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Tigecycline, a broad-spectrum antibiotic used for treating serious bacterial infections in adults, may be suitable for pediatric use once an appropriate dosage is determined. The aim of this study was to assess the pharmacokinetic (PK) properties, safety profile, and descriptive efficacy of tigecycline. In this Phase II, multicenter, open-label clinical trial, children aged 8 to 11 years with community-acquired pneumonia (CAP), complicated intra-abdominal infection (cIAI), or complicated skin and skin structure infections (cSSSI) were administered tigecycline 0.75, 1, or 1.25 mg/kg. A total of 58 patients received ≥1 dose of tigecycline (31 boys; 44 white; mean age, 10 years; mean weight, 35 kg); 47 had data from samples available for PK analysis. The mean (SD) PK values were: Cmax, 1899 (2954) ng/mL; Tmax, 0.56 (0.18) hour; between-dose AUC, 2833 (1557) ng · h/mL; weight-normalized clearance, 0.503 (0.293) L/h/kg; and Vdss, 4.88 (4.84) L/kg. Overall clinical cure rates at test-of-cure were 94% (16/17), 76% (16/21), and 75% (15/20) in the 0.75-, 1-, and 1.25-mg/kg cohorts, respectively. The rates of protocol violations were higher in the 1- and 1.25-mg/kg groups, resulting in higher proportions of indeterminate clinical cure assessments relative to the 0.75-mg/kg cohort (19% and 15% vs 0%). The most frequent adverse event was nausea, which occurred in 50% of patients overall (29/58) and the prevalence of which was significantly higher in the 1.25-mg/kg group versus the 0.75-mg/kg group (65% vs 18%; P = 0.007). Pharmacodynamic simulations using MIC data from an ongoing microbiological surveillance trial predicted that a dosage of 1.2 mg/kg q12h would lead to therapeutic target attainment levels of up to 82% for the target AUC0–24/MIC ratios. A tigecycline dosage of ∼1.2 mg/kg q12h may represent the most appropriate dosage for subsequent evaluation in Phase III clinical trials in children aged 8 to 11 years with selected serious bacterial infections. ClinicalTrials.gov identifier: NCT00488345.

Background Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. Methods This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. Results Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had ‘confirmed’ proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had ‘non-confirmed’ invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813–21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P  < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. Conclusions These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. Trial registration NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007)

Ceftaroline fosamil has demonstrated superior clinical efficacy versus ceftriaxone for hospitalized adults with moderate-to-severe community-acquired pneumonia (CAP) in a Phase 3 trial in Asia and in a meta-analysis of three trials in Asia, North America, and Europe. Efficacy and safety outcomes for the subset of patients in China in the ASIA CAP trial were analyzed to determine if the same conclusions hold in the China subpopulation. Hospitalized adults with Pneumonia Outcomes Research Team risk class III-IV CAP were randomized (1:1) to receive either intravenous ceftaroline fosamil 600 mg every 12 h or ceftriaxone 2 g every 24 h for 5-7 days. The primary efficacy variable was clinical response at test-of-cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included microbiological responses and safety. Of 302 patients randomized in China, 205 were included in the CE population. Clinical cure rates at TOC were 80/105 (76.2%) for ceftaroline fosamil and 61/100 (61.0%) for ceftriaxone (difference 15.2%, 95% CI 2.5, 27.6), thereby meeting predefined non-inferiority and superiority criteria for the overall study. Subgroup analyses of the primary endpoint demonstrated consistency of favourable efficacy of ceftaroline fosamil across age groups, Pneumonia Outcomes Research Team risk classes and CURB-65 scores. Microbiological responses were presumed from clinical outcomes. Adverse events were consistent with the study treatments' known safety profiles. The China subset results are consistent with the overall study population, despite the smaller sample size. Ceftaroline fosamil was both non-inferior and superior to ceftriaxone for empiric treatment of Chinese patients with moderate-to-severe CAP. ClinicalTrials.gov identifier NCT01371838.

IntroductionIn three phase III randomized controlled trials, ceftaroline fosamil was shown to be non-inferior to vancomycin plus aztreonam for the treatment of complicated skin and soft tissue infections (cSSTIs). This exploratory analysis evaluated the impact of underlying comorbidities on clinical outcomes in patients with cSSTI pooled from these three studies.MethodsCANVAS 1 and 2 and COVERS evaluated ceftaroline fosamil (600 mg every 12 h [q12h]; 600 mg every 8 h [q8h; COVERS]) versus vancomycin plus aztreonam (1 g q12h each [CANVAS 1 and 2]; vancomycin 15 mg/kg q12h and aztreonam 1 g q8h [COVERS]) in hospitalized adults with cSSTI. The primary efficacy variable in each trial was clinical response at the test-of-cure (TOC) visit. Subgroup analyses were performed on the pooled clinically evaluable (CE) population, exploring the impact of age and various baseline comorbidities.ResultsOverall, 1808 patients were included in the CE population (1005 ceftaroline fosamil; 803 vancomycin plus aztreonam). Clinical cure rates at TOC were 89.7% (ceftaroline fosamil) and 90.8% (vancomycin plus aztreonam) (difference [95% confidence interval] − 1.13 [− 3.87, 1.67]). Clinical response rates were similar between treatment groups, regardless of age (≤ 65 years or > 65 years), and in subgroups of patients with and without diabetes mellitus, peripheral vascular disease, cancer/malignancy, renal impairment, and obesity; within these subgroups, efficacy and safety results were generally consistent with those of the overall cSSTI population.ConclusionsThis analysis provides supportive evidence of the efficacy of ceftaroline fosamil in patients with cSSTI and underlying comorbidities.Trial RegistrationCANVAS 1, NCT00424190 and CANVAS 2, NCT00423657 (both trials first posted on ClinicalTrials.gov 18/01/2007); COVERS, NCT01499277 (first posted on ClinicalTrials.gov 26/12/2011).

AimExploratory analyses evaluated patient characteristics and outcomes among patients with complicated skin and soft tissue infection (cSSTI) in the phase 3 COVERS study who were admitted to an intensive care unit (ICU).MethodsAdults with cSSTI (surface area ≥ 75 cm2) and evidence of systemic inflammation and/or underlying comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h [q8h]) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g q8h) for 5–14 days. Clinical response and ICU length of stay (LOS) within first hospitalization were evaluated in the modified intent-to-treat (MITT) and clinically evaluable (CE) populations; a Cox proportional hazards model identified factors associated with increased hospital LOS.ResultsOverall, 42 of 761 randomized patients were admitted to the ICU (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10) prior to, or at start of, study treatment. Baseline differences between the ICU and non-ICU populations were indicative of more severe disease in ICU patients; within this subset, there were also some notable imbalances between treatment groups. Clinical cure rates at test-of-cure (ceftaroline fosamil vs. vancomycin plus aztreonam) were generally similar in the non-ICU and ICU subsets (MITT population 79% vs. 79% and 69% vs. 90.0%, respectively; CE population 87% vs. 85% and 80% vs. 89%, respectively). Median ICU LOS was 8 vs. 13 days, respectively. ICU admission was a risk factor predicting increased hospital LOS (P < 0.001).ConclusionsClinical outcomes for patients admitted to the ICU were generally similar to non-ICU patients, despite more severe baseline disease, with shorter median treatment duration in the ceftaroline fosamil group. ICU admission was associated with longer hospital LOS. Given the small sample size and unbalanced patient and disease characteristics within the ICU subgroup, differences between treatment groups should be interpreted with caution.Trial registrationClinicalTrials.gov identifier, NCT01499277.

Background Solid tumors are a common predisposing factor for invasive candidiasis (IC) or candidemia due to IC. Objectives Post hoc analysis of patient-level efficacy and safety data from six studies of anidulafungin (with similar protocols/endpoints) in adults with IC/candidemia summarized by past or recent diagnosis of solid tumors. Patients/methods Patients received a single intravenous (IV) dose of anidulafungin 200 mg, followed by 100 mg once daily. After ≥ 5 to ≥ 10 days of IV treatment, switch to oral voriconazole/fluconazole was permitted in all but one study. Time of solid tumor diagnosis was defined as past, ≥ 6; and recent, < 6 months prior to study entry. Primary endpoint: global response of success (GRS) rate at the end of IV therapy (EOIVT). Secondary endpoints included the GRS rate at the end of all therapy (EOT), all-cause mortality, and safety. Results The GRS rate in the overall population was 73.4% at EOIVT and 65.5% at EOT. Past or recent solid tumor diagnosis did not affect GRS at EOIVT or EOT (past: 75.5% and 71.4%; recent: 72.2% and 62.2%, respectively). All-cause mortality was 14.4% on day 14 and 20.1% at day 28. Most treatment-emergent adverse events were mild/moderate in severity (81.6%). Conclusions Treatment of IC was effective regardless of the time of solid tumor diagnosis. Trial Registration Data were pooled from six studies: NCT00496197 (first posted on ClinicalTrials.gov on July 4, 2007); NCT00548262 (first posted on ClinicalTrials.gov on October 23, 2007); NCT00537329 (first posted on ClinicalTrials.gov on October 1, 2007); NCT00689338 (first posted on ClinicalTrials.gov on June 3, 2008); NCT00806351 (first posted on ClinicalTrials.gov on December 10, 2008); NCT00805740 (first posted on ClinicalTrials.gov on December 10, 2008). Plain Language Summary Patients with solid tumor cancers (cancer of internal organs) have increased risk of fungal infections that can spread in the body through the blood. Infection with Candida species, known as invasive candidiasis (IC) (Candida invades the body in places normally free from germs) or candidemia (Candida infection in the blood), can cause severe illness and/or death. Anidulafungin is an antifungal drug recommended to treat IC/candidemia. This post hoc analysis looked at how effective and safe anidulafungin was in adult patients with IC/candidemia with ‘recent’ or ‘past’ history of solid tumors. The analysis included patients diagnosed with cancer less than 6 months before (recent history) or more than 6 months before (past history) they first received anidulafungin. Patients received anidulafungin by injection (intravenously [IV]) into the veins and, for continued treatment, were able to take a different antifungal drug orally. Of 539 patients from six studies, 139 had confirmed IC/candidemia and a history of solid tumors. Approximately 7 out of 10 (72%) patients were cured or no longer had signs of Candida infection at the end of IV anidulafungin treatment. Results were similar in patients with past or recent diagnosis of solid tumors. Treatment side effects reported in approximately 8 out of 10 (82%) patients were mild-to-moderate in severity. This analysis suggests anidulafungin was well tolerated and effective at treating IC/candidemia in patients with solid tumors, whether diagnosed recently or in the past.

Abstract Background Treatment with an echinocandin is recommended as first-line therapy of patients with invasive candidiasis including candidemia (ICC). Little is known about the efficacy and safety of anidulafungin (ANID) for the management of ICC in children. Methods Subjects aged 1 months to 17 years with ICC were enrolled into a prospective, open-label, non-comparative, multi-center, global study (NCT00761267) to receive ANID (3 mg/kg on day 1, 1.5 mg/kg daily thereafter). An interim analysis was completed in children 2–17 years. Subjects were to receive ANID for at least 10 days up to 35 days. A central venous catheter suspected as a site of infection was to be removed. A switch to oral fluconazole could be made after day 10. Treatment was required for at least 14 days after two negative cultures separated by 24 hours. Efficacy, based on a determination of global response (combination of clinical and microbiological response), was assessed at end of IV treatment (EOIVT), end of treatment (EOT), 2- and 6-week follow-up. Safety was assessed through 6-week follow-up. Results In total, 48 subjects (18, 2 to <5 years; 30, 5–17 years) received at least 1 dose of ANID (mean 11 days; range 1–35 days) and were assessed for safety. Forty-seven subjects had microbiologically confirmed ICC and were evaluated for efficacy. The most common baseline pathogens were C. albicans (38%) and C. parapsilosis (26%). Forty-four (93.6%) subjects had candidemia only. Global response success rates at EOIVT and EOT were 72.3 and 74.5%, respectively. All subjects reported at least one treatment emergent adverse event (AE) with diarrhea (22.9%), vomiting (22.9%), and pyrexia (18.8%) being most frequent. Five subjects discontinued treatment due to AEs of which four [increased transaminases (2), vomiting, pruritus generalis] were considered related to ANID. All-cause mortality by the 2- and 6-week follow-up visit was 12.5 and 14.6%, respectively. Of the seven deaths during the study, one was considered related to ICC; two were related to disease progression (Ewing’s sarcoma, medulloblastoma); the remaining were related to other conditions (intracranial hemorrhage, sepsis/septic shock, and respiratory failure). Conclusion Anidulafungin was effective with an acceptable tolerability and safety profile in children aged 2–17 years diagnosed with ICC. Disclosures E. Roilides, Pfizer: Grant Investigator, Investigator, Research Contractor and Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium. H. Leister-Tebbe, Pfizer: Employee, Salary. U. Conte, Pfizer Inc.: Employee, Salary. J. L. Yan, Pfizer: Employee, Salary. P. Liu, Pfizer: Employee, Salary. M. Tawadrous, Pfizer: Employee, Salary. J. Aram, Pfizer Inc.: Employee, Salary. F. Queiroz-Telles, Pfizer: Grant Investigator, Research grant

Background：Among HlV-infected patients initiating antiretroviral therapy （ART）,early changes in CD4＋ T-cell subsets are well described.However,HIV-infected late presenters initiating treatment present with a suboptimal CD4＋ T-cell reconstitution and remain at a higher risk for AIDS and non-AIDS events.Therefore,factors associated with CD4＋ T-cell reconstitution need to be determined in this population,which will allow designing effective immunotherapeutic strategies.Methods：Thirty-one adult patients with baseline CD4＋ T-cell count 〈350 cells/mm^3 exhibiting viral suppression after ART initiation were followed in the HIV/AIDS research center of Peking Union Medical College Hospital in Beijing,China,from October 2002 to September 2013.Changes in T-cell subsets and associated determinants were measured.Results：Median baseline CD4＋ T-cell count was 70 cells/mm3.We found a biphasic reconstitution ofT-cell subsets and immune activation：a rapid change during the first 6 months followed by a more gradual change over the subsequent 8 years.Baseline CD4＋ T-cell count 〉200 cells/ mm3 in comparison to CD4＋ T-cell count ≤200 cells/mm3 was associated with more complete immune Reconstitution （77.8% vs.27.3% respectively;P =0.017） and normalized CD4/CD8 ratio.We showed that the baseline percentage of naive CD4＋ T-cell was a predictive marker for complete immune reconstitution （area under receiver operating characteristic curve 0.907）,and 12.4% as cutoffvalue had a sensitivity of 84.6% and a specificity of 88.2%.Conclusions：Baseline naive CD4＋ T-cell percentage may serve as a predictive marker for optimal immune reconstitution during long-term therapy.Such study findings suggest that increasing thymic output should represent an avenue to improve patients who are diagnosed late in the course of infection.

Aim： To find new antagonists on human melanin-concentrating hormone receptor-1 （MCHR-1） through high-throughput screening （HTS） of a diverse compound library. Methods： MCHR-1, [^3H]SNAP7941, and FlashBlue G-proteincoupled receptor beads were used to measure the receptor-binding activities of various compounds based on scintillation proximity assay （SPA） technology. The guanosine 5＇ （γ-[^35S]thio） triphosphate （[^35S]GTPγS） binding assay was subsequently applied to functionally characterize the ＂hits＂ identified by the HTS campaign. Results： Of the 48 240 compounds screened with the SPA method, 12 hits were confirmed to possess MCHR-1 binding activities, 8 were functionally studied subsequently with the [^35S]GTPγS binding assay, and only 1 compound （NC 127816） displayed moderate human MCHR- 1 binding affinity （Ki=115.7 nmol/L） and relatively potent antagonism （KB=23.8 nmol/L）. This compound shares a novel scaffold （1-ethoxy-2H-2-aza-1-phospha-naphthalene 1-oxide） with 3 other analogs in the group. Conclusion： Considering the marked difference in molecular shape and electrostatic status between NC 127816 and the structures reported elsewhere, we anticipate that its derivatives may represent a new class of potent MCHR-1 modulators.

Recent evidence shows that high glucose levels recruit carbohydrate response element-binding protein, which binds the promoter of thioredoxin-interacting protein （txnip）, thereby regulating its expression in β-cells. Overexpression of txnip not only induces β-cell apoptosis but also reduces insulin production. Thus, the discovery of compounds that either inhibit TXNIP activity or suppress its expression was the focus of the present study. INS-IE cells stably transfected with either a txnip proximal glucose response element connected to a luciferase reporter plasmid （BG73） or full-length txnip promoter connected to a luciferase reporter plasmid （CL108） were used in primary and secondary high-throughput screening campaigns, respectively. From 256 000 synthetic compounds, a small molecule compound, W2476 [9-（（1-（4-acetyl-phenyloxy）-ethyl）-2-）adenine], was identified as a modulator of the TXNIP-regulated signaling pathway following the screening and characterized using a battery of bioassays. The preventive and therapeutic properties of W2476 were further examined in streptozotocin-induced diabetic and diet-induced obese mice. Treatment with W2476 （1, 5, and 15 pmol/L） dose-dependently inhibited high glucose-induced TXNIP expression at the mRNA and protein levels in INS-1E cells and rat pancreatic islets. Furthermore, W2476 treatment prevented INS-IE cells from apoptosis induced by chronic exposure of high glucose and enhanced insulin production in vitro. Oral administration of W2476 （200 mg-kg-1.d-1） rescued streptozotocin-induced diabetic mice by promoting β-cell survival and enhancing insulin secretion. This therapeutic property of W2476 was further demonstrated by its ability to improve glucose homeostasis and insulin sensitivity in diet-induced obese mice. Thus, chemical intervention of the TXNIP- regulated signaling pathway might present a viable approach to manage diabetes.