Eravacycline (TP-434) Is Efficacious in Animal Models of Infection

Eravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD₅₀) values of ≤1 mg/kg of body weight once a day (q.d.) against Staphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes. The PD₅₀ values against Escherichia coli isolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitive S. aureus (MSSA) and S. pyogenes, eravacycline produced 2 log₁₀ reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistant Streptococcus pneumoniae in a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log₁₀ CFU reduction in kidney bacterial burden in a model challenged with a uropathogenic E. coli isolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens.     

Health-related workplace productivity measurement: general and migraine-specific recommendations from the ACOEM Expert Panel.

An establishment of health-related productivity measurements and critical evaluation of health-related productivity tools is needed. An expert panel was created. A literature search was conducted to identify health-related productivity measurement tools. Each instrument was reviewed for: 1) supporting scientific evidence (e.g., reliability and validity); 2) applicability to various types of occupations, diseases, and level of severity of disease; 3) ability to translate data into a monetary unit; and 4) practicality. A modified Delphi technique was used to build consensus. The expert panel recommended absenteeism, presenteeism, and employee turnover/replacement costs as key elements of workplace health-related productivity measurement. The panel also recommended that productivity instruments should: 1) have supporting scientific evidence, 2) be applicable to the particular work setting, 3) be supportive of effective business decision-making, and 4) be practical. Six productivity measurement tools were reviewed. The panel recommended necessary elements of workplace health-related productivity measurement, key characteristics for evaluating instruments, and tools for measuring work loss. Continued research, validation, and on-going evaluation of health-related productivity instruments are needed.     

Identifying neonatal and pediatric cardiac and congenital diaphragmatic hernia extracorporeal membrane oxygenation patients at increased mortality risk

A previous review from our institution established clinically measured cut-points that defined the late implementation of extracorporeal membrane oxygenation (ECMO) correlating to increased mortality in neonatal and pediatric respiratory patients. Using the same methods, this review evaluates pediatric and neonatal cardiac and congenital diaphragmatic hernia (CDH) patients to determine if the same cut-points exist in this higher risk patient population. Neonatal and pediatric cardiac and CDH patients placed on ECMO between November 1989 and December 2008 were retrospectively reviewed to determine the first adjusted anion gap (AGc), the first venoarterial carbon dioxide (CO2) gradient (p[v-a]CO2), and the first Viability Index (AGc + p[v-a]CO2 = INDEX) on ECMO. These markers were then analyzed to identify the presence of specific cut-points that marked an increased risk of mortality. The timing of surgery was also reviewed to assess the surgical morbidity on survival. The review of neonatal and pediatric cardiac and CDH patients (n = 205) with an overall survival of 46% showed that all three markers were elevated to varying degrees in the expired patients (n = 110). Histograms identified the following specific cut-points for increased mortality: the AGc > or = 23 mEq/L, the p[v-a]CO2 _ 16 mmHg, and the INDEX > or = 28. An elevated AGc and INDEX correlated with a significantly higher risk for mortality (p < .05), survival to discharge being 20% or less. Patients under the cut-points had survival rates of 51% or higher. The timing of surgery (before or after ECMO initiation) did not significantly impact survival in the combined cardiac and CDH group. An INDEX > or = 28 correlates with non-survival. We speculate that the late implementation of ECMO may lead to reperfusion injury, which causes reduced survival, and that ECMO intervention prior to reaching the cut-points may improve survival in neonatal and pediatric cardiac and CDH patients. Keywords: cardiac, congenital, diaphragmatic, extracorporeal membrane oxygenation, neonate, pediatric.     

Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs

Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.     

Cryosurgical modification of retrograde atrioventricular conduction. Implications for the surgical treatment of atrioventricular nodal reentry tachycardia

Paroxysmal supraventricular tachycardia resulting from atrioventricular nodal reentry is a common arrhythmia that usually responds to medical therapy. When atrioventricular nodal reentry tachycardia is refractory to medical therapy, cryoablation or endocardial catheter ablation of the His bundle has been employed to protect the ventricles from the tachycardia. However, these techniques necessitate implantation of a permanent ventricular pacemaker. A cryosurgical procedure that ablates the anatomic-electrophysiologic substrate for atrioventricular nodal reentry tachycardia while preserving antegrade atrioventricular conduction has been described. The purpose of the present study was to determine the effects of this procedure on retrograde atrioventricular conduction and on the ventricular echo phenomenon in particular. Thirty adult mongrel dogs underwent either the cryosurgical procedure (n = 20) or a sham operation (n = 10). The animals were studied either immediately postoperatively (acute cryosurgery group and control group, n = 10 for each group) or 14 weeks postoperatively (chronic cryosurgery group, n = 10). Decremental ventricular pacing and programmed premature ventricular pacing protocols were used to determine the retrograde atrioventricular nodal conduction time, Wenckebach point, atrioventricular nodal refractory periods, and ventricular echo reflection time. No electrophysiologic alterations were noted in the sham-operated group. In the acute cryosurgery group, the retrograde Wenckebach point, atrioventricular nodal conduction time, functional refractory period of the atrioventricular node, effective refractory period of the atrioventricular node, and ventricular echo reflection time were all significantly prolonged. In the chronic cryosurgery group, no significant change in ventriculoatrial conduction was noted, but the ventricular echo phenomenon was eliminated in all but one animal. These data further document that this cryosurgical procedure is capable of ablating the anatomic-electrophysiologic substrate necessary for atrioventricular nodal reentry tachycardia while preserving atrioventricular conduction.     

Cholesterol metabolism in squirrel monkeys: Analysis of long-term kinetic studies in plasma and body tissues

Thirty adult male Brazilian-type squirrel monkeys (Saimiri sciureus) were fed a semipurified diet containing 45% of the calories as fat. One milligram of cholesterol per calorie was added to the diet of one-half of the animals. After 4 months on their respective diets, a single intravenous dose of [³H] cholesterol was administered to each animal. At 2, 4, and 6 months following intravenous labeling, five animals from the cholesterol-fed group and five animals from the non-cholesterol-fed group were killed for analysis of tissue cholesterol specific activity. The analysis of ratios between cholesterol specific activity of various tissues to the specific activity of terminal blood samples of the cholesterol-fed group indicated to us that cholesterol in liver, spleen, adrenal gland, ileum, stomach, kidney, testes, lung, heart, skin, tendon, fascia, and skeletal muscle had reached equilibrium with plasma cholesterol radio-activity by 2 months. The tissue/plasma ratios of adipose tissue, aorta, and gallstones demonstrated a slower rate of exchange. In the non-cholesterol-fed group the tissue/plasma ratios of all the tissues mentioned above remained close to unity in all three subgroups, indicating equilibration with plasma by 2 months. As before, the tissue/plasma ratios in adipose tissue and aorta had a slower rate of exchange. In both groups, cerebrum and spinal cord had a very slow rate of exchange with plasma cholesterol. Computer analysis of the plasma cholesterol specific activity time curve suggested to us a significantly better three-exponential fit rather than a two-exponential fit in $\text{5}\text{14}$ of the cholesterol-fed group and in none of the non-cholesterol-fed group. The minimal mass of the miscible body pool of cholesterol derived from kinetic analysis agreed reasonably well with, but consistently overestimated, the whole-body miscible pool determined by carcass analysis in both groups.