bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamics of Telavancin Studied in an
In Vitro
Pharmacokinetic Model of Infection
Authors: MacGowan Alasdair P. , Noel Alan R. , Tomaselli Sharon , Elliott Heather C. , Bowker Karen E. 
Published: November 2010

ABSTRACT

The antibacterial effects of telavancin, vancomycin, and teicoplanin against six
Staphylococcus aureus
strains (1 methicillin-susceptible
S. aureus
[MSSA] strain, 4 methicillin-resistant
S. aureus
[MRSA] strains, and 1 vancomycin-intermediate
S. aureus
[VISA] strain) and three
Enterococcus
sp. strains (1
Enterococcus faecalis
strain, 1
Enterococcus faecium
strain, and 1 vancomycin-resistant
E. faecium
[VREF] strain) were compared using an
in vitro
pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible
S. aureus
(VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC
24
) and 48 h (AUBKC
48
) in comparison to vancomycin or teicoplanin (
P
< 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (
P
< 0.05). Against the three
Enterococcus
spp. tested, telavancin was superior to vancomycin in terms of its AUBKC
24
, AUBKC
48
, and greater early bactericidal effect (
P
< 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3
Enterococcus
strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the
Enterococcus
spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with
S. aureus
, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against
Enterococcus
spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both
S. aureus
and
Enterococcus
spp.
Limited Ability ofPlasmodium falciparum pfcrt,pfmdr1, andpfnhe1Polymorphisms To Predict QuinineIn VitroSensitivity or Clinical Effectiveness in Uganda
Authors: Baliraine Frederick N. , Nsobya Samuel L. , Achan Jane , Tibenderana James K. , Talisuna Ambrose O. , Greenhouse Bryan , Rosenthal Philip J. 
Published: November 2010

ABSTRACTQuinine is a standard drug for treating severe malaria in Africa, and it is also increasingly used to treat uncomplicated disease. However, failures of quinine therapy are common, and it is unknown if failures in Africa are due to drug resistance. Recent studies have identified associations betweenin vitroquinine sensitivity and polymorphisms in genes encoding putative transporters, including well-described polymorphisms inpfcrtandpfmdr1and varied numbers of DNNND or DDNHNDNHNND repeats in microsatellite 4760 (ms4760) of the predicted sodium-hydrogen exchanger,pfnhe1. To better characterize mediators of quinine response, we assessed associations between genetic polymorphisms,in vitroquinine sensitivity, and quinine treatment responses in Kampala, Uganda. Among 172 fresh clinical isolates testedin vitro, decreasing sensitivity to quinine was associated with accumulation ofpfmdr1mutations at codons 86, 184, and 1246. Nearly all parasites hadpfcrt76T, preventing analysis of associations with this mutation.pfnhe1ms4760 was highly polymorphic. Parasites with 2 copies of either ms4760 repeat showed modest decreases in quinine sensitivity compared to those with 1 or ≥3 repeats, but the differences were not statistically significant. None of the above polymorphisms predicted treatment failure among 66 subjects treated with quinine for uncomplicated malaria. Our data suggest that quinine sensitivity is a complex trait and that known polymorphisms inpfcrt,pfmdr1, andpfnhe1, while associated with quinine sensitivity, are not robust markers for quinine resistance.
Oral Hexadecyloxypropyl-Cidofovir Therapy in Pregnant Guinea Pigs Improves Outcome in the Congenital Model of Cytomegalovirus Infection
Authors: Bravo Fernando J. , Bernstein David I. , Beadle James R. , Hostetler Karl Y. , Cardin Rhonda D. 
Published: November 2010

ABSTRACTCytomegalovirus (CMV) infection is the leading cause of congenital infection, producing both sensorineural hearing loss and mental retardation. We evaluated thein vivoefficacy of an orally bioavailable analog of cidofovir, hexadecyloxypropyl-cidofovir (HDP-CDV), against guinea pig CMV (GPCMV) in a guinea pig model of congenital CMV infection. HDP-CDV exhibited antiviral activity against GPCMV with a 50% effective concentration (EC50) of 0.004 μM ± 0.001 μM. To evaluatein vivoefficacy, pregnant Hartley guinea pigs were inoculated with GPCMV during the late second/early third trimester of gestation. Animals were administered 20 mg HDP-CDV/kg body weight orally at 24 h postinfection (hpi) and again at 7 days postinfection (dpi) or administered 4 mg/kg HDP-CDV orally each day for 5 days or 9 days. Virus levels in dam and pup tissues were evaluated following delivery, or levels from dam, placenta, and fetal tissues were evaluated following sacrifice of dams at 10 dpi. All HDP-CDV regimens significantly improved pup survival, from 50 to 60% in control animals to 93 to 100% in treated animals (P≤ 0.019). Treatment with 20 mg/kg HDP-CDV significantly reduced the viral load in pup spleen (P= 0.017) and liver (P= 0.029). Virus levels in the placenta were significantly reduced at 10 dpi following daily treatment with 4 mg/kg HDP-CDV for 5 or 9 days. The 9-day treatment also significantly reduced the viral levels in the dam spleen and liver. Although the 4-mg/kg treatment improved pup survival, virus levels in the fetal tissues were similar to those in control tissues. Taken together, HDP-CDV shows potential as a well-tolerated antiviral candidate for treatment of congenital human CMV (HCMV) infection.
Cold Shock Induces
qnrA
Expression in
Shewanella algae
Authors: Kim Hong Bin , Park Chi Hye , Gavin Mariah , Jacoby George A. , Hooper David C. 
Published: November 2010

ABSTRACT

Plasmid-carried quinolone resistance genes, like
qnrA
, are widespread in
Enterobacteriaceae
. To gain insight into its little-understood native functions, we studied the effect of environmental conditions on chromosomal
qnrA
expression in
Shewanella algae
. Among conditions of DNA damage, oxidative and osmotic stress, starvation, heat, and cold, only cold shock increased gene expression, as measured by quantitative reverse transcription-PCR (qRT-PCR). Induction was graded and occurred during growth arrest, suggesting that
qnrA
may contribute to the adaptation of
Shewanella
to low temperatures.
Systematic Review and Meta-Analysis of the Significance of Heterogeneous Vancomycin-Intermediate
Staphylococcus aureus
Isolates
Authors: van Hal Sebastiaan J. , Paterson David L. 
Published: November 2010

ABSTRACT

The prevalence of heteroresistant vancomycin-intermediate
Staphylococcus aureus
(hVISA) is 1.3% in published studies. Clinical associations include high-inoculum infections and glycopeptide failure, with hVISA infections associated with a 2.37-times-greater failure rate (95% confidence interval [CI], 1.53 to 3.67) compared to vancomycin-sensitive
Staphylococcus aureus
(VSSA) infections. Despite this, 30-day mortality rates were similar to those for VSSA infections (odds ratio [OR], 1.18; 95% CI, 0.81 to 1.74). The optimal therapy for hVISA requires further study.
In Vivo
Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043
Authors: Zhou Nannan , Nowicka-Sans Beata , Zhang Sharon , Fan Li , Fang Jie , Fang Hua , Gong Yi-Fei , Eggers Betsy , Langley David R. , Wang Tao , Kadow John , Grasela Dennis , Hanna George J. , Alexander Louis , Colonno Richard , Krystal Mark , Lin Pin-Fang 
Published: November 2010

ABSTRACT

Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4
+
lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC
50
] >10-fold greater than the baseline value) and four had high baseline EC
50
s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.
Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis
Authors: Wallis Robert S. , Jakubiec Wesley , Kumar Vikas , Bedarida Gabriella , Silvia Annette , Paige Darcy , Zhu Tong , Mitton-Fry Mark , Ladutko Lynn , Campbell Sheldon , Miller Paul F. 
Published: November 2010

ABSTRACT

Tuberculosis is a serious global health threat for which new treatments are urgently needed. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the oxazolidinone PNU-100480 in healthy volunteers, using biomarkers for safety and efficacy. Subjects were randomly assigned to PNU-100480 or placebo (4:1) at schedules of 100, 300, or 600 mg twice daily or 1,200 mg daily for 14 days or a schedule of 600 mg twice daily for 28 days to which pyrazinamide was added on days 27 and 28. A sixth cohort was given linezolid at 300 mg daily for 4 days. Signs, symptoms, and routine safety tests were monitored. Bactericidal activity against
Mycobacterium tuberculosis
was measured in
ex vivo
whole-blood culture. Plasma drug and metabolite concentrations were compared to the levels required for inhibition of
M. tuberculosis
growth and 50% inhibition of mitochondrial protein synthesis. All doses were safe and well tolerated. There were no hematologic or other safety signals during 28 days of dosing at 600 mg twice daily. Plasma concentrations of PNU-100480 and metabolites at this dose remained below those required for 50% inhibition of mitochondrial protein synthesis. Cumulative whole-blood bactericidal activity of PNU-100480 at this dose (−0.316 ± 0.04 log) was superior to the activities of all other doses tested (
P
< 0.001) and was significantly augmented by pyrazinamide (−0.420 ± 0.06 log) (
P
= 0.002). In conclusion, PNU-100480 was safe and well tolerated at all tested doses. Further studies in patients with tuberculosis are warranted. Biomarkers can accelerate early development of new tuberculosis treatments.
Determinants of Individual Variation in Intracellular Accumulation of Anti-HIV Nucleoside Analog Metabolites
Authors: Paintsil Elijah , Dutschman Ginger E. , Hu Rong , Grill Susan P. , Wang Chuan-Jen , Lam Wing , Li Fang-Yong , Ghebremichael Musie , Northrup Veronika , Cheng Yung-Chi 
Published: November 2010

ABSTRACTIndividual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated the determinants of intracellular concentrations of nucleoside analogs using peripheral blood mononuclear cells from 40 healthy donors. We observed individual differences in the concentrations of the intracellular nucleoside analogs; the mean concentrations of the triphosphate metabolite of ethynylstavudine (4′-Ed4T), zidovudine (AZT), and lamivudine (3TC) were 0.71 pmol/106cells (minimum and maximum, 0.10 and 3.00 pmol/106cells, respectively), 0.88 pmol/106cells (minimum and maximum, 0.10 and 15.18 pmol/106cells, respectively), and 1.70 pmol/106cells (minimum and maximum, 0.20 and 7.73 pmol/106cells, respectively). Gender and ethnicity had no effect on the concentration of 4′-Ed4T and 3TC metabolites. There was a trend for moderation of the concentrations of AZT metabolites by gender (P= 0.17 for gender·metabolite concentration). We observed variability in the activity and expression of cellular kinases. There was no statistically significant correlation between thymidine kinase 1 (TK-1) activity or expression and thymidine analog metabolite concentrations. The correlation between the activity of deoxycytidine kinase (dCK) and the 3TC monophosphate metabolite concentration showed a trend toward significance (P= 0.1). We observed an inverse correlation between the multidrug-resistant protein 2 (MRP2) expression index and the concentrations of AZT monophosphate, AZT triphosphate, and total AZT metabolites. Our findings suggest that the observed variation in clinical response to nucleoside analogs may be due partly to the individual differences in the intracellular concentrations, which in turn may be affected by the cellular kinases involved in the phosphorylation pathway and ATP-binding cassette (ABC) transport proteins.
Granuloma Formation around Filarial Larvae Triggered by Host Responses to an Excretory/Secretory Antigen
Authors: Dash Yashodhara , Ramesh Manish , Kalyanasundaram Ramaswamy , Munirathinam Gnanasekar , Shultz Leonard D. , Rajan T. V. 
Published: November 2010

ABSTRACTIn previous studies using a murine model of filarial infection, granuloma formation was found to be a most important host-protective mechanism. We have also shown thatin vitrocytoadherence is a surrogate for the formation of antifilarial granulomasin vivoand that it requires “alternatively activated” host cells and a source of antifilarial antibody. We show here that antibodies against L3 excretory/secretory (E/S) products can facilitatein vitrocytoadherence. We generated a set of hybridomas reactive with filarial E/S products and screened them for their ability to mediatein vitrocytoadherence. One clone (no. 1E9) was positive in this assay. We then screened a novel expression library of filarial antigens displayed on the surface of T7 bacteriophage for reactivity with 1E9. Phage expressing two filarial antigens (TCTP and BmALT-2) reacted with 1E9. Immunization of mice showed that the cohort immunized with BmALT-2 cleared a challenge infection with infectiveBrugia pahangiL3 in an accelerated manner, whereas cohorts immunized with TCTP cleared larvae with the same kinetics as in unimmunized mice. These data confirm that BmALT-2 is the antigenic target of granuloma-mediated killing ofB. pahangiL3. Our findings also confirm previous studies that BmALT-2 is a potential vaccine candidate for filarial infection. Our data reinforce the work of others and also provide a possible mechanism by which immune responses to BmALT-2 may provide host protection.
Host and Pathogen Glycosaminoglycan-Binding Proteins Modulate Antimicrobial Peptide Responses inDrosophila melanogaster
Authors: Wang Zhipeng , Flax Lindsay A. , Kemp Melissa M. , Linhardt Robert J. , Baron Miriam J. 
Published: November 2010

ABSTRACTDuring group B streptococcal infection, the alpha C protein (ACP) on the bacterial surface binds to host cell surface heparan sulfate proteoglycans (HSPGs) and facilitates entry of bacteria into human epithelial cells. Previous studies in aDrosophila melanogastermodel showed that binding of ACP to the sulfated polysaccharide chains (glycosaminoglycans) of HSPGs promotes host death and is associated with higher bacterial burdens. We hypothesized that ACP-glycosaminoglycan binding might determine infection outcome by altering host responses to infection, such as expression of antimicrobial peptides. As glycosaminoglycans/HSPGs also interact with a number of endogenous secreted signaling molecules inDrosophila, we examined the effects of host and pathogen glycosaminoglycan/HSPG-binding structures in host survival of infection and antimicrobial peptide expression. Strikingly, host survival after infection with wild-type streptococci was enhanced among flies overexpressing the endogenous glycosaminoglycan/HSPG-binding morphogen Decapentaplegic—a transforming growth factor β-likeDrosophilahomolog of mammalian bone morphogenetic proteins—but not by flies overexpressing a mutant, non-glycosaminoglycan-binding Decapentaplegic, or the other endogenous glycosaminoglycan/HSPG-binding morphogens, Hedgehog and Wingless. While ACP-glycosaminoglycan binding was associated with enhanced transcription of peptidoglycan recognition proteins and antimicrobial peptides, Decapentaplegic overexpression suppressed transcription of these genes during streptococcal infection. Further, the glycosaminoglycan-binding domain of ACP competed with Decapentaplegic for binding to the soluble glycosaminoglycan heparin in anin vitroassay. These data suggest that, in addition to promoting bacterial entry into host cells, ACP competes with Decapentaplegic for binding to glycosaminoglycans/HSPGs during infection and that these bacterial and endogenous glycosaminoglycan-binding structures determine host survival and regulate antimicrobial peptide transcription.
Downregulation of GbpB, a Component of the VicRK Regulon, Affects Biofilm Formation and Cell Surface Characteristics of
Streptococcus mutans
Authors: Duque Cristiane , Stipp Rafael N. , Wang Bing , Smith Daniel J. , Höfling José F. , Kuramitsu Howard K. , Duncan Margaret J. , Mattos-Graner Renata O. 
Published: November 2010

ABSTRACT

The virulence of the dental caries pathogen
Streptococcus mutans
relies in part on the sucrose-dependent synthesis of and interaction with glucan, a major component of the extracellular matrix of tooth biofilms. However, the mechanisms by which secreted and/or cell-associated glucan-binding proteins (Gbps) produced by
S. mutans
participate in biofilm growth remain to be elucidated. In this study, we further investigate GbpB, an essential immunodominant protein with similarity to murein hydrolases. A conditional knockdown mutant that expressed
gbpB
antisense RNA under the control of a tetracycline-inducible promoter was constructed in strain UA159 (UACA2) and used to investigate the effects of GbpB depletion on biofilm formation and cell surface-associated characteristics. Additionally, regulation of
g
bpB
by the two-component system VicRK was investigated, and phenotypic analysis of a
vicK
mutant (UA
vicK
) was performed. GbpB was directly regulated by VicR, and several phenotypic changes were comparable between UACA2 and UA
vicK
, although differences between these strains existed. It was established that GbpB depletion impaired initial phases of sucrose-dependent biofilm formation, while exogenous native GbpB partially restored the biofilm phenotype. Several cellular traits were significantly affected by GbpB depletion, including altered cell shape, decreased autolysis, increased cell hydrophobicity, and sensitivity to antibiotics and osmotic and oxidative stresses. These data provide the first experimental evidence for GbpB participation in sucrose-dependent biofilm formation and in cell surface properties.
Mycobacterium tuberculosis
Lipoproteins Directly Regulate Human Memory CD4
+
T Cell Activation via Toll-Like Receptors 1 and 2
Authors: Lancioni Christina L. , Li Qing , Thomas Jeremy J. , Ding XueDong , Thiel Bonnie , Drage Michael G. , Pecora Nicole D. , Ziady Assem G. , Shank Samuel , Harding Clifford V. , Boom W. Henry , Rojas Roxana E. 
Published: November 2010

ABSTRACT

The success of
Mycobacterium tuberculosis
as a pathogen relies on its ability to regulate the host immune response.
M. tuberculosis
can manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role of
M. tuberculosis
molecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules in
M. tuberculosis
lysate responsible for costimulation of primary human CD4
+
T cells. In the absence of APCs, activation of memory CD4
+
T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4
+
T cells can use TLR2/TLR1 heterodimers to directly respond to
M. tuberculosis
products.
M. tuberculosis
lipoproteins induced NF-κB activation in CD4
+
T cells in the absence of TCR co-engagement. Thus, TLR2/TLR1 engagement alone by
M. tuberculosis
lipoprotein triggered intracellular signaling, but upregulation of cytokine production and proliferation required co-engagement of the TCR. In conclusion, our results demonstrate that
M. tuberculosis
lipoproteins LprG and LpqH participate in the regulation of adaptive immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes.