Characterization of Early Plasma Concentrations of Midazolam in Pigs after Administration by an Autoinjector

ABSTRACT: The treatment of organophosphate-induced poisoning is based mainly on atropine and an oxime. Prompt anticonvulsive intervention is usually also required to terminate the ensuing seizure activity and to prevent delayed permanent brain damage. Midazolam, a water-soluble benzodiazepine agonist, has the advantage of rapid absorption following intramuscular administration. In mass casualty situations, the availability of an autoinjector, filled with midazolam, might be a further advantage. In the present study, the plasma pharmacokinetics of midazolam after administration by an autoinjector was compared with conventional intramuscular (i.m.) administration in two groups of four pigs each. During the first 15 min after injection, significantly higher plasma concentrations of midazolam were detected following autoinjector administration, compared with the i.m. injection. The physiological reflection of the accelerated midazolam absorption was a marked reduction in the time interval required for muscle relaxation, induced by midazolam. It is concluded that a midazolam autoinjector might be helpful in the mass casualty scenario following organophosphate poisoning

Minimum 2-Year Radiographic and Clinical Outcomes of Kinematic Alignment Total Knee Arthroplasty in the Valgus Knee

Kinematic alignment (KA) total knee arthroplasty (TKA) has gained popularity in the past decade, but outcomes of KA-TKA in the valgus knee have never been specifically evaluated. In this retrospective single institution study, we analyzed patient reported outcomes and radiographic measurements at minimum 2 years following KA-TKA for valgus knees (n = 51) and compared the results to KA-TKA performed for non-valgus knees (n = 275). The same approach, technique, and implants were used in both groups without the need to release soft tissues or use constrained implants. Surgery duration was similar between groups (p = 0.353). Lateral distal femoral angle was lower in the valgus group postoperatively (p = 0.036). In both groups significant improvement was seen in relieving pain and improving function, while average scores were superior in the non-valgus group for visual analog score (p = 0.005), oxford knee score (p = 0.013), and knee injury and osteoarthritis outcome score (p = 0.009). However, these differences did not translate to statistically significant differences in minimal clinical important difference achievement rates. In conclusion, KA-TKA is efficient in relieving pain and improving function, as reported in subjective questionnaires, and holds advantage in patients with valgus alignment by avoiding soft tissue releases and use of constrained implants. Future studies should examine whether bone loss occurs in the lateral distal femur

Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration

Refractory Pseudomonas aeruginosa infections treated with phage PASA16: A compassionate use case series

BACKGROUND: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. METHODS: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. FINDINGS: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. CONCLUSIONS: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. FUNDING: The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program