bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of TNF‐alpha blockade on coagulopathy and endothelial cell activation in xenoperfused porcine kidneys
Authors: Ramackers Wolf , Klose Johannes , Tiede Andreas , Werwitzke Sonja , Rataj Dennis , Friedrich Lars , Johanning Kai , Vondran Florian W. R. , Bergmann Sabine , Schuettler Wolfgang , Bockmeyer Clemens Luitpold , Becker Jan Ulrich , Klempnauer Jürgen , Winkler Michael 
Published: July 2015

AbstractBackgroundFollowing pig‐to‐primate kidney transplantation, endothelial cell activation and xenogenic activation of the recipient's coagulation eventually leading to organ dysfunction and microthrombosis can be observed. In this study, we examined the effect of a TNF‐receptor fusion protein (TNF‐RFP) on endothelial cell activation and coagulopathy utilizing an appropriate ex vivo perfusion system.MethodsUsing an ex vivo perfusion circuit based on C1‐Inhibitor (C1‐Inh) and low‐dose heparin administration, we have analyzed consumptive coagulopathy following contact of human blood with porcine endothelium. Porcine kidneys were recovered following in situ cold perfusion with Histidine‐tryptophan‐ketoglutarate (HTK) organ preservation solution and were immediately connected to a perfusion circuit utilizing freshly drawn pooled porcine or human AB blood. The experiments were performed in three individual groups: autologous perfusion (n = 5), xenogenic perfusion without any further pharmacological intervention (n = 10), or with addition of TNF‐RFP (n = 5). After perfusion, tissue samples were obtained for real‐time PCR and immunohistological analyses. Endothelial cell activation was assessed by measuring the expression levels of E‐selectin, ICAM‐1, and VCAM‐1.ResultsKidney survival during organ perfusion with human blood, C1‐Inh, and heparin, but without any further pharmacological intervention was 126 ± 78 min. Coagulopathy was observed with significantly elevated concentrations of D‐dimer and thrombin–antithrombin complex (TAT), resulting in the formation of multiple microthrombi. Endothelial cell activation was pronounced, as shown by increased expression of E‐selectin and VCAM‐1. In contrast, pharmacological intervention with TNF‐RFP prolonged organ survival to 240 ± 0 min (max. perfusion time; no difference to autologous control). Formation of microthrombi was slightly reduced, although not significantly, if compared to the xenogenic control. D‐dimer and TAT were elevated at similar levels to the xenogenic control experiments. In contrast, endothelial cell activation, as shown by real‐time PCR, was significantly reduced in the TNF‐RFP group.ConclusionWe conclude that although coagulopathy was not affected, TNF‐RFP is able to suppress inflammation occurring after xenoperfusion in this ex vivo perfusion model.
Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery
Authors: Wittau Mathias , Scheele Jan , Kurlbaum Max , Brockschmidt Claas , Wolf Anna M. , Hemper Evelyn , Henne-Bruns Doris , Bulitta Jürgen B. 
Published: July 2015

ABSTRACT

Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m
2
). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.)
In Vitro
Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia
Authors: Chen Ko-Hung , Huang Yu-Tsung , Liao Chun-Hsing , Sheng Wang-Hui , Hsueh Po-Ren 
Published: July 2015

ABSTRACT

Tedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram-positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptible
Staphylococcus aureus
(MSSA) (
n
= 100), methicillin-resistant
Staphylococcus aureus
(MRSA) (
n
= 100),
Streptococcus pyogenes
(
n
= 50),
Streptococcus agalactiae
(
n
= 50),
Streptococcus anginosus
group (
n
= 75),
Enterococcus faecalis
(
n
= 50), and vancomycin-resistant enterococci (VRE) (
Enterococcus faecium
) (
n
= 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited better
in vitro
activities than linezolid against MSSA (MIC
90
s, 0.5 versus 2 μg/ml), MRSA (MIC
90
s, 0.5 versus 2 μg/ml),
S. pyogenes
(MIC
90
s, 0.5 versus 2 μg/ml),
S. agalactiae
(MIC
90
s, 0.5 versus 2 μg/ml),
Streptococcus anginosus
group (MIC
90
s, 0.5 versus 2 μg/ml),
E. faecalis
(MIC
90
s, 0.5 versus 2 μg/ml), and VRE (MIC
90
s, 0.5 versus 2 μg/ml). The tedizolid MICs against
E. faecalis
(
n
= 3) and VRE (
n
= 2) intermediate to linezolid (MICs, 4 μg/ml) were 1 μg/ml and 0.5 μg/ml, respectively. The tedizolid MIC
90
s against S
. anginosus
,
S. constellatus
, and
S. intermedius
were 0.5, 1, and 0.5 μg/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2- to 4-fold better
in vitro
activities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates of
S. anginosus
and
S. constellatus
than against those of
S. intermedius
in Taiwan were noted.
Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection
Authors: Louie Thomas , Nord Carl Erik , Talbot George H. , Wilcox Mark , Gerding Dale N. , Buitrago Martha , Kracker Hilke , Charef Pascal , Cornely Oliver A. 
Published: July 2015

ABSTRACT

Cadazolid, a novel fluoroquinolone-oxazolidinone antibiotic, exhibits potent
in vitro
activity against
Clostridium difficile
, including the epidemic BI/NAP1/027 strain. This multicenter, randomized, double-blind, active reference group, phase 2 study evaluated the efficacy and safety of oral cadazolid in treatment of adult patients with
C. difficile
infection (CDI). Eligible patients with first occurrence/first recurrence of CDI were randomized 1:1:1:1 to 250, 500, or 1,000 mg cadazolid twice daily (BID) or oral 125 mg vancomycin four times daily (QID) for 10 days. The primary endpoint was clinical cure at test of cure (48 ± 24 h after the end of treatment; modified intent-to-treat population), defined as resolution of diarrhea with no further CDI treatment required. Secondary endpoints included recurrence rate, sustained clinical response (clinical cure without recurrence), and time to diarrhea resolution. Of 84 patients enrolled, 20, 22, 20, and 22 received 250, 500, or 1,000 mg cadazolid BID or 125 mg vancomycin QID, respectively. The primary endpoint was achieved in 76.5% (80% confidence interval [CI], 58.4, 89.3), 80.0% (63.9, 91.0), 68.4% (51.1, 82.5), and 68.2% (52.3, 81.3) of patients, respectively. There was no evidence of a cadazolid dosage-dependent response. Each dosage of cadazolid resulted in a lower recurrence rate than with vancomycin (18.2 to 25.0% versus 50%). Consequently, higher sustained clinical response rates were observed with cadazolid (46.7 to 60.0%) than with vancomycin (33.3%). The times to diarrhea resolution were similar for cadazolid and vancomycin. Cadazolid was well tolerated, with no safety signal observed. The results of this phase 2 study support further clinical development of cadazolid. (This study has been registered in the United States at ClinicalTrials.gov under registration no. NCT01222702 and in Europe with the European Medicines Agency under registration no. EUDRA-CT 2010-020941-29.)
New Insights Regarding Yeast Survival following Exposure to Liposomal Amphotericin B
Authors: Teixeira-Santos Rita , Ricardo Elisabete , Guerreiro Susana Gomes , Costa-de-Oliveira Sofia , Rodrigues Acácio Gonçalves , Pina-Vaz Cidália 
Published: July 2015

ABSTRACT

In vitro
resistance to amphotericin B is an extremely rare event among pathogenic yeasts. However,
in vivo
response is sometimes reduced, resulting in an unfavorable outcome. Such adverse outcomes might be related to subfungicidal plasma concentrations. We aimed to clarify the mechanisms of liposomal amphotericin B (AMB-L; AmBisome)-induced lesions and the mechanisms responsible for yeast cell recovery following exposure at plasma concentrations. The physiological statuses developing following exposure to AMB-L at simulated plasma concentrations (20 to 0.1 mg/liter) and at a constant concentration (3 mg/liter) were assessed in a 24-h time course assay. Time-kill experiments also were carried out under the same AMB-L treatment conditions. Our results suggest that yeast cells develop compensatory responses related to membrane polarization, metabolic activity, and reactive oxygen species (ROS) production after exposure to high plasma concentrations (20 to 5 mg/liter) during the first 6 h; in the remaining 18 h, when exposed to lower concentrations, cells reveal almost full recovery with no evidence of fungicidal activity. In contrast, whenever cells are exposed to a constant concentration above the MIC, despite initially exhibiting compensatory stress responses, soon afterwards they exhibit membrane depolarization, a decrease of metabolic activity, increasing ROS production, and lastly, programmed cell death and necrosis, resulting in succumbing to AMB-L fungicidal effects. This study may represent a step forward in the support of AMB-L use for clinical treatment of invasive fungal infections, since it demonstrates the importance of maintaining levels of AMB-L above the MIC in plasma and tissues to ensure it produces its fungicidal effects.
Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria
Authors: Tenero David , Green Justin A. , Goyal Navin 
Published: July 2015

ABSTRACT

Tafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of the
Plasmodium vivax
life cycle, is being developed for the radical cure of acute
P. vivax
malaria in combination with chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects with
P. vivax
malaria. TQ exposure (i.e., area under the concentration-time curve [AUC]) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals [CI], 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 μg · h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 μg · h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.)
Racial Differences in Clostridium difficile Infection Rates Are Attributable to Disparities in Health Care Access
Authors: Mao Eric J. , Kelly Colleen R. , Machan Jason T. 
Published: July 2015

ABSTRACT

This study confirms previously reported racial differences in
Clostridium difficile
infection (CDI) rates in the United States and explores the nature of those differences. We conducted a retrospective study using the 2010 Nationwide Inpatient Sample, the largest all-payer database of hospital discharges in the United States. We identified hospital stays most likely to include antibiotic treatment for infections, based on hospital discharge diagnoses, and we examined how CDI rates varied, in an attempt to distinguish between genotypic and environmental racial differences. Logistic regressions for the survey design were used to test hypotheses. Among patients likely to have received antibiotics, white patients had higher CDI rates than black, Hispanic, Asian, and Native American patients (
P
< 0.0001). CDI rates increased with higher income levels and were higher for hospitalizations paid by private insurance versus those paid by Medicaid or classified as self-pay or free care (
P
< 0.0001). Among patients admitted from skilled nursing facilities, where racial bias in health care access is less, racial differences in CDI rates disappeared (
P
= 1.0). Infected patients did not show racial differences in rates of complicated CDI or death (
P
= 1.0). Although white patients had greater CDI rates than nonwhite patients, racial differences in CDI rates disappeared in a population for which health care access was presumed to be less racially biased. This provides evidence that apparent racial differences in CDI risks may represent health care access disparities, rather than genotypic differences. CDI represents a deviation from the paradigm that increased health care access is associated with less morbidity.
Mutations in β-Lactamase AmpC Increase Resistance of Pseudomonas aeruginosa Isolates to Antipseudomonal Cephalosporins
Authors: Berrazeg M. , Jeannot K. , Ntsogo Enguéné Véronique Yvette , Broutin I. , Loeffert S. , Fournier D. , Plésiat P. 
Published: July 2015

ABSTRACT

Mutation-dependent overproduction of intrinsic β-lactamase AmpC is considered the main cause of resistance of clinical strains of
Pseudomonas aeruginosa
to antipseudomonal penicillins and cephalosporins. Analysis of 31 AmpC-overproducing clinical isolates exhibiting a greater resistance to ceftazidime than to piperacillin-tazobactam revealed the presence of 17 mutations in the β-lactamase, combined with various polymorphic amino acid substitutions. When overexpressed in AmpC-deficient
P. aeruginosa
4098, the genes coding for 20/23 of these AmpC variants were found to confer a higher (2-fold to >64-fold) resistance to ceftazidime and ceftolozane-tazobactam than did the gene from reference strain PAO1. The mutations had variable effects on the MICs of ticarcillin, piperacillin-tazobactam, aztreonam, and cefepime. Depending on their location in the AmpC structure and their impact on β-lactam MICs, they could be assigned to 4 distinct groups. Most of the mutations affecting the omega loop, the R2 domain, and the C-terminal end of the protein were shared with extended-spectrum AmpCs (ESACs) from other Gram-negative species. Interestingly, two new mutations (F121L and P154L) were predicted to enlarge the substrate binding pocket by disrupting the stacking between residues F121 and P154. We also found that the reported ESACs emerged locally in a variety of clones, some of which are epidemic and did not require hypermutability. Taken together, our results show that
P. aeruginosa
is able to adapt to efficacious β-lactams, including the newer cephalosporin ceftolozane, through a variety of mutations affecting its intrinsic β-lactamase, AmpC. Data suggest that the rates of ESAC-producing mutants are ≥1.5% in the clinical setting.
The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir
Authors: Kraft Thomas E. , Armstrong Christopher , Heitmeier Monique R. , Odom Audrey R. , Hruz Paul W. 
Published: July 2015

ABSTRACT

Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of
Plasmodium
species to existing therapies has increased the need for new therapeutic approaches. The
Plasmodium
glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.
Role of Interleukin-12 in Protection against Pulmonary Infection with Methicillin-Resistant Staphylococcus aureus
Authors: Nguyen Quang-Tam , Furuya Yoichi , Roberts Sean , Metzger Dennis W. 
Published: July 2015

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) is a common pathogen associated with nosocomial pneumonia and is an increasing threat for severe community-acquired pneumonia. We have now investigated the role of interleukin-12 (IL-12) in protective immunity against lung infection with MRSA. The importance of IL-12 in protection from pulmonary MRSA infection was demonstrated by the finding that IL-12p35-deficient mice had a lower survival rate, higher bacterial burdens in lung and spleen, and decreased expression of interferon gamma (IFN-γ) in the lung compared to wild-type mice. These effects were completely reversed by replacement intranasal therapy with recombinant IL-12. Furthermore, exogenous IL-12 treatment of wild-type mice 24 h before pulmonary challenge with a lethal dose of MRSA significantly improved bacterial clearance and resulted in protection from death. The IL-12-treated mice had increased numbers of lung natural killer (NK) cells and neutrophils and higher levels of IFN-γ in the lung and serum compared to untreated mice. The major source of IL-12-driven IFN-γ expression in the lung was the NK cell, and the direct target of pulmonary IFN-γ was the lung macrophage, as shown using mice with a macrophage-specific defect in interferon gamma (IFN-γ) signaling (MIIG mice). Importantly, combination therapy with linezolid and IL-12 following intranasal MRSA infection significantly increased survival compared to that of mice receiving linezolid or IL-12 alone. These results indicate that IL-12-based immunotherapy may hold promise for treatment of MRSA pneumonia.
Modulation of
ccrAB
Expression and SCC
mec
Excision by an Inverted Repeat Element and SarS in Methicillin-Resistant Staphylococcus aureus
Authors: Zhang Shijie , Ma Ronghua , Liu Xiaoyu , Zhang Xu , Sun Baolin 
Published: July 2015

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) is a notorious human pathogen that can cause a broad spectrum of infections. MRSA strains are resistant to almost the entire family of β-lactam antibiotics due to the acquisition of staphylococcal cassette chromosome
mec
(SCC
mec
). The chromosome cassette recombinases A and B, encoded by
ccrAB
genes located on SCC
mec
, play a key role in the excision of SCC
mec
. Studies have shown that
ccrAB
genes are expressed in only a minority of cells, suggesting the involvement of a subtle regulatory mechanism in
ccrAB
expression which has not been uncovered. Here, we found that an inverted repeat (IR) element, existing extensively and conservatively within the
ccrAB
promoter of different SCC
mec
types, played a repressive role in
ccrAB
expression and SCC
mec
excision in MRSA strain N315. Replacement of the IR sequence led to a significant increase in
ccrAB
expression and curing of SCC
mec
from strain N315 cells. In addition, we identified the transcriptional regulator SarS using DNA-affinity chromatography and further demonstrated that SarS can bind to the IR sequence and upregulate
ccrAB
expression and SCC
mec
excision. These findings reveal a molecular mechanism regulating
ccrAB
expression and SCC
mec
excision and may provide mechanic insights into the lateral transfer of SCC
mec
and spread of antibiotic resistance in
S. aureus
.
Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients
Authors: Modongo Chawangwa , Pasipanodya Jotam G. , Zetola Nicola M. , Williams Scott M. , Sirugo Giorgio , Gumbo Tawanda 
Published: July 2015

ABSTRACT
Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis.