was assessed for its drug susceptibility and growth kinetics in cell culture. Computer-assisted three-dimensional (3D) modeling of the polymerase was also used to position each of the mutations in one of four proposed structural domains and to predict their influence on structural stability of the protein. Among the 10 DNA polymerase mutations selected with ganciclovir, 7 (P488R, C539R, L545S, V787L, V812L, P829S, and L862F) were associated with ganciclovir resistance, whereas 2 (F595I and V946L) conferred only foscarnet resistance. Among the eight mutations selected with foscarnet, only two (T552N and S585A) conferred foscarnet resistance, whereas four (N408D, K500N, L802V, and L957F) had an impact on ganciclovir susceptibility. Surprisingly, the combination of mutations, some of which were not associated with resistance for a specific antiviral, resulted in increasing resistance effects. 3D modeling suggested that none of the mutated residues were directly involved in the polymerase catalytic site but rather had an influence on drug susceptibility by modifying the structural flexibility of the protein. Our study significantly adds to the number of DNA polymerase mutations conferringin vitrodrug resistance and emphasizes the point that evaluation of individual mutations may not accurately reflect the phenotype conferred by multiple mutations.
Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using
In Vivo
Microdialysis
Authors: Wiskirchen Dora E. , Shepard Ashley , Kuti Joseph L. , Nicolau David P. 
Published: June 2011

ABSTRACT

Staphylococcus aureus
and other Gram-positive organisms, including methicillin-resistant
S. aureus
, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of
in vivo
microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum (
C
max
), the volume of distribution at terminal phase (

V
z

), and the half-life (
t
1/2
) for linezolid in plasma were 11.99 ± 3.67 μg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (
f
AUC
0–12
values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 μg · h/ml, respectively. Tissue penetration ratios (tissue
f
AUC to plasma
f
AUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (
P
= 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients.
Knockdown of USP18 Increases Alpha 2a Interferon Signaling and Induction of Interferon-Stimulating Genes but Does Not Increase Antiviral Activity in Huh7 Cells
Authors: Murray E. J. , Burden Frances , Horscroft Nigel , Smith-Burchnell Caroline , Westby Mike 
Published: June 2011

ABSTRACT
The current standard of care for hepatitis C virus (HCV) patients is cotreatment with human alpha interferon (IFN-α) and ribavirin. The host factor USP18 functions to regulate the interferon signaling pathway by acting as an off-switch. In order to understand whether the inhibition of USP18 represents a valid target for the enhancement of interferon treatment for chronic viral diseases, we have used a wide range of RNA interference (RNAi) reagents to suppress USP18 gene expression in Huh7 cell lines. We demonstrate that a USP18 knockdown results in IFN-α2a signaling (measured by increased IFN-stimulated response element [ISRE] reporter gene activity, 2′,5′-oligoadenylate synthetase [2-5 OAS] expression, and ISG15 induction) that is increased by ∼100-fold, whereas the antiviral (AV) potency in both the Huh7 HCV subgenomic replicon assay and the Huh7.5 HCV infectious virus assay increased by ∼3-fold. While the degree of the USP18 knockdown of USP18 elicited by the different RNAi reagents correlated with the enhancement of IFN-α2a signaling, it did not correlate with the enhancement of AV activity. The failure of increased IFN-α2a signaling to fully translate into increased AV potency was also observed for encephalomyocarditis virus (EMCV) assays using Huh7.5 cells. These data suggest that the IFN-mediated AV response in Huh7.5 cells has only a limited dependence on USP18 activity.
Evaluation of the Antimicrobial Activity of Lysostaphin-Coated Hernia Repair Meshes
Authors: Satishkumar Rohan , Sankar Sriram , Yurko Yuliya , Lincourt Amy , Shipp John , Heniford B. Todd , Vertegel Alexey 
Published: June 2011

ABSTRACTBacterial infections by antibiotic-resistantStaphylococcus aureusstrains are among the most common postoperative complications in surgical hernia repair with synthetic mesh. Surface coating of medical devices/implants using antibacterial peptides and enzymes has recently emerged as a potentially effective method for preventing infections. The objective of this study was to evaluate thein vitroantimicrobial activity of hernia repair meshes coated by the antimicrobial enzyme lysostaphin at different initial concentrations. Lysostaphin was adsorbed on pieces of polypropylene (Ultrapro) mesh with binding yields of ∼10 to 40% at different coating concentrations of between 10 and 500 μg/ml. Leaching of enzyme from the surface of all the samples was studied in 2% (wt/vol) bovine serum albumin in phosphate-buffered saline buffer at 37°C, and it was found that less than 3% of adsorbed enzyme desorbed from the surface after 24 h of incubation. Studies of antibacterial activity against a cell suspension ofS. aureuswere performed using turbidity assay and demonstrated that the small amount of enzyme leaching from the mesh surface contributes to the lytic activity of the lysostaphin-coated samples. Colony counting data from the broth count (model for bacteria in wound fluid) and wash count (model for colonized bacteria) for the enzyme-coated samples showed significantly decreased numbers of CFU compared to uncoated samples (P< 0.05). A pilotin vivostudy showed a dose-dependent efficacy of lysostaphin-coated meshes in a rat model ofS. aureusinfection. The antimicrobial activity of the lysostaphin-coated meshes suggests that such enzyme-leaching surfaces could be efficient at actively resisting initial bacterial adhesion and preventing subsequent colonization of hernia repair meshes.
Genetic Organization and Mode of Action of a Novel Bacteriocin, Bacteriocin 51: Determinant of VanA-Type Vancomycin-Resistant Enterococcus faecium
Authors: Yamashita Hitoshi , Tomita Haruyoshi , Inoue Takako , Ike Yasuyoshi 
Published: June 2011

ABSTRACT

Bacteriocin 51 (Bac 51) is encoded on the mobile plasmid pHY (6,037 bp), which was isolated from vancomycin-resistant
Enterococcus faecium
VRE38. Bacteriocin 51 is active against
E. faecium
,
E. hirae
, and
E. durans
. Sequence analysis of pHY showed that it encodes nine open reading frames (ORFs) from ORF1 to ORF9 (in that order). Genetic analysis suggested that ORF1 and ORF2, which were designated
bacA
and
bacB
, respectively, are the bacteriocin and immunity genes.
bacA
encodes a 144-amino-acid protein. The deduced BacA protein has a typical signal sequence at its amino terminus, and a potential signal peptidase-processing site corresponding to the V-E-A sequence is located between the 37th and 39th amino acids. The predicted mature BacA protein consists of 105 amino acids. A potential promoter sequence was identified upstream of the start codon.
bacB
encodes a 55-amino-acid protein. No obvious promoter or terminator sequence was identified between
bacA
and
bacB
. Northern blot analysis of
bacA
and
bacB
with a
bacA
RNA probe produced a transcript of approximately 700 nucleotides, which corresponded to the combined nucleotide sizes of
bacA
and
bacB
, indicating that transcription was initiated from the promoter upstream of
bacA
, continued through
bacB
, and was terminated at the terminator downstream of
bacB
. The transcription start site was determined to be the T nucleotide located 6 nucleotides downstream from the −10 promoter sequence. These results indicate that
bacA
and
bacB
constitute an operon and that
bacA
is the bacteriocin structural gene while
bacB
is the immunity gene. The purified C-terminally His tagged BacA protein of Bac 51 showed bacteriostatic activity against the indicator strain. The purified C-terminally His tagged BacA protein of Bac 32 (whose mature BacA protein has 54 amino acids) and the culture filtrates of the Bac 31- and Bac 43-producing
E. faecalis
strain FA2-2 showed bactericidal activity. Bac 31 and Bac 43 are pore-forming bacteriocins, unlike the newly characterized bacteriocin Bac 51.
Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation
Authors: Boffito Marta , Jackson Akil , Amara Alieu , Back David , Khoo Saye , Higgs Chris , Seymour Natalia , Gazzard Brian , Moyle Graeme 
Published: June 2011

ABSTRACTThe object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC50] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC50for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.
Genomewide Scan Reveals Amplification of
mdr1
as a Common Denominator of Resistance to Mefloquine, Lumefantrine, and Artemisinin in Plasmodium chabaudi Malaria Parasites
Authors: Borges Sofia , Cravo Pedro , Creasey Alison , Fawcett Richard , Modrzynska Katarzyna , Rodrigues Louise , Martinelli Axel , Hunt Paul 
Published: June 2011

ABSTRACT

Multidrug-resistant
Plasmodium falciparum
malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite
P. chabaudi
, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment. Genomewide scans of selection showed that parasites surviving each drug treatment bore a duplication of a segment of chromosome 12 (translocated to chromosome 04) present in AS-15MF. Whole-genome resequencing identified the size of the duplicated segment and its position on chromosome 4. The duplicated fragment extends for ∼393 kbp and contains over 100 genes, including
mdr1
, encoding the multidrug resistance P-glycoprotein homologue 1. We therefore show that resistance to chemically distinct components of ACTs is mediated by the same genetic mutation, highlighting a possible limitation of these therapies.
Borrelia burgdorferi Linear Plasmid 38 Is Dispensable for Completion of the Mouse-Tick Infectious Cycle
Authors: Dulebohn Daniel P. , Bestor Aaron , Rego Ryan O. M. , Stewart Philip E. , Rosa Patricia A. 
Published: June 2011

ABSTRACT

Borrelia burgdorferi
, the causative agent of Lyme disease, exists in a complex enzootic cycle, transiting between its vector,
Ixodes
ticks, and a diverse range of vertebrate hosts.
B. burgdorferi
linear plasmid 38 (lp38) contains several genes that are differentially regulated in response to conditions mimicking the tick or mouse environments, suggesting that these plasmid-borne genes may encode proteins important for the
B. burgdorferi
infectious cycle. Some of these genes encode potential virulence factors, including hypothetical lipoproteins as well as a putative membrane transport system. To characterize the role of lp38 in the
B. burgdorferi
infectious cycle, we constructed a shuttle vector to selectively displace lp38 from the
B. burgdorferi
genome and analyzed the resulting clones to confirm the loss of lp38. We found that,
in vitro
, clones lacking lp38 were similar to isogenic wild-type bacteria, both in growth rate and in antigenic protein production. We analyzed these strains in an experimental mouse-tick infectious cycle, and our results demonstrate that clones lacking lp38 are fully infectious in a mouse, can efficiently colonize the tick vector, and are readily transmitted to a naive host.
The Neisseria meningitidis Macrophage Infectivity Potentiator Protein Induces Cross-Strain Serum Bactericidal Activity and Is a Potential Serogroup B Vaccine Candidate
Authors: Hung Miao-Chiu , Salim Omar , Williams Jeannette N. , Heckels John E. , Christodoulides Myron 
Published: June 2011

ABSTRACT

A gene encoding a 29-kDa protein from
Neisseria meningitidis
serogroup B strain MC58 with homology to the macrophage infectivity potentiator (MIP) protein of
Legionella pneumophila
was cloned and expressed in
Escherichia coli
, and the purified soluble recombinant protein (rMIP) was used for immunization studies. Analysis of the predicted amino acid sequences of MIP from 13 well-characterized meningococcal strains, isolated from carriers or patients and differing in serogroup, serotype, and subtype, showed that the protein was highly conserved (98 to 100%), with only three distinct sequence types (designated I, II, and III) found. Western blotting showed that the MIP protein was expressed at similar levels by all of these strains. Immunization of mice with type I MC58 rMIP in detergent micelles and liposomes containing monophosphoryl lipid A (MPLA) induced high levels of surface-reactive antibodies with serum bactericidal activity (SBA) titers of 1/1,024 against the homologous strain. Bactericidal antibodies were also induced with the protein in saline alone and liposomes alone (titers, 1/128) but not following adsorption to Al(OH)
3
. Significantly, antisera raised against type I rMIP administered in saline or liposomes killed strains of heterologous sequence types II and III with similar SBA titers (1/128 to 1/256). Taken together, these findings suggest that rMIP can provide cross-strain protection against meningococci and should be considered a potential antigen for inclusion in new vaccines against meningococcal infection.
The Sbi Protein Is a Multifunctional Immune Evasion Factor of Staphylococcus aureus
Authors: Smith Emma Jane , Visai Livia , Kerrigan Steven W. , Speziale Pietro , Foster Timothy J. 
Published: June 2011

ABSTRACT

The second immunoglobulin-binding protein (Sbi) of
Staphylococcus aureus
has two N-terminal domains that bind the Fc region of IgG in a fashion similar to that of protein A and two domains that can bind to the complement protein C3 and promote its futile consumption in the fluid phase. It has been proposed that Sbi helps bacteria to avoid innate immune defenses. By comparing a mutant defective in Sbi with mutants defective in protein A, clumping factor A, iron-regulated surface determinant H, and capsular polysaccharide, it was shown that Sbi is indeed an immune evasion factor that promotes bacterial survival in whole human blood and the avoidance of neutrophil-mediated opsonophagocytosis. Sbi is present in the culture supernatant and is also associated with the cell envelope.
S. aureus
strains that expressed truncates of Sbi lacking N-terminal domains D1 and D2 (D1D2) or D3 and D4 (D3D4) or a C-terminal truncate that was no longer retained in the cell envelope were analyzed. Both the secreted and envelope-associated forms of Sbi contributed to immune evasion. The IgG-binding domains contributed only when Sbi was attached to the cell, while only the secreted C3-binding domains were biologically active.