Oritavancin vs Standard of Care for Treatment of Nonendovascular Gram-Positive Bloodstream Infections.

Background: Data is limited comparing oritavancin (ORT) to the standard-of-care (SOC) for the treatment gram-positive blood stream infections (BSI). Methods: This was a retrospective study of all patients in the Veteran's Affairs Health Care System treated with at least 1 dose of oritavancin or at least 5 days of vancomycin, daptomycin, ceftaroline, ampicillin, ampicillin-sulbactam, nafcillin, oxacillin, or cefazolin for a documented gram-positive BSI from 1 January 2015 to 30 June 2021. Patients with polymicrobial blood cultures or positive cultures from other sites were included if the organisms were sensitive to the incident antimicrobial; no concomitant antimicrobials could be used once the incident agent was started. Individuals were also excluded if they were diagnosed with endocarditis, had a neutrophil count 96-hours of treatment before the incident antimicrobial was started.The primary composite outcome was clinical failure, defined as all-cause mortality within 30-days from the end of therapy, or blood cultures positive for the incident organisms ≥72 hours after administration of the first dose and ≤30 days after the administration of the final dose of the study antimicrobial, or any drug or line-related readmissions within 30-days of hospital discharge. Results: Two hundred-forty patients were identified for screening with 96 meeting criteria (27 in ORT and 69 in SOC groups). Baseline characteristics were generally balanced between groups except more patients in the ORT group received >96-hours of treatment before the incident antimicrobial was started (70.3% (19/27) vs 13.04% 9/69); P < .001). The pathogen most prevalent was methicillin susceptible Staphylococcus aureus (MSSA) (ORT 33.3% (9/27) vs SOC 46.4% (32/69)). Clinical failure occurred in 7.4% (2/27) in the ORT group and 17.4% (12/69) in SOC (P = .34). No components of the primary outcome were significantly different between groups, but AKI did occur more commonly in the SOC group (27.5% (19/69) vs 3.7% (1/27); P = .01). Conclusions: ORT appears to be a safe and effective option when directly compared to the SOC for non-endocarditis BSIs.

Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration.

Aging is associated with a progressive decline of innate and adaptive immune responses, called immunosenescence. This phenomenon links to different multiple sclerosis (MS) disease courses among different age groups. While clinical relapse and active demyelination are mainly related to the altered adaptive immunity, including invasion of T- and B-lymphocytes, impairment of innate immune cell (e.g., microglia, astrocyte) function is the main contributor to disability progression and neurodegeneration. Most patients with MS manifest the relapsing-remitting phenotype at a younger age, while progressive phenotypes are mainly seen in older patients. Current disease-modifying therapies (DMTs) primarily targeting adaptive immunity are less efficacious in older patients, suggesting that immunosenescence plays a role in treatment response. This review summarizes the recent immune mechanistic studies regarding immunosenescence in patients with MS and discusses the clinical implications of these findings.

Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections.

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

Potent inhibitors of LpxC for the treatment of Gram-negative infections.

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.

Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.

There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.

Structure-activity relationships and hepatic safety risks of thiazole agonists of the thrombopoietin receptor.

5-F substitution of an aminothiazole moiety within a series of thrombopoietin receptor agonists leads to potent agents with an improved hepatic safety profile in rodent toxicology studies.

The identification of orally bioavailable thrombopoietin agonists.

Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

The specificity of JAK3 kinase inhibitors.

PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.

Pyrimidine benzamide-based thrombopoietin receptor agonists.

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.

Analysis of unknown primary carcinomas metastatic to the neck: diagnosis, treatment, and outcomes.

Metastatic squamous cell carcinoma presenting in the neck from an unknown primary site represetns 2% to 6% of head and neck cancers. Optimal management of these cases remains controversial and continues to evolve with experience. We performed a retrospective analysis involving patients treated for unknown primary squamous cell carcinomas with metastases to cervical lymph nodes who presented to either the University of Kentucky or the Veterans Affairs Hospital of Lexington, Kentucky, from 1990 to 2000. Thirty-five out of 173 patients met inclusion criteria for carcinoma of unknown primary. The following data subsets were analyzed: age, gender, smoking and alcohol use, family history, diagnostic studies performed, radiation dose, surgical intervention, number and location of pathologic nodes, presence or absence of extracapsular extension, time between surgery and radiation, disease-specific and overall survival, response to treatment, emergence of a primary tumor, and duration of follow-up. Overall and disease-specific survivals were analyzed using, the Kaplan-Meier method and the log-rank test was used to assess differences in survival curves. The actuarial 5-year overall and disease-specific survival of all patients in this study was 54% and 63%, respectively. At 10 years, the overall survival declined to 37% with a disease-specific survival rate of 49%. The 5-year survival rates stratified by nodal stage were 80% for N1 patients, 64.7% for N2, 55.6% for N3, and 0% for any M disease. These rates declined to 60% for N1, 52.9% for N2, 11.1% for N3, and 0% for any M disease at 10 years (p<.0001). The presence of extracapsular spread, increased number of positive lymph nodes, and eventual discovery of a primary tumor did not significantly decrease survival in this series. The mean follow-up period for patients in this study was 54.8 months. We continue to refine our diagnostic and treatment strategies in this group of patients in an effort to improve long-term survival and reduce patient morbidity.

Biomechanical evaluation of fixation techniques for bridging segmental mandibular defects.

OBJECTIVE: To compare biomechanical properties of currently available plating systems used to reconstruct segmental mandibular defects. DESIGN: Controlled in vitro investigation. SETTING: Academic medical center laboratory. INTERVENTIONS: Thirty-two polyurethane mandibles were equally divided among 4 groups: mandibles with a 4-cm lateral segmental defect that was bridged with a (1) 3.0-mm locking-screw reconstruction plate, (2) 2.4-mm low-profile reconstruction plate, or (3) 2.4-mm reconstruction plate and (4) uncut (control) mandibles. All plates were contoured and secured to the synthetic mandibles with 4 bicortical screws on either side of the defect. Three constructs from each group were subjected to contralateral-molar single-load-to-failure testing. Mean yield displacement, yield load, and bending stiffness were quantified and compared among the 4 groups. The single-load-to-failure data were used to establish conditions for fatigue testing; such testing was then performed on the remaining 5 samples in each group. Mean cycles to failure were measured and compared among the 4 groups. RESULTS: Mean yield displacement, yield load, and bending stiffness were comparable among the plated groups. Both the 3.0-mm locking-screw and 2.4-mm low-profile reconstruction plate designs withstood 1580 and 1124 times more cycles to failure, respectively (P = .005), than did the control group. The other reconstruction plate was also superior to the unplated controls, offering an 865-fold improvement. CONCLUSIONS: All 3 mandibular fixation device systems tested produce comparable levels of single load to failure biomechanical integrity; however, the higher-profile plating system design offered slightly superior fatigue performance. No differences in performance were observed between the locking and nonlocking designs; neither failed at the screw-substrate interface.

Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity.

Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.