Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline

Omadacycline is a novel first-in-class aminomethylcycline with potent activity against important skin and pneumonia pathogens, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA), β-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, and Legionella. In this work, the mechanism of action for omadacycline was further elucidated using a variety of models. Functional assays demonstrated that omadacycline is active against strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection). Macromolecular synthesis experiments confirmed that the primary effect of omadacycline is on bacterial protein synthesis, inhibiting protein synthesis with a potency greater than that of tetracycline. Biophysical studies with isolated ribosomes confirmed that the binding site for omadacycline is similar to that for tetracycline. In addition, unlike tetracycline, omadacycline is active in vitro in the presence of the ribosomal protection protein Tet(O).     

An evaluation of outcome from intensive care in major medical centers

We prospectively studied treatment and outcome in 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p less than 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p less than 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.     

Steroidogenic activity of fragments of adrenocorticotropin with arginine in residue positions 3 and 5.

The maximal steroidogenic response (Smax) to adrenocorticotropin (ACTH) is enhanced by the substitution of arginine in position 3. Though the Smax of adrenocorticotropin-(3-10)-octapeptide [ACTH-(3-10)] is only 20% of ACTH-(1-24) in isolated rabbit adrenal cells and 10% in rat cells, [Arg3]ACTH-(3-10) has an Smax comparable to that of the longer peptide. Activity determined from the midpoints of dose-response curves (A50), however, is several orders of magnitude less. The Smax of ACTH-(4-10) is not significantly different from that of the 3-10 analog. Substitution of arginine in the 5 position of ACTH-(4-10) decreases activity for rabbit cells, but does not affect activity for rat cells. The substitution of arginine in the 5 position of ACTH-(1-20) markedly decreases Smax in rabbit but not rat cells. The Smax of [Arg 3,5)]ACTH-(3-10), containing both substitutions, is greater than that of ACTH-(3-10), but much less than that of [Arg3]acth-(3-10) in both species studied. These findings contrast with those in the rabbit adipocyte, where both arginine-containing ACTH analogs have enhanced activity and the effects of both substitutions in a single peptide are additive.     

Identification of low-risk monitor admissions to medical-surgical ICUs

A total of 5,790 intensive care unit (ICU) admissions from 13 tertiary care institutions were studied to identify patients who were at such low risk of receiving unique ICU therapies that admission might have been avoided or the length of ICU stay reduced. We used acute severity of disease on admission to the ICU along with the type of disease or surgery to risk stratify individual ICU patients. Among 1,941 patients who only received monitoring services on admission to the ICU, 1,358 (70 percent) were predicted to have less than a 10 percent risk of requiring subsequent active ICU treatment. Only 58 (4.3 percent) of these low-risk patients actually received active treatment. The identification of low-risk patients was equally accurate in estimation and validation data sets. Our methods should allow physicians and hospitals to assess their current ICU utilization and, if appropriate, guide reductions in use.