Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profiles of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.

Screening for novel bacteria from the bioenergy feedstock switchgrass (Panicum virgatum L.).

Switchgrass is considered as a good candidate for biofuel, especially ethanol production due to its huge biomass output and high cellulose content. In a search for novel microorganisms capable of using and degrading switchgrass to produce sugars and ethanol, enrichment experiments were established to screen for microorganisms from soil samples obtained at the University of Tennessee Agricultural Research Station, Jackson, Tennessee. Three enrichments were prepared and incubated at different pH and temperatures: (1) 30 degrees C, pH 5, (2) 30 degrees C, pH 8 and (3) 60 degrees C, pH5. Bulk community DNA was directly extracted from the enrichments. Microbial community structures were determined by phylogenetic analysis of 16S rRNA gene sequences retrieved from the enrichment cultures containing switchgrass as the carbon source. The mesophilic enrichments were dominated by Sarcina, Anaerobacter, and Clostrium, which were not found in the thermophilic enrichment. The thermophilic enrichment selected for two types of bacteria belonging to the class Bacilli (Geobacillus and Saccharococcus). The thermophilic enrichments were dominated by the Geobacillus spp. (Firmicutes, class Bacilli), and Saccharococcus (Firmicutes, class Bacilli); both containing thermophilic microorganisms with some cellulolytic members. Enzymatic assays detected the presence of enzymes involved in cellulose (beta-glucosidase and cellobiohydrolase) and hemicellulose degradations (beta-xylosidase); and the activity tends to be higher in the enrichments incubated at 30 degrees C.

In vitro potency and fungicidal activity of CD101, a novel echinocandin, against recent clinical isolates of Candida spp.

Candida infections vary in severity and manifestation. Common infections include invasive bloodstream infections among hospitalized/immunocompromised patients and vulvovaginal candidiasis among women. Echinocandins and azoles are commonly utilized to treat Candida infections, although echinocandin use has been restricted to indications amenable to once-daily IV administration. CD101, a novel echinocandin with a long plasma half-life and enhanced stability, is in development for once-weekly IV administration for the treatment of candidemia and invasive candidiasis. In this study, the MIC of CD101 and comparators against 500 recent clinical Candida isolates was determined per Clinical and Laboratory Standards Institute guidelines. For select isolates, the minimum fungicidal concentration (MFC; n=49) and time-kill (n=9) of CD101 and comparators was evaluated. The MIC50/90s (µg/mL; n=100/species) for CD101, anidulafungin, fluconazole, and amphotericin B, respectively, were: C. albicans (0.008/0.03, 0.004/0.008, 0.25/4, 0.25/0.5), C. tropicalis (0.008/0.03, 0.004/0.015, 0.5/2, 0.5/1), C. parapsilosis (1/1, 0.5/2, 0.5/1, 0.5/1), C. glabrata (0.03/0.03, 0.03/0.03, 8/>32, 0.5/0.5), and C. krusei (0.03/0.03, 0.03/0.03, 32/>32, 1/1). CD101 MICs were comparable to anidulafungin and both maintained potency against fluconazole-resistant isolates. Against rare anidulafungin-resistant isolates, the MICs of CD101 and anidulafungin were elevated vs. anidulafungin-susceptible isolates. Similar to anidulafungin, CD101 was fungicidal with an MFC:MIC ratio ≤4 for 95% of evaluable isolates and resulted in 3-log killing by 24-48h for all isolates evaluated by time-kill. The potent fungicidal activity of CD101 highlights the potential clinical utility of CD101 IV for the treatment of invasive candidiasis and candidemia.

Clinical practice guideline adherence before and after implementation of the HEARTFELT (HEART Failure Effectiveness & Leadership Team) intervention.

HEART Failure Effectiveness & Leadership Team (HEARTFELT) is a multifaceted intervention designed to improve adherence with the American College of Cardiology/American Heart Association practice guidelines for heart failure (HF). The purpose of this study was to assess differences in clinician adherence with clinical practice guidelines before and after implementation of HEARTFELT. A quasi-experimental, untreated control group design with separate pretest/posttest samples was employed at a community hospital in Connecticut. The untreated historical control group included patients aged 65 years or older with HF and a nonequivalent comparison group of patients with stroke. The posttest samples included patients with the diagnosis of HF and stroke admitted after implementation of the HEARTFELT intervention. The HEARTFELT intervention included automated pathway in electronic medical record (order sets, interdisciplinary plan of care, self-management plan), access to evidence for clinicians and patients, HF self-management education tools, and ongoing discipline-specific feedback regarding adherence. Data were analyzed using parametric and nonparametric methods. The HEARTFELT intervention significantly improved clinician adherence with addressing all self-management categories in the electronic medical record (P = .000) and adherence with self-management education given to the patient in writing at discharge (P = .000). There were no significant differences in adherence with medical interventions (P = .39). While guideline adherence is associated with less practice variation and improved processes, methods of integration into practice in community hospital settings have been largely unexplored. The multifaceted HEARTFELT intervention is promising for its potential to integrate evidence at the point of care, to reduce unwarranted variation in practice, and ultimately to improve the outcomes of individuals with HF.