Evaluation of a Capped Dosing Telavancin Regimen Compared to Standard Dosing at a Large Community Teaching Hospital.

Telavancin, a lipoglycopeptide antibiotic, is traditionally dosed at 10 mg/kg based on total body weight but is associated with toxicities that limit its use. This study supports the use of a capped dosing regimen of 750 mg in obese patients, which is associated with equal efficacy and fewer adverse effects compared to traditional dosing.

Effect of microbiology comment nudging on antibiotic use in asymptomatic bacteriuria: A before-and-after quasi-experimental study.

OBJECTIVE: To describe the effect of a microbiology comment nudge on antibiotic use for asymptomatic bacteriuria (ASB). DESIGN: Single-center, before-and-after, quasi-experimental study. SETTING: Community-based, public, not-for-profit teaching hospital in the southeastern United States. PARTICIPANTS: Adult inpatients with a positive urine culture and the absence of urinary tract infection signs and symptoms. INTERVENTION: Implementation of a microbiology comment nudge on urine cultures. RESULTS: In total, 204 patients were included in the study. Antibiotics were less likely to be continued beyond 72 hours in the postimplementation group: 57 (55%) of 104 versus 38 (38%) of 100 (P = .016). They were less likely to have antibiotics continued beyond 48 hours: 60 (58%) of 104 versus 43 (43%) of 100 (P = .036). They were also less likely to have antibiotics prescribed at discharge 35 (34%) of 104 versus 20 (20%) of 100 (P = .028). In addition, they had fewer total antibiotic days of therapy: 4 (IQR, 1-6) versus 1 (IQR, 0-6) (P = .022). CONCLUSION: Microbiology comment nudging may contribute to less antibiotic utilization in patients with ASB.

Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN lacking exon 7 (SMNDelta7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMNDelta7 SMA mice.

Evaluation of area under the concentration-time curve-guided vancomycin dosing with or without piperacillin-tazobactam on the incidence of acute kidney injury.

OBJECTIVES: Recent studies suggest that the combination of piperacillin-tazobactam (P-T) and vancomycin increases the risk for acute kidney injury (AKI). The purpose of this study was to determine if area under the concentration-time curve (AUC)-guided vancomycin dosing reduced the incidence of AKI in a sample of patients who also received P-T. METHODS: This single-centre, retrospective, pre-post quasi-experimental study compared the incidence of AKI before and after a health-system-wide change from trough- to AUC-guided vancomycin dosing using two post-distribution levels. The primary outcome was AKI, defined as an increase in serum creatinine ≥0.5 mg/dL or 50% from baseline for two consecutive measurements, in patients who received vancomycin with or without concomitant P-T. RESULTS: In total, 636 patients were included in this study (308 trough-guided, 328 AUC-guided); of these, 118 patients in each group received concomitant P-T. The primary outcome occurred in 35 (11.4%) patients in the trough-guided group and 24 (7.3%) patients in the AUC-guided group (P=0.105). There was no difference in the incidence of AKI in the population receiving concomitant P-T between dosing strategies. The incidence of AKI was significantly higher in patients who received concomitant P-T compared with patients who did not receive concomitant P-T in both the trough-guided group [21/118 (17.8%) versus 14/190 (7.4%), respectively; P=0.003] and the AUC-guided group [16/118 (13.6%) versus 8/210 (3.8%), respectively; P=0.0011]. CONCLUSIONS: The incidence of AKI did not differ significantly between trough- and AUC-guided vancomycin dosing. Caution should be taken when combining vancomycin and P-T regardless of dosing strategy. Larger studies are needed to confirm these findings.

A novel method for oral delivery of drug compounds to the neonatal SMNDelta7 mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating motor neuron disease that is one of the leading genetic causes of infant mortality. Currently, there is no cure for SMA. Mouse models that genetically and phenotypically resemble SMA have been generated and have the potential to be used for the discovery of novel therapeutics. Oral administration is a commonly used mode of drug delivery in humans as well as in rodents. Unfortunately, there is no method of drug delivery that can accurately and reliably deliver drug compounds orally to neonatal mice. In this report, we describe a novel method to orally administer compounds to neonatal SMA mice. Oral delivery to neonatal mice, usually starting at postnatal day 4 (PND04), is both rapid and safe to the pup. Oral delivery of two different commonly used vehicle formulations, distilled water and 2-hydroxypropyl-beta-cyclodextrin, does not affect the survival of SMA mice. After oral delivery for 3 days, 5-bromo-2'-deoxyuridine could be detected in the kidneys, brains and spinal cords of treated non-SMA as well as SMA neonatal pups. In conclusion, we have developed a method by which drugs can be safely and reliably administered orally to neural targets of neonatal mice. This approach offers a simple and rapid means by which potential therapeutics for SMA can be identified.

Federal Directions in Radiation Regulations: Making the "Old" New Again.

The radiation regulatory scheme in the United States must periodically evolve and adapt to ensure that public health, workers, and the environment are properly protected in view of accepted societal values and the advance of science, technology, and medical practices. Federal regulators must use best judgment in weighing a multitude of factors and considerations. In the early 21st century, a few dependable but tired and antiquated "workhorses" of regulation have been reworked already--but many more remain that likely need reworking. Three primary points of discussion on current directional influences on federal radiation regulation merit examination: • In 2015, what are the stressors driving societal and policy changes and how might these dynamics be forcing reexamination of old regulations? • What are the things that make a "good" regulation and an effective rule? • What are the thorny issues that the federal government is wrestling with and what are some of the notable activities in federal radiation regulations and guidance that are underway? This journal article was presented at the 2015 Annual Meeting of the National Council on Radiation Protection and Measurements and served as a broad overview of federal regulatory actions and issues.

Effect of the Butyrate Prodrug Pivaloyloxymethyl Butyrate (AN9) on a Mouse Model for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analog (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs-glyceryl tributyrate (BA3G) and VX563-on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3ß, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favorable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling.

Aminoglycoside-induced nephrotoxicity.

Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.

Abnormal motor phenotype in the SMNDelta7 mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a recessive motor neuron disease that affects motor neurons in the anterior horn of the spinal cord. SMA results from the reduction of SMN (survival motor neuron) protein. Even though SMN is ubiquitously expressed, motor neurons are more sensitive to the reduction in SMN than other cell types. We have previously generated mouse models of SMA with varying degrees of clinical severity. So as to more clearly understand the pathogenesis of motor neuron degeneration in SMA, we have characterized the phenotype of the SMNDelta7 SMA mouse which normally lives for 13.6+/-0.7 days. These mice are smaller than their non-SMA littermates and begin to lose body mass at 10.4+/-0.4 days. SMNDelta7 SMA mice exhibit impaired responses to surface righting, negative geotaxis and cliff aversion but not to tactile stimulation. Spontaneous motor activity and grip strength are also significantly impaired in SMNDelta7 SMA mice. In summary, we have demonstrated an impairment of neonatal motor responses in SMNDelta7 SMA mice. This phenotype characterization could be used to assess the effectiveness of potential therapies for SMA.

Claudin-5 localizes to the lateral membranes of cardiomyocytes and is altered in utrophin/dystrophin-deficient cardiomyopathic mice.

Remodeling of adherens junction, gap junction, and desmosomal proteins at the intercalated discs of cardiomyocytes in heart characterizes several animal models of cardiomyopathy, especially dilated cardiac myopathy (DCM). In this study, we show that the tight junction protein, claudin-5, is present in cardiac muscle and localizes to the lateral membranes of cardiomyocytes in normal mice. We further examined claudin-5 in utrophin/dystrophin-deficient (double knockout, dko) mice, a mouse model of muscular dystrophy with cardiomyopathy, and found that claudin-5 mRNA and protein levels are decreased in dko hearts as compared with normal. Intercalated disc cell junction proteins, and another tight junction protein, zonula occludens-1 (ZO-1), are not altered in the dko mouse. Ultrastructural data from dko hearts also shows that the lateral membranes of cardiomyocytes exhibit an abnormal wavy appearance. These data demonstrate that claudin-5 is specifically altered in dko hearts, suggesting that alterations of the lateral membranes of cardiomyocytes, rather than intercalated discs, are associated with cardiomyopathy in the dko mouse.