In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu.

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.

The thickness of the temporal squama and its implication for transcranial sonography.

BACKGROUND AND PURPOSE: The difficult transtemporal ultrasound window is a relatively frequent occurrence. The authors assessed if the thickness of the temporal bone squama as measured in the "bone window" of the head computerized tomography (CT) scan can predict the transtemporal acoustic window. METHODS: The authors retrospectively reviewed the head CTs on their bone window setting of patients in which nonimaging transcranial Dopplers (TCDs) had been performed. The thickness of the temporal squama in its thinnest portion was measured. The temporal TCD windows were graded in three classes: class 1 as good, class 2 when only a partial study is possible, and class 3 as an impossible ultrasonic window. In a case-control design, for every patient with any class 2 and 3 TCD temporal window, a patient with a class 1 window was randomly included from the same time period. RESULTS: Fifty-five temporal bones (56%) were class 1, 17 (17%) were class 2, and 27 (27%) were class 3. Bone thicknesses (in mm, mean +/- SD) were greater in those with poorer windows: class 1 = 2.67 +/- 0.70, class 2 = 4.06 +/- 0.56, and class 3 = 5.04 +/- 1.06, P < or = .0001 by Cusick's nonparametric test of trend. Temporal squama thickness of > or = 5 mm portends 86% sensitivity, 90% specificity, 70% positive predictive value, and a positive likelihood ratio of 8.6 for a class 3 transtemporal ultrasound window. CONCLUSION: Measurement of temporal bone thickness on the bone window setting of the head CT scan may be useful in identifying patients who are poor candidates for transcranial ultrasound.

Preliminary evaluation of iron phytate (inositol hexaphosphate) as a gastrointestinal MR contrast agent.

A simple, effective, safe, and well-tolerated contrast agent is needed as a bowel marker for magnetic resonance (MR) imaging. The authors tested a variety of foodstuffs admixed with ferric iron as potential gastrointestinal MR contrast agents. Phytate (inositol hexaphosphate) more than doubled the relaxivity of solutions of ferric iron. Because of the improved relaxivity of iron phytate, the concentration of iron could be reduced substantially relative to free ferric iron (eg, ferric chloride or ferric ammonium citrate). Imaging studies were performed in five volunteers to determine the optimal dose of iron phytate and in five additional volunteers to test its effectiveness. A 200 mg/L concentration of ferric iron with phytate functions as an effective gastrointestinal MR contrast agent for T1-weighted abdominal MR imaging, significantly improving bowel contrast (P < .01). Blood studies after contrast agent administration showed no appreciable increase in serum iron. Compared with standard chelate complexes that decrease the relaxivity of a given paramagnetic ion, phytate not only decreases the absorption of the iron but increases its relaxivity.