IntroductionAdverse drug reactions (ADRs) are a major global clinical problem, causing substantial mortality and morbidity especially in hospitals. Healthcare professionals (HCPs) knowledges’, attitude and practices are crucial points to evaluate the hospital safety environment. Objective of the study was to investigate the knowledge, attitudes, and practices of HCPs regarding the ADRs reporting system.MethodsA cross-sectional survey was conducted between January and February of 2013 in nine tertiary care hospitals (governmental and private) that provide highly specialized medical services in Riyadh, Qassim, and the Eastern region of the Kingdom of Saudi Arabia. A validated questionnaire was used to assess the knowledge, attitudes, and practices of HCPs regarding the ADR reporting system. All statistical analyses were performed using SAS version 9.2.ResultsIn total, 480 questionnaires were distributed, and the response rate was 70% (n = 336). Only 33% of the participants were aware of the National Pharmacovigilance Centre (NPC). Of those HCPs who were familiar with the NPC and their responsibility to report ADRs, most (50%) were pharmacists, followed by physicians (24%) and nurses (16%), and these differences were statistically significant (p < 0.01). Twenty-seven percent of the participants were involved in reporting ADRs; among these HCPs, 62% were pharmacists, 26% were nurses, and 6% were physicians. Most participants (95%) favoured reporting ADRs caused by antibiotics and new/old drugs. The prominent factors discouraging ADR reporting included fear that the report might be incorrect (46%) and lack of time (44%).ConclusionsA significant lack of knowledge, positive attitudes, and practices regarding ADRs and reporting was observed in hospital HCPs. This finding represents an international concern, and urgent action is needed to promote drug safety and pharmacovigilance in this region.

OBJECTIVE To assess pharmacokinetics of tranexamic acid (TXA) in dogs and assess antifibrinolytic properties of TXA in canine blood by use of a thromboelastography-based in vitro model of hyperfibrinolysis. ANIMALS 6 healthy adult dogs. PROCEDURES Dogs received each of 4 TXA treatments (10 mg/kg, IV; 20 mg/kg, IV; approx 15 mg/kg, PO; and approx 20 mg/kg, PO) in a randomized crossover-design study. Blood samples were collected at baseline (time 0; immediately prior to drug administration) and predetermined time points afterward for pharmacokinetic analysis and pharmacodynamic (thromboelastography) analysis by use of an in vitro hyperfibrinolysis model. RESULTS Maximum amplitude (MA [representing maximum clot strength]) significantly increased from baseline at all time points for all treatments. The MA was lower at 360 minutes for the 10-mg/kg IV treatment than for other treatments. Percentage of clot lysis 30 minutes after MA was detected was significantly decreased from baseline at all time points for all treatments; at 360 minutes, this value was higher for the 10-mg/kg IV treatment than for other treatments and higher for the 20-mg/kg IV treatment than for the 20-mg/kg PO treatment. Maximum plasma TXA concentrations were dose dependent. At 20 mg/kg, IV, plasma TXA concentrations briefly exceeded concentrations suggested for complete inhibition of fibrinolysis. Oral drug administration resulted in a later peak antifibrinolytic effect than did IV administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of TXA improved clot strength and decreased fibrinolysis in blood samples from healthy dogs in an in vitro hyperfibrinolysis model. Further research is needed to determine clinical effects of TXA in dogs with hyperfibrinolysis.

The Mycobacterium tuberculosis drug discovery effort has generated a substantial number of new/repurposed drugs for therapy of this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Having single agent therapy is insufficient for patients with late stage tuberculosis, because of resistance emergence. To achieve our therapeutic ends, it is requisite to identify optimal combination regimens. These regimens go through a lengthy and expensive evaluative process. If we have a modest group of 6-8 new or repurposed agents, this translates into 15-28 possible 2-drug combinations. There is neither time nor resources to give an extensive evaluation for all combinations. We sought a screening procedure that would identify combinations that had a high likelihood of achieving good bacterial burden decline. We examined pretomanid, moxifloxacin, linezolid and bedaquiline in Log-phase growth, Acid-phase growth and NRP (Non-Replicative Persister)-phase in the Greco interaction model. We employed the interaction term α and the calculated bacterial burden decline as metrics to rank different regimens in different metabolic states. No relationship was found between α and bacterial kill. We chose bacterial kill as the prime metric. The combination of pretomanid plus moxifloxacin emerged as the clear frontrunner, as the largest bacterial declines were seen in Log-phase and Acid-phase with this regimen and it was second best in NRP-phase. Bedaquiline also produced good kill. This screening process may identify optimal combinations that can be further evaluated in both the Hollow Fiber Infection Model and in animal models of Mycobacterium tuberculosis infection.

The repurposed agent moxifloxacin has become an important addition to the physician’s armamentarium for the therapy of Mycobacterium tuberculosis. When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the Hollow Fiber Infection Model. We examined 12, 24 and 48 hr dosing intervals with doses of 200 mg, 400 mg and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8 and 4 hr were simulated. We attempted to keep the CAvg (AUC) constant across arms. We found that susceptible bacterial load decline was linked to CAvg, as we had indicated previously. Resistance suppression, a non-monotonic function, had CMin as the linked index. The 48 hr interval with the 4 hr half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (CPeak-linked) and adherence, we conclude that the 400 mg dose daily is optimal for moxifloxacin.