Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option?

Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 106 CFU/mL. Ceftriaxone dosing regimens of 1 g once and twice daily and 2 g once and twice daily were simulated. Ceftriaxone 1 g dosing regimens did not substantially impact bacterial killing within the first 12 h. Conversely, when administered as a 2 g dose either once or twice daily, an approximate 1-log10 bacterial reduction was observed where it plateaued for up to 96 h. No resistance was identified. Only a high ceftriaxone dose of 2 g twice daily achieves bacterial killing and sustained inhibition of bacterial growth. Ceftriaxone at routinely used doses is unsuitable for the treatment of MSSA infections and alternative agents should be preferentially used.

Can a virtual microbiology simulation be as effective as the traditional Wetlab for pharmacy student education?

BACKGROUND: Pharmacy practice education requires the development of proficiencies and an understanding of clinical microbiology. Learning in this area could be delivered using practical laboratory exercises, or potentially, simulation-based education. Simulation has previously successfully enhanced learning in health professional education. The current global climate due to COVID-19 has further highlighted the important role of technology-enhanced learning in delivering outcomes that meet the requisite learning objectives of a course. The aim of the present study was to compare the impact of a commercially available virtual microbiology simulation (VUMIE™) with a traditional wet laboratory (wetlab) on learner knowledge, skills and confidence in a second-year integrated pharmacotherapeutics course for Bachelor of Pharmacy students. METHODS: A randomised, crossover study was employed to determine whether the simulation intervention (VUMIE™) improves learning outcomes (knowledge, skills and confidence) of pharmacy students, when compared to a traditional wetlab intervention. Each student completed three 1-2 h length sessions, for both the wetlab and VUMIE™ interventions (6 sessions total). Data was collected using surveys deployed at baseline (pre-interventions), post-intervention 1 or 2 (VUMIE™ or wetlab) and endpoint (post-interventions 1 and 2). Statistical analysis was conducted using SPSS Statistics 25 and Instat™ software. RESULTS: Response rates were approximately 50% at initial survey and approximately 25% at endpoint survey. VUMIE™ produced higher post-intervention knowledge scores for the multiple-choice questions compared to the wetlab, however, the highest score was achieved at endpoint. Both interventions produced statistically significant differences for mean scores compared to baseline (pre-VUMIE™ and wetlab) across the domains of knowledge, skills and confidence. VUMIE™ produced higher post-intervention mean scores for knowledge, skills and confidence compared to post-intervention mean scores for the wetlab, however there was no statistical significance between the mean score for the two interventions, thus the VUMIE™ activity produced learning outcomes comparable to the wetlab activity. CONCLUSION: These findings suggest VUMIE™ provides similar effects on students' knowledge, skills, and confidence as a wetlab. The simulation's implementation was not cost-prohibitive, provided students with a physically and psychologically safe learning environment, and the benefit of being able to repeat activities, supporting deliberate practice.

Differences in statin associated neuroprotection corresponds with either decreased production of IL-1ß or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0-100 µM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration. To achieve this, HAPI microglia were treated with LPS (0.1 µg/mL; 24 h), resulting in increased reactive oxygen species (ROS), nitric oxide, and IL-1ß, TNF-α and PGE2 release. Conditioned media ("HAPI-CM") was then transferred to SH-SY5Y neuroblastoma cells, and effects on cellular viability, mitochondrial membrane permeability, apoptosis, autophagy and ROS production assessed. Of the statins investigated, only atorvastatin, pravastatin and rosuvastatin protected SH-SY5Y cells from LPS-induced decreases in cellular viability; this appeared mediated through reduced caspase 3/7 activation and was associated with decreased IL-1ß (atorvastatin, pravastatin) and/or TNF-α (atorvastatin, pravastatin, rosuvastatin). Only pravastatin conferred protection at all tested concentrations. ROS production and autophagic vacuole formation was decreased by all statins, suggesting these two mechanisms are unlikely to be sole mediators of neuroprotection seen with selected statins. Ultimately, our model suggests that despite all statins reducing microglial inflammation, subsequent effects on neuronal viability and cell death signalling pathways varies between statins. Our findings highlight the need to consider individual statins as inducing discrete pharmacological effects within the CNS in future in vitro/in vivo studies and in clinical practice.

Pharmacists' self-perceptions in relation to the 'Advanced Pharmacy Practice Framework'.

BACKGROUND: The Australian Pharmacy Practice Framework was developed by the Advanced Pharmacy Practice Steering Committee and endorsed by the Pharmacy Board of Australia in October 2012. The Steering Committee conducted a study that found practice portfolios to be the preferred method to assess and credential Advanced Pharmacy Practitioner, which is currently being piloted by the Australian Pharmacy Council. Credentialing is predicted to open to all pharmacists practising in Australia by November 2015. OBJECTIVE: To explore how Australian pharmacists self-perceived being advanced in practice and how they related their level of practice to the Australian Advanced Pharmacy Practice Framework. METHOD: This was an explorative, cross-sectional study with mixed methods analysis. Advanced Pharmacy Practice Framework, a review of the recent explorative study on Advanced Practice conducted by the Advanced Pharmacy Practice Framework Steering Committee and semi-structured interviews (n = 10) were utilized to create, refine and pilot the questionnaire. The questionnaire was advertised across pharmacy-organizational websites via a purposive sampling method. The target population were pharmacists currently registered in Australia. RESULTS: Seventy-two participants responded to the questionnaire. The participants were mostly female (56.9%) and in the 30-40 age group (26.4%). The pharmacists self-perceived their levels of practice as either entry, transition, consolidation or advanced, with the majority selecting the consolidation level (38.9%). Although nearly half (43.1%) of the participants had not seen the Framework beforehand, they defined Advanced Pharmacy Practice similarly to the definition outlined in the Framework, but also added specialization as a requirement. Pharmacists explained why they were practising at their level of practice, stating that not having more years of practice, lacking experience, or postgraduate/post-registration qualifications, and more involvement and recognition in practice were the main reasons for not considering themselves as an Advanced Pharmacy Practitioner. To be considered advanced by the Framework, pharmacists would need to fulfill at least 70% of the Advanced Practice competency standards at an advanced level. More than half of the pharmacists (64.7%) that self-perceived as being advanced managed to fulfill 70% or more of these Advanced Practice competency standards at the advanced level. However, none of the self-perceived entry level pharmacists managed to match at least 70% of the competencies at the entry level. CONCLUSION: Participants' self-perception of the term Advanced Practice was similar to the definition in the Advanced Pharmacy Practice Framework. Pharmacists working at an advanced level were largely able to demonstrate and justify their reasons for being advanced practitioners. However, pharmacists practising at the other levels of practice (entry, transition, consolidation) require further guidance regarding their advancement in practice.

Alterations in acetylcholine, PGE2 and IL6 release from urothelial cells following treatment with pyocyanin and lipopolysaccharide.

The effects of pseudomonal virulence factor pyocyanin, and LPS from Pseudomonas aeruginosa and Escherichia coli on urothelial mediator release and cytokine production were examined. RT4 urothelial cells were treated with pyocyanin (1-100 µM) or LPS (1-100 ng/mL) for 24-h. Effects were measured in terms of changes in cell viability, basal and stretch-induced acetylcholine (Ach) and PGE2 release, and inflammatory cytokines (IL-6 and IL-12) production. Twenty-four hour pyocyanin (100 µM) treatment significantly decreased urothelial cell viability, while stretch-induced Ach release response was inhibited. E. coli LPS (100 ng/mL) produced a similar response with an additional significant increase in basal Ach release. All three virulence factors significantly increased urothelial PGE2 release; under basal release for pyocyanin (100 µM), stretch-induced release for pseudomonal LPS (≥ 10 ng/mL) and both basal and stimulated release for E. coli LPS (≥ 10 ng/mL). IL-6 and IL-12 were not detected in control samples, however 24h treatment with pyocyanin (100 µM) or LPS (100 ng/mL) resulted in IL-6 release from urothelial cells. The changes in urothelial Ach and PGE2, and release of inflammatory cytokine IL-6 induced by exposure to the bacterial virulence factors may play a role in the symptoms of pain and urinary urgency experienced with urinary tract infections.

The effects of creatine on the retrogradely perfused isolated rat heart.

Although the role of creatine in muscle metabolism is well understood, there is still uncertainty as to its effects at supplemented levels. With this in mind, this study was designed to investigate the direct effects of commercially available creatine on the isolated rat heart, retrogradely perfused and infused with varying concentrations of creatine (1.25, 2.5, 5 and 10 mM) to determine its effects on heart rate, coronary flow and ventricular pressure. Furthermore, tissue from these hearts was used to investigate the cardiotoxic potential of supplemented levels of creatine. Results indicate that creatine directly improves the functioning of the heart under normal conditions with respect to heart rate and ventricular pressure, but may be detrimental to the functioning of energy-deprived hearts. It also showed no cardiotoxic properties since it increased the baseline levels of adenosine triphosphate (ATP) and decreased the levels of isocitrate dehydrogenase (lCD), indicating a decrease in cellular death compared with non-supplemented control hearts.

Cyclic dipeptides in the induction of maturation for cancer therapy.

Studies have suggested a possible form of therapy based on the use of maturation-inducing compounds to induce differentiation of neoplastic cells and stimulate faster recovery of the normal cell population. The study of the effects of nine cyclic dipeptides on biochemical markers of differentiation implicated their potential to induce differentiation. Studies were undertaken to determine the specificity of these agents for HT-29 cell cultures as well as the identification of the signal transduction pathways affected by these agents inducing the differential gene expression observed in the cells. The cyclic dipeptides studied showed a high degree of specificity, having no significant effect on Caco-2 cells (P > 0.05), representing the normal gastrointestinal mucosa. All inducers administered were shown to affect the total energy state of HT-29 cells, an effect which increased the probability of HT-29 cell differentiation. Results indicated that those agents which induced differential gene expression acted at different steps in the isolated signal transduction pathway. Cyclo(Trp-Trp) and cyclo(Phe-Pro) induced a high degree of acetylation of histones (P < 0.05), while the remaining cyclic dipeptides induced a high degree of phosphorylation of histones (P < 0.05) (cyclo(Trp-Trp) induced a moderate degree of histone phosphorylation). The results from histone phosphorylation and acetylation and cyclic AMP responsive element binding protein phosphorylation studies suggest that the cyclic dipeptides activate a chromatin switch, which leads to the increase in accessibility of lineage-specific genes for transcription.

Meta-analysis of pediatric cochlear implant literature.

We analyzed published reports of the effect of age at implantation and the cause of and age at onset of deafness on speech perception benefit in children with cochlear implants, and compared these results with those of unreported trials of multichannel cochlear implants. Combining data from published and unpublished patient series was constrained by differences in test protocols between studies, but was made feasible by employing a meta-analysis in which data were converted into an ordinal classification scale that represented levels of communicative benefit. Results showed that more rapid gains in speech perception are associated with earlier age at implantation, and that speech perception results are independent of cause of or age at onset of deafness after 1 year of implant use. Moreover, with minor exceptions, there was no statistical difference between published and unpublished data, thereby indicating no publication bias in the literature. A meta-analytic approach is useful because it can clarify the quality of reported data and the direction of future research and, hopefully, foster collaboration in conducting and reporting future research. A standardized approach to reporting results in children is advised in order to produce a balanced interpretation of implant benefit and to facilitate wider understanding and dissemination of study conclusions.

Vitamin E and retrolental fibroplasia: prevention of serious ocular sequelae.

In an attempt to determine the role of vitamin E in retrolental fibroplasia (RLF) we report our experience with 191 infants of less than 1500 g birth weight. Of these infants, 16.75% had evidence of acute RLF in hospital, 8.4% had cicatricial RLF at follow-up, and four infants (2.1%) were blind, none of whom had received supplementary vitamin E. The incidence of cicatricial RLF at follow-up was significantly lower in infants who received vitamin E early after birth (12 h) than in those who did not (3 of 105 versus 13 of 86, X2 = 9.26, P = 0.002), as was the incidence of Grade III or greater cicatrix (0 of 105 versus 7 of 86, X2 with Yates = 6.72, P = 0.01). Stepwise multiple linear regression analysis revealed three factors distinguishing infants who developed cicatricial RLF from those who did not: the lack of early vitamin E supplements (P = 0.0023), the significantly larger number of arterial PO2 values over 100 mmHg (P = 0.0056), and the presence of an intraventricular haemorrhage (P = 0.0032). The incidence and severity of necrotizing enterocolitis was similar in infants who received vitamin E and in those who did not. It is recommended that vitamin E be given within the first 12 hours of birth to all infants of less than 1500 g who require supplementary oxygen.

The ultrasonographic and radiologic features of a histologically proven case of alveolar soft-part sarcoma of the orbit.

An 18-year-old woman had a rapidly progressive proptosis, vascular congestion, and orbital pain. Ultrasonographic and radiologic tests supported the diagnosis of a solid vascularized mass that proved histologically to be an alveolar soft-part sarcoma of the orbit. Uncertainty as to the histogenesis of alveolar soft-part sarcoma still exists, but prognosis for patient survival is poor.